The Management of Myelodysplastic Syndromes (MDS)

June 21, 2013 Chemotherapy, Cytogenetics, Hematology, Pharmacotherapy, Therapeutics, Transplantation 3 comments , , , ,

The myelodysplastic syndromes (MDS) are a collection of myeloid malignancies characterized by one or more peripheral blood cytopenias. MDS are diagnosed in slightly more than 10,000 people in the United States yearly, for an annual age-adjusted incidence rate of approximately 4.4 to 4.6 cases per 100,000 people. They are more common in men and whites. The syndromes may arise de novo or secondarily after treatment with chemotherapy and/or radiation therapy for other cancers or, rarely, after environmental exposures. De novo MDS is called primary MDS while the other is called secondary MDS. Indeed, the natural history of secondary MDS is expected to be worse than primary MDS. In this post we mainly focus on primary MDS and any recommendations for therapies here should be interpreted with caution when considering patients with secondary MDS.

Risk and Prognosis

There are three scoring system to evaluate the risk and prognosis of myelodysplastic syndromes (MDS) including: IPSS (International Prognostic Scoring System, 1997), WPSS (the WHO classification-based Prognostic Scoring System), and IPSS-R (Revised-IPSS, 2012).

IPSS (table 1) is the most widely used classification system for patients with MDS. 3 factors including the percentage of bone marrow myeloblasts, the diagnostic cytogenetics, and the number of cytopenias are used to generate a prognostic score. However, there are some limitations of IPSS: 1. the lack of inclusion of secondary (after prior cytotoxic therapy) MDS cases, 2. the inclusion of many patients now considered to have AML, 3. the lack of “treated” cases, and 4. the unknown impact of currently available therapies.

Table 1. The International Prognostic Scoring System (IPSS) for MDS.

Prognostic variable00.
Bone marrow blasts (%)< 55-1011-2021-30
Cytopenias, n0 or 12 or 3


ScoreIPSS subgroupMedian survival (years)
> 2.5High0.4

*Good: normal, -Y, del(5q), del(20q); intermediate: other abnormalities; poor: complex (≥ 3 abnormalities) or chromosome 7 anomalies.
†Platelets < 100,000/μL; hemoglobin < 10 g/dL; neutrophils < 1,800/μL.

Reproduced from Greenberg P, et al. Blood. 1997;89:2079-88 © 1997 by The American Society of Hematology.

WPSS (table 2) makes use of the WHO subclassifications and supports the intuitive notion that the need for red cell transfusions predicts for a worse prognosis. The risk groups of WPSS are very low (0 point), low (1 point), intermediate (2 points), high (3 to 4 points), or very high (5 to 6 points). The median survival and risk of progression to AML at 5 years is 140 months/3%, 66months/14%, 48 months/33%, 26 months/54%, and 9 months/84%, respectively. Note that two categories of RAEB were recognised by the WHO classification, in which RAEB-1 and RAEB-2 with 5-9% and 10-19% blasts, respectively.

Table 2. WHO classification-based Prognostic Scoring System.

WHO classification-based Prognostic Scoring System for MDS.

In IPSS-R (table 3) bone marrow cytogenetics, marrow blast percentage, and cytopenias remained the basis of the new system. Novel components of the current analysis included: 5 rather than 3 cytogenetic prognostic subgroups with specific and new classifications of a number of less common cytogenetic subsets, splitting the low marrow blast percentage value, and depth of cytopenias. This model defined 5 rather than the 4 major prognostic categories that are present in the IPSS. Patient age, performance status, serum ferritin, and lactate dehydrogenase were significant additive features for survival but not for acute myeloid leukemia transformation.

Table 3. Revised-IPSS

Compared with IPSS, the IPSS-R model showed effective separation of the IPSS patient risk categories and more effectively discriminated prognostic risk for these patients than the IPSS. Data indicated that 99% of the patients in the IPSS-R Very low and Low risk subgroups encompassed those who had been classified as IPSS Low and Intermediate-1; 81% of those in the IPSS-R High and Very high risk subgroups had been classified as IPSS Intermediate-2 and High.

