The Role of Hematopoietic Stem Cell Transplantation in Myelodysplastic Syndrome

April 1, 2005

Supportive care remains the mainstay of therapy for patients withmyelodysplastic syndrome (MDS). Although allogeneic bone marrowtransplantation is the only known curative therapy for MDS, its risksmake this treatment prohibitive in many patients, who tend to be olderand have other medical problems. With advances in hematopoietic stemcell transplantation (HSCT), we can offer transplant to an increasingnumber of patients. It is, however, necessary to assess each patient andhis or her disease individually and evaluate prognostic factors, treatmentoptions, appropriateness of HSCT, and, if appropriate, type andtiming of HSCT. We will review the data on HSCT in MDS in order toexamine each of these issues and clarify the decision-making process.

Supportive care remains the mainstay of therapy for patients with myelodysplastic syndrome (MDS). Although allogeneic bone marrow transplantation is the only known curative therapy for MDS, its risks make this treatment prohibitive in many patients, who tend to be older and have other medical problems. With advances in hematopoietic stem cell transplantation (HSCT), we can offer transplant to an increasing number of patients. It is, however, necessary to assess each patient and his or her disease individually and evaluate prognostic factors, treatment options, appropriateness of HSCT, and, if appropriate, type and timing of HSCT. We will review the data on HSCT in MDS in order to examine each of these issues and clarify the decision-making process.

The myelodysplastic syndromes (MDS) are a heterogeneous group of acquired clonal hematologic disorders that are characterized by ineffective hematopoiesis resulting in cytopenias and a variable risk of progression to acute leukemia.[ 1] Although these disorders were once called "pre-leukemia," the majority of patients actually die of complications related to the cytopenias.[2] The disease course is highly variable- an indolent stable course in some, and a very aggressive course in others-with median life expectancies ranging from a few months to several years.

Classifications Systems

The diagnosis of MDS has traditionally been classified according to a 1982 French, American, and British (FAB) consensus (Table 1).[3,4] This classification system requires the presence of dysplasia in two lineages for a diagnosis of MDS. Based primarily on percentage of bone marrow blasts, patients are categorized into one of five diagnostic groups: refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-t), and chronic myelomonocytic leukemia (CMML). The FAB classification system, in addition to facilitating diagnosis, is somewhat useful in determining prognosis in that patients with more advanced disease (ie, more blasts) have a decreased survival compared to those with fewer blasts. In patients with fewer than 5% blasts (RA, RARS), the disease is generally indolent, with blood counts remaining stable for at least several months if not years. In patients with 5% to 30% blasts (RAEB, RAEB-t), the prognosis is generally poor, with a median survival ranging from 7 to 25 months.[2] This system is somewhat limited in its prognostic ability, however, as there is great variability in outcome within FAB subtypes.[3,4] Although the morphology is characteristic and clearly diagnostic in a large proportion of patients, there are patients with clinical features of MDS in whom the morphologic assessment fails to confirm a diagnosis of MDS. The World Health Organization (WHO) recently proposed a new classification system for MDS,[5] which among other changes, requires dysplasia in only one lineage and defines patients with 20% to 30% blasts as having acute myelogenous leukemia (AML) rather than MDS. The WHO classification system does identify several patient subgroups, such as "5q- syndrome" and "multilineage dysplasia," which have prognostic implications, but overall the scheme remains limited prognostically.[6]

Following a risk analysis study, an International Prognostic Scoring System (IPSS) was published in 1997[2] that further assists in assessing prognosis. A prognostic score can be assigned based on the following three factors: the marrow blast percentage, the karyotype of the clone, and the number of cytopenias present. Based on a numeric score, patients can be stratified into four risk groups-low, intermediate (int)-1, int-2, and high (Table 2). For low-risk patients with few blasts, normal karyotype, and one or no cytopenias, the median survival is 5 to 6 years, whereas for those with high-risk features, survival estimates range from 4 to 14 months. Furthermore, among patients with low-risk disease, younger patients (age ≤ 60 years) have a median survival of nearly 12 years (Table 3). This system is also useful in determining the risk of progression to leukemia, in that the median time for 25% of patients to develop leukemia in the low-risk group is 9.4 years, as compared to 2.4 months in the high-risk group.

