How to Treat MDS without Stem Cell Transplantation

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Norbert Gattermann

Although allogeneic hematopoietic cell transplantation (HCT) is the only proven curative treatment for mye-lodysplastic syndromes (MDS), it is only used to treat a minority of MDS patients. The majority of patients are too old or suffer from comorbidities rendering allogeneic HCT too risky. Alternative treatment strategies for patients with higher risk MDS try to alter the natural course of disease by preventing or delaying leukemic transformation. In patients with lower risk MDS, treatment is mainly focused on maintaining or improving the quality of life.

Biol Blood Marrow Transplant 16: S30-S36 (2010) Ó 2010 American Society for Blood and Marrow Transplantation KEY WORDS: Myelodysplastic syndromes, epigenetic treatment, lenalidomide, iron chelation therapy

SUPPORTIVE CARE

For elderly patients with comorbidities, or those electing not to recieve aggressive therapy, supportive care is the mainstay of treatment. Supportive care in-cludes red blood cell (RBC) or platelet transfusions, hematopoietic growth factors, and antimicrobial agents. Although chronic transfusion therapy is rou-tine, it is not entirely without problems. RBC transfu-sions may cause transfusion reactions and lead to transfusion-related iron overload. The latter calls for iron chelation therapy, which is another component of supportive care. Platelet transfusions can cause HLA sensitization, leading to a lack of platelet incre-ments with subsequent transfusions. Patients with myelodysplastic syndromes (MDS) often present with neutropenia, and may also have granulocyte dysfunction. Accordingly, antibiotic treatment is frequently given. Granulocyte transfusions, which are laborious and provide only short-term benefit, are not widely used, nor recommended.

About 80% of MDS patients have a hemoglobin of \10 g/dL at diagnosis [1], and the majority of these become transfusion dependent. Anemia impairs the quality of life, and has a detrimental effect on cardiac function[2], which in turn, contributes to fatigue and an increased risk of heart failure. There is a direct rela-tionship between hemoglobin increases and improved quality of life in patients with anemia. In MDS, it is

common practice to maintain hemoglobin levels be-tween 8 and 10 g/dL. However, it is not possible to define a universally applicable hemoglobin threshold for triggering transfusion. Transfusion therapy must be adapted to the patient’s age, level of activity, comor-bidities, and preference. Very likely a proportion of MDS patients does not receive adequate support in terms of RBC transfusions. This may reflect the at-tempt to use available resources sparingly, but it has not been systematically studied whether maintaining a higher level of hemoglobin actually requires a more intensive transfusion regimen.

HEMATOPOIETIC GROWTH FACTORS Erythropoietic Growth Factors

To circumvent the need for blood transfusions, hematopoietic growth factors can be administered. There is no evidence that MDS is caused by growth factor deficiency, but treatment with erythropoietin leads to increased hemoglobin levels or decreased transfusion requirements in about 30% of patients. High dosages are needed, and various dosing regimens have been proposed. Recombinant human erythropoi-etin (Epo) is given as subcutaneous injection 1 to 3 times per week, in a weekly dose of 30,000 to 80,000 units. Epo treatment is most promising if the endoge-nous Epo levels are \200 U/L. Darbepoetin-alpha, a long-acting form of Epo, is administered subcutane-ously with intervals of 7 to 21 days, at doses of 150 to 300 mg per week. The response rates with Epo and darbepoietin were almost identical (58% and 59%, respectively) in a recent meta-analysis using unified response criteria according to the international working group (IWG)[3].

Several studies suggested that Epo achieves stronger erythroid responses when combined with

Klinik fu¨r Ha¨matologie, Onkologie u. klinische Immunology Heinrich-Heine-Universita¨t Moorenstr. 5D-40225 Du¨sseldorf, Germany.