The Management of MDS

After the evaluation of risk and prognosis, comes the management of MDS. Which patient should be treated and how?

Figure 1. Approach to Therapy of MDS Patients

Myelodysplasia is an incurable disease with non-transplantation therapy, but highly variable in its natural history. Treatment considerations must take into account many factors, including the pathologic diagnosis, the prognosis based on the IPSS, WPSS, or IPSS-R, the unique disease features in that particular patient, feasibility of performing a clinical trial, the appropriateness of a bone marrow transplantation, and indeed the philosophy of the patient and the family concerning his or her care.

In addition, if the patient has secondary MDS, tolerability of therapy is probably worse because of previous exposure to DNA-damaging agents and predicting how patients with secondary MDS will respond is difficult because of a lack of data and exclusion of such patients from most clinical trials.

Until now MDS remains a challenge for clinicians because of the older patient milieu, the disease heterogeneity, and the lack of effective medical therapy. And the choice between therapies is hampered by a relative lack of prospecitve randomized trials.

Firstly, what we should do after evaluation is to determine whether to treat or not. There are patients who have MDS based on sound pathologic and clinical criteria who might best be served by observation. Treatment should be reserved, and potentially the diagnosis transmitted to the patient and family, only if there are symptoms resulting from anemia or other cytopenias or perhaps presymptomatic anemia or severe thrombocytopenia.

Once the decision to treat is made, different approaches are available. However, we don’t know the standard algorithm beacuse lack of prospective randomized trials. We lack of effecive therapeuitc approach for this disease at present.

Supportive Care

Supportive care includes blood components transfusion, treatment of neutropenia and possible infections, and bone marrow stimulation.

Patients with moderate-to-severe anemia require RBC replacement. Transfusing packed RBCs for severe or symptomatic anemia benefits the patient temporarily, only for the life span of the transfused RBCs (2-4 wk). Patients with congestive heart failure may not tolerate the same degree of anemia as young patients with normal cardiac function, and slow or small-volume (eg, packed RBCs) transfusions with judicious use of diuretics should be considered.

Patients with multiple RBC transfusions might develop transfusion-induced iron overload which can incur significant damage of the liver, heart, pancreas, and other tissues. Current guidelines recommend starting iron chelation therapy in those patients who have received 20-25 units of packed RBCs or who have a serum ferritin level of >1000 μg/L. However, there are absolutely no definitive data concerning the frequency of such complications, let alone whether patient outcomes might be improved by the use of chronic iron chelation therapy. Tow iron chelation agents have been approved by FDA for the indication of iron overload: deferoxamine and deferasirox.

The notion of using hematopoietic growth factors to treat the cytopenias of patients with MDS is attractive but certainly limited by the problem of an intrinsically deranged and therefore potentially unresponsive marrow stem cell. Nonetheless, virtually every patient with MDS and anemia at some point receive an erythropoietic growth factor. However, there is incomplete information and confusion about the likelihood of response, the optimal dose, and whether to use a short- or long-acting agent. 25% of patients with anemia will respond (reduce their transfusion requirement by at least 50% or increase hemoglobin by 1g/dL) and response can take 8 weeks or more. It is common practice to increase the dose of erythropoietic growth factor once or even twice before concluding that the patient is unresponsive to single-agent erythropoietin. Patients who are not ransfusion dependent at baseline or who have relatively low intrinsic levels of serum erythropoietin (< 500 mIU/mL) are more likely to respond with response duration in 1 to 2 years. Lack of response could be the result of insufficient iron stores, but the presumptive usual problem is an intrinsically unresponsive marrow. The hemoglobin response to erythropoietin may be improved from 25% to 40% with the addition of low-dose granulocyte colony-stimulating factor.

Platelet transfusion is beneficial to stop active bleeding in thrombocytopenic patients, but the life span for transfused platelets is only 3-7 days. Routine use of platelet transfusions to support nonbleeding (even severly) thrombocytopenic patients is not advisable. The ASCO clinical guideline for prophylactic platelet transfusion also suggests that many of these patients can be observed without prophylactic transfusion, reserving platelet transfusion for episodes of hemmorrhage or during times of active treatment.