Treatment Options in the Myelodysplastic Syndromes

The median age of diagnosis of MDS ranges from 65 to 70 years. While the incidence of MDS in the general population is only 5 per 100,000, among individuals over age 70, the incidence rises to between 20 and 50 per 100,000. In this patient population, comorbidities often limit therapeutic options. Although advances are being made in the biology of MDS that will hopefully allow for more effective and less toxic therapies in the future, the current standard of care in the community is supportive care. This generally involves monitoring of blood counts and clinical status, with transfusion support as the mainstay of treatment. Cytokine support is sometimes used and antifibrinolytic agents such as aminocaproic acid can be used in patients with refractory thrombocytopenia. Additionally, iron chelation is considered in patients with low-risk disease who have received more than 20 to 30 units of blood. Several novel therapies for MDS are being studied. Based on the increasing understanding of the biology of the disease, targeted therapies are being developed in an attempt to inhibit presumed pathogenetic mechanisms. Agents currently in clinical trials include thalidomide (Thalomid) and CC-5013 (Revlimid) as immunomodulatory agents, arsenic trioxide (Trisenox), farnesyl transferase inhibitors such as tipifarnib (Zarnestra), tumor necrosis factor inhibitors such as etanercept (Enbrel), hypomethylating agents such as decitabine (Dacogen) and azacitidine (Vidaza), and histone deacetylase inhibitors such as valproic acid, MS-275, and suberoylanilide hydroxamic acid (SAHA). Data are limited, but trials are ongoing.[7-10] Once we more fully understand the mechanisms of action of these agents, we may be better able to select patients who are likely to respond. The National Comprehensive Cancer Network (NCCN) has divided treatment options for MDS into several categories: (1) supportive care, as discussed above, (2) low-intensity therapy-including the use of lowdose chemotherapy or biologic agents, and (3) high-intensity therapy, including intensive induction therapy or hematopoietic stem cell transplant (HSCT).[11] The NCCN guidelines stratify patients into groups based on age, performance status, and IPSS risk category in order to make treatment recommendations. Based on these factors as well as an assessment of the pace and course of the disease, they recommend that patients be considered for low-intensity or high-intensity treatment. In general, they recommend that patients with a low or int-1 IPSS (low-risk disease) should receive supportive care or low-intensity therapy until they develop evidence of progressive disease. Patients with int-2 or high IPSS (high-risk disease) should be considered for high-intensity therapy if they have an adequate performance status. The only treatment, however, that has been shown to alter the natural history of MDS is allogeneic bone marrow transplantation. With leukemic induction chemotherapy alone, a proportion of patients may achieve complete remission (CR), but this is rarely durable. While CR rates are 50% to 60%, median CR duration is only 6 to 12 months and the longterm disease-free survival rate is only 10% to 20%.[12] As such, HSCT, in eligible patients when an appropriate donor is available, is the preferred high-intensity therapy option for patients with high-risk disease. Furthermore, 40% to 45% of patients with low-risk MDS die of complications of cytopenias (infections or hemorrhage) without ever developing leukemia. This is the justification for HSCT as a treatment strategy in early stages of the disease, despite the inherent risk of regimen-related morbidity and mortality.