Financial disclosure: See Acknowledgments on page S35. E-mail:gattermann@med.uni-duesseldorf.de

Ó2010 American Society for Blood and Marrow Transplantation 1083-8791/10/161S-0007$36.00/0

doi:10.1016/j.bbmt.2009.10.017 S30

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granulocyte-colony stimulating factor (G-CSF) or granulocyte macrophage-colony stimulating factor (GM-CSF). However, a recent meta-analysis found that response rates were comparable for the 2 Epo-based therapeutic strategies [4]. Furthermore, Epo monotherapy at higher doses of 60,000 to 80,000 U weekly produced significantly higher response rates (64.5%) than did standard oncology doses of 30,000 to 40,000 U weekly, either as a single agent (49%) or in combination with G-CSF/GM-CSF (50.6%). In addition, when transfusion-dependent patients were assessed separately, both Epo monotherapy and its combination with G-CSF/GM-CSF produced com-parable and appreciable levels of transfusion indepen-dence (28.8% and 24.8%, respectively). Nevertheless, the combination with granulocyte-colony stimulating factor (G-CSF) appears to be particularly beneficial in patients with refractory anemia with ring sidero-blasts (RARS) [5,6], where the 2 growth factors have a synergistic antiapoptotic effect on erythroid precursor cells[7].

The Scandinavian MDS Group has validated a decision model for treating MDS patients with Epo plus G-CSF [8]. A simple scoring system predicts a good response if the endogenous serum Epo level is relatively low and the patient needs less than 2 units of red cells per month. Unfortunately, patients who are in particular need of improvement usually do not fulfill these criteria. For patients with a good or intermediate score, responses to Epo plus G-CSF have median durations of almost 2 years. Epo plus G-CSF does not increase the risk of leukemic transformation and is associated with improved survival[9].

G-CSF

The use of G-CSF for infectious complications is not supported by randomized clinical trials. Neverthe-less, guidelines recommend the temporary use of G-CSF for patients with neutropenia and recurrent severe infections. Prophylaxis with G-CSF is not endorsed, partly because it may increase the risk of bleeding through deterioration of thrombocytopenia. Thrombopoietin-Like Factors

Stimulation of platelet production would be a wel-come modality for patients with thrombocytopenia and hemorrhagic diathesis. Unfortunately, recombi-nant thrombopoietin (TPO) was shown to be immu-nogenic, being neutralized by developing antibodies. Interleukin (IL)-11 has been approved for treating thrombocytopenia postchemotherapy. A phase II trial in patients with MDS was disappointing (major plate-let responses in 15%, and minor responses in 13% of patients).

However, boosting platelet production is now ex-periencing a renaissance. In patients with idiopathic thrombocytopenic purpura, where increased platelet removal by splenic macrophages is accompanied by impaired platelet production in the bone marrow (BM), new thrombopoietin receptor agonists can achieve substantial augmentation of healthy megakar-yocyte maturation and platelet production. Currently, 2 platelet receptor agonists are available.

Romiplostim (NplateÒ) is a peptibody consisting of an IgG-Fc fragment plus 2 peptide chains with 4 TPO receptor binding sites, which show no sequence homology with endogenous TPO and are not immu-nogenic. Romiplostim is given subcutaneously.

Elthrombopag (PromactaÒ), the second TPO re-ceptor agonist, is administered orally. Clinical trials in patients with MDS are ongoing. Romiplostim has been shown to ameliorate thrombocytopenia induced by treatment with azacytidine or lenalidomide. Immunosuppressive Treatment

The rationale for immunosuppressive treatment in MDS is based on findings suggesting that an autoim-mune attack against hematopoietic precursor cells contributes to hematopoietic failure. Treatment with antithymocyte globulin (ATG), given alone or in com-bination with cyclosporine (CsA) or other agents, im-proves cell counts in approximately a third of patients; responses may be delayed by several months. As yet, there is no clear evidence of a survival advantage with this treatment. BM hypoplasia, shorter duration of transfusion dependence, and the presence of HLA-DR15 may be associated with a higher probability of response. Other immunosuppressive agents, for exam-ple, alemtuzumab, are currently being investigated. Lenalidomide

Thalidomide, by incompletely understood mecha-nisms of action, produced response rates of 20% to 35% in patients with MDS, more so in low-risk than in high-risk disease, and primarily in the erythroid lin-eage. Interestingly, some patients experienced cytoge-netic remissions[10]. Responses are generally of short duration and because of significant side effects, mainly fatigue and peripheral neuropathy, thalidomide tends to be tolerated only for limited periods of time.

