Myelodysplastic syndrome (MDS)
When in the course of just one week I hear from three (count them, three!) patients from three different countries that have just been told that they have myelodysplasia, I decided karma is knocking on my door and I had better write about this possible serious complication.
Production of Blood Cells
Before we dive into the nuts and bolts of myelodysplasia (also known as myelodysplastic syndrome, MDS), let us learn just a bit about myeloid cells in general. As you know, blood stem cells (hematopoietic stem cells) are crucial in the production of new blood cells of all types. The oldest and grandest of the stem cells have the option of doing many things. Some of them decide to specialize in making lymphoid cells; they become the lymphoid progenitors and make lymphocytes – B-cells, T-cells and NK cells. Some stem cells make up their minds to become myeloid progenitors. Myeloid progenitors make red blood cells, platelets (“thrombocytes”), neutrophils and macrophages and a few more cell types for good measure. The diagram below illustrates this.
MDS – symptoms, progression
As you can see, if the myeloid lineage cell production gets screwed up in some fashion, the patient can develop anemia (too few red blood cells), bleeding disorders (reduced platelet counts – thrombocytopenia) or be prone to infections (reduced numbers of neutrophils – neutropenia). Depending on how “lucky” the MDS patient is, he may have one or more of these cytopenias. Symptoms of MDS are therefore symptoms of the underlying cytopenias – tiredness due to anemia, bleeding disorders due to thrombocytopenia, frequent infections due to neutropenia.
Most often, anemia dominates the early stages of MDS. Patients often complain of the gradual onset of fatigue and weakness, shortness of breath and pallor – significant loss of quality of life. But not all patients show symptoms and roughly half the patients are asymptomatic and their MDS is discovered after a routine CBC blood test. Previous exposure to chemotherapy or radiation is an important red flag and we will talk more about that further down in this article
Over time, one or more of these chronic cytopenias can become progressively worse in MDS patients. MDS used to be called “preleukemia” because approximately one third of patients with MDS progress to full fledged AML (acute myelogenous leukemia) anywhere from a few months to a few years. I am sure you agree with me that fighting a two front war is no fun at all. That is what makes second cancers in CLL patients so very dangerous.
Causes of MDS
It is generally accepted that one of the causes of MDS is exposure to environmental toxins such as benzene or radiation. Workers in some industries such as the oil industry with heavy exposure to hydrocarbons have a slightly higher risk of contracting MDS. (I would have been a perfect candidate for MDS, with more than 20 years mucking around refineries and petrochemical plants). Males are slightly more frequently affected than females. Vietnam Veterans that were exposed to Agent Orange are at risk of developing MDS. Average age for MDS diagnosis is 65.
MDS can also be caused by inherent toxicity of many commonly used chemotherapy agents – in particular, alkylating agents. Aha. That should have caused a few raised eyebrows, since CLL patients are no strangers to alkylating agents. Some of the more famous alkylating agents our guys use are chlorambucil, cyclophosphamide – and perhaps Treanda (bendamustine) if present theories about its method of action hold true.
Prognosis and Therapy Options
- In a FISH test, patients with MDS often show a deletion in the long arm of the 5th chromosome: 5q deletion. Ideally, the FISH test should be done on a bone marrow aspirate. Remember, the results of a bone marrow biopsy are only as accurate as the competence and experience of the pathologist examining the biopsy slides.
- Fortunately, it has recently been shown that Revlimid is particularly effective in treating MDS and the FDA approved Revlimid for this use in December 2005. For this reason, MDS accompanied by 5q deletions is considered good prognosis version of the disease.
- MDS diagnosis must first rule out other reasons for cytopenias. This is not always a slam dunk thing to do in CLL patients who have many other reasons for low blood counts. Please read earlier articles on reduced counts of red blood cells, platelets and neutrophils before you self-diagnose yourself with MDS. There is a real distinction between keeping a watchful eye for things that go bump in the night and scaring yourself silly with imagined dangers.
