Why is chronic lymphocytic leukemia (CLL) most common leukemia in the West but so rare in Asia?

In "Advances in Chronic Lymphocytic Leukemia" (2013, Edited by Sami Malek), several times it is stated that CLL is very common in Western countries.

However, it is quite rare in Asia. (I do not have data regarding other regions in the world.)

Why would this be? I am familiar with cancers being related to lifestyle, which varies by country. (The obvious example would be how countries with high rates of smoking have higher rates of lung cancer.)

Do we have any reasons why this is? Thanks for any help.

This paper should help get you started. The exact reason is not yet known, but is most likely related to germline genetic differences between the two ethnic groups, as Asian immigrants to the US continue to have a low incidence of CLL.


  • KAWAMATA N, MOREILHON C, SAITOH T, et al. Genetic differences between Asian and Caucasian chronic lymphocytic leukemia. International Journal of Oncology. 2013;43(2):561-565. DOI:10.3892/ijo.2013.1966.
  • American Cancer Society: What are the risk factors for chronic lymphocytic leukemia?

Disease Characteristics

A new article has been published in Blood Journal on the subject of long term survival of CLL patients. The paper, based on SEER survey data, is reviewed in our article titled Are CLL Patients Living Longer? (3/2/2008)

When You Have Been Around the Track a Few Times

Salavge Therapy Produces Grim Statistics

There are not many good therapy choices for CLL patients who become resistant to fludarabine and Campath. While a number of salvage therapies are in use, the results are variable and the survival statistics are grim. We agree with the experts in the field that a wider range of approaches and more effective agents are desperately needed for these patients. Refractory CLL is our review the literature and the latest reported results of salvage treatment for refractory CLL. (10/14/2007)

The New Think on CLL Is Finally Here

An important new review article has been published in the New England Journal of Medicine. The Rai/Binet staging systems have been important in triggering therapy decisions. In this article the authors, who include Dr. Kanti Rai himself, bluntly state that the staging system with its emphasis on watch & wait should be replaced by better methods using modern prognostic indicators. We cover this important article as well as several other related works in The Dawn of a New Era. (2/24/2005)

Insight, Advances and Research

Tracking Down Clues in Population Data

Dr. Tim Call is a hematologist/oncologist at Mayo Clinic, Rochester, MN and an Assistant Professor of Medicine at the Mayo Clinic College of Medicine. He has done much important work in the area of familial CLL and lymphoma, and is responsible for developing a database at Mayo Clinic on the familial incidence of B-cell malignancies including CLL, B-cell lymphomas and a few related diseases. You might recall his name as an author on the Mayo Best Practices article &ndash Current Approach to Diagnosis and Management of CLL. We are pleased that he has written this article, Familial CLL, addressed to the patient community. We strongly encourage that our readers register in one of the recommended databases when appropriate. (7/13/2004)

Familial CLL: Not the Worst Day in Your Life

Genetic Predisposition and Anticipation

To Know or Not to Know: That Is the Question

Not the Worst Day of Your Life is a review of the research findings on the familial aspects of CLL. It is well documented that CLL strikes more than one person in some families, there is clearly a predisposition to the disease that has been passed on from one generation to the next in these families. Some day, this type of research may prove to be the key that unlocks the CLL puzzle. In addition the data show that in families where the disease strikes several generations, the children of a CLL patient are likely to be diagnosed with the disease at an younger age compared to the parent. Finally, we discuss some of the difficult issues involved in testing children for potential problems down the road that may never materialize. (2/12/2004)

Adhesion, Homing and Resistance to Therapy

Why Peripheral Blood Numbers Do Not Tell the Whole Story and Why CLL Cells are Hard to Kill.

It's a Tale of Adhesion Factors, Chemokine Trails, Receptors and Blockers

The behavior of CLL as a disease and the different characteristics exhibited by strains with different clonal genetic aberrations are all related to cellular chemistry. We examine a number of critical aspects such as resistance to therapies, bulkiness of lymph nodes, infiltration of bone marrow and the support structure for CLL cells in their preferred environments. We also look at some futuristic possibilities for therapies in this article titled Adhesion, Homing and Resistance to Therapy. (12/8/2003)

Clonal Evolution: How the Disease Grows and Evolves

In this article, Clonal Evolution, we review important new research into the mechanisms by which clonal B-CLL cells become more aggressive and harder to kill. We look at the implications for treatment strategy and offer a new approach to managing the disease. (11/7/2003)

The Case for Risk Rating: Staging Does Not Measure Closeness of Bone Marrow Failure

Rai/Binet Staging Do Not Predict Survival

Staging Does Not Predict Survival examines a newly published journal article which draws attention to the criteria used in the Rai and Binet staging systems in the light of current understanding of the causes of clinical measurements. The Rai-Binet systems are not good predictors of survival because they do not consider why anemia and thrombocytopenia occur in different CLL patients. (11/3/2002)

Night Sweats, Fever and Fatigue and Their Causes and Treatment

Disease Progression Correlates to Increasing B Symptoms

A number of papers examine the immediate causes of the symptoms associated with advanced blood cancers. An alphabet soup of cytokines can be identified as the culprits. The available treatments for these symptoms are, of course, palliative in nature. Curing the cancer would be the best way of eliminating the symptoms. To get the details, read our review of B-Symptoms. (7/30/2003)

Genetic Mutations and Their Effect on Overall Survival

Important Paper Identifies Common Genetic Abnormalities

The difference between good prognosis and poor prognosis for a CLL patient resides at least in part on the particular genetic abnormality that characterizes the patient's disease. Stilgenbauer, Dohner, et al., lay out some basic correlative data on common mutations and survival expectations associated with them. Therapy choices should be made based on the risk associated with each type of abnormality. To learn more, read our review of their paper, Genetic Abnormalities in Blood Cancers. (5/22/2002)

The following are short articles on various aspects of Disease Characteristics of CLL, presented most recent first.

There is really not much mystery about swollen lymph nodes in CLL. Enough CLL patients have had lymph node biopsies so we know what makes them large: they get stuffed with lots and lots of clonal CLL cells, and the structure of the lymph node grows in order to make space for all these new residents. Why do some patients have large lymph nodes and relatively low WBC numbers? Think of it this way: there are three buckets. one is the bone marrow, the second is lymph nodes, and the third is peripheral blood. The CLL cells distribute themselves between these three buckets. Those with most of the CLL cells in the bone marrow and a puny 5-10% left over in the blood are at the “leukemic” end of the spectrum. Those with most of the CLL cells residing in the swollen lymph nodes are more the “lymphoma” type. In fact, there is no real distinction between CLL, a leukemia, versus SLL, a lymphoma, except in the sense that the cancer cells seem to prefer one location more than the other in the two types. Get this point folks: bulky lymph nodes represent a reservoir of a large number of CLL cells, that can multiply quite happily in the lymph nodes, providing more copies of themselves. Very often, with most therapies, the cancer cells in the blood are the most accessible, and therefore the easiest to kill. From everything I have read, CLL cells in peripheral blood pose little danger, over and beyond providing a pool of cancer cells for future proliferation. It is the accumulation of these cancer cells in the bone marrow that is the real danger, at sufficiently high levels it shuts down the absolutely vital production of other cell lines like red blood cells, that can only be made in the bone marrow. Heavy infiltration of the lymph nodes, to the tune where they are bulky means that when the CLL decides to go into a higher proliferation mode, maybe kicked off by something as innocent as a slight viral infection, the numbers can go up very quickly indeed. This is why we have the definitions of PR, NPR, CR etc. All of these various definitions of response to therapy take into account the response of the lymph nodes. They are a serious aspect of the disease, more so if they threaten other vital functions, such as squeezing shut blood flow in adjoining arteries, etc.

Inflammation, Infections and Cancer

I have been interested in the connection between chronic inflammation and cancer for some time. Attached below is an URL of a paper that discusses this relationship in some detail.

Most researchers seem to agree that this relationship exists, and manipulating it provides a route for the potential control or even prevention of cancer. We have published several articles on CLL Topics on the role of drugs such as Celebrex in the inhibition of Cox-2, and the inflammatory pathways associated with it. Also “nutraceuticals” such as curcumin (from the spice turmeric), catechins (from green tea) etc which are known to be anti-inflammatory and also considered to be of great interest in cancer prevention / control strategies.

Much more specifically, there has been a lot of discussion on this site on the Nf-KB pathway, which is triggered when the body goes into an inflammatory mode. It is known that when this important pathway is triggered, the cells on which this switch is “ turned on” go into a proliferative mode, as well as become protected from apoptosis (cell death). Normally, the Nf-KB pathway is not routinely turned on, but it now known that this pathway is stuck in the “on” position for large majority of cancer cells, including CLL cells, making it possible that this contributes to greater proliferation rates for the cancer cells, as well as making them harder to kill. A number of drugs, including simple ones like aspirin, are known to be blockers of the Nf-KB pathway. One of them which is similar to aspirin, a simple molecule called methyl salicylate is actually in clinical trials for B-cell cancer.

I also hear rumors that a new small molecule drug of unspecified nature is likely to be in clinical trials soon at M. D. Anderson, and this molecule is supposed to be an extremely effective blocker of the Nf-KB pathway. If successful, this orally administered drug is expected to provide a non-toxic and simple method for maintaining patients in long term remission. I understand it is a derivative or variant of an already well known anti-inflammatory drug.

IDEC-152 is another very interesting monoclonal antibody. As we have discussed before, this monoclonal targets CD23 marker on CLL cells. CD23 is the activation marker for cells, high levels of this marker means the Nf-KB pathway is activated on these cells and they are in a proliferative mode. It is an elegant concept, killing specifically the very cancer cells that are multiplying rapidly and trying to protect themselves from death. Even more interesting is the combination of this monoclonal antibody with Rituxan. Combination of the two monoclonals gets the cancer cells in the cross-hairs, as it were, and has the potential for much higher levels of efficacy, without increasing the toxicity. This kind of a combination would be of particular interest to those of us who do not exhibit either marker (CD20 or CD23) to very high levels, and the combination of the two may get us to the critical levels required for efficient CLL cell kill. In fact, I have written about murine (mouse) studies where the survival of animals with lymphoma was much higher when both monoclonals were co-administered, a classic case of synergy where 2 plus 2 is more than four. I am aware there is an ongoing clinical trial (phase-1) using IDEC-152 by itself for CLL patients. I would very much like to see this trial get beyond the phase-1 stage, and especially see combinations of the two monoclonals used together in CLL.

The following is a link to a technical paper that discusses this topic in some detail: Chronic Inflammation and Cancer.

Blood Counts are a Dim Reflection of Disease Progression

Here are some fundamentals of what this disease is all about.:

The source of the disease is the bone marrow and in the lymphatic system. That is where all the action is. That is where the new generations of blood cells are created. Not in the peripheral blood. Think of the former as the factory, the later as the highways leading to and from the factory. Clearing up the traffic on the highways does not solve the problem if the factory is not functioning right, not making the right widgets.

Since we cannot easily measure the populations of the various cell types in the bone marrow or lymph nodes (imagine having a lymph node biopsy or a bone marrow biopsy done as frequently as a simple blood test), doctors and patients depend upon the ever popular CBC (Complete Blood Counts). Normally, when the bone marrow, lymph nodes and peripheral blood are in equilibrium, the counts in the peripheral blood reflect, very roughly, what is happening in the bone marrow and lymph nodes. The CBC therefore has some limited diagnostic value. Some patients have very advanced disease, as measured by swollen nodes, spleen, infiltrated marrow and other complications, but relatively low WBC, and vice versa.

CLL patients do not die because there are too many white blood cells (WBC) in their peripheral blood, CLL cells or otherwise. Yes, the blood's viscosity increases slightly, and the pumping action of the heart becomes more difficult, when the WBC reach very, very high numbers. I am talking about ranges in excess of 200K. This is very rare phenomenon. Several of the consortium experts don't believe this is ever a real problem, other more immediate problems (see below) will get you first.

One of the things that kills CLL patients is the bone marrow getting so packed with cancer cells that it stops producing the good infection fighting cells of the immune system, and simple infections that are easily shaken off by normal people become life threatening in the case of CLL patients. Viral, bacterial and fungal infections are what kill majority of CLL patients.

Also, the gradual decay of immune surveillance means that secondary cancers can take hold. MALT, the topic of discussion in recent articles, is one of them. It may be triggered by H. Pylori, a bug that lives in the stomach and gut. It becomes active and takes advantage of the situation to proliferate, when there is no immune system able to fight it.