There are no useful currently available cytokines for thrombocytopenic MDS patients.

Neutropenia without a history of infection is a poor justification for initiation of therapy. Randomized studies did not demonstrate any real clinical benefit of granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor. If neutropenia with infection, manage patients with board-spectrum antibotics necessary. If with systematic serious fungal infection antifungal agents should be given.


The HSCT is the only modality to cure this disease. But it dose not mean every patient diagnosed with MDS should be referred for such a procedure. Patients can reasonably safely be transplanted in the standard (myeloablative) conditioning regimen up to age 55 to 60 years. The outcome after transplantation for those with indolent disease is superior to that in patients with more aggressive MDS. Recent data suggest that lower risk paitents (according to the WHO or WPSS) do very well with allogeneic transplanation, whereas those with 5% to 20% marrow blasts have only a 25% to 28% 5-year overall survival.

Because of the possibility of diminishing overall life expectancy resulting from treatment-related mortality in those with good prognosis, it is recommended that allogeneic transplantation be used in low and intermediate-1 IPSS patients only after disease progression, whereas patients with more aggressive histology/prognosis should be transplanted immediately on recognition that a donor exists.

Treatment-related mortality difference between matched-sibling transplantation and matched unrelated donor transplantation is very small, as a result there is no distinction about whether there is a family donor or a unrelated donor.

For patients between 55 and 70 to 75 years of age, it is reasonable to consider a reduced-intensity conditioning (RIC) regimen. It is clear that treatment-related mortality associated with RIC is no higher than that seen with full transplantations in younger patients. However, the major problem of this approach is that we lack of long-term data with regard to disease relapse.

Another problem for transplantation, particularly for RIC, is the excess marrow myeloblasts or the relevance of disease control. It is clear that in AML patients fewer marrow blasts at the time of transplantation portend for a better outcome than if the transplantation is done in the presence of more fulminant disease. But in MDS patients the indication of chemoresponsivity or the value of pretransplantation cytoreduction is unclear. Nonetheless, the presence of more than 5% to 10% blasts in the marrow of an MDS patient probably makes transplantation, particularly with RIC, less likely to succeed. So it is therefore reasonable to administer one or 2 cycles of “MDS-induction therapy” with a DNA-hypomethylating agent in an attempt to “perform an in vivo purge” of the marrow blasts before the allogeneic procedure.


For MDS patients with “5q-” syndrome, or with 5q- cytogenetic abnormality alone without the syndrome, or 5q- with other cytogenetic abnormalities, an effective therapy has emerged. Lenalidomide produces a 67% rate of transfusion independence and major increases in the hemoglobin. Although the FDA-approved label for lenalidomide calls for dose modification if myelosuppression is noted, recent data suggest that a more aggressive dosing scheme might be considered if optimal support can be provided. The median time to response is 4.4 weeks; the median duration of the response has not yet been reached. However, the clinical trial detailing this impressive responsive rate was restricted to those with low-risk and IPSS-1 disease, platelet counts greater than 50,000, and neutrophil counts greater than 500.

But with the rationale of lenalidomide implying that major disease-modifying activity is possible because of likelihood of elimination of the karyotypically abnormal clone, lenalidomide dose appear to be a major advance for patients with 5q- chromosome abnormalities and should be used as initial therapy in such patients who require treatment.

Immunosuppressive Therapy

The patient subgroup who might benefit from immunosuppressive is difficult to define. The rationale of immunosuppressive therapy is that immune-mediated suppression of normal stem cell function, analogous to the situation in aplastic anemia, has been postulated to account for cytopenias in some MDS patients. Selected patients treated with either cyclosporine A or an antihympcyte-globulin (ATG) based regimen can experience improvements in cytopenia in about one-third to one-half of the cases. Patients who are HLA D15 positive, who tend to be younger, or who have lower platelet count irrespective of marrow cellularity are more likely to respond to such immunosuppressive manipulations. Conversely, another study suggests that hypocellularity and low IPSS score are predictors of response to immunosuppressive therapy. Of note, studies to define the optimal patients in whom such therapy is appropriate remain to be developed.