- Severe neutropenia and thrombocytopenia indicates poor prognosis in MDS patients. Chromosomal abnormalities in the 7th chromosome, or complex karyotype with more than three defects identified by FISH test suggest poor prognosis as well. As always, elderly patients or those with other medical conditions are at more risk.
- The frontline therapy goal of newly diagnosed MDS patients is to control the symptoms of cytopenias. In other words, improve the quality of life of patients by using transfusions, growth factors (Neupogen, Procrit etc) etc to bring blood counts up.
- Three drugs have been approved for treating MDS: decitabine, valproic acid and Revlimid (lenalidomide).
- In the final analysis, the curative option for MDS (and its bigger cousin with fangs – full blown AML) is an allogeneic stem cell transplant. In that sense this pre-cancer and its grown up version of AML are no different than aggressive CLL.
Special Relevance to CLL Patients
Back in March of 2006 (how time flies!) I wrote about increased risk of MDS when purine analogs such as fludarabine are combined with alkylating agents such as cyclophosphamide. I think many of the points I make in this F versus F+C comparison may also be plausible in the context of FCR versus FR. The abstract below was an important piece of the puzzle in evaluating risk of MDS. As you can see, it is authored by some of our best and brightest CLL experts.
J Clin Oncol. 2002 Sep 15;20(18):3878-84.
Therapy-related myeloid leukemias are observed in patients with chronic lymphocytic leukemia after treatment with fludarabine and chlorambucil: results of an intergroup study, cancer and leukemia group B 9011.
Morrison VA, Rai KR, Peterson BL, Kolitz JE, Elias L, Appelbaum FR, Hines JD, Shepherd L, Larson RA, Schiffer CA.
Section of Hematology/Oncology, Veterans Affairs Medical Center, Minneapolis, MN 55417, USA.
PURPOSE: Patients with chronic lymphocytic leukemia (CLL) may have disease transformation to non-Hodgkin’s lymphoma or prolymphocytic leukemia; however, development of therapy-related acute myeloid leukemia (t-AML) is unusual. A series of patients enrolled onto an intergroup CLL trial were examined for this complication.
PATIENTS AND METHODS: A total of 544 previously untreated B-cell CLL patients were enrolled onto a randomized intergroup study comparing treatment with chlorambucil, fludarabine, or fludarabine plus chlorambucil. Case report forms from 521 patients were reviewed for t-AML.
RESULTS: With a median follow-up of 4.2 years, six patients (1.2%) to date have developed therapy-related myelodysplastic syndrome (t-MDS; n = 3), t-AML (n = 2), or t-MDS evolving to t-AML (n = 1), from 27 to 53 months (median, 34 months) after study entry. This included five (3.5%) of 142 patients treated with fludarabine plus chlorambucil and one (0.5%) of 188 receiving fludarabine; no chlorambucil-treated patients developed t-MDS or t-AML (P =.007). At study entry, the median age among these six patients was 56 years (range, 44 to 72 years); three were male; the CLL Rai stage was I/II (n = 4) or III/IV (n = 2). Response to CLL therapy was complete (n = 4) or partial remission (n = 1) and stable disease (n = 1). Marrow cytogenetics, obtained in three of six cases at diagnosis of t-MDS or t-AML, were complex, with abnormalities in either or both chromosomes 5 and 7. Other abnormalities involved chromosomes X, 1, 8, 12, 17, and 19. Median survival after diagnosis of t-MDS/AML was 3.5 months (range, 0.5 to 10.1 months).
CONCLUSION: Our findings raise the possibility that alkylator-purine analog combination therapy may increase the risk of therapy-related myeloid malignancies, which is of particular relevance with regard to ongoing trials using these combination therapies.
PMID: 12228208
Please notice this abstract is talking about combination of fludarabine with chlorambucil, not cyclophosphamide. But since both chlorambucil and cyclophosphamide are classified as alkylating agents, I think it is reasonable to consider both of them carry similar risk factors.