A chemical modification of thalidomide resulted in lenalidomide, which is better tolerated primarily because its basically lacking neurological toxicity. Lenalidomide was approved by the U.S. Food and Drug Administration (FDA) in December 2005, for treatment of MDS with del(5q) cytogenetic abnormal-ities. Two-thirds of such patients became transfusion-independent in a large trial. The median time to response was about 1 month. Responses were impressive, with a median increase in hemoglobin of

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5.4 g/dL. The median response duration was around 2 years. Patients reaching complete remissions (CRs) may benefit even longer. The frequency of cytogenetic response was not significantly different between pa-tients with an isolated 5q deletion, papa-tients who had 1 additional abnormality, and patients with a complex karyotype. However, treatment is less effective in pa-tients with increased BM blasts.

Lenalidomide was also tested in lower risk MDS patients without del 5q[11]. Achieving transfusion in-dependence was unrelated to karyotype, but occurred in only 27% of patients. Erythroid improvement was achieved in 43%, and the median duration of transfu-sion independence was 10 months.

Neutropenia and thrombocytopenia are the most common adverse events, occurring less frequently in ’’non-5q‘‘ than in del(5q) patients where lenalidomide is more potent. The cytopenias are usually manageable with dose reduction or interruption of therapy.

Although lenalidomide appears to be a major step forward in the management of lower risk MDS, the drug is not yet approved by the European Medicines Agency (EMEA), because of concern about leukemic transformations that were observed in a German cen-ter on extended follow-up afcen-ter a clinical trial. How-ever, data from the large Du¨sseldorf MDS Registry show that the rate of spontaneous acute myelogenous leukemia (AML) development in patients with del5q (not treated with lenalidomide) is practically the same as in patients treated with lenalidomide. A new randomized trial has recently been started in Germany that will address this issue.

Low-Dose Chemotherapy

Low-dose chemotherapy with cytosine arabino-side has minimal organ toxicity, but can cause signifi-cant BM suppression. There are reports of CRs, but there is no evidence of significantly improved survival with this treatment. Low-dose AraC was clearly infe-rior to 5-azacitidine in the randomized prospective AZA-001 trial (see the following section).

Low-dose melphalan (Mel) is also well tolerated, but useful mainly in patients with hypoplastic MDS

[12]. In our experience, temporary improvement in blood cell counts comes at the price of a high rate of leukemic transformation.

Intensive Chemotherapy

Intensive chemotherapy yields lower remission rates in MDS than in AML, and long-term remission is achieved in \20% of patients. Intensive chemother-apy is an option for patients with a high risk of leuke-mic transformation. It requires the absence of severe comorbidities and the absence of complex cytogenetic abnormalities. A complex karyotype is associated with a poor chance to achieve CR and a high risk of early

relapse. In our view, intensive chemotherapy is not in-dicated for elderly patients with high-risk MDS or AML if a complex karyotype is present[13]. In youn-ger patients with a more favorable karyotype, high-dose chemotherapy may induce CRs and thereby open the door to allogeneic hematopoietic cell trans-plantation (HCT).