Conventional Allogeneic Bone Marrow Transplant

Data from single institutions and from European and International transplant registries indicate that at least one-third of MDS patients receiving marrow transplants from human leukocyte antigen (HLA)-identical siblings are cured of their disease.[ 13-17] Transplant-related mortality, however, remains over 20% even in younger patients with lowrisk disease. Although a large number of single- and multi-institution series have been reported, a formal meta-analysis of these studies is precluded by their great variability. The patient populations in these studies have varying proportions of de novo MDS, secondary MDS (t-MDS), and secondary AML-categories that can be quite different in their biology, natural history, and response to treatment. Furthermore, the ages of the patients, the pretransplant treatments (ranging from none to successful induction of CR), the duration of disease before transplant, the conditioning regimens, the type of graft-vs-host disease (GVHD) prophylaxis, the donor's relation and match, and the source of stem cells vary considerably both within and between studies. Nevertheless, we can use the available data to try and determine factors that affect the outcome in the patient population. In singleinstitution studies, factors that consistently appear to influence survival, transplant-related mortality, and relapse are FAB classification, cytogenetics, IPSS score, and age. The largest experience in allogeneic bone marrow transplant comes from the European Group for Blood and Marrow Transplantation (EBMT).[18] This group reported a 36% disease-free survival rate at 3 years and 37% nonrelapse mortality in the 885 patients who underwent allogeneic bone marrow transplantation from HLA-identical sibling donors between 1983 and 1998. Disease-free survival and relapse rates are 55% and 13%, respectively, in patients with RA/RARS, while corresponding figures for more advanced disease are 28% and 43%.

The largest single-center study is from Seattle investigators, who reported their experience in 251 MDS patients.[ 13] The disease-free survival rate at 6 years was 40%, with an 18% relapse rate and 44% nonrelapse mortality rate. Age as well as IPSS score were highly predictive of disease-free survival. Patients under age 20 had a 60% disease-free survival as compared to 20% for those over age 50, in whom this rate was secondary to a high nonrelapse mortality. Features that predicted relapse were a higher blast percentage and poor-risk karyotype, whereas higher nonrelapse mortality was predicted by disease duration, older age, t-MDS, male sex, and mismatched or unrelated donors. A report from the International Bone Marrow Transplant Registry (IBMTR) on 452 patients transplanted from HLA-identical siblings between 1989 and 1997 showed relapse-free survival at 3 years to be 40%. The incidence of relapse was 23%, and nonrelapse mortality was 37%. Percentage of marrow blasts before transplantation was the strongest predictor of relapse and relapse-free survival, and younger age was correlated with better survival. Table 4 summarizes the factors that influence outcome when conventional HSCT is used in patients with MDS.

Conditioning Regimen

The variety of treatment protocols utilized in reported studies demonstrates that there is little consensus on the appropriate conditioning regimen for patients undergoing transplant. The challenge is that of balancing regimen- related toxicity against relapse risk. The two most common regimens employed in this setting are busulfan (Busulfex, Myleran)/cyclophosphamide or cyclophosphamide/total-body irradiation (TBI). Although high doses of TBI have been associated with increased nonrelapse mortality, radiotherapy dose intensity has been correlated with lower relapse rates. Attempts at decreasing toxicity by shielding the liver and lung have also led to unacceptable relapse rates.[19] In a study comparing 46 historical controls to 14 patients who underwent allogeneic bone marrow transplantation with customized Cerrobend blocks, the shielded patients had a similar nonrelapse mortality (29% vs 37%) but a higher relapse rate. Busulfan-containing regimens seem to have a high risk of venoocclusive disease. The use of targeted busulfan has resulted in improved outcomes. In a study of cyclophosphamide and targeted busulfan in 109 patients aged 6 to 66, relapse-free survival at 3 years was 56% with matched related donors and 59% with matched unrelated donors, with a nonrelapse mortality of 28% to 30%.[20] In a previous study by the same investigators, patients who received this regimen lived longer than those who received other regimens (either busulfan at 16 mg/kg and cyclophosphamide, or busulfan and TBI, or cyclophosphamide and TBI).[21] T-cell depletion of the allograft, although decreasing the risk of GVHD, results in higher rates of graft failure and relapse.[14]