The potential risk of MDS after treatment with alkylating agents is not a new concept. Many researchers have reported on therapy induced MDS and AML in patients undergoing therapy with fludarabine and/or alkylating agents. Our own Terry Hamblin has written (on ACOR) about increased incidence of MDS in CLL patients. Here is the link to his thoughts on the subject.
In their seminal 2005 article in the Journal of Clinical Oncology researchers at M. D. Anderson report on a cohort of 177 patients who underwent FCR therapy at their institution. Five of these patients developed MDS, and one of them went on to have full fledged AML. I have not seen more recent updates on this aspect of FCR therapy but I am willing to bet it has not gone away.
Treanda – Does it Increase the Risk of MDS?
How about Treanda (bendamustine)? After all this new (old!) drug is thought to work like a combination of alkylating agent and purine analog. Does using Treanda increase the risk of MDS? This is what the manufacturer has to say on the subject in their package insert accompanying Treanda:
“There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined.”
As we reported in a recent article on this website, the FDA had this to say in their recent report on Treanda’s potential risks:
“Other malignant neoplasms were added to warnings and precautions, noting reports of premalignant and malignant diseases that developed in patients treated with bendamustine. The link of bendamustine with these diseases has not been determined. Conditions included myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma”
In other words, we have to wait and see how this plays out. The jury is still out on Treanda causing increased risk of MDS / AML. Something tells me Cephalon (the manufacturer of Treanda) is not going to break any speed records in disclosing potential risks on this front, if this warning letter from the FDA is any indication.
My Two Cents
I think the risk of MDS/AML in the context of using alkylating agents (chlorambucil, cyclophosphamide) – especially in combination with fludarabine – is real and worth thinking about. How does this risk weigh against the potential reward of deeper and longer remissions by adding cyclophosphamide to combinations such as FR, i.e. the present day gold standard of FCR?
Life with CLL is full of interesting and important questions such as this. Unfortunately for us there are no slam dunk correct answers – not yet. I am sure many of you have strong (and widely different!) opinions on this subject. In the absence of rock solid science we do the best we can in choosing our particular brand of kool-aid. Once we have made our decisions and bet on the therapy of choice with our very lives, it is very hard to accept a different point of view.
Our best protection is better information and all too often the published information on drug induced adverse effects is skimpy. Part of the problem is inadequate post-marketing adverse effect monitoring program. Local oncologists are too busy to bother reporting all that they see to the FDA, pharmaceutical companies funding clinical trials are not anxious to report adverse effects that they would just as soon forget. Many years can go by before the trickle of news percolates down to us chickens making life and death decisions.
Very often I get a heads-up about an under-reported adverse effect from the many emails I receive from our members. It is getting to the point where I have more patient profiles and stories in my files than most CLL experts! Sure, it is anecdotal information and does not get much respect from health-care professionals. But patient feedback on creditable advocacy sites such as this is the next best thing to formal studies.
I and the rest of our members would like to hear from any of you out there who have been through FCR or FC combinations and have subsequently been diagnosed with MDS or AML. If you are a member, please take the time to log-in and share your experience with the rest of us. If you are not a member, may I respectfully ask why not? Membership registration is free and we are extremely careful to protect the confidentiality of your registration information. You cannot participate in the discussions that follow each of my articles unless you are a registered member. What you do not know can really hurt you in this game.
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32 comments on "Myelodysplastic syndrome"
Thanks Chaya, As one of the three people reporting MDS after FCR I was hoping you would write about it. Since CLL is still under control and because I only have 2%blasts we are going for the mini allo transplant in 3-4 weeks or as soon as they can set a donor up for me. My doc in Boston said he “overwhelmingly” recommends the transplant asap. Feel free to write if you want updates
Marci
Marci:
Thanks for taking the time to comment. Can you share any of the details? When and how were you diagnosed with MDS? Does your doctor think the prior FCR therapy had anything to do with it? What are the MDS specific symptoms you have had to deal with? Is your doctor’s recommendation for mini-allo transplant ASAP based on prognostic risk factors? I am sure our members would like to know more about this potential complication from someone who has been there. Thanks again and all the best with the mini-allo transplant. I will be thinking of you.
chaya:
you continue to amaze me – with you knowledge, insight, perspectives and information. you are truly awesome! once again (as i have done numerous times during the past 4 years) thank you so very much for doing what you do!