Epigenetic Treatment

If chemotherapy is not an option, epigenetic treat-ment offers another chance, particularly for patients with higher risk MDS. Epigenetic changes refer to heritable, but potentially reversible, modifications of DNA and chromatin that regulate gene transcription but are not caused by irreversible changes such as mu-tations or deletions. Epigenetic control of gene expres-sion involves DNA methylation, particularly in the promotor region of genes, as well as a combination of different modifications, for example, acetylation, of the ’’tails’’ of histone proteins. These histone mod-ifications alter the activity of DNA wrapped around them. Open chromatin is transcriptionally active be-cause it allows transcription factors to access their tar-get genes. Condensed chromatin, on the other hand, is transcriptionally inactive. To reverse the process of chromatin condensation, inhibitors of histone deace-tylases or inhibitors of DNA methyltransferases (or both) can be employed. Such a reexpressor strategy is now widely pursued, in hopes that improved gene ex-pression leads to improved maturation of hematopoi-etic cells and, thus, to more effective hematopoiesis.

A study by Silverman et al. [14] using the DNA methyltransferase inhibitor 5-azacitidine showed that AML transformation can be significantly delayed. This result has recently been reproduced by a large in-ternational confirmatory trial [15], which compared subcutaneous azacitidine (plus best supportive care [BSC]) with conventional care regimens, including BSC only, low-dose AraC plus BSC, and standard in-duction chemotherapy plus BSC. Azacitidine increased the median length of survival from 15 months to 2 years, and doubled the 2-year survival rate from 26% to 51%. Comparison with BSC, low-dose AraC, and standard chemotherapy, respectively, consistently showed a dif-ference of about 9.5 months in favor of azacitidine. Besides increased time to AML or death, there was improvement in terms of RBC transfusion dependence and also a reduction of infections requiring intravenous antibiotics. 5-Aza was well tolerated in the elderly patient population of this trial.

The overall survival (OS) benefit was achieved with 5-Aza reatment for a median of 9 cycles. After 6 treat-ment cycles, 87% of the responders had obtained their first response. Therefore, epigenetic treatment requires perseverance. It is also important to know that patients do not have to reach CR to achieve prolonged

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survival; hematologic improvement was associated with a clear survival benefit. Accordingly, treatment with 5-Aza should be continued as long as there is no evidence of disease progression.

Decitabine (5-aza-20deoxycytidine) is structurally very similar to 5-azacitidine. Preliminary clinical results with decitabine were reported 2 years before the Silver-man study [16]. The overall response rate was about 50%. Interestingly, the best results were achieved in pa-tients with a high risk profile, in particular, papa-tients with high-risk karyotypes such as monosomy 7/del(7q). Sim-ilar to 5-azacitidine, decitabine was capable of inducing cytogenetic remissions. The mean number of treatment cycles necessary to reach the best observed response was 3.2. More recently, Kantarjian et al. [17] performed a phase III randomized study of decitabine versus BSC in MDS and showed that decitabine significantly pro-longed the time to AML transformation, particularly in higher risk patients. Decitabin-treated patients were also compared with historical controls who received intensive chemotherapy at the same institution. The groups were matched for age, cytogenetics, and International Prostate Symptom Score (IPSS) score. There was a highly significant advantage for treatment with decitabine[18].

However, a decitabine trial initiated by the EORTC in 2002 and reported in 2008, found no sig-nificant survival benefit. This phase III opened-label, randomized, multicenter, controlled trial compared BSC plus decitabin with BSC only[19]. The trial in-cluded 233 patients over 60 years of age, predomi-nantly with high-risk or intermediate-2 risk MDS and marrow blasts between 11% and 30%. Although response rates were similar to those observed in other trials of decitabine (13% CR, 6% partial remission [PR], 15% haematologic improvement) and progres-sion-free survival (PFS) showed significant improve-ment (6.6 versus 3 months), the difference in OS (median 10.2 versus 8.5 months) was not statistically significant. Possible causes include shorter duration of drug exposure (6 months of decitabine, compared to 9 months of 5-Aza in the AZA-001 trial), differences in postprogression treatment, and a shorter interval between diagnosis and treatment, which may have led to inclusion of high-risk patients who would not have been included in the AZA-001 trial because of rapid progression. Although decitabine has been ap-proved in the United States since 2006, approval in Europe remains uncertain. A new EORTC trial is cur-rently being planned, featuring a head-to-head com-parison between decitabine and 5-azacitidine.