Also at issue is the effect of diseased spleen and liver, which not only stop doing their normal functions but may start chewing up perfectly good red blood cells and platelets as they get progressively more diseased. This is the onset of autoimmune hemolytic anemia (AIHA) and thrombocytopenia, both of which are alarmingly common in CLL patients. The former causes anemia, progressive fatigue and inability for the body to carry out its vital oxygen transport, the later can result in strokes, uncontrolled bleeding etc.

So. Immediately after therapy, especially if the drug used differentially takes care of CLL cells in the peripheral blood but not in the bone marrow or lymph nodes or swollen spleen, nothing much has been accomplished. This is a very small part of the total population of cancer cells, it will soon be replenished from the vast stores in the lymph nodes etc. Does it diminish the other risks of the disease? Not in my opinion. The bone marrow is still infiltrated and producing the wrong type of cells. The patient is still at risk of developing conditions that lead to sudden and serious infections, anemia, thrombocytopenia, etc.

Think of the peripheral blood CBC as a dim reflection of what is actually happening in the other more important sites of the infection. At best, it gives us some idea of what is going on, and it is used because it is done easily, and it is cheap. At worst, it totally fails to reflect the reality of swollen lymph nodes, swollen spleen, potentially infiltrated bone marrow.

There is no such thing as a free lunch. Here are some of the "costs" of an ineffective (repeat, ineffective) bout of Rituxan:

  • All b-cells can carry CD20 marker, as well as several other important cell lines, it is not specific to CLL b-cells only. Rituxan therefore kills all b-cells, good and bad. B-cells are the source of a big chunk the antibody defenses of the body against infections. Rituxan therapy leaves us without these defenses for a good period of time. When the remission is over, brief or otherwise, the b-cells grow back, a few good ones, and mostly those darned CLL type b-cells. Same as before. Nothing has changed, since the source of the problem, the bone marrow and lymphatic system had not been cleaned out.
  • There is a huge dollar cost to this therapy. Not every one has health insurance that covers these sorts of costs. Besides, even with health insurance, guess who finally pays for these drugs. That's right, we the consumers pay for every thing, either up front or later on as higher insurance premiums, or cancelled insurance coverage's when insurance companies go broke. This group talks to the wide variety of patients, not just the fortunate ones. Ironic, to think of any CLL patients as fortunate.. but guess how much worse this disease feels, if you are broke, laid off, without insurance, and a family to support. You get precious little respect from big name doctors, if you do not have money to back you up.
  • The other thing an ineffective bout of Rituxan uses up is the window of opportunity. We have seen in several individual cases that Rituxan takes a significant amount of time to show its full function. It is not possible to make a good call on whether or not it worked, right off the bat. If it did not work, and we are looking at a person with one of the high risk profiles, the individual may be significantly worse off for not having initiated a more aggressive and hopefully more effective therapy right away worse off in the sense of more infiltrated bone marrow, more swollen and intractable lymph nodes and more diseased spleen/liver.

Don't get me wrong, I am a big fan of Rituxan and the other monoclonals, you can judge by the number of articles I have produced on the subject. Rituxan, Campath, IDEC152 and their combinations with immunomodulatory drugs like Interleukin-2, low dose Prednisone, GM- CSF, Interferon alpha etc are the wave of the future. I am rooting for these interesting studies to become the new standards, in our lifetimes.

But it bothers me to see the phrase "at worst, Rituxan does no harm". A small percentage of people are quite allergic to it, can have very severe responses. As "Granny" Barb can attest. A risk worth taking, since the percentage is small, if and I repeat, if one is a good candidate for this particular drug. It comes back to the good old idea, there is no such thing as a free lunch. And I for one would rather know whether or not I have the variety of CLL that is likely to respond well to Rituxan only therapy, **before** I put myself through it. Why not know what your odds are, ahead of time? I know there are no guarantees, our understanding of how these drugs work is far from perfect. But why not line up the odds a little better with prior information? As for the other questions of a more philosophical and emotional nature, I am certainly not competent to comment. Also, I am not about to tell any one what their therapy choices ought to be, it is an individuals right and responsibility to do that for himself or herself. In life, we all live with the choices we make, the roads we choose to walk.

Inherited Predisposition to CLL Is Real

As the mother of a talented and much beloved daughter, it is with reluctance and dread that I read this latest article in "Blood". Healthy, first degree relatives of CLL patients are likely to have an inherited predisposition to CLL, at a rate that is statistically four times higher than the normal population. Sounds scary.

Then some level of logic came to my rescue: I am personally convinced that we are a lot better off in therapy options today than we were even just a few years ago. And the rate at which new information is becoming available is increasing rapidly. Down the road, many years from now, if your son or daughter develops CLL, they will probably fix it with a quick vaccine inoculation, in the doctor's office, and that will be that.

Meanwhile, prior warned is prior armed, get your kids to stay healthy, develop life long habits of healthy living, exercise and nutrition, and not miss those routine annual check-ups. Kids think they are immortal, nothing will ever go wrong with them, until it does.


Blood, 1 October 2002, Vol. 100, No. 7, pp. 2289-2290

Inherited predisposition to CLL is detectable as subclinical monoclonal B-lymphocyte expansion
Andy C. Rawstron, Martin R. Yuille, Julie Fuller, Matthew Cullen, Ben Kennedy, Stephen J. Richards, Andrew S. Jack, Estella Matutes, Daniel Catovsky, Peter Hillmen, and Richard S. Houlston

From the Academic Unit of Haematology and Oncology, University of Leeds, HMDS, West Yorkshire Academic Department of Haematology and Cytogenetics, Institute of Cancer Research, Surrey Section of Cancer Genetics, Institute of Cancer Research, Surrey, United Kingdom.

Monoclonal chronic lymphocytic leukemia (CLL)-phenotype cells are detectable in 3.5% of otherwise healthy persons using flow cytometric analysis of CD5/CD20/CD79b expression on CD19-gated B cells. To determine whether detection of such CLL-phenotype cells is indicative of an inherited predisposition, we examined 59 healthy, first-degree relatives of patients from 21 families with CLL. CLL-phenotype cells were detected in 8 of 59 (13.5%) relatives, representing a highly significant increase in risk (P = .00002). CLL-phenotype cell levels were stable with time and had the characteristics of indolent CLL. Indolent and aggressive clinical forms were found in family members, suggesting that initiation and proliferation involves distinct factors. The detection of CLL-phenotype cells provides a surrogate marker of carrier status, potentially facilitating gene identification through mapping in families and direct analysis of isolated CLL-phenotype cells.

For those of us with children (or siblings), the abstract below is like a kick in the stomach.

These researchers examined first degree relatives of CLL patients, people who are in apparent good health. Flow cytometry done on 33 relatives showed that 6 out of the 33, a whopping 18% of the relatives examined, showed the tell-tale CD5/CD19/CD20/CD23 positivity, the classic pattern for monoclonal B-cell phenotype. This 18% is to be compared with 0.7% or so one would expect in a normal population.

Just to be clear, this does not mean the 6 relatives above have CLL. Some or even all of them may be ultimate smolderers that continue indefinitely below the threshold defined for CLL diagnosis, never even aware that they had a sub-detection level of B-CLL monoclonal phenotype. If a tree falls in the forest, and there is no one to see it, does it matter?

All the same, I am happy that there is continuous and encouraging spate of new drugs and new therapy protocols being investigated. For those of you who chose to participate in clinical trials, thank you, there is a new generation out there whose lives may some day be saved because of your generosity.


Cytometry 2003 Mar52B(1):1-12

B-cell monoclonal lymphocytosis and B-cell abnormalities in the setting of familial B-cell chronic lymphocytic leukemia.

Marti GE, Carter P, Abbasi F, Washington GC, Jain N, Zenger VE, Ishibe N, Goldin L, Fontaine L, Weissman N, Sgambati M, Fauget G, Bertin P, Vogt RF Jr, Slade B, Noguchi PD, Stetler-Stevenson MA, Caporaso N.

Flow and Image Cytometry Section, Laboratory Stem Cell Biology, Division of Cell and Gene Therapies, Center for Biologics Research and Evaluation, Food and Drug Administration, Bethesda, MD

BACKGROUND: Among all hematologic malignancies, B-cell chronic lymphocytic leukemia (BCLL) has the highest familial clustering (three- to sevenfold increase), strongly suggesting a genetic component to its etiology. Familial BCLL can be used as a model to study the early pathogenesis of this disease.
METHODS: We examined nine kindreds from the National Cancer Institute's Familial BCLL Registry, consisting of 19 affected members with BCLL and 33 clinically unaffected first-degree relatives. Flow cytometric immunophenotyping to detect a B-cell monoclonal lymphocytosis (BCML) was performed. Monoclonality was confirmed by polymerase chain reaction analysis of whole blood DNA. Cell cycle analysis for aneuploidy was conducted.
RESULTS: In all affected individuals, we observed the classic BCLL CD5/CD19/CD20/CD23 immunophenotypic patterns. Six of the 33 unaffected individuals (18%) had evidence of BCML. Additional individuals (13/33, 39%) showed some other abnormality, whereas 14 individuals (42%) were normal. Based on an estimated prevalence of 0.7% for BCML in the general population, the finding of six subjects (18%) with clonal abnormalities in this relatively modest sample was significantly greater than expected (i.e., 18% vs. 0.7%, P < 5.7 x 10(-9)).
CONCLUSIONS: Individual components of BCML and other B-cell abnormalities were observed in almost half of the apparently unaffected individuals. Our findings suggested that BCML may be an early detectable abnormality in BCLL. The spectrum of some of these observed abnormalities suggested the involvement of different B-cell subpopulations or different pathways in clonal evolution. Population-based, longitudinal studies will be required to determine the incidence of BCML and other B-cell abnormalities and their relation to disease progression in BCLL and other closely related B-cell lymphoproliferative disorders. Cytometry Part B (Clin. Cytometry) 52B:1-12, 2003. Published 2003 Wiley-Liss, Inc.

PMID: 12599176

Probability of a Cure for CLL

Some patients are under the impression that CLL cells do not die. CLL cells do die, they are not immortal. The problem is that they live longer than they should, and just as in human populations, when life spans increase, even without any change in the birth rate, there is an overall population explosion. Billions upon billions of new cells are created daily. If the CLL cells are truly immortal and did not die at all, they would accumulate so fast we would all be giant lymph nodes and nothing else, in a matter of days and months.

Now, since the net accumulation of CLL cells is due to the cancer cells dying at a slower rate than they are being produced, the progression of the disease can be stopped, and reversed, if we introduce a new mechanism that increases the death rate. All it takes is for the cancer cells to die faster than they are being made.

This is what sets apart indolent disease versus rapidly growing disease, it all depends on the difference between the rate of death versus rate of birth of cancer cells.

Another point to remember: majority of people have a few cancer cells in their body, caused by some random mutation or the other, and they never even know about it. The reason is that these cancer cells are rapidly killed by the immune system, before they have a chance to gain a foothold.

In a full blown case of cancer, the cancer cells have obviously won the first battle(s), gained that all-important foothold. They can now start their subversive campaign to make the immune system cells inactive and inefficient. The snowball effect will get out of hand, unless we intervene to change the rules of the game. If we give the immune system a hand, through some form of therapy, kill off the major bulk of the cancer cells, and thereby remove the chemical signals put out by the cancer cells that ties the hands of the immune system, it is possible to get back to a situation where the immune system can start doing its job again, hold the cancer at bay, eventually eradicate it.

Think of the cancer cells as the Mob. If they are allowed to flourish and get out of hand, they begin to subvert and bribe into inaction the very system (judges, police, FBI) that are supposed to control them. Get in some law enforcement from the outside, put away the majority of the mobsters for life, the remaining dregs are no longer able to bribe the local police force into inaction, and gradually they too will get cleaned out.

Bottom-line, we have to get away from the totally wrong notion that cancer cells do not die. They do. Just not fast enough. Anything we can do to increase the rate of death and slow down the rate of birth will control the cancer's progression. A cure is not only logically possible, in the case of CLL, everything I have read says it is likely to happen, in our lifetimes. I am no starry eyed optimist, but it is my considered opinion that we will start seeing indefinite "remissions", at least in some patients, sooner than many of us think. That is the basis of my motto, "stay healthy today, live to fight another day".

We are told to watch out for unexplained weight loss, since it is one of the "b-symptoms" that indicates the CLL may be progressing more rapidly, and treatment of some sort may be indicated in the near future. Not all cancers are alike, in fact patients with hematologic malignancies have significantly smaller problem with weight loss, compared to patients with other solid tumors. Count your blessings.