Chaya, This is a good subject to expand the considerations for which of the growing number of treatment protocols may give us an edge. Now that FCR is the new “gold standard” It is good that you draw attention to the risks because those that fail FCR, as you have warned in the past, are left in a very bad place with greatly diminished options.
Decisions for first time treatment can be tough and emphasis can be placed differently regarding the reasoning behind why one treatment (TX) is preferred over another. In my case, opinions of two CLL experts that felt FR would be better but one of the most prominent CLL experts felt that FCR was the best choice for me. My final decision to go with FR concurrent TX took in a variety of reasons, one of which was the association of Cyclophosphamide (C)with MDS plus adding increasingly to the infection risk during an escalating H1N1 flu season. The mutagenic properties of alkylating agents like “C” and the damage “C” can do on fast growing epithelial cells helped to steer me away from FCR.
Being young of spirit but old of prostate means I am slow to empty the bladder and did not want urine retention ladened with “C” in the bladder, particularly since the only cancer in my immediate family was that of my father’s bladder.
I also questioned whether being a veteran exposed to agent orange, I might be at increased risk for collateral damage by adding “C” to the treatment.
I have read that the combination of F&C or F&R is less likely to produce F related toxicity. At least one study in my files suggests and immune restorative effect from Rituxan, but that may be independent from F related toxicity.
Much to learn much to decide.
WWW
Chaya,
Thank you so much for this valuable update. I have two more 2/day treatments of R/B and wish they were over with already.
I appreciate your honesty and intelligence.
Blessings,
Rita
I’m just wondering if, it is safe to assume that if MDS were to develop after treatment,that it would be quickly, and not several months down the road? If too much time elapses following treatment to the development of MDS can one really point the finger at the treatment?? Again this is not an exact science, so who knows.
Krazyleggs:
It seems the time frame over which MDS can develop is significantly longer than you expect. Here is a quote from Terry Hamblin’s ACOR posts (I have a link to it in the article).
“I am afraid I cannot put a time limit on the risk of MDS or Richter’s syndrome after fludarabine. Generally, MDS occurs in the first 7 years after chemotherapy, and Richter’s syndrome seems to be dependent on imunodeficiency, which is at its greatest in the first 2 years after fludarabine.”
I know I have asked before, but anything comments on the PCO (Pentostatin, Cyclophosphamide & Ofatumumab) combo for the chemo virgin. I am cross-eyed and overwhelmed. I’ve been trying to read all I can, and fluctuate between feeling like I think I’ve got it figured out to feeling like I’m in a vacuum and to a sinking whirlpool.
Any tips, head’s up, do’s, don’ts, eat lots of this or none of that, warnings, and especially any good news about any of this? What helps, what doesn’t. I’m supposed to start all this next week. No other options were offered, which only adds to the confusion, chaos and brings more questions to mind with unclear answers.
I basically went from W&W since ’03. (WBC from 17k to almost 200k now) – gradual and mostly sorta, kinda OK. I did have one IVIG last summer, but no other treatments or meds or even any suggestions, or shared information. When I was at my regular visit last week, where I was actually thinking I was improving and expecting to see better numbers, I was basically floored. Apparently my spleen is now enlarged. I tried/thought I was asking half-way intelligent questions about when or how would one know if a splenectomy was needed, if it would improve things, etc., but I was told it would help, but would ‘never’ be done, and then a mention of malpractice to do such a thing was basically the end of that discussion. What kind of answer is that? I thought it might help or so I’ve read.
And now, rather quickly, I am also anemic, with low platelets, and will need another (my second) IVIG this week. When I inquired about treatment for this, blood transfusions, cord blood, and various other things I’d read about, again was told none would be done. The medications were not covered by Medicare and one alone was over $100k. Apparently my only hope to get necessary treatment is in this trial.