The mechanisms of action of decitabine and 5-azacitidine differ. For example, decitabine is only incorporated into DNA, whereas 90% of 5-Aza is in-corporated into RNA. Azacytidine and decitabine (as well as zebularine) exert differential effects on cancer gene expression in AML cells[20]. Such

pharmaco-logical differences may contribute to differences in clinical results. Borthakur et al.[21] reported on 14 patients with MDS who had experienced azacytidine failure or intolerance and were subsequently treated with decitabine; 3 achieved CRs and 1 showed hema-tological improvement, for instance, an overall

re-sponse rate of 28%. Mo¨ller et al. [22] observed

repeated responses of an elderly patient with high-risk MDS to tipifarnib, 5-azacitidine, and decitabine. However, most hematologists would probably agree that neither of the demethylating agents is greatly superior to the other.

Considering that histone deacetylation and DNA hypermethylation cooperate in the process of gene si-lencing, it appears attractive to combine inhibitors of both mechanisms. For instance, experience has been gained with valproic acid, an antiepileptic drug that also acts as a histone deacetylase (HDAC) inhibitor. We observed responses according to the IWG criteria in about 50% of patients with a normal marrow blast count, but rarely in cases with excess of blasts [23]. The average response rate over all types of MDS was about 30%, which is in agreement with results from other groups. We then combined valproic acid with 5-azacitidine in a poor-risk cohort of 24 patients, 7 of whom had received previous intensive chemotherapy, and observed an overall response rate of 33%[24]. As a conclusion from this and other trials, one could con-clude that combining a demethylating agent with an HDAC inhibitor leads to faster responses in some pa-tients. However, this approach does not seem to obviate the need for prolonged treatment. Patients achieving at least stable disease should be kept on treatment unless there is evidence of disease progression[25].

The search for effective drug combinations must continue. We are about to start a trial of valproic acid and lenalidomide, including patients with primary MDS who have a low or intermediate-1 risk profile according to IPSS and \10% BM blasts.

Iron Chelation Therapy

Unfortunately, many patients with MDS do not respond, or respond only temporarily, to available treat-ment strategies, and therefore require chronic transfu-sion therapy, which eventually leads to iron overload. The role of iron chelation therapy in MDS is controver-sial, because there is a lack of controlled clinical trials. Based on inferences from patients with thalassemia ma-jor, cardiac problems are the most dreaded complication of iron overload in elderly MDS patients. However, car-diac iron accumulation is detectable by magnetic reso-nance imaging only in a minority of MDS patients. On the other hand, the presence of nontransferrin bound iron (NTBI) and labile plasma iron (LPI) may ex-ert toxic effects before large amounts of iron have accu-mulated in organ parenchyma. NTBI is readily taken up

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by the liver, heart, and endocrine glands, where it cata-lyzes the generation of hydroxyl radicals. Experience in thalassemia major shows that patients in heart failure can be rescued by intensive chelation therapy before much iron has been removed from the heart, suggesting that substantial clinical benefit can be derived from de-toxification of NTBI.

It has also been argued that, besides preventing cardiac complications, iron chelation may lower infec-tion risk, improve outcome after allogeneic HCT, and delay leukemic transformation in patients with MDS

[26]. Transplant physicians are aware of studies corre-lating iron overload and the presence of high LPI, on the 1 hand, with increased transplant-associated morbidity and mortality, particularly owing to infec-tious complications, on the other hand. Physicians are perhaps less well aware of the increased risk that may arise in MDS from the unfortunate combination of neutropenia/granulocyte dysfunction and hemosi-derosis-related susceptibility to bacterial infections. For many clinicians, it may also be surprising to learn that iron overload is a risk factor for leukemic transfor-mation, independent of transfusion requirement[27]. Why should iron overload affect the rate of leukemic transformation? A possible explanation is that iron overload causes oxidative stress that aggravates geno-mic instability of the MDS clone, thereby promoting clonal evolution toward acute leukemia. This hypoth-esis needs to be corroborated by experimental evidence as well as clinical trials.