There are many reasons for cancer related weight loss (the technical term is "cachexia", pronounced ka-hex-ia). Side effects of chemotherapy or radiation such as nausea, vomiting, food not tasting good, constipation and diarrhea can all contribute to weight loss. So also depression, anxiety, and changes in normal social interactions, all of which are associated with cancer. The Eastern Cooperative Oncology Group (ECOG), which analyzed 12 different clinical trials and found that weight loss predicted a shorter survival than patients who did not experience weight loss. Not only did the weight loss predict an overall poorer prognosis, but it also indicated a trend toward lower chemotherapy response rates. When looking at the prognostic effect of various cancer symptoms, it was also found that loss of appetite predicted a poor outcome for cancer patients. The best way to treat cancer cachexia is to cure the cancer. But this may not always be possible, and a number of attempts have been made to address the more immediate problem of halting unwanted weight loss. Till recently, the efforts centered on nutritional counseling, and drugs to improve appetite. While steroids undoubtedly make some patients feel better, they do not appear to affect the process of cachexia. Serotonin has been tried, since is thought to have a role in appetite control. Melatonin has also been suggested to influence TNF-alpha production, one of the cytokines implicated in cachexia.

If you have read my previous articles on changes in metabolism as a result of cancer, you will remember that while normal cells get their energy by the very efficient Krebs cycle, cancer cells are wasteful and use a very much less efficient mechanism for converting glucose to energy. Hydrazine inhibits phosphoenolpyruvate carboxykinase, an enzyme responsible for gluconeogenesis from lactate (the Cori cycle), the mechanism used by cancer cells. It was hoped that interrupting this process would normalize some aspects of glucose metabolism in cachexic cancer patients and so improve nutritional status. However, recent studies have not demonstrated any real benefit of this compound.

A combination of a relatively non-toxic drug and a food supplement have shown the most promise. Ibuprofen (and several other non-steroidal anti-inflammatory drugs, or NSAIDs), in combination with fish oil seems to work best. Promising results have been seen in weight gain, improved quality of life and physical performance status in well documented studies, where nutritional counseling, appetite stimulants, NSAIDs and fish oil have been combined.

This country is obsessed with weight loss, but surely we know that unintentional weight loss in a cancer setting can be quite dangerous. If you find yourself losing weight, becoming less energetic and generally "wasting away", you may wish to click on the URL below.

Advances in the Management of Tumor-Induced Weight Loss

It is an excellent article in Medscape that should be more widely read. You may have to register to be able to read this article, but the Medscape registration is free of charge. Please keep a record of your registration information since we will use Medscape references often. The information is provided in a patient-friendly manner, and even if you do not have the energy to read it, make sure your care-giver reads it. Families can do a lot to help in this regard.

People, there are some areas where you can influence the outcome of your condition. Better nutrition, better information, more exercise, more water, and a generally optimistic view of life will all help greatly. They will improve the quality of your life, as well as improve your chances with any therapies that you may undertake down the road. Our motto should be "stay healthy today, live to fight another day".

A reader asked for my help in composing a short description of the disease for a presentation he had to give. I thought it (my response) might help our new members.

There are approximately 10,000 new cases of B-cell chronic Lymphocytic leukemia (CLL) diagnosed each year, making it the most common form of leukemia in the Western hemisphere. At this stage, CLL is considered to be an incurable disease. The good news is that the median survival of about 7 years for CLL patients is longer than that for more acute forms of leukemia. However, until very recently, the majority of the patients did not achieve complete remissions after undergoing "standard" chemotherapy regimes and all patients seemed to relapse sooner or later. Some patients become resistant to the drugs, severely limiting therapy options. Many of the chemotherapy drugs used to treat CLL have substantial toxicity associated with their use. It is often a tragic choice between the patient succumbing to the disease and being unable to tolerate the toxicity of the drugs that may help hold the disease at bay.

The birth of new cells and death of old cells that have outlived their usefulness are fundamental and strictly controlled mechanisms of all living things. Old and unwanted cells obediently commit suicide (" apoptosis ") when commanded to do so by chemical signals from the body, or if they become defective in some way, they are attacked and killed by the cells of the immune system. New cells are created as needed and the balance is preserved.

When this fine-tuned balance goes awry there is an unwanted accumulation of cells and the result is cancer of one sort or another. In the case of CLL, the problem appears not to be the accelerated formation of new B-cells but rather the refusal of the old ones to die on command. The malignant cells are able to accumulate in vast numbers because they have developed an ability to circumvent the death signals from the body. They are also very good at hiding from the surveillance of the immune system, since they are, in fact, an important part of the immune system themselves. This survival advantage allows the CLL cells to accumulate gradually over time.

This gradual but relentless accumulation of defective immune system cells leads to many complications. Mild infections that are readily shaken by healthy individuals may become life threatening, since the ability of the immune system to protect the body against invading bacteria or viruses is compromised. Sometimes the damaged immune system inappropriately attacks other cells in the blood, such as red blood cells and platelets, creating severe anemia (low hemoglobin) and thrombocytopenia (low platelets). Major organs such as the liver and spleen may get badly damaged, as the disease progresses. One of the major consequences of advanced CLL is that the bone marrow gets progressively packed with these dysfunctional CLL cells and becomes unable to produce all the other cell lines required for proper functioning of the body. The majority of deaths caused by CLL are due to these reasons and infections of the weakened system by pathogens.

After many decades of status quo, things are finally beginning to change for CLL patients. Recent advances in "smart drugs" such as monoclonal antibodies and radio labeled antibodies has led to more effective therapies with fewer toxic side-effects. Our understanding of how the immune system works is increasing by leaps and bounds. Designer drugs that target the cancer cells without harming the healthy cells of the body, and immunotherapy approaches that use the body's own defense systems to fight the remaining traces of cancer are making it possible to dream of a day in the near future when CLL is no longer an incurable disease.

A reader raised the topic of the significance of the growth, size and distribution of lymph nodes in CLL.

First of all, I would not stick with a doctor or specialist that is too fastidious to do a **physical** exam. Cripes, the very name implies touching the patient physically! How will he/she know what your nodes feel like, what size they are, and even more important, how your spleen and liver feel, are they enlarged etc, without the sense of touch?

Nodes are important. If they get too big, they can pose problems with therapy down the road. It is easier to clear CLL cells from the blood than it is to clear it from the bone marrow or the lymph nodes. The larger the nodes, the harder it is to get the drugs to them, since the vascularization is not always sufficient to get good blood flow through out the large nodes, and the drugs can only travel with blood flow. Campath, for example, is not recommended for anyone who has large nodes, since it has a hard time clearing CLL from lymph nodes.

Nodes can cause pain, if they are distended, or if they begin pressing on other organs or nerves and blood vessels. The anecdotal information (and I do not have any higher authority than that to vouch for it) is that hot compresses and gentle massage will help the lymphatic circulation, and that will help ease the pain. Unlike the blood circulation, which is carried out by an active pump, the heart, the parallel lymphatic system's flow is sustained only by large muscle activity. Physical activity (walking, jogging, swimming) are good ways to get the lymph system going, and not be a stagnant pool.

I think it was Dr. Keating who mentioned in one of his interviews, the percentage of the b-cells in the lymph nodes, spleen and liver add up to about 90-95% of the total. The peripheral blood has only about 5-10%. Like toothpaste, which moves from one side of the tube to the other when you squeeze it, I understand that lymph nodes wax and wane, as more b-cells enter or leave them, and from/into the blood. That is why there is some scatter in the CBC numbers, depending upon if you have just gone through a vigorous bout of exercise just prior to the blood draw. As you can imagine, the lymph nodes with 90-95% of the hoard of b-cells have to shrink just a little and put out b-cells into the blood, to have that register as a huge increase in the blood counts. One more reason not to panic with every little up-tick in the CBC numbers, you need to keep in mind the bigger picture.


Disclaimer: The content of this website is intended for information only and is NOT meant to be medical advice. Please be sure to consult and follow the advice of your doctors on all medical matters.

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Materials and Methods

Study populations

A total of 71 patients diagnosed with CLL/SLL between September 2001 and October 2013 at Seoul National University Hospital (SNUH, n = 58) and Asan Medical Center (n = 13) were enrolled. All of the patients were Korean. The diagnosis of CLL/SLL was based on the World Health Organization (WHO, 2008) classification criteria [20] and the 2008 International Workshop on Chronic Lymphocytic Leukemia-National Cancer Institute criteria (IWCLL-NCI) [21]. Fluorescence in situ hybridization (FISH) for IgH/CCND1 translocations was performed to confirm that the disease was not a leukemic phase of mantle cell lymphoma. Clinical staging was performed using the Binet staging system (classes A, B and C) [21]. Laboratory data including age, sex, diagnosis and therapy start date, complete blood count, and bone marrow (BM) pathology were reviewed. All BM and lymph node samples were collected with informed consent, and the study was approved by the Institutional Review Board of SNUH (1307-090-505). Participants provide their written informed consent to participate in this study.

Bone marrow examination and Leukemia-lymphoma marker study

Hematopathologists reviewed the Wright-stained BM smears and hematoxylin and eosin—stained sections of BM trephine biopsies to determine the percentages and patterns of BM infiltration by lymphocytes. The median lymphoid cell percentage was 70% (range, 5–95%). The median BM cellularity was 65% (range, 15–95%). The leukemia-lymphoma marker study (TdT, CD2, CD3, CD5, CD7, CD10, CD19, CD20, CD22, CD23, FMC7, CD45, CytoCD3, CD56, Kappa, and Lambda (BD Biosciences, San Jose, CA, USA) was performed. Six patients were negative for CD5, being categorized as atypical CLL. ZAP-70 immunohistochemical staining (Cell Marque, Rocklin, CA, USA) was performed on BM section.

G-banding and Fluorescence in situ hybridization

For G-banding, B cell-mitogen, tetradecanoylphorbol acetate (TPA phorbol-12-myristate-13-acetate) was added with subsequent culture for 4 days. FISH for enumeration of chromosome 12 and for detection of 13q14.3 deletion, 17p13 deletion, 11q22 deletion and IgH/CCND1 translocations (to exclude mantle cell lymphoma) was performed: the LSI D13S319/LSI13q34/CEP12 Multi-color Probe, LSI TP53 (17p13.1) SpectrumOrange Probe, Vysis IGH/CCND1 XT DF FISH Probe (all from Abbott Molecular/Vysis, Des Plaines, IL, USA), and XL ATM/TP53 Probe (Metasystems, GmbH, Altlussheim, Germany). Interphase FISH was performed on stored BM nuclear cells according to the manufacturer’s instruction. The cut-off values for the deletion, amplification, or translocation of chromosomal regions were based on the mean ±3 standard deviations of the normal controls (n = 20). Among 71 patients, we applied 2 different set of reference ranges since we had reset the reference ranges during study period (from patient 1–11: 1.06% for trisomy 12, 4.58% for 13q14.3 deletion, 7.39% for 17p13 deletion, 5.59% for 11q22 deletion/from patients 12–71: 1.5% for trisomy 12, 4.01% for 13q14.3 deletion, 1.7% for 17p13 deletion, 5% for 11q22 deletion).

Targeted sequencing

To gain insight into the genetic lesions that drive CLL, we performed targeted sequencing for 87 hematology malignancy-related genes (S1 Table). Using Agilent 2200 TapeStation system (Santa Clara, CA, USA), we performed quality control (QC) of the input material for subsequent library preparation and hybridization capture step. If the DIN (DNA Integrity Number, provided in the instrument’s internal algorithm) value was low, we did not further process DNA because it was highly degraded and these low-quality DNAs cannot be used for library preparation step. We collected 71 patients’ samples, but 19 samples’ DIN value were low, so only 48 samples were sequenced. And we did not purified tumor cells only, but the mean percentage of CD20+ B lymphocytes was 70% (n = 48), we assumed tumor cells are included as those percentages. Besides, we used THetA (Tumor Heterogeneity Analysis) [22] to calculate the proportion of cancer cells in the admixture. The tumor purity of CLL samples ranged from 80 to 95%.

gDNA shearing to generate the standard library and the hybridization step targeting only exonic regions were performed by Celemics Inc. (Seoul, Korea). Briefly,

500 ng of sequencing library was denatured at 95°C for 5 min and then incubated at 65°C before addition of the customized-baitset reagent and Cot, Salmon sperm and adaptor-specific blocker DNA in hybridization buffer. After 24-h incubation, the library was captured on T1 Magnetic Beads and off-target library was washed. Then, the target captured library was amplified (16 cycles). After amplification, the samples were purified using AMPure XP Beads. The final quality was assessed using the Agilent 2200 TapeStation System (Santa Clara, CA, USA). We sequenced a total target length of 259-kb regions using the paired-end 150-bp rapid-run sequencing mode on an Illumina HiSeq 2500 platform. The mean sequencing depth for the targeted regions (259 kb) was 231-fold (n = 48). Because a matched control sample was not included in this study, we applied a stringent variant selection pipeline to prioritize the high-confidence set of somatic mutations (Fig 1).