All the above discussion on the alkylating agent(s) issues for some of my above mentioned conditions I am more informed, yes, and yet more confused as how to proceed. Also what about the other drugs and the combo of all three. I am really on overload. In put, insights, etc., from the experienced would be most grateful. Thanks. And thank you Chaya for all your input. More appreciated than I can say.
I have kept up my search these past couple hours. I’d like to find answers to my inquiries, and if not answers, at least a better understanding and what one might expect on any level.
I’ll check back here tomorrow to see if anyone adds their 2 cents. I hope so.
In the mean time, my search landed me on the blog site, ‘clldiary’. I was able to learn quite a bit from one who knows from first hand experience. I read some from this site a bit ago, but this time I founds even more helpful details.
Thank you David for sharing your experiences. It helps more than you could know, than again, maybe you do know. This road is difficult enough especially for one without a support system. Knowing even a bit of what to expect – the good, the bad and the not so good – all helps.
Thank you.
Thank you, Chaya, You have a blessed ability to par jargon down to the basics.
I will take the time to read the “leads”, they often widen and/or clarify the reasoning.
Much appreciated,
Mette
I think I need to emphasize that MDS in CLL is very rare and difficult to diagnose. It is also true that MDS and CLL may occur together without chemotherapy. I wrote about the co-incidence of MDS and lymphoid tumors back in 1986: Immunological abnormalities in myelodysplasia: II. Co existent lymphoid or plasma cell neoplasms. A report of 20 cases unrelated to chemotherapy. JA Copplestone, GJ Mufti, TJ Hamblin and DG Oscier. British Journal of Haematology 1986 63: 149-159.
In CLL, where the bone marrow is full of small lymphocytes, it is very difficult to recognize most types of MDS (apart from sideroblastic anemia, which was first spotted by Danny Catovsky in 1974).
There are many pitfalls in diagnosis and the marrow may need to be looked at by a pathologist with expertise in this area, such as John Bennett at Rochester, New York, or Barbara Bain at St Mary’s London. In particular, it is dangerous to make the diagnosis if the patient has recently received Neupogen or also has AIDS. The marrow picture can be very similar. It is also important to check the B12 and red cell folate levels since megaloblastic anemia can also mimic MDS.
Chlorambucil alone almost never causes MDS. The Kanti Rai trial referred to in Chaya’s article had no MDS cases in patients who only received chlorambucil. Neither Danny Catovsky or I have seen either MDS or AML developing in CLL treated with chlorambucil. (This amounts to thousands of cases.) I think the combination of purine analogue and alkylating agent is particularly risky, though it has to be stressed that it is still very rare. In the REACH trial of FCR in previously treated patients, we looked very carefully for MDS in patients who had prolonged neutropenia or thrombocytopemia after FCR, but we did not find it. There is no theoretical reason to believe that Pentostatin or Cladribine would be any safer than fludarabine, and I don’t think that Bendamustine has any purine analogue activbity despite its structural similarities. Cyclophosphamide is more likely than most alkylating agents to cause MDS in my experience.
Thank you, Chaya, for keeping us inform.
Stay well,
Monique
To Terry: If I understand you correctly, then, although FCR gives an overall superior response rate, the cyclophosphamide can bite you in the behind at a future date. Is this another reason for “watchful waiting”? Thanks to you and of course Chaya for your input on this.
Patrick
The risk of MDS is small and the advantage of FCR is greater in most cases.
Hi Chaya, my husbands first BMB in Nov ’09 (post 4 rounds of fcr) was normal however after 2 months of worsening thrombocytopenia and anemia, another BMB was done end in Jan ’10 that shows a new mutation of 20q del indicating MDS. A second opinion in Boston last week agreed with the BMB but the specialist said the number of 20q del seen wasn’t seen in high enough numbers for him to be diagnosed with MDS. The specialist said it is unusual to see this mutation so soon after chemo so once again its watch and wait to see if the 20q del progresses or stays as it is now. He will need BMB’s every 4 months for now. I wonder if this 20q showed up so unusually soon post FCR chemo if that is a poor prognostic sign or not? Any ideas from you or Dr Hamblin on that? As Rosanne Rosannadanna said….”if its not one thing its another…” Thanks for the article, ironic you posted it just after our disappointing news. Blessings, Eileen
Chaya–Thank you for another readable explanation of a complex subject. I appreciate your linking to sources cited, such as Dr. Hamblin’s.