Pretransplant Treatment and Timing of Transplant

While all transplant series for MDS have shown that patients in remission or with low burden of disease have better outcomes, controversy still exists regarding the value of standard induction chemotherapy prior to transplant. Some centers report higher survival rates in patients in CR,[22,23] but this has not been confirmed in other trials.[24,25] The data from 44 of the EBMT centers showed an overall survival rate of 41% at 5 years, and none of these patients had undergone prior induction.[14] It is possible that patients who achieve remission have favorable characteristics that would bode well for success with transplant, regardless of pretreatment strategies. Additionally, although disease progression is associated with a poorer outcome, it is not clear that duration of disease (in the absence of progression) is of any prognostic significance. The IBMTR has reported a decision analysis performed to determine the optimal timing of conventional allogeneic transplantation in patients under age 60.[26] Using data on 260 patients with MDS and 230 patients with transformed AML who underwent HSCT from HLA-identical siblings and 184 patients with MDS who did not undergo transplantation, they constructed a Markov model to examine three transplantation strategies for newly diagnosed MDS: HSCT at diagnosis, HSCT at leukemic progression, and HSCT at an interval from diagnosis but prior to leukemic progression. Using the IPSS score for risk stratification, they found that the median survival for patients with low-risk IPSS scores was higher in patients who did not undergo allogeneic HSCT than in those who did undergo transplantation (141.1 and 62.9 months vs 40.2 and 20.5 months for low and int-1 risk IPSS, respectively). Among patients with the highest-risk disease, median survival was greater for those who underwent HSCT at diagnosis, with an improved life expectancy when compared to no transplant, delayed transplantation, or HSCT at the time of AML progression. Based on their decision analysis, immediate HSCT resulted in the best survival in patients with high-risk IPSS scores. In patients with low-risk IPSS scores, however, maximal survival was associated with HSCT at an interval from the time of diagnosis, prior to development of AML (median time to leukemic progression was 84.6 and 19.2 months for low and int-1 risk IPSS, respectively). This finding was particularly true in patients with low-risk disease under the age of 40, who could enjoy a prolonged survival without transplantation. These results suggest that young patients with high-risk disease with an available HLA-identical sibling donor should undergo HSCT as soon as possible. We need better techniques to predict disease progression in patients with low-risk disease, to optimize the timing of transplant in that population.

Alternative Donors

Although several studies have suggested that the use of mismatched or unrelated donors increases the risk of nonrelapse mortality, reports from the Fred Hutchinson Cancer Research Center[20] as well as a European group[15] demonstrated that relapsefree survival rates for unrelated donors and mismatched family members were similar to those for genotypically identical family donors. The National Marrow Donor Program recently reported a retrospective analysis of 510 patients with MDS transplanted with stem cells from unrelated donors.[27] The median age of recipients was 38 years (range: < 1-62 years). Multivariate analysis demonstrated an impact of acute GVHD, advanced disease, cell dose, recipient cytomegalovirus serology, time to transplantation, and year of infusion on survival. Relapse occurred in 14% of patients and was independently associated with advanced MDS subtype and lack of acute GVHD. Patients with advanced MDS who had been induced into CR or a less advanced form of MDS prior to conditioning had better disease-free survivals and lower relapse rates than patients who underwent HSCT without a change in disease status. The 2-year cumulative incidence of transplant-related mortality was 54%.[27] Infections, GVHD, and regimen- related toxicity were the most frequent complications leading to death. On multivariate analysis, acute GVHD, HLA disparities, recipient cytomegalovirus serology, recipient age, and donor age were independently associated with treatment-related mortality. With a 2-year probability of disease-free and overall survival of 29% and 30%, respectively, this remains an option for younger patients who do not have HLA-identical sibling donors. Reports of the use of unrelated cord blood[28] have been promising as well and provide a further possible source of cells for transplantation. Given the older age of the majority of patients with this disease, however, this option is unfeasible in most patients.