Analysis of Illumina sequencing and variant prioritization

First, we trimmed raw fastq files with bases with Phred-like quality below 20. Then, data was mapped to the reference genome (hg19) with Burrows-Wheeler Aligner (BWA, v0.6.2). PCR duplicate read was removed using Picard 1.98. Indel realignment and base quality recalibration was performed using GATK (v.2.7–2). Then, single nucleotide variants and indels were called using “HaplotypeCaller” module in GATK was used which is based on local re-assembly of potential variant regions combined with likelihood estimation of candidate haplotypes. We annotated variants with ANNOVAR and VEP. Further, we retain variants if they were found in >2 reads among >10 total reads. Benign mutations (Synonymous mutation) were further removed. Moreover, two additional control sets were applied to discard possible polymorphisms (variants with a frequency less than 1% in the 1000genomes as well as ESP6500 database). Known SNPs in private database dbSNP132 were also removed. Finally, we discarded variants presented in in-house healthy Korean exome controls (n = 276) (strict cutoff based on very rare incidence of CLL in Korea (0.13 /100,000)) [23].

We retained variants in the COSMIC (v68) database and known somatic mutations by exhaustively searching PubMed database to confirm somatic origin. Additionally, we manually inspected error-prone mapping regions and removed potential false positive variant and regions with highly repetitive sequences were removed.

Oncogenic driver selection

After filtering low confidence polymorphisms, we further narrowed down remaining potential pathogenic candidate mutations using known functional amino acid change prediction algorithms (SIFT [24], PolyPhen-2 [25]). Also, we scored all variants with CADD [26] (URL: algorithm and prioritized variants based on the scaled Phred-like c-score. This algorithm uses machine-learning models to distinguish deleterious variants from neutral ones. Lastly, we chose final variant set based on the scheme as follows:

  1. Retain if more than 2 algorithm predicted as damaging (prediction results for SIFT and Polyphen-2 as “Damaging or Probably damaging” and classified CADD c-score > 20 as damaging)
  2. Alternatively, when one of the 3 predictions is annotated as NA (not available), we rescued if damaging in one (1/2) or two algorithms (2/2). When 2 of the 3 prediction algorithms are annotated as NA, we rescued variants if remaining one algorithm predicted as damaging (1/1).

Hereafter, mutated genes refer to those with any variant that has passed the above criteria.

Validation with Sanger sequencing

For validation of the targeted sequencing, we have selected random subset of mutation, ATM, TP53, SF3B1, LAMB4 and EZH2. Primers (S2 Table) for PCR were designed from ±150 bp upstream and downstream of the target gene. The conditions for PCR were as follows: 1) 3 min of initial heating at 98°C followed by 20 cycles of 98°C 30 s, 60°C 30 s, 72°C 1 min and a final elongation step at 72°C for 10 min. Sequence analysis was performed using Lasergene 10/SeqMan 5.01 (DNASTAR Inc., USA).

Since the cost for validating all the mutations called by variant caller would be cost-demanding [27], we have selected sixteen random subset of mutations (in wide range of variant allele frequencies) for Sanger sequencing for validation purpose. All of these samples had mutations.

Statistical analysis

Chi-squared test, Fisher’s exact test, Pearson's product-moment correlation, log-rank test, the Kaplan-Meier method, and the Cox proportional hazards model for differences between the survival curves and hazard ratios with 95% confidence interval (CI). Statistical analyses were performed using R software (version 3.3.0, False discovery rate (FDR) was applied in our study for multiple comparisons [28]. Raw P-values<0.05 were mentioned, and adjusted P-values<0.05 considered statistically significant.

Pure Red Cell Aplasia (PRCA)

Acquired Pure Red Cell Aplasia: This is a very rare condition and usually affects adults. It is characterized by an absence of red cell precursors (reticulocytes) in the marrow and a low red blood cell count. The amounts of white blood cells and platelet remain normal.

Transient or Acute Self-limited PRCA: This is the most common type of PRCA. It is identical to acquired PRCA except that, at some point, it simply goes away. Transient PRCA is usually triggered by a virus or drug. In most cases, when the virus clears, or the responsible drugs are eliminated, the PRCA will disappear. This is most dangerous to patients who already have a chronic hemolytic anemia . Patients with otherwise normal functioning bone marrow may even recover without having known they had it.

Inherited or Congenital Pure Red Cell Aplasia (Diamond-Blackfan Anemia ): Diamond-Blackfan anemia is a genetic condition usually diagnosed during the first two years of life. About half of patients also have physical malformations or mental retardation. Only several hundred cases have been reported worldwide. The severity of the disease varies by patient.

Relation to bone marrow failure diseases:

The major difference between PRCA and aplastic anemia is that, in PRCA, only the red blood cell line is affected, while the white blood cells and platelets remain at normal levels. In aplastic anemia, all three blood cell types are typically affected.


3.1 Subjects

The characteristics of 595 patients were summarized in Table 1. The median age was 61.4 years (range 16-92) and 60.9% were male. Twenty-eight patients were diagnosed with SLL and the rest of 567 were CLL patients. 214 (39.9%) patients were in Binet A, 148 (25.8%) in Binet B, and 184 (34.3%) in Binet C. Sixteen (2.7%) patients suffered from Richter's syndrome.

Variables N = 595
Age 61.4 (16-92)
Male 380 (63.9%)
Binet stage (n = 536)
A 214 (39.9%)
B 138 (25.8%)
C 184 (34.3%)
White blood cell count (×10 9 /L) (n = 522) 42.6 (5.7-426.2)
Absolute lymphocyte count (×10 9 /L) (n = 522) 36.1 (3.5-416.2)
Hemoglobin (g/L) (n = 522) 120 (26-196)
Platelet (×10 9 /L) (n = 522) 139 (4-477)
IGHV unmutated 248 (41.3%)
β2-microglobulin (mg/L) (n = 490) 3.99 (1-22)
CD38 positive (n = 572) 175 (31%)
ZAP70 positive (n = 566) 222 (40%)
Hepatitis B virus positive (n = 462)a a We defined Hepatitis B virus positive as positive for surface antigen and/or HBV-DNA positive.
41 (8.9%)
Molecular abnormalities
TP53 mutation (n = 490) 70 (14.3%)
SF3B1 mutation (n = 413) 24 (5.8%)
NOTCH1 mutation (n = 465) 34 (7.3%)
MYD88 mutation (n = 409) 32 (7.8%)
Del (17p13) (n = 507) 75 (14.8%)
Del (11q22.3) (n = 486) 77 (15.8%)
Trisomy 12 (n = 429) 103 (24%)
  • a We defined Hepatitis B virus positive as positive for surface antigen and/or HBV-DNA positive.

After a median follow-up of 45 months (range 1-279 months), 359 (61.8%) patients were treated (median numbers of therapies: 2). Three hundred and four patients had unequivocal initial treatment information as follows: 115 (37.8%) patients received rituximab-based therapy (rituximab alone or immunochemotherapy), 181 (59.5%) patients received chemotherapy alone, five (1.6%) patients received ibrutinib as single agent, and three (0.99%) patients received other therapies (one patient treated with decitabine, two patients treated with high-dose methylprednisolone).

3.2 IGHV usage

IGHV-D-J sequencing was conducted on all the 595 patients. A total of 600 sequences were obtained as five (0.8%) patients held double rearrangements (Table S1). With the exception of Patient 4, the mutational rates of the two sequences in the rest of the patients were similar. We included both sequences of each patient in subsequent analyses. Six hundred sequences were unevenly distributed among seven IGHV families, showing the overuse of IGHV3 (51.2%), followed by IGHV4 (26.2%), IGHV1 (15.2%), IGHV2 (2.8%), IGHV7 (1.2%), and IGHV6 (0.8%) (Figure 1A). The most frequent IGHV subgroups were IGHV3-23 (61, 10.7%), IGHV4-34 (59, 9.8%), IGHV3-7 (45, 7.5%), IGHV4-39 (39, 6.5%), IGHV1-69 (37, 6.2%), IGHV3-30 (34, 5.7%), IGHV4-59 (26, 4.3%), IGHV3-48 (23, 3.8%), IGHV3-21 (19, 3.2%), and IGHV3-33 (19, 3.2%) (Figure 1B).

3.3 Influence of mutational load on clinical outcomes

About 352 (58.7%) cases were M, while 248 (41.3%) cases were UM if we used the classical 98% classification by ERIC. In order to determine the optimal cutoff value, we used 1% as the interval to divide the entire cohort into seven groups according to the mutational rate, which were <95%, 95%-95.99%, 96%-96.99%, 97%-97.99%, 98%-98.99%, 99%-99.99%, and 100%, respectively. First, we investigated the best cutoff value in Binet A patients (n = 213,with one patient lost to follow-up). Cox regression analysis showed that only the 100% group (hazard ratio (HR): 2.46, P = .001) was significantly different in TTFT when compared with the <95% group (Table 2A). Then, we compared TTFT in the whole cohort (n = 586,with nine patients lost to follow-up). Significant difference appeared at the 98% interval with a HR of 2.3 (P < .001), while intervals less than 98% had no significant difference compared with the <95% group (HR: 0.93 for subgroup 95%-95.99%, 0.78 for subgroup 96%-96.99%, 1.37 for subgroup 97%-97.99%, Figure 2A). Similarly, there were no clear dissimilarities in HR among the 98%-98.99%, 99%-99.99%, and 100% subgroups which were 2.3, 2.9, and 2.34, respectively (Table 2B). The same 98% cutoff was also desirable in the OS prediction for the whole study cohort (Figure 2B, only 23 cases in the Binet A cohort died, failing to evaluate OS): comparing to the < 95% group, patients in 95%-95.99%, 96%-96.99%, and 97%-97.99% subgroups tended to have lower HR (0.5-1.02) while patients in 98%-98.99%, 99%-99.99% and 100% subgroups had significantly higher HR (2.94, 3.44 4.25, respectively, Table 2C).

IGHV% identities Numbers Mean (month) Median (month) HR 95% CI P
(A) Cox remission of TTFT in the Binet A cohort
<95% 113 134.7 139 1.00
95%-95.99% 19 85.2 100 0.57 (0.21,1.61) .29
96%-96.99% 17 96.0 Not reached 0.34 (0.08,1.41) .14
97%-97.99% 9 91.8 Not reached 1.17 (0.42,3.31) .76
98%-98.99% 10 60.8 Not reached 1.55 (0.55,4.35) .41
99%-99.99% 9 53.6 88 2.03 (0.80,5.16) .14
100.00% 36 49.6 34.5 2.46 (1.44,4.21) .001* * P values < 0.05 and with significant difference.
(B) Cox remission of TTFT in the whole cohort
<94.99% 230 99.4 58 1.00
95%-95.99% 46 66.3 92 0.93 (0.59,1.47) .75
96%-96.99% 36 66.2 71 0.78 (0.45,1.34) .37
97%-97.99% 31 57.2 19 1.37 (0.85,2,2) .19
98%-98.99% 37 27.7 13 2.30 (1.53,3.48) <.001* * P values < 0.05 and with significant difference.
99%-99.99% 64 20.6 4 2.90 (2.08,4.06) <.001* * P values < 0.05 and with significant difference.
100.00% 142 28.5 11 2.34 (1.79,3.06) <.001* * P values < 0.05 and with significant difference.
(C) Cox remission of OS in the whole cohort
<94.99% 230 195.5 230.3 1.00
95%-95.99% 46 120.6 119.7 1.02 (0.43,2.42) .97
96%-96.99% 36 191.3 219.1 0.50 (0.15,1.62) .25
97%-97.99% 31 131.8 Not reached 0.83 (0.30,2.34) .73
98%-98.99% 37 113.2 98 2.94 (1.30,4.42) .005* * P values < 0.05 and with significant difference.
99%-99.99% 64 93.5 106.5 3.44 (2.05,5.78) <.001* * P values < 0.05 and with significant difference.
100.00% 142 82.1 69 4.25 (2.78,6.5) <.001* * P values < 0.05 and with significant difference.

It has been reported that up to 30% of CLL patients belong to B cell receptor (BCR) stereotypy and with “some” subsets conferring specific clinical outcomes, especially those who belong to subset#2 characterized with IGHV3-21 usage and predominantly mutated IGHV status. 11, 19, 20 Lacking the CDR3 information in 131 patients limited further identification of subsets. However, we still identified subsets of the remaining 469 sequences. There was only one patient belonging to subset#2 in 469 evaluable sequences and the result was consistent with our previous study. 15 Since the rarity of subset#2 in our research, we thought the isolated case could not affect the result of cutoff analysis, so we reached a compromise by excluding all the IGHV3-21 cases that tend to have poor prognosis, though there have been controversies over the prognosis of them. 21, 22 98% cutoff value could still better predict TTFT and OS in cohort without IGHV3-21 cases than any other cutoff values (Table S2).