Carter
Thank you for the article, but I think it is important for CLLers to read the original information on the FDA website. Cephalon’s data indicates that myelosuppression, which is not a malignancy like MDS or AML, is a concern, along with other side effects in the clinical trials. The information indicates that MDS and AML developed in a number of people participating in the NHL clinical trials, but there wasn’t a causal link established between use of Treanda and CLL. Clinical trials involved both CLL and NHL participants, and judging by the data, Treanda seemed to have a far more extensive list of side effects for NHL than CLL. People with CLL are at a greater risk for developing secondary cancers, but as there is much fear out there on that issue, we should be reading the original data and judging for ourselves what the risks and causal links are, if they have been noted.
The link to the FDA Treanda information is: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/022303lbl.pdf
CLL and NHL are two different cancers, and must be kept separate.
Ojibwak
ojibwak:
I commend your advice that patients should read the full background information and judge for themselves. I could not agree more.
If you read my article above carefully, I quote a paragraph from the FDA’s recent changes to Treanda’s label. But I go further than that. I cite and give a link to an earlier article I wrote where the FDA changes were fully detailed, as well as a link provided to the full text PDF of the FDA labeling information. As it turns out, you provide the same link in your comment. I do my homework, and I always (repeat, ALWAYS) try to provide links to the original information on which I base my reviews.
As for the actual dangers Treanda poses to CLL patients, my comment was “In other words, we have to wait and see how this plays out. The jury is still out on Treanda causing increased risk of MDS / AML.” I stand behind that evaluation – the jury is out, we have to wait.
Does that mean we should not be aware of potential concerns? I fully agree NHL and CLL are different cancers. Unfortunately for us, since the numbers of CLL patients are much smaller than those of NHL, the first glimpses are often from NHL arena. Since both CLL and NHL are B-cell cancers, I continue to read NHL literature in an attempt to get potential early warning flags that may or may not prove to be relevant to CLL patients.
Bottom line, you may disagree with my perspective on Treanda, but I must insist I have made every effort to spell out the caveats as well as provide links to the original information. As always, it does take careful reading to get all the nuances – something both you and I agree is a good thing to do – and that goes for my reviews too.
Thank you, Chaya, for the clarification. I think readers can derive their own conclusions from the FDA site, as well as other sources, while valuing your input on the data. My scientific expertise is minimal, but I did have a family member with both CLL and lymphoma, with differences noted.
Diverse interpretations are the lifeblood of education and learning.
I learn from whatever you write in any case.
Chaya, Thank you for the information. It’s been a bit of a whirlwind this past week – my husband has been being treated for an auto immune problem – red blood and platelet transfusions every 10 days or so for the past 3 months and neutropenia for the past year+ – but a recent bone marrow biopsy’s initial lean (pending results) is towards Richter’s Transformation. He was part of the FCR clinical trial in 2003-2004 and had a wonderful 4 year remission. Received 5 rounds of Treanda in 2009 with severe problems developing 4 months later. The culprit? A combination of it all along with a lot of poor prognostic markers?
I apologize for introducing such a simple question but I am confused by the statements that NHL and CLL are different cancers. All the basic definitions I found said CLL and /or SLL are types of NHL. Although I have read the excellent material on this site, I must have missed something essential or simply failed to understand an important distinction. Is a line being drawn between B cell and non-B cell cancers?
qb
Older classification systems included SLL (and even CLL) in the list of NHL cancers. All are B-cell cancers. However, as our understanding of CLL and SLL has grown, it is now more accurate to distinguish CLL/SLL from more classical NHL cancers such as follicular lymphoma. Please read the recent article on SLL to see how it compares and contrasts to CLL.