Table 4. Proposed Modified International WorkingGroup (IWG) Response Criteria for MDS

Table 5. Proposed Modified International WorkingGroup (IWG) Response Criteria for Hematologic Improvement

Cheson et al. Blood. 2006;108:419‐425.

Cheson et al. Blood. 2000;96:3671‐3674. (The old IWG response criteria)

Patients who are non 5q- and ineligible for immunosuppressive therapy and transplantation

Lenalidomide. A trial including 214 patients with non 5q- MDS were treated with lenalidomide at a starting dose of 10 mg daily (either continuously or on a cycle of 21 days on, 7 days off) were recently published. A total of 26% of these patients experienced a reduction in their transfusional needs, which is roughly comparable with what is often obtained with erythropoietin or DNA-hypomethylating agents. The median time to response was 4 weeks and the duration of response was 7 months.

However, the eligibility for this trial required low or intermediate-1 IPSS risk MDS and excluded patients with secondary MDS or those who platelet counts were less than 50,000/μL or whose neutrophil counts were less than 1000/μL.

DNA-hypomethylating agent. Clinically, those with MDS subtypes with excessive numbers of marrow myeloblasts resemble the situation in high-risk (older patient or adverse chromosome prognosis) AML. The class of drugs most useful in MDS and applicable to all subtypes are the DNA-hypomethylating agents 5-azacitidine and decitabine.

Azacitidine is a pyrimidine nucleoside analog of cytidine. Azacitidine is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. The concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are critical for differentiation and proliferation. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating cells are relatively insensitive to azacitidine.

Ont clinical trial showed that an early crossover design dampened any potential survival benefit attributable to azacitidine. However, the results demonstrated a delay in time to transformation to AML in those initially randomized to the study drug. There was a much higher response rate in the experimental  arm, and an ancillary quality of life study proved that patients randomized to azacitidine fared better.

We administer 4 cycles at 75 mg/m2 subcutaneously for 7 days every 28 days, rarely make dose adjustments, and do a bone marrow after cycle 4 to determine whether additional cycles are indicated. However, for many, the decision to continue or not is relatively difficult.

Myelofibrosis (Part One)

April 23, 2013 Cytogenetics, Hematology, Pharmacotherapy, Therapeutics 1 comment , , , ,


Myelofibrosis (MF) is a clonal proliferative disease of hematopoietic stem cells, leading to an inappropriate cytokines release, fibrosis of the bone marrow, constitutive mobilization of committed progenitor cells into the peripheral blood and extramedullary hematopoiesis. MF is the most symptomatic and has the worst prognosis among the Philadelphia-chromosome-negative chronic myeloproliferative neoplasms (MPNs).

This disease may present either as idiopathic (primary myelofibrosis, PMF) or as transformation of an antecedent polycythemia vera (PV) or essential thrombocythemia (ET). PV and ET are phenotypically overlapping with PMF and manifestations and therapeutic approaches are virtually the same in PMF and PV/ET.

Myleofibrosis is characterized by a progressive clinical course. Established prognostic factors including age, hemoglobin level, and white blood cell count have been used for risk assessment, but these characteristics do not fully explain the risk of death or major clinical events.

Morbidity and mortality of myelofibrosis are usually the result of leukemic transformation, spleno-portal hypertension, and infections, as well as thrombosis and hemorrhage.

Table 1 Poor Prognosis Factors – International Working Group-derived International Prognostic Scoring System (IPSS)

Poor Prognosis Risk Factors
1Age > 65 yrs
2Presence of constitutional Symptoms
3Anemia (Hemoglobin < 10 g/dL)
4Leukocytosis (White blood cell count > 25 x 103/mm3)
5Circulating blast cells of 1% or greater

The presence of the factors in the table above defines risk degree of myelofibrosis:

  • No risk factors – low-risk
  • One risk factor – intermediate-1-risk
  • Two risk factors – intermediate-2-risk
  • Three or more risk factors – high-risk

What must be paied attention is that this system (IPSS) is used for risk evaluating from time of diagnosis. There is another assessment criteria called Dynamic IPSS plus (DIPSS-Plus) which can be used for risk evaluating at any time during the disease course. The DIPSS-Plus has three additional independent risk factors including red cell transfusion need, platelet count < 100 × 109/L, and unfavorable karyotype. The unfavorable karyotype includes complex karyotype or sole or 2 abnormalities that include +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p-, or 11q23 rearrangement.