3.4 Clinical correlations

Although 98% was the appropriate cutoff for TTFT and OS in our study, we still wanted to know if there were a maldistribution of other prognostic factors in the M/UM groups and whether it was due to the increase of these poor prognostic factors that led to a gradual increase in the HR of OS among three intervals that are ≥98% (2.94, 3.44, 4.25, respectively).

If we dichotomized the whole cohort by 98%, patients in ≥98% group were more likely to be male (P = .009), with higher levels of β2-MG at diagnosis (P < .001) and in advanced Binet stages (P < .001). The distribution of TP53, NOTCH1, SF3B1, and MYD88 mutations was significantly different (P < .001, P < .001, P = .034, and P < .001, respectively), so was the distribution of del(17p13), del(11q22.3), CD38 + , and ZAP-70 + (P = .01, P < .001, P < .001, and P = .005, respectively, Table 3).

Numbers TTFT OS Distributions between <98% and ≥98% Distributions among 98%-98.99%, 99%-99.99%, and 100%
Del(17p13) 504 <0.001 <0.001 0.01 × × Distributions among the three intervals were not significantly different.
TP53 485 <0.001 <0.001 <0.001 × × Distributions among the three intervals were not significantly different.
Del(11q22.3) 481 <0.002 0.169# # Without significant difference but P ≤ .2.
<0.001 × × Distributions among the three intervals were not significantly different.
Trisomy 12 429 0.443* * Without significant difference.
0.254* * Without significant difference.
0.47* * Without significant difference.
× × Distributions among the three intervals were not significantly different.
MYD88 409 0.715* * Without significant difference.
0.087* * Without significant difference.
<0.001 × × Distributions among the three intervals were not significantly different.
NOTCH1 465 <0.001 <0.001 <0.001 × × Distributions among the three intervals were not significantly different.
SF3B1 413 0.054# # Without significant difference but P ≤ .2.
0.056# # Without significant difference but P ≤ .2.
0.034 ✓ ✓ Distributions among the three intervals were significantly different.
CD38 569 <0.001 0.024 <0.001 × × Distributions among the three intervals were not significantly different.
ZAP-70 564 0.036 0.2# # Without significant difference but P ≤ .2.
0.005 × × Distributions among the three intervals were not significantly different.
β2-MG 493 <0.001 <0.001 <0.001 × × Distributions among the three intervals were not significantly different.
Binet stage 534 <0.001 <0.001 <0.001 × × Distributions among the three intervals were not significantly different.
Gender 586 0.01 0.01 0.009 × × Distributions among the three intervals were not significantly different.
HBV 462 0.978* * Without significant difference.
0.439* * Without significant difference.
0.216* * Without significant difference.
× × Distributions among the three intervals were not significantly different.
Age 586 0.872* * Without significant difference.
0.351* * Without significant difference.
0.283 × × Distributions among the three intervals were not significantly different.
  • * Without significant difference.
  • # Without significant difference but P ≤ .2.
  • × Distributions among the three intervals were not significantly different.
  • ✓ Distributions among the three intervals were significantly different.

There were no statistically significant differences in the distribution of these prognostic factors in the three subgroups that are ≥98% with the exception of SF3B1 mutation. The frequency of SF3B1 mutation in the 98%-98.99% group was significantly higher than that in the 99%-99.99% and 100% groups (P = .032, P = .004, respectively, Table 3). But given that SF3B1 mutation was not a prognostic factor for TTFT and OS in our study, it did not change our conclusion. On the other hand, due to the low mutation rate of SF3B1, theoretical frequencies were less than 5 in some groups.

Therefore, we conclude that within the ≥98% group, the gradual increase in HR was more likely due to the decrease in IGHV mutational rate rather than other concurrent effects of poor prognostic factors we have known. The lower the mutational rate of IGHV is, the higher the HR of OS is.

3.5 Multivariate analyses

In univariate analyses, we found out that clinical features (Binet staging, gender, and β2-microglobulin (β2-MG)>3.5 mg/L), cytogenetic aberrations (TP53 mutations, NOTCH1 mutations, and del(17p13)), and immunophenotyping (CD38 positive and ZAP-70 positive) were prognostic factors for both TTFT and OS. Del(11q22.3) was the prognostic factor for TTFT.

Then we conducted Multivariate Cox regression analyses containing prognostic factors above. UM-IGHV (HR: 1.68 95% CI: (1.26,2.25) P < .001) and advanced Binet stages (stage B: HR: 4.04 95% CI: (2.85,5.74) P < .001 stage C: HR: 3.10 95% CI: (2.14,4.49) P < .001) were independently correlated with TTFT. UM-IGHV (HR: 2.30 95% CI: (1.36,3.89) P = .002), advanced Binet stages (stage B: HR: 2.68 95% CI: (1.41,5.12) P = .003), the presence of TP53 mutations (HR: 1.87 95% CI: (1.07,3.28) P = .029), del(17p13) (HR: 2.26 95% CI: (1.21,4.19) P = .01), NOTCH1 mutations (HR: 2.21 95% CI: (1.15,4.25) P = .017), and male (HR: 1.77 95% CI: (1.06,2.95) P = .03) were independently correlated with OS (details in Table 4). β2-MG showed marginal significance in multivariate analysis of TTFT (P = .053). It should be noted that neither TP53 mutation nor del(17p13) was independent prognostic factors for TTFT in this cohort, probably due to their weak power as indications for treatment of CLL.

Variables P HR 95% CI
(A) TTFT* * Totally 305 patients were available in analysis.
98% as cutoff value <0.001 1.68 (1.26,2.25)
Binet A <0.001
Binet B <0.001 4.04 (2.85,5.74)
Binet C <0.001 3.10 (2.14,4.49)
(B) OS* * Totally 305 patients were available in analysis.
98% as cutoff value 0.002 2.30 (1.36,3.89)
Binet A 0.01
Binet B 0.03 2.68 (1.40,5.12)
Binet C 0.09 1.86 (0.91,3.80)
TP53 mutations 0.029 1.87 (1.07,3.29)
NOTCH1 mutations 0.017 2.22 (1.15,4.25)
Del(17p13) 0.01 2.26 (1.21,4.19)
Gender 0.01 1.77 (1.06,2.95)

EXAM 2 Study guide

Hypoxemia, reduced oxygen levels in the blood, further contributes to cardiovascular dysfunction by causing dilation of arterioles, capillaries, and venules, thus leading to decreased vascular resistance and increased flow. Increased peripheral blood flow and accelerated venous return further contribute to an increase in heart rate and stroke volume in a continuing effort to meet normal oxygen demand and prevent cardiopulmonary congestion. These compensatory mechanisms may lead to heart failure.

Tissue hypoxia creates additional demands and compensatory actions on the pulmonary and hematologic systems. The rate and depth of breathing increase in an attempt to increase the availability of oxygen. These demands are accompanied by an increase in the release of oxygen from hemoglobin. (Mechanisms of oxygen transport and release by hemoglobin are described in Chapter 28.) All of these compensatory mechanisms may cause individuals to experience shortness of breath (dyspnea) a rapid, pounding heartbeat (palpitations) dizziness and fatigue. In mild, chronic conditions, these symptoms might be present only when the demand for oxygen is increased (e.g., during physical exertion), but in severe conditions they may be experienced at rest.

Manifestations of anemia may be observed in other parts of the body. The skin, mucous membranes, lips, nail beds, and conjunctivae become pale as a result of reduced hemoglobin concentration. If anemia is caused by RBC destruction (hemolysis), the skin may become yellowish because of accumulation of the products of hemolysis. Tissue hypoxia of the skin results in impaired healing and loss of elasticity, as well as thinning and early graying of the hair. Nervous system manifestations can occur if the anemia is caused by a vitamin B12 deficiency. Myelin degeneration may occur, causing a loss of nerve fibers in the spinal cord and producing paresthesias (numbness), gait disturbances, extreme weakness, spasticity, and reflex abnormalities. Decreased oxygen supply to the gastrointestinal (GI) tract often produces abdominal pain, nausea, vomiting, and anorexia. A low-grade fever of less than 38.5°C (less than about 101°F) occurs in some anemic individuals and may result from the release of leukocyte pyrogens from ischemic tissues.

Hepatic Manifestations in Hematological Disorders

Liver involvement is often observed in several hematological disorders, resulting in abnormal liver function tests, abnormalities in liver imaging studies, or clinical symptoms presenting with hepatic manifestations. In hemolytic anemia, jaundice and hepatosplenomegaly are often seen mimicking liver diseases. In hematologic malignancies, malignant cells often infiltrate the liver and may demonstrate abnormal liver function test results accompanied by hepatosplenomegaly or formation of multiple nodules in the liver and/or spleen. These cases may further evolve into fulminant hepatic failure.

1. Introduction

Hepatologists or general physicians sometimes encounter hepatic manifestations of various hematologic disorders in daily practice, including various abnormalities in liver function tests or imaging studies of the liver. Some hematologic disorders also mimic liver diseases. While review articles regarding hematologic disorders and liver diseases have been published previously [1–3], we also review more recent topics in this paper.

2. Red Blood Cell (RBC) Disorders

2.1. Hemolytic Anemia (HA)
2.1.1. Classification according to the RBC Destruction Site

When the RBC membrane is severely damaged, immediate lysis occurs within the circulation (intravascular hemolysis). In cases of less severe damage, the cells may be destroyed within the monocyte-macrophage system in the spleen, liver, bone marrow, and lymph nodes (extravascular hemolysis) [4–6].

2.1.2. Clinical Presentation

Patients with HA typically present with the following findings: rapid onset of anemia, jaundice, history of pigmented (bilirubin) gallstones, and splenomegaly. Mild hepatomegaly can also occur [4].

2.1.3. Liver Function Tests in HA

In hemolysis, serum lactate dehydrogenase (LDH) levels (specifically the LDH1 and LDH2 isoforms) increase because of lysed erythrocytes [4]. Serum aspartate transaminase (AST) levels are also mildly elevated in hemolysis, with the LDH/AST ratio mostly over 30 [7]. Total bilirubin levels can uncommonly exceed 5 mg/dL if hepatic function is normal, except in the case of acute hemolysis caused by sickle cell crisis. Liver dysfunction can also be caused by blood transfusion for anemia in sickle cell disease (SCD) and thalassemia [1, 3].

2.1.4. Hemolysis in Liver Disease

Hemolysis can be caused by either abnormalities in the erythrocyte membranes (intrinsic) or environmental (extrinsic) factors. Most intrinsic causes are hereditary, except for paroxysmal nocturnal hemoglobinuria (PNH) or rare conditions of acquired alpha thalassemia [4].

Extrinsic HA is caused by immune or nonimmune mechanisms. Extrinsic nonimmune HA is caused by systemic diseases, including some infectious diseases and liver or renal diseases. Various liver diseases may induce HA, and the two major causes of extrinsic HA in patients with liver disease are destruction of RBCs in an enlarged spleen (hypersplenism) and acquired alterations in the red cell membrane (e.g., target cells, acanthocytes, echinocytes, and stomatocytes). Liver diseases, especially those caused by alcohol intoxication, induce severe hypophosphatemia [8–10], which presumably results in low red cell adenosine triphosphate levels, leading to red cell membrane fragility and spheroidicity. These red cells are easily trapped in the spleen because of their reduced deformability. When excess alcohol consumption is the predominant cause, the condition rapidly improves when alcohol consumption is stopped.

Zieve syndrome is a poorly understood entity characterized by fatty liver/cirrhosis, severe upper abdominal and right upper quadrant pain, jaundice, hyperlipidemia, and HA [11–13].

2.2. Autoimmune HA (AIHA)

AIHA is characterized by increased breakdown of RBCs due to autoantibodies with or without complement activation. Diagnosis of AIHA includes a combination of clinical and laboratory signs of RBC hemolysis together with detection of autoantibodies and/or complement deposition on RBCs detected by the direct antiglobulin test, also known as the direct Coombs test [14]. In more than half of affected patients, AIHA is associated with an underlying disease including some type of infectious disease, immune disorder, or lymphoproliferative disorder (secondary AIHA), whereas other patients do not have any evidence of underlying disorders (idiopathic or primary AIHA) [15].

2.2.1. Liver Function Tests in AIHA

Laboratory findings of AIHA are not different from those of other causes of hemolysis, that is, reduction in serum haptoglobin, indirect bilirubinemia, and elevated levels of serum LDH (I > II predominant) and AST (mostly LDH/AST > 30). Serum total bilirubin uncommonly exceeds 5 mg/dL, and polyclonal hypergammaglobulinemia is often seen.