Several guidelines recommend iron chelation for transfusion-dependent MDS patients with a ‘‘reason-able’’ life expectancy who have serum ferritin levels

exceeding 1000 or 1500 ng/mL. In fact, there is no uni-versally applicable ferritin threshold that would or should trigger iron chelation, because the intensity of the individual patient’s transfusion regimen must be taken into account. For many years, deferoxamine given as subcutaneous or intravenous infusion or subcutaneous bolus injection has been the first-line therapy. Meanwhile, 2 oral chelators have become available: deferiprone and deferasirox. Deferasirox has undergone extensive clinical trials, mainly in patients with thalassemia major, but also in other transfusion dependent anemias, including MDS [28-30]. A dose of at least 20 mg/kg/d is needed to achieve a negative iron balance, as determined by a decrease in serum ferritin levels and liver iron content.

To show that deferasirox not only reduces total-body iron but also results in clinical benefit, a prospec-tive, randomized, double-blinded, placebo-controlled trial has recently been started. The goal is to determine in low/Intermediate-1 risk MDS patients, treated as per standard practice, the clinical superiority of defer-asirox to placebo in terms of OS, cardiac function, and liver function, which potentially can be affected by iron overload complications.

MDS Treatment Algorithm

At our center, we have a developed a treatment algorithm for patients with MDS (seeFigure 1): 1. For patients with low or intermediate-1 risk who

suffer from symptomatic anemia, transfusion ther-apy is indicated, combined with iron chelation if necessary.

MDS Treatment Algorithm (Düsseldorf)

Intermediate-2 and High-risk < 60 y > 60 y Donor available No donor Allogeneic transplantation conventional Intensive chemotherapy, 5-Azacitidin / (Decitabine),

Normal karyotype 5-Azacitidin / (Decitabine),

Intensive chemotherapy

Abnormal karyotype 5-Azacitidin / (Decitabine),

Allogeneic HSCT(RIC), Clinical Trial

CMML Leukocytosis if allogeneic HSCT

not possible

Cytoreduction with hydroxyurea, (or ara-C, VP16, thioguanine) 5-Azacytidin / (Decitabine) Low-risk and Intermediate-1 Anemia / Neutropenia / Thrombocytopenia Transfusion therapy Iron chelation del 5q Epo < 500 Epo > 500 Lenalidomide Epo G-CSF ATG/CsA Clinical Trial Valproic acid Reduced intensity (RIC)

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2. Cytogenetic analysis is important to identify pa-tients with del(5q) who should receive the benefit of lenalidomide treatment.

3. Patients with endogenous Epo levels \500 should be treated with Epo1/2 G-CSF, those with Epo levels .500 should be considered for immunosup-pressive treatment (ATG) or valproic acid, or par-ticipation in a clinical trial.

4. For patients with intermediate-2 or high-risk MDS who are fit and in the acceptable age range, allogeneic HCT should be considered, with both conventional (high dose) and reduced-intensity conditioning (RIC) being options.

5. If no donor is available, intensive chemotherapy is an option. However, epigenetic treatment with 5-azacitidine is probably the treatment of choice in the majority of patients.

6. If the karyotype is complex or includes abnormali-ties of chromosome 7, intensive chemotherapy is not recommended. Instead, allogeneic HCT or epi-genetic treatment should be tried.

7. Chronic myelomonocytic leukemia (CMML) is still included in our algorithm, even though it has been removed from the WHO classification of MDS. If leukocytosis requires treatment, and allogeneic HCT is not possible, cytoreduction with hydroxy-urea or treatment with other cytotoxic drugs is recommended. Epigenetic treatment is another op-tion, because demethylating agents have achieved re-sponses in about 50% of CMML patients.

ACKNOWLEDGMENTS

Financial disclosure: The authors have nothing to disclose.

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