NHL cancers such as follicular lymphoma have different phenotype – sufficient that they react differently to therapies. For example, single agent Rituxan is a lot more effective in follicular lymphoma than it is for CLL. The standard therapy for many NHL cancers is CHOP or R+CHOP – these options are hardly the standard of therapy for CLL patients. Another example is the role of radioimmunotherapy such as Bexxar or Zevalin. Both of these have been shown to be remarkably effective in NHL cancers. BUt since CLL patients almost always have bone marrow involvement, radioimmunotherapy can only be used under strict safety protocols, if at all. Recent trials at the Hutch have insisted biopsies to confirm bone marrow involvement is less than 20% prior to use of radioimmunotherapy.
Bottom line, NHL cancers are LYMPHOMAs, where the disease is mostly centered in lymph nodes – very little in the bone marrow or blood until very late stage of the lymphoma. CLL and SLL are leukemias where the disease is alsmost always present in the blood and bone marrow right from the start and lymph nodes get involved only in later stages. Of course, some CLL (especially SLL) patients have bulky nodes from the start. That makes the distinction between classical lymphomas and classical leukemias a little harder to make. Nothing is easy in this game. I hope I have not confused everyone even more by this short-hand explanation.
Excellent description of the differences between Non Hodgkins Lymphoma and Chronic Lymphocytic Leukemia, Chaya. Absolutely different cancers, for the reasons you state, and what I have seen in terms of symptomology. One comment on Bexxar and Zevalin. My family member was assessed for these two, and we were told there needs to be a 35% threshold of healthy to cancer cells in the bone marrow to go ahead with treatment. Bexxar and Zevalin pretty much wipe out most cells to the point where significant and fairly rapid cell regeneration is anticipated. I understood that radioimmunotherapy isn’t such a good idea for the elderly at a more advanced cancer stage, because healthy cell regeneration won’t take place rapidly enough and there is a likelihood of secondary infections without an immune system in the interim. Any differences of opinion are welcome.
This article and following discussion is timely. I did try to email Chaya, but have had no answer as yet.
My husband was diagnosed with CLL in November 2007. All his prognostic history is as follows: mutated (96.5% homology to IgVH3-33, Bata 2 microglobulin 1.6, Zap70 neg, CD38 neg, original FISH revealed no cytogenetic abnormalities, IGG is a bit low (mid 600s), platelets 260s, no anemia. WBC has gone from 20K at diagnosis (Dec 07) to 49K currently (Mar 10). My husband has a enlarged gut, we thought due to a long history of Crohn’s (has been in remission for many years) but his spleen may be enlarged (this is not definitive and there are some very small palpable nodes that I believe have been there for many years as well.
Another FISH was done recently. This showed a single abnormality, Trisomy 21 (3 of 20 cells checked) and the lab report states it is consistent with MSD or AML. He is scheduled to be rechecked in July and possibly have a bone marrow biopsy. It is suggested he may need some therapy with Revlimid by the end of the year. We have no idea what this means. I cannot find any information anywhere. Dr. Kipps says he does not really know what it means. Thus far, he has had no treatment. Any ideas of what could be going on? I did try posting on CLL Forum, but I believe they though II was talking about Trisomy 12. That is not the case, it is Trisomy 21. Dr. Hamblin was responsive and said he did not think this development was a prelude to a secondary leukemia. . . but if not, then what?
ncdaniels:
I was aware that Trisomy 21 (where there are three copies of the 21st chromosome, as opposed to the normal 2 copies that should be present) is associated with Down’s syndrome. But until I started digging after your email, I was not aware that it had anything to do with myeloid cancers.
It seems that in some instances translocation of genetic material (bit of the DNA getting snipped off of its original location and sticking to another chromosome or position where it is not supposed to be) have been associated with several types of cancers of the myeloid line. Some of them are pediatric cancers and not relevant to this discussion. But there are references to acute myeloid leukemia (AML) associated with translocation between chromosome 8 and 21.