2.2.2. Liver Failure in AIHA

Immunoglobulin (Ig)G antibodies (rarely IgM antibodies) generally react with antigens on the RBC surface at body temperature and are thus referred to as “warm agglutinins,” whereas IgM antibodies (rarely IgG type) react with antigens on the RBC surface below body temperature and are thus referred to as “cold agglutinins.” Warm-reacting IgM antibodies may lead to hepatic failure by in vivo autoagglutination [16]. A fatal case with primary AIHA presenting as acute liver failure has been reported [16]. The patient experienced recurrent episodes of intravascular hemolysis. Despite corticosteroid therapy, splenectomy, and multiple blood transfusions, the patient eventually succumbed to liver failure.

2.3. PNH

PNH is an uncommon type of acquired hemolysis, which occurs in middle-aged adults [17, 18]. Patients present with dark urine (hemoglobinuria), usually the morning samples. PNH has been proven to be an acquired clonal genetic disease caused by somatic mutation of the X-linked PIG-A gene in hematopoietic stem cells [19].

2.3.1. Clinical Presentation

The clinical manifestations of PNH are primarily related to abnormalities in the hematopoietic function, HA, a hypercoagulable state, bone marrow hypoplasia or aplasia, and progression to myelodysplastic syndrome or acute leukemia [18].

2.3.2. Diagnosis of PNH

PNH was indirectly diagnosed formerly on the basis of the sensitivity of PNH red cells to be lysed by complement. The sucrose lysis test is used as a screening test, and diagnosis is confirmed by the Ham acid hemolysis test [20–22]. However, detection of glycosylinositol phospholipid-linked protein deficiency in PNH by flow cytometric analysis has been developed for diagnosis [23].

2.3.3. PNH-Associated Liver Disease

One of the serious complications of PNH is development of a hypercoagulable state and formation of thrombi. Thrombosis in PNH typically occurs in the intracranial, hepatic, or portal vessels. PNH is one of the most common causes of de novo presentation of portal vein thrombosis and a rare cause of Budd-Chiari syndrome [24].

2.4. Sickle Cell Disease (SCD)

SCD is an autosomal recessive genetic disorder resulting from inheritance of the hemoglobin S (Hb S) variant of the β-globin chain. The most severe form with homozygosity for Hb S (Hb SS) is called sickle cell anemia (SCA). Less severe forms possess heterozygosity for Hb S and C (Hb SC) or Hb β-thalassemia (Hb β-thal). The erythrocytes deform to a crescent shape (sickling) prone to hemolysis, often forming clumps in the vasculature (vaso-occlusive crisis), causing organ damages [25].

2.4.1. Hepatic Manifestation in SCD

The liver can be affected by the disease with vascular complications from the sickling process. Moreover, multiple transfusions required for treatment could increase the risk of viral hepatitis, iron overload, and development of pigmented gallstones, all of which may contribute to development of a liver disease called “sickle cell hepatopathy” [26–28]. Acute abdominal pain and abnormal liver function tests as well as jaundice can be caused by acute sickle hepatic crisis, sickle cell intrahepatic cholestasis, cholecystitis, and choledocholithiasis with common bile duct obstruction.

2.4.2. Liver Function Tests in SCD

Liver function test abnormalities are common in patients with SCD. Elevation in indirect bilirubin, LDH, and AST without other evidence of liver disease is found in 72% of patients with SCA, which is related to the hemolysis and/or ineffective erythropoiesis [29]. Total bilirubin concentrations are usually <6 mg/dL but may double (<15 mg/L) during sickle hepatic crisis [30]. Serum ALT levels may more accurately reflect hepatocyte injury [29]. Serum alkaline phosphatase (ALP), predominantly bone derived, is commonly elevated [31].

Acute elevation in serum aminotransferase can be seen with hepatic ischemia in vaso-occlusive crisis, whereas chronic liver dysfunctions are found in 9%–25% of the patients [29, 32], usually caused by coexisting hepatic diseases, such as chronic hepatitis B or C, common bile duct obstruction, or alcohol consumption.

2.4.3. Hyperammonemia due to Zinc Deficiency in SCD

Low zinc plasma levels are reported in 44% of SCD patients [33], which may lead to development of encephalopathy due to hyperammonemia in cirrhotic patients with SCA that can be corrected by zinc administration [34].

2.4.4. Liver Imaging Studies in SCD

The CT findings of patients with homozygous SCA reveal diffuse hepatomegaly. The spleen is usually small and atrophic and may have dense calcifications due to repeated splenic infarction. Double heterozygotes (Hb SC and Hb Sβ-thal) usually have splenomegaly and may show infarcts, rupture, hemorrhage, or abscesses of the spleen.

MRI may show decreased signal intensity in the liver and pancreas [35] due to iron deposition in the SCD patients receiving chronic transfusions [36–39]. Abdominal ultrasound can reveal gallstones or increased echogenicity of the liver and pancreas due to iron deposition [37].

3. Coagulation Disorders

3.1. Disseminated Intravascular Coagulation (DIC)

DIC is a systemic process causing both thrombosis and hemorrhage. The pathogenesis of DIC is primarily due to excessive production of thrombin, leading to widespread and systemic intravascular thrombus formation. Major initiating factors are the release or expression of tissue factor secondary to extensive injury to the vascular endothelium or enhanced expression by monocytes in response to endotoxin and various cytokines. The most common causes of DIC are sepsis, trauma and tissue destruction, cancer, and obstetrical complications.

3.1.1. Diagnosis of DIC

Diagnosis of DIC is suggested by the history and symptoms, thrombocytopenia, and presence of blood smear microangiopathic changes. The diagnosis is confirmed by laboratory tests that demonstrate evidence of both increased thrombus generation (e.g., decreased fibrinogen) as and increased fibrinolysis (e.g., elevated fibrin degradation products or D-dimer).

3.1.2. Hepatic Manifestation in DIC

Jaundice is common in patients with DIC and may be due to liver injury and increased bilirubin production secondary to hemolysis. In addition, hepatocellular injury may be produced by sepsis and hypotension. Common manifestations of acute DIC, in addition to bleeding, include thromboembolism and dysfunction of the kidney, liver, lungs, and central nervous system. In a series of 118 patients with acute DIC, hepatic dysfunction was found in 19% [38]. Severe liver disease involves decreased synthesis of coagulation factors and inhibitors [39], fibrinolysis, fibrinogenolysis, and elevated levels of fibrin degradation products. Thrombocytopenia may be induced by hypersplenism secondary to portal hypertension.

3.2. The Antiphospholipid Antibody Syndrome (APS)

The antiphospholipid antibody syndrome (APS) or APLA syndrome is characterized by the presence of one of antiphospholipid antibody (aPL) in the plasma and occurrence of any clinical manifestations including venous or arterial thromboses, or pregnancy morbidity.

3.2.1. Clinical Presentation

APS occurs either as a primary or secondary from underlying diseases such as systemic lupus erythematosus (SLE). In a series of primary or secondary APS, deep vein thrombosis (DVT) (32%) thrombocytopenia (22%), livedo reticularis (20%), stroke (13%) superficial thrombophlebitis (9%), pulmonary embolism (9%), fetal loss (8%), transient ischemic attack (7%) and hemolytic anemia (7%) are often observed [40], and venous thromboses are more common than arterial thromboses [41, 42]. Although the most common sites where DVT occurs are the calf and the renal veins, hepatic, axillary, subclavian, and retinal veins, cerebral sinuses, and the vena cava may also be involved.

3.2.2. Hepatic Manifestation in APS

The liver involvement may include hepatic or portal venous thrombosis, which could result in Budd-Chiari syndrome, hepatic veno-occlusive disease, hepatic infarction, portal hypertension and cirrhosis. [40, 43].

3.3. HELLP Syndrome

HELLP syndrome is defined by hemolysis with a microangiopathic blood smear, elevated liver enzymes, and a low platelet count [44]. HELLP syndrome occurs in approximately 1 to 2 per 1000 pregnancies and in 10 to 20 percent of women with severe preeclampsia/eclampsia.

3.3.1. Clinical Presentation

The most common clinical presentation is abdominal pain [45], nausea, vomiting, and malaise, which may resemble viral hepatitis, particularly if the serums AST and LDH are markedly elevated [46]. Hypertension and proteinuria are present in approximately 85 percent of the cases. Differential diagnosis includes acute fatty liver of pregnancy (AFLP). Prolongation of the prothrombin time activated partial thromboplastin time (aPTT), low glucose and elevated creatinine concentrations are more common in women with AFLP than those with HELLP.

3.3.2. Hepatic Manifestation in HELLP Syndrome

HELLP syndrome and severe preeclampsia may be associated with hepatic manifestations, including infarction, hemorrhage, and rupture.

4. Cryoglobulinemia

4.1. Definition and Classification

Precipitates in serum at temperatures below 37°C referred to cryoglobulin (CG). CG consists of immunoglobulin (Ig) and complement components [47], and the cryoglobulinemia refers to the presence of CG in a patient’s serum. There are three types of CG according to Brouet classification, which is based on the clonality of Ig [48]. Type I CG (monoclonal Ig) is usually associated with a hematologic malignancy such as Waldenstrom’s macroglobulinemia or multiple myeloma. Type II CG (polyclonal and monoclonal Ig) is often secondary to chronic infections such as hepatitic C or human immunodeficiency virus infection. Type III CG (polyclonal Ig) is often secondary to systemic rheumatic diseases.

4.2. Clinical Presentation

Clinical features of Type I CG (monoclonal Ig) include hyperviscosity syndrome due to hematological malignancies. While Type II and III CGs (mixed and polyclonal Ig, resp.) are present with “Meltzer’s triad” of palpable purpura, arthralgia, and myalgia, caused by vasculitis in small- to medium-sized vessels [49].

Secondary lymphoproliferative disorders occur in less than 5 to 10 percent of patients in type II CG patients 5 to 10 years after diagnosis [50–52]. The primary malignancies include B cell non-Hodgkin lymphoma, both intermediate-to-high grade lymphoma and low-grade lymphoma such as immunocytoma, mucosa-associated lymphoid tumors, and centrocytic follicular lymphoma. Among patients with hepatitis C-associated type II cryoglobulinemia, the incidence of non-Hodgkin lymphoma is estimated to be 35-fold higher than that in the general population.

4.3. Cryoglobulinemia in HCV Infection

The pathogenesis of CG has been most studied in chronic HCV infection. B cell hyperactivation may result from HCV infection into B cells via the cell surface protein CD81 [53], chronic, antigen-nonspecific stimulation by macromolecular serum complexes containing HCV, including HCV-IgG and HCV-lipoprotein [54, 55], or from an HCV antigen-specific mechanism [56], resulting in expansion of specific B cell clones expressing the WA idiotype [57] or V(H)1-69 [58]. HCV particles are often found in the CG complexes, but CG development in hepatitis C infection does not necessarily require HCV virion or its components [59].

Among patients with HCV infection, the number of circulating regulatory T cells was compared between patients with symptomatic and asymptomatic CG [60], and the mean levels of regulatory T cells were found to be significantly lower in patients with symptomatic HCV-associated CG than asymptomatic subjects.

4.4. Hepatic Manifestation of Cryoglobulinemia

Hepatic manifestations have been reported as hepatomegaly, abnormal liver function tests, or abnormal liver biopsy in up to 90 percent possibly due to chronic hepatitis itself [61].

5. Hematological Neoplasms

5.1. Classification of Neoplasms of Hematopoietic Origin

Neoplasms derived from hematopoietic and lymphoid tissues are classified according to their morphologic, immunophenotypic, genetic, and clinical features and by the type of originating cell lineage and differentiation stage according to the widely used and accepted World Health Organization classification system of 2001, which was updated in 2008 [62].

Myeloid neoplasms include chronic myeloproliferative neoplasms (MPNs), MDS, or acute leukemias with myeloid lineages. Lymphoid neoplasms are divided into acute lymphoblastic leukemia/lymphoma derived from B or T lymphoid progenitors, or ones derived from mature T or B lymphocytes including plasma cells. Histiocytic/dendritic cell neoplasms are derived from antigen presenting cells or tissue macrophages. Rare cases can be unclassifiable to myeloid or lymphoid lineage [62].

6. Myeloid Neoplasms

Chronic MPNs, also called myeloproliferative disorders, classically include chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia, and primary idiopathic myelofibrosis.