Autologous Transplant

The utility of autologous transplant depends on the collection of unaffected hematopoietic progenitor cells. A few published studies have indicated that polyclonal, karyotypically normal peripheral blood stem cells can be successfully collected from patients with MDS.[29] Hence, autologous transplant is theoretically justified and has been studied in patients for whom allogeneic donors were not available.[30,31] In a retrospective review of transplantation in MDS, the European Organization Organization for Research and Treatment of Cancer-Autologous Bone Marrow Transplantation study group reported on 184 patients who underwent autologous stem cell transplantation.[ 15] They reported a 33% disease-free survival with a 55% relapse rate. In two reports from the EBMT, de Witte and colleagues have published results on patients with MDS or transformed AML who have undergone autologous HSCT in first remission.[ 18,32] The 2-year disease-free survival rate was 34% (28% for patients with MDS). In a prospective phase II trial of autologous and allogeneic HSCT in such patients,[15] 3-year survival for patients who underwent autologous transplant was not significantly different from the results for those with an HLA-identical donor who were in CR after similar pretransplant therapy. However, the study was not powered to evaluate that comparison. Nonrelapse mortality was 39% in patients over 40 years old. The IPSS cytogenetic risk groups were of prognostic importance; however, the IPSS score did not correlate with survival. In Wattel's report of a prospective study of autologous HSCT for patients with MDS, 50% were alive 8 to 55 months after transplantation, for an estimated disease-free survival of 42% at 4 years.[33] Only 42 of the original 132 patients were eligible to proceed to autologous HSCT after achieving a CR from induction chemotherapy. Of this group, 24 patients received an autologous transplant. A recent report by Oosterveld et al,[34] presented results on 117 patients with MDS who had received induction chemotherapy followed by HLA-identical sibling transplant if available, or otherwise, an autologous HSCT. An analysis of the patients who underwent transplant demonstrates a 23% 4-year relapse-free survival for patients with a donor, compared to 22% for those without a donor. The higher incidence of relapse following autologous HSCT is counterbalanced by the lower nonrelapse mortality compared to allogeneic HSCT. These studies suggest that there is a subset of MDS patients who can attain durable remission with an autologous transplant. Although it is not proven that autologous transplant is better than traditional consolidation following CR, it is a reasonable strategy for younger patients without an appropriate donor, or for older patients who may not tolerate allogeneic transplant and achieve a CR with conventional chemotherapy. New techniques that can better identify residual disease in patients thought to be in CR may improve our capacity to appropriately recommend this treatment strategy.

Reduced-Intensity Allogeneic Stem Cell Transplantation

While alternative donor transplants are potentially an option for patients who do not have an appropriate HLAcompatible sibling, given the advanced age of the majority of patients with this disease, recent efforts have focused on transplant regimens that employ nonmyeloablative or reducedintensity conditioning, in an attempt to decrease the risks associated with transplantation. Traditional transplant has been successful in the treatment of both malignant and nonmalignant disorders, but both autologous and allogeneic transplant rely on the efficacy of myeloablative chemotherapy. It has become increasingly clear, however, that some of the success of allogeneic bone marrow transplant is not dependent on myeloablative chemotherapy, but rather, due to the immunologic reaction caused by the allograft. This has been inferred from the correlation between GVHD and decreased relapse rates suggesting a graft-vs-tumor (GVT) effect,[35] increased relapse after allogeneic bone marrow transplant in T-cell depleted grafts,[36,37] and the superiority of allogeneic transplant over syngeneic and autologous bone marrow transplant for many hematologic malignancies.[38] As proof of principle, donor lymphocyte infusion given after allogeneic bone marrow transplant has eradicated residual or recurrent disease, thus confirming the hypothesis that allogeneic cells could be used to induce a direct antitumor effect that may be a critical component in the treatment of these patients.[39] As we have developed a better understanding of both host and donor immune function, these findings have allowed for the development of alternative strategies of allogeneic stem cell transplantation that do not rely on the myeloablative effects of chemo/ radiotherapy, but rather, exploit the GVT effect associated with allogeneic transplantation. This strategy has been used to treat patients with hematologic malignancies, solid tumors, and nonmalignant hematologic disorders. Given the lack of a myeloablative, toxic conditioning regimen, it allows for the treatment of patients who would not be considered candidates for traditional allogeneic stem cell transplantation, whether because of age, organ dysfunction, concurrent medical illness, or prior stem cell transplantation. The principle of the reducedintensity conditioning or nonmyeloablative allogeneic transplant is that of designing a conditioning regimen that will allow for donor engraftment and abrogate host immune responses, but have less toxicity than traditional myeloablative regimens. Preclinical models have suggested that immunosuppressive conditioning regimens can be sufficient to induce durable engraftment, tolerance, and GVT effect in the mixed chimeras with reduced GVHD. Such regimens commonly include fludarabine (Fludara), antithymocyte globulin (Atgam), low-dose TBI, or alemtuzumab (Campath) in combination with other agents.[40-43] Although conditioning regimen- related toxicity can still be seen, reduced-intensity conditioning or nonmyeloablative transplantation is much better tolerated when compared to conventional myeloablative allogeneic transplant. Transplant-related morbidity and mortality is much decreased. Toxicity is generally related to GVHD and/or infection.[44] While acute GVHD greater than grade 2 is less common (6% to 62%), it is often responsive to supplemental immunosuppressive therapy, perhaps because of the lack of superimposed tissue damage resulting from the conditioning regimens used for standard allogeneic transplantation. Rates of up to 40% for chronic GVHD have been reported. Immunosuppressive agents are still employed to both prevent graft rejection and reduce the risk of GVHD.