I also found two PubMed (http://www.ncbi.nlm.nih.gov/pubmed) articles -see below – that discuss trisomy 21 and possible links to myeloid cancers. You can see the abstracts by visiting the PubMed website and typing in the PMID identification number associated with each abstract. I hope this can help kick-start your search process.
In your shoes I think I would also want to ask for a repeat FISH test, just to rule out silly stuff like lab errors etc.
All in all, this is complicated stuff and I am out of my depth. It is fortunate you have access to experts that can help you and your husband sort through it. Best wishes.
———————-
Leuk Res. 1999 Nov;23(11):1079-83.
Trisomy 21 as the sole acquired karyotypic abnormality in acute myeloid leukemia and myelodysplastic syndrome.
Wan TS, Au WY, Chan JC, Chan LC, Ma SK.
Department of Pathology, The University of Hong Kong, Queen Mary Hospital, PR China.
PMID: 10576514
————————
Cancer Genet Cytogenet. 1997 Mar;94(1):8-12.
Acute lymphoblastic leukemia and chromosome 21.
Berger R.
Institute of Molecular Genetics, INSERM/CNRS, Paris, France.
PMID: 9078285
Deep thanks for your comments. Yes, this is complex and murky stuff. I will request a repeat FISH, a good idea. I take some comfort that Dr. Hamblin feels this is of no relevance. At least that was my reading of his response to me. I will check the articles you cite. The other I have seen is:
http://bloodjournal.hematologylibrary.org/cgi/content/full/100/5/1787
All very confusing.
Again, thank you for your response. We have great confidence in Dr. K at UCSD and will ultimately rely on his recommendations.
n
I just wanted to thank you for your research and presentation of MDS. I am one of those people that has CLL (in remission)as well as MDS (with ringed sideroblasts) Interestingly enough I am now being seen by Dr. Besa at Thomas Jefferson University in Philadelphia – I am the only patient he has had with both diseases. I do not have chromosone damage – My hemotologist thinks that Fleudara is the cause. I am being treated with procrit and neupogen once a week and tend to need transfusions about once a year.
Thank you so much for your continued work on behalf of the CLL community.
Postscript ~ Dr. Besa is now suggesting that I become part of a clinical trial (phaseI/II)to try out a larger dose of revlimid. Apparantly the usual dose is 80% beneficial for patients with 5q negative, but only 30% helpful for paitients without 5q. My hemoglobin has remained fairly steady – between 8 and 9. Dr. Besa thinks that if the hem. is trending down, we do the trial earlier rather than later to prevent AML. Or are they just eager for subjects? I am not eager to do this, but will certainly spend some time thinking about it and getting opinions from anyone with expertise on the subject. Any thoughts Chaya?
Hi Chaya, Thank you for your wonderful website. I was diag. in 1998 with Cll had no problems until about 4 years ago when I had 2 treatments of FR ( I think about 6 months each)with short PR in between. Then a bmb showed 50% CLL cells in the bone marrow so my Onc. put me on Campath. I ended up after some treatment ( my memory is rather fuzzy on the dates) in hospital with nutrapenia, gmv(?), pneumonia and had everyone rather worried for quite a while I don’t remember much about the whole thing. In the hospital a month, rehab for 2 weeks, came home for a couple of weeks and back in the hosptial with gmv and pneumonia again. In another month, came home and was home for a couple of months I think, was getting nupogen during all this time. Back in the hospital for 3 weeks with just pnuemonia ( BOOP this time and 3 bacterial infections). home again. My Oncologist did a bmb again and this time very few cll cells but showed I have mds with not too many blasts. My platelets had been getting lower and lower but along with the nupogen he has me on Danazol 3x day,also vit. b6 and folic acid. Have been home for a few months now and of course am worried about the mds turning into aml. I am 76 yrs old so too old for transplant or anything.
Thanks for your wonderful website again. It is so helpful to look up different things that I do not understand,
Joy Cully
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