Note that leukocytosis can happen in patients after splenectomy due to “myeloproliferative” reaction and it does not necessarily imply disease progression.

Figure 1 The Dynamic International Prognostic Scoring System (DIPSS) plus prognostic model for primary myelofibrosis (PMF).

  • No risk factors – low risk
  • 1 risk factor – intermediate 1
  • 2 or 3 risk factors – intermediate 2
  • ≥ 3 risk factors – high

These four risk groups are with respective median survivals of 15.4, 6.5, 2.9, and 1.3 years. Leukemic transformation was predicted by the presence of unfavorable karyotype or platelet count < 100 × 109/L.

Clinical Manifestations

Symptomatic myelofibrosis can present with anemia, significant splenomegaly, aberrant production of proinflammatory cytokines (which causes constitutional symptoms such as weight loss, night sweats, fever of unknow origin), severe fatigue, cachexia, and pruritis.

These manifestations include anemia (either moderate or transfusion dependent), splenomegaly and/or hepatomegaly, the development of foci of nonhepatosplenic hematopoiesis, myeloproliferation manifesting with marked leukocytosis or thrombocytosis. and increased risk of thrombohemorrhagic complications, and a spectrum of debilitating constitutional symptoms.


JAK2V617F (Janus kinase 2 mutation V617F) mutation plays an important role in the pathogenesis of myelofibrosis. JAK2V617F has been identified in approxmiately 60% of patients with myelofibrosis (half of patients with PMF and post-ET myelofibrosis and in nearly all of those with a secondary form following a previous PV). Despite its crucial role in pathogenetic role, the clinical relevance of JAK2V617F in myelofibrosis is not completely understood. In a large retrospective survey showed that JAK2V617F mutation plays a significant and independent influence on the disease phenotype and showed that many clinical manifestations are correlated with the expansion of clonal hematopoietic cells harboring the JAK2V617F mutant allele.

Management of Myelofibrosis

The treatment of MF is guided by risk stratification and the patient’s clinical needs. As we mentioned before, the risk stratification are:

  • No risk factors – low risk
  • 1 risk factor – intermediate 1
  • 2 or 3 risk factors – intermediate 2
  • ≥ 3 risk factors – high

For low- or intermediate 1-risk disease, the respective median survival of patients exceeds 15 and 6 years and even longer for patients younger than age 65 years. Therefore, the risk of allo-SCT-associated mortality and morbidity is not justified in such patients, and it is also not prudent to subject them to investigational drug therapy, considering the limited information about long-term safety of new therapeutic agents. Similarly, there is no evidence to support the value of conventional drug therapy in asymptomatic patients with low- or intermediate 1-risk diseases. For this group of patients without symptoms, “watch and wait” is preferred.

For this group of patients with symptoms, they may occasionally experience splenomegaly, nonhepatosplenic extramedullary hematopoiesis, extramedullary hematopoiesis (EMH)-associated pulmonary hypertension, fatigue, bone (extremity) pain, pruritus, or thrombocytosis with a thrombosis history. Intermediate 1-risk patients might in addition display symptomatic anemia, marked leukocytosis, or constitutional symptoms such as drenching night sweats, fever, or weight loss (cachexia). If clinical needed, it is reasonable to start with conventional drug therapy.

However, if the patient is del(5q) present, lenalidomide is the recommended first-line therapy because significant improvement.

Figure 2 Risk-adapted therapy in primary myelofibrosis.

For patients with high- or intermediate 2-risk disease can be managed by conventional drug therapy, splenectomy, radiotherapy, allo-SCT, or experimental drug therapy. With each one of these treatment modalities except allo-SCT, the primary goal is palliation of anemia, symptomatic splenomegaly, constitutional symptoms, or disease complications from EMH (extramedullary hematopoiesis).