6.1. CML

CML is an MPN characterized by dysregulated production and uncontrolled proliferation of mature and immature granulocytes with normal morphology. The tumor cells are derived from a pluripotent hematopoietic stem cell having the acquired BCR-ABL1 fusion gene, usually through translocation between chromosomes 9 and 22, t(9 22)(q34 q11), referred to as the Philadelphia (Ph) chromosome. BCR-ABL1 induces leukemogenesis through kinase dependent and independent signaling pathways. The natural history of CML is variable from the chronic phase to the accelerated phase or blast crisis, but the progression process is not fully understood [62].

6.1.1. Clinical Symptoms and Hepatic Manifestation of CML

At presentation, 20%–50% of patients are asymptomatic. Laboratory findings include leukocytosis with immature cells of the granulocytic series and basophilia, mild anemia, and thrombocytosis. Symptoms include fatigue, malaise, sweating, and weight loss. Abdominal pain and discomfort may occur in the left upper quadrant (sometimes referred to the left shoulder), and early satiety due to splenomegaly with or without perisplenitis and/or splenic infarction may be present. Variable degrees of hepatomegaly are also observed. Tenderness over the lower sternum is sometimes present due to expanding bone marrow, and bleeding episodes due to platelet dysfunction are often encountered [63, 64].

In the chronic phase, approximately 50% of patients with CML show mild to moderate hepatomegaly at presentation, with no liver function abnormalities [65]. At the time of blastic crisis, however, liver sinusoidal infiltration by immature cells may lead to liver enlargement and elevated serum ALP levels [66].

6.2. PV

PV is one of the chronic MPNs, and the clinical features include an increased red cell count, splenomegaly, thrombocytosis and/or leukocytosis, thrombotic complications, erythromelalgia, or pruritus. On physical examination, splenomegaly, facial plethora (ruddy cyanosis), and hepatomegaly can be seen in 70%, 67%, and 40% of patients, respectively [67]. Nonpalpable splenomegaly is recognized in most patients on imaging studies [68, 69].

Gastrointestinal complaints are common in PV, with a high incidence of epigastric distress, peptic ulcers, and gastroduodenal erosions on upper endoscopy [70]. These have been attributed to alterations in gastric mucosal blood flow due to altered blood viscosity and/or increased histamine release from tissue basophils, although one study has indicated a high incidence of positivity for infection with Helicobacter pylori [70]. While direct liver involvement is uncommon, some patients may present with acute or chronic Budd-Chiari syndrome [71].

6.3. Primary Myelofibrosis (PMF)

Primary myelofibrosis (PMF) is a chronic, malignant hematologicdisorder characterized by splenomegaly, leukoerythroblastosis, bone marrow fibrosis, and extramedullary hematopoiesis.

6.3.1. Hepatic Manifestation of PMF

At the time of PMF diagnosis, hepatomegaly is observed in 40%–70% of patients and splenomegaly in at least 90% [72–74]. Hepatosplenomegaly is caused by marked extramedullary hematopoiesis, which may develop after splenectomy, especially in the liver [75, 76]. In a report of 10 patients with PMF, a significant increase in the liver size and serum concentrations of ALP, bilirubin, and/or γ-GTP was seen in all of the patients who subsequently developed acute liver failure, resulting in death 3-4 weeks after splenectomy [76].

6.3.2. Abnormal Liver Function Tests in PMF

Patients with PMF may have nonspecific laboratory test abnormalities, including elevation in serum concentrations of ALP, LDH, uric acid, leukocyte ALP, and vitamin B12 [77, 78]. Increase in ALP may be due to liver or bone involvement of the disease, while increase in LDH may result from ineffective hematopoiesis.

6.4. MPNs and Portal Vein Thrombosis

MPNs can be an uncommon cause of portal vein tyrosine kinase (V617F) thrombosis with unexplained etiology [79–81]. JAK2 mutation may be detected in such cases [82, 83].

6.5. MPNs and Budd-Chiari Syndrome

A JAK2 mutation can be found in almost all patients with PV and approximately 50 percent of patients with essential thrombocythemia (ET) or PMF. JAK2 (V617F) mutations have been described in 26 to 59 percent of patients with Budd-Chiari syndrome without apparent findings of MPNs [84–87]. These findings suggest the presence of occult MPNs in some patients with so-called “idiopathic” Budd-Chiari syndrome.

7. Lymphoid Neoplasms

7.1. Hodgkin Lymphoma (HL)

HL, formerly called Hodgkin’s disease, is the first recognized lymphoid tumor, which usually arises in lymph nodes and spreads in a contiguous manner via the lymphatic system. HL is histologically characterized by giant cells called Hodgkin/Reed-Sternberg (H/RS) cells, most of which are transformed Epstein-Barr virus-positive B cells present in a reactive cellular background composed of granulocytes, plasma cells, and lymphocytes.

7.1.1. Hepatic Manifestations of HL

Liver infiltration of malignant cells has been reported in 14% of patients with HL. Hepatomegaly is found in 9% of patients with disease stages I-II and in 45% of patients with stages III-IV [88]. Mild elevation of aminotransferase and moderate elevation of ALP can occur due to tumor infiltration or extrahepatic bile duct obstruction [88]. Cholestasis can be caused by direct infiltration of lymphoma cells, extrahepatic biliary obstruction, viral hepatitis, drug hepatotoxicity, or vanishing bile duct syndrome [89–91]. Approximately 3%–13% of patients with HL present with jaundice [90]. Acute liver failure can be caused by ischemia secondary to compression of the hepatic sinusoids by infiltrating lymphoma cells [92, 93].

7.2. Non-Hodgkin Lymphoma (NHL)

NHL has been classified by cell morphology as small to large cell type and according to the natural history of the clinical aggressiveness of the disease as low, intermediate, or high grade.

7.2.1. Hepatic Manifestation of NHL

Lymphoma cell infiltration of the liver with hepatomegaly is more common in NHL than in HL, with 16%–43% of cases showing hepatic involvement [88]. Extrahepatic obstruction is also more common in NHL than in HL, and hepatic infiltration is more common in low-grade B-cell lymphomas than in high-grade lymphomas [94]. Acute hepatic failure can occur in NHL as seen in HL [95], which is caused by sudden ischemia related to massive infiltration of the sinusoids or replacement of liver parenchyma by malignant cells [95]. Although liver involvement in both HL and NHL may present as acute hepatic failure [96–101], liver transplantation should be avoided [102].

Acute liver failure due to lymphoma can be suspected in cases of acute onset of hepatic enlargement and lactic acidosis different from other causes of liver failure [2, 103].

7.2.2. Abnormal Liver Function Tests in NHL

Liver function tests of NHL patients show mild to moderate elevation in serum ALP [88]. Elevated level of serum LDH is also often seen in patients with NHL, especially in highly aggressive type such as Burkitt or lymphoblastic lymphoma, reflecting high tumor burden, extensive infiltration of the liver, and coincident immune-mediated HA, which are associated with poor prognosis.

7.2.3. Imaging Studies of the Liver in NHL

Although diffuse hepatosplenomegaly is commonly observed in patients with indolent lymphomas, liver function is usually preserved in NHL. On the other hand, discrete hepatic masses are more common in the highly aggressive subtypes [104, 105]. However, not all focal liver lesions in patients with NHL are due to lymphoma. In a report of 414 consecutive patients with NHL, only 39% of focal liver lesions detected at disease onset were due to NHL and 58% were benign [106], whereas 74% of lesions detected during followup were due to NHL and 15% were due to a malignancy other than NHL (e.g., hepatocellular carcinoma, metastatic tumor from other secondary malignancy). Ascites may be present and can be chylous in cases of lymphatic obstruction.

7.3. Primary Hepatic NHL

Primary NHL of the liver is a rare condition, accounting for <1% of all extranodal lymphomas. Two-thirds of cases occur in men aged approximately 50 years. Presenting symptoms include abdominal pain, fever, hepatomegaly, and abnormal liver function tests with elevation of LDH higher than that of ALT [107, 108]. The most common histological subtype of primary hepatic NHL is diffuse large B-cell lymphoma, comprising 80%–90% of cases. This disease may present with nodules in the liver or diffuse portal infiltration and sinusoidal spread [109].

Acute liver failure from primary hepatic lymphoma has been treated with liver transplantation and subsequent chemotherapy [110]. Although primary hepatic lymphoma is rare, persistent inflammatory processes associated with HCV infection or autoimmune disease may play a role in the lymphomagenesis of hepatic B cells [111].

7.4. Primary Hepatosplenic NHL

Primary hepatosplenic diffuse large B-cell lymphoma associated with HCV has been reported [112], and fetal acute liver failure can also occur [113]. Although the etiological role of HCV in lymphoma is unknown, HCV-positive lymphomas tend to arise in extranodal sites, especially in the liver, spleen, or salivary glands where HCV resides and chronic infiltration of lymphocytes occurs.

7.5. Intravascular Diffuse Large B-Cell Lymphoma

Intravascular diffuse large B-cell lymphoma or intravascular lymphoma is an uncommon but important condition in patients with rapidly presenting fever, rash, or ischemic, neurologic, or respiratory signs. With this condition, tumor cells usually evolve exclusively within small vessels in the skin, brain, liver, or lung. Biopsies from these organs are required for a histologic diagnosis.

Symptoms of fever, night sweats, and weight loss are seen in 55%–85% of B-cell lymphoma patients [114, 115]. The organs affected differ according to the area. In Western countries, symptoms related to the central nervous system (39%) and skin (39%) are mostly commonly experienced [114, 116, 117], whereas those involving the bone marrow (32%), liver (26%), and spleen (26%) are less common. In Asia, symptoms related to involvement of the bone marrow (75%), spleen (67%), and liver (55%) are more common [118–121], whereas those involving the central nervous system (27%) and skin lesions (15%) are less common [122]. Hemophagocytic syndrome has also been reported in a Japanese series (Asian variant) [120].

Diagnosis of intravascular large cell lymphoma can be established by random skin biopsy [123] or biopsy of organs suspected to be involved for example, biopsies of the liver if unexplained abnormal liver function tests are seen, lung if unexplained pulmonary symptoms are present, and brain if unexplained neurological symptoms exist [124–127].

7.6. Hepatosplenic T-Cell Lymphoma
7.6.1. Clinical Presentation

Hepatosplenic T-cell lymphoma is a rare type of aggressive NHL associated with patients receiving antitumor necrosis factor-alpha therapy and purine analogues to treat inflammatory bowel disease [128].

7.6.2. Hepatic Manifestation of Hepatosplenic T-Cell Lymphoma

Clinical features include hepatosplenomegaly, fever, weight loss, night sweats, pancytopenia, and peripheral lymphocytosis. Liver function tests are elevated in approximately 50% of patients with slight elevation in AST, ALT, or ALP. Serum LDH levels are also elevated in approximately 50% of patients, ranging from mild to extremely high. Immunosuppression, especially of T cells, by antitumor necrosis factor-alpha therapy and purine analogues may increase the risk of this disease [129].

7.7. Hemophagocytic Syndrome (HPS)
7.7.1. Clinical Presentation

HPS is a condition presenting with systemic inflammatory symptoms such as fever, hepatosplenomegaly, cytopenias, and hemophagocytosis in bone marrow, spleen, and lymph nodes [130, 131]. HPS is caused by hypercytokinemia, which is triggered by highly stimulated natural killer and cytotoxic T cells. The underlying disorders include viral infections, usually the Epstein-Barr virus in younger patients, rheumatic disorders, immunodeficiency syndromes, and aggressive lymphomas [132]. An aggressive form of NK-cell lymphoma or intravascular lymphoma of an Asian variant was reported to be complicated by HPS [133]. HPS should be suspected if patients meet at least five of the following eight criteria: fever, splenomegaly, cytopenia, hypertriglyceridemia, low fibrinogen level, hemophagocytosis on bone marrow biopsy, low or absent NK cell activity, or elevated levels of ferritin or soluble IL2 receptor [130].

7.7.2. Hepatic Manifestation of HPS

HPS can cause hepatomegaly, jaundice with cholestasis, moderate transaminase elevation, hyperferritinemia, decreased hepatic synthetic function, and fulminant hepatic failure. Hepatotoxicity is caused by hemophagocytosis in the hepatic sinusoids and portal tracts or by focal hepatocellular necrosis [132].

8. Leukemia

8.1. Acute Leukemia
8.1.1. Clinical Presentation

Acute leukemias are neoplasms originated from precursors of myeloid or lymphoid lineage (rarely ambiguous lineage). Although ALL is the most common malignancy in children, the incidence is increased also in the elderly. The incidence of AML increases with age and AML is the most common types of adult leukemias.

8.1.2. Hepatic Manifestation of Acute Leukemia

Although hepatic involvement in acute leukemia is usually mild and silent at the time of diagnosis [134], a postmortem study showed liver infiltration in >95% of acute lymphoblastic leukemia (ALL) cases and up to 75% of acute myeloid leukemia (AML) cases [135]. In ALL, infiltration was confined to the portal tracts, whereas in AML, infiltration was observed in both portal tracts and sinusoids. Massive leukemic cell infiltration of the liver may present as fulminant hepatic failure [136]. In patients with acute leukemia, drug-induced liver injury and bacterial or fungal infections may also affect the liver.