Clinical Trials and Case Reports
Most trials of this approach report results on a heterogeneous, often heavily pretreated group of patients. Nevertheless, response rates of 20% to 55% have been reported in studies of small numbers of patients with various malignancies. Complete responses have occurred in up to 50% of patients. As the responses rely on the immunomodulatory effect of the donor lymphocytes, evidence of response may take months if not longer.[45] Long-term follow-up is not yet available on sufficient numbers of patients to assess the duration of these responses. The success of engraftment can be measured by chimerism analysis, which is the measurement of the proportion of donor and recipient cells present in the recipient. It is anticipated that over time, the donor cells will eventually replace the recipient cells, or that donor cells will become tolerant to alloantigens from the recipient and reconstitute hematopoiesis while maintaining the GVT effect. The success of this type of transplant does, however, depend on demonstration of a GVT effect that results in response in the disorder being treated. In the case of hematologic malignancies, it is likely that full donor chimerism will be required to sustain a complete remission and that monitoring of chimerism will be important so that donor lymphocyte infusions may be considered if there is evidence of loss of chimerism.[46] Several small studies and case reports demonstrate the feasibility of donor lymphocyte infusion to treat MDS patients who have relapsed after standard allogeneic transplant.[47] In Shiobara's report, 5 of 11 patients with relapsed MDS achieved CR after a cell dose of 3 * 107/kg of recipient's body weight. In a group of 37 patients with MDS or AML who underwent allogeneic peripheral blood stem cell transplant following reduced-intensity conditioning,[35] there was a 5% incidence of grade 3/4 acute GVHD and a 46% incidence of chronic extensive GVHD. With a median follow-up of 297 days, the 1-year probability of nonrelapse mortality was 5%, and the 1-year relapse-free survival rate was 66%. The relapse rate at 1 year was 13% for patients who developed GVHD (either grade 2-4 acute or chronic GVHD) as compared to 58% for those who did not develop GVHD. These results argue in favor of a GVT effect in AML and MDS following transplant using reduced-intensity conditioning.

