Myelodysplastic syndrome (MDS)

myelodysplasiaWhen 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.

myeloid and lymphoid lines

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.

MagnoliaBloom