8.1.3. AML and Hepatosplenomegaly

Palpable organomegaly as a presentation of AML is uncommon, and significant lymph node enlargement is rare in patients with AML. Marked hepatosplenomegaly is also uncommon however, if present, the patient is likely to have ALL or evolution of AML from a prior myeloproliferative disorder (blast crisis of CML).

8.2. ALL in Children

At presentation, several abnormalities, including hepatic dysfunction, coagulation abnormalities, hypercalcemia, hypocalcemia, hyperkalemia, and hyperphosphatemia, may be noted in children with ALL [137].

8.3. Precursor B-ALL/Lymphoblastic Lymphoma (LBL) in Adults

Precursor B-cell ALL is associated with decrease in normal blood cells caused by replacement of the bone marrow with tumor cells. The clinical presentations of patients include anemia, bleeding tendency, or susceptibility to infections. B-symptoms such as fever, night sweats, and weight loss are often present but may be mild. Hepatomegaly, splenomegaly, or lymphadenopathy can be seen in up to half of the adult patients upon presentation.

8.4. Precursor T-ALL/LBL

Precursor T-ALL/LBL originating from thymic precursor T-cells usually occurs in males aged approximately 20 years old. The clinical presentation includes lymphadenopathy (50%) or an anterior bulky mediastinal mass (50%–75%) [138]. Abdominal involvement is rare, but it could be found primarily in the liver and spleen. More than 80% of patients present with stage III or stage IV disease, and almost 50% have B-symptoms and serum LDH levels are usually elevated. Although the bone marrow is frequently normal at presentation, approximately 60% of patients develop bone marrow infiltration and a subsequent leukemic phase indistinguishable from T-cell ALL [139].

8.5. Chronic Lymphoid Leukemia (CLL)
8.5.1. Clinical Presentation

Chronic lymphocytic leukemia (CLL) is one of the chronic lymphoproliferative disorders, characterized by a progressive accumulation of monoclonal lymphoid cells. CLL is considered to be identical to small lymphocytic lymphoma (SLL), which is one of the indolent non-Hodgkin lymphomas [62, 140]. CLL is the most common leukemia in Western countries, accounting for approximately 30 percent of all leukemias in the United States. Although CLL lymphocytes resemble normal small lymphocytes in morphology, they are activated clonal B cells at the stage between pre-B and mature B cells. [141–143]. B-CLL lymphocytes are positive for B-cell-associated antigens (CD19, CD20, CD21, and CD23) and CD5 and express extremely low levels of surface membrane immunoglobulins (IgM or both IgM and IgD).

8.5.2. Clinical Staging of CLL

The natural history of CLL is heterogenous. The staging systems that are widely used to predict patient prognosis and determine the therapeutic strategies are the Rai system [144] and the Binet system [145].

8.5.3. Clinical Features of CLL

The most common physical finding is lymphadenopathy, which is present in 50 to 90 percent of the patients. The other lymphoid organ frequently enlarged in CLL is spleen, being palpable in 25 to 55 percent of the cases.

8.5.4. Hepatic manifestation of CLL

Patients with CLL often show mild to moderate liver enlargement at the time of initial diagnosis in 15%–25% of cases [145, 146]. The liver is usually only mildly enlarged, ranging from 2 to 6 cm below the right costal margin, with a span of dullness to percussion of approximately 10–16 cm. Upon palpation, the liver is usually nontender and firm with a smooth surface. An enlarged liver in patients with CLL often displays extensive lymphocytic infiltration in the portal tracts with functional impairment of the liver in late stages [147, 148].

8.6. Hairy Cell Leukemia (HCL)
8.6.1. Clinical Presentation

Clinical presentation of HCL includes the following [144, 149]: (1) abdominal fullness due to splenomegaly, which may cause spontaneous splenic rupture [150], (2) systemic symptoms such as fatigue, weakness, and weight loss without fever or night sweats, (3) bleeding tendency secondary to severe thrombocytopenia or recurrent infections, and (4) asymptomatic splenomegaly or cytopenias which may be incidentally recognized, and the most common physical sign of HCL is palpable splenomegaly (80%–90% of cases). Massive splenomegaly extending more than 8 cm below the left costal margin is observed in 25% of cases.

8.6.2. Hepatic Manifestation of HCL

Hepatomegaly and lymphadenopathy are not common in HCL, presenting in approximately 20% and 10% of patients, respectively.

8.6.3. Laboratory Findings

Most patients with HCL present with pancytopenia (60%–80%), anemia (85%), and thrombocytopenia and neutropenia (80%). Leukocytosis may be present in 10%–20% of cases. Abnormal liver function tests and hypergammaglobulinemia are seen in 20% of cases. Leukemia cells often infiltrate the liver, in both the portal tracts and sinusoids, and liver enlargement has been observed in up to 40% of patients [151].

9. Myeloma and Related Disorder

9.1. Multiple Myeloma
9.1.1. Clinical Presentation

Multiple myeloma is one of the neoplasms of plasma cells (i.e., terminally differentiated B cells) and is increasingly frequent with age. It commonly involves bone marrow and produces a monoclonal immunoglobulin and can cause dysfunction or damages of various organs. Most patients with multiple myeloma present with signs or symptoms related to the infiltration of plasma cells into the bone or to kidney damage from excess light chains [152].

9.1.2. Hepatic Manifestation of MM

Hepatomegaly has been observed in 15%–40% of patients and may sometimes be accompanied by splenomegaly [153, 154]. A Mayo clinic series of 1027 cases from this single institution reported relatively rare symptoms and signs of hepatomegaly (4%) and splenomegaly (1%).

9.2. Amyloidosis
9.2.1. Clinical Presentation

Amyloidosis refers to the extracellular tissue deposition of amyloid fibrils composed of low molecular weight subunits of proteins. Two major common causes of systemic amyloid deposition are AL and AA amyloidosis. Immunoglobulin light chain (AL) amyloidosis (primary amyloidosis) is composed of monoclonal light chains, with or without plasma cell dyscrasias (multiple myeloma and Waldenstrom’s macroglobulinemia). AA amyloidosis is composed of fragments of the acute phase reactant called serum amyloid A. AA amyloidosis is typically reactive (secondary) to chronic inflammation. The symptoms in amyloidosis are nonspecific including fatigue and weight loss. Organomegaly and dysfunction of affected organs, including nephrotic syndrome, restrictive cardiomyopathy, peripheral neuropathy, macroglossia, purpura, or a coagulopathy, are often observed [155].

9.2.2. Hepatic Manifestation of Amyloidosis

Hepatomegaly with or without splenomegaly is seen in 70 percent of the patients. A cholestatic pattern with elevated liver enzymes is seen in approximately 25 percent. Hepatic involvement can occur in all types of amyloidosis, and histologically proven liver involvement in systemic amyloidosis is found in 17% to 98% of the patients [156–158]. In hepatic amyloidosis, deposition of AA amyloid is generally seen in vessels, while the non-AA amyloid deposits appear in a mixed pattern in vessels, sinusoidal cells, and portal stroma [159].

Primary hepatic AL amyloidosis is a rare condition. Hepatomegaly and elevated ALP are present in most patients, which could be associated with poor prognosis [160].


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Copyright © 2013 Jun Murakami and Yukihiro Shimizu. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


B-cell chronic lymphocytic leukemia (BCLL) is a malignancy of small-sized B-cells in the blood and bone marrow and a common form of leukemia in dogs. It represented 8% of all samples with suspicion of lymphoproliferative disease (of any site) in 1 study 1 and 36% of CLL cases in dogs in another study. 2 Diagnostic criteria for BCLL vary, generally requiring >5000 to 6000 lymphocytes/μL in the blood and identification of B-cell expansion by immunophenotyping. 1, 3-6 Some studies incorporate small mature cytomorphology or small cell size by flow cytometry as inclusion criteria, and some exclude cases with moderate-to-severe lymphadenopathy or splenomegaly. The disease generally affects older dogs (median age, 10-11.9 years). 1, 3, 6 A previous study indicated that certain small dog breeds have increased risk of BCLL, and approximately half of cases have lymphadenopathy or splenomegaly. 1

In people, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a common B-cell neoplasm in the blood, bone marrow, lymph nodes, and spleen. 7 A diagnosis of CLL requires >5000 B-cells/μL in the blood and SLL requires lymphadenopathy, splenomegaly, or both with <5000 B-cells/μL, but these entities are considered different manifestations of the same disease. 8 In humans, CLL/SLL has a highly variable clinical course and genetic and clinical variables are used to assess prognosis. 7, 9, 10 In dogs, BCLL generally is considered an indolent disease, but studies indicate a wide range in survival times. 3, 11

The goal of our study was to assess survival and prognostic factors in a larger number of dogs with BCLL, defined by an expansion of small-sized B-cells in the blood by flow cytometry. We did not exclude cases with lymphadenopathy, splenomegaly or cytopenias, because doing so may exclude true BCLL cases. Although it is possible some cases in our study had a different small B-cell neoplasm, we wanted to include all cases with small cell B-cell lymphocytosis in the blood, because it is unknown whether cases with tissue infiltration are a different manifestation of BCLL vs an entirely different neoplasm. We evaluated Ki67 expression for association with survival. It is a marker of proliferation with prognostic value in high-grade B-cell lymphomas of dogs when measured by flow cytometry. 12 In humans with CLL, high Ki67 expression is associated with poorer outcome, whether measured in neoplastic peripheral lymphocytes, lymph node proliferation centers, or plasma. 13-15 Additionally, Boxers with BCLL preferentially rearrange unmutated immunoglobulin heavy variable region genes, which is a poor prognostic indicator in humans with CLL, and our study aimed to examine breed-related differences in presentation and outcome. 16-18 We hypothesized that BCLL in dogs has a variable clinical course similar to CLL in humans and that Boxers and dogs with high Ki67 expression would have more aggressive disease.

Allogenic Stem-Cell Transplantation in High Risk CLL Patients

Despite novel treatment possibilities, allogenic stem-cell transplantation (alloPBSCT) still remains an option for patients with CLL. 54 However, the cohort of patients that should be qualified to the procedure seem to change. Therapy with novel drugs gives a chance of durable remission in patients with del(17), so one must be careful not to overweight the risks of alloPBSCT over the benefits of therapy with new agents. OS at 6 years from alloPBSCT is 50�%. Treatment related mortality in CLL was estimated 16�% and graft vs host disease was observed in 50�% of patients. As alloPBSCT is the only treatment that offers a full recovery, it could be relevant for young, high-risk patients, without comorbidities, with a perfectly matched donor. 54,84

Leukemia (Blood Cancer) 11 Important Signs & Symptoms of Leukemia

Leukemia , also known as blood cancer is a bit different from other types of cancer, and it may become a bit difficult to understand at first. Instead of having a tumor in one organ growing larger and larger, and then spreading to other tissues, in leukemia cancer starts in the stem cells that will ultimately become blood cells. These stem cells may grow into various types of blood cells, and, depending on which group is taken, we can have either lymphocytic leukemia or myelogenous leukemia. The former affects our circulating lymphocytes or white blood cells, and the latter affects the myeloid stem cells, which give rise to red blood cells, platelets, and other immune cells in the blood.

Since there are various types of leukemia, there will be various signs and symptoms for each one of them. The prognosis and how the disease behaves over time would also change accordingly. You can also have either acute leukemias that develop within a few days or chronic leukemias which are slowly developed over a few months or years.

The most important signs and symptoms you will find in leukemia are as follows:

Chronic fatigue

Chronic fatigue

One of the most common symptoms in leukemia is having chronic fatigue, which translates into feeling worn out and tired, even after waking up after a good night’s sleep. Having no energy to get up from the bed and unusual tiredness should be a warning sign that something is not going as it should. Patients would also describe how their day-to-day activities are deeply influenced by this debilitating symptom. They feel physically and mentally overwhelmed and drained, and this mental state may influence their work or study.

There are plenty of reasons why patients with leukemia experience fatigue. The blood carries nutrients and oxygen to the rest of the body, and blood cancer affects the normal function of the blood. One of the most common alterations is anemia, a reduction in the functioning red blood cells with a decrease in oxygen delivery to the tissues. Less oxygen would turn into lower energy levels available in the cells, which explains chronic fatigue.

Another source of fatigue in leukemia patients comes from the emotional stress, anxiety and depression associated with the diagnosis of the disease. It may also result from poor sleep, chemotherapy or radiotherapy.