Toxicity and Mortality Rates
Given the advanced age of most patients with MDS, the potential reduced toxicity of these regimens has made this approach of particular interest. Variable rates of response and toxicity have been observed. Slavin has reported results of reduced-intensity condition transplant in patients with AML or MDS.[42] In a recent abstract,[56] they included 53 patients with MDS. The 1-year disease-free survival rate was 100% in two patients with RA/RARS and 62% in those with more advanced disease, with a 48% treatment-related mortality in that group. Transplants in all patients engrafted. Among the eight patients with MDS, disease-free survival was 100% in three patients with RAEB and 40% in those with RAEB-t. Kroger reported on 12 patients with high-risk MDS who were treated with a fludarabine-based reduced-intensity conditioning regimen followed by HLA-matched allogeneic stem cell transplantation.[48] Seven of the patients had unrelated donors. All patients had successful engraftment. Four of the patients died of treatmentrelated toxicity, and four had grade 2 to 4 GVHD. The 2-year disease-free survival rate was 12%, and overall survival was 26%. Morbidity and mortality rates were high in this study, but these were high-risk patients who were ineligible for conventional allogeneic treatment. Parker et al reported their results in 23 MDS patients who underwent reduced-intensity conditioning and compared them to 29 patients who underwent standard volunteer unrelated donor or sibling allogeneic transplant for MDS.[49] Of 19 evaluable patients who received reduced-intensity conditioning, 18 achieved 100% donor engraftment. When compared with 29 patients who underwent standard allogeneic transplant, reducedintensity conditioning was associated with reduced aplasia, mucositis, antibiotic use, total parenteral nutrition use, and acute and chronic GVHD. Early nonrelapse mortality was 9% compared to 31%. Six patients who received reduced-intensity conditioning subsequently developed mixed chimerism and relapsed. The 2-year overall/disease-free survival was therefore 48%/39% in the reducedintensity conditioning arm, compared to 44%/44% in the standard group. The 2-year nonrelapse mortality was 31% compared to 50%. For volunteer unrelated donor recipients, overall survival was 49% for reduced-intensity conditioning compared to 34%. The response rates and toxicity profile after nonmyeloablative or reduced- intensity allogeneic cell therapy for patients with MDS have been encouraging.[ 42,47,50-53] Regimens designed to further minimize conditioning regimen toxicity, enhance donor cell engraftment, maximize GVT and minimize GVHD could further enhance the promise of this therapeutic modality.

Novel Regimen
A novel conditioning regimen employing photopheresis, pentostatin (Nipent) and low-dose TBI has been employed in a pilot study of nonmyeloablative allogeneic HSCT at the New England Medical Center.[54,55] Although the exact mechanism of photopheresis is not known, the treatment is both immunosuppressive and cytotoxic. Pentostatin is a potent inhibitor of the enzyme adenosine deaminase and is active against memory T cells, which may be important mediators of GVHD. Moreover, pentostatin has demonstrated activity in acute and chronic GVHD. Low-dose TBI (2-4 Gy in a single fraction) has been used as part of less intensive preparative regimens. In their initial report,[54] patients with various hematologic malignancies and a median age of 48 years (range: 23-59 years) underwent conditioning with this regimen followed by bone marrow infusion from an HLA-identical sibling, 5/6 antigenmatched related or unrelated donor. Donor hematopoiesis in sex-mismatched transplants was 100% at the time of engraftment. The 100-day overall survival was 100%. The preparative regimen was well tolerated in all patients. All patients experienced grade 4 neutropenia and thrombocytopenia, but none developed venoocclusive disease. Data are now available on 18 MDS patients who underwent transplants with this regimen, including patients up to age 72.[55] Sixteen of 18 patients developed full donor chimerism (> 90% donor) by day 100, with no nonrelapse mortality at day 100. Grade 2-4 acute GVHD developed in 19% of patients. Of the 16 patients with durable engraftment, 14 achieved clinical CR. Disease relapse occurred in two patients. At a median followup of 14 months (range: 1-35 months), the 1-year disease-free and overall survival were 64% and 65%, respectively. Based on these results, the Eastern Cooperative Oncology Group is initiating a phase II trial of photopheresis, pentostatin, and TBI as a reduced-intensity conditioning regimen for allogeneic transplant in patients with MDS. Conclusions The myelodysplastic syndromes are a heterogeneous group of disorders associated with a risk of lifethreatening complications secondary to cytopenias and a variable rate of progression to leukemia. Although criteria have been developed to assist us in estimating the risk of leukemic progression as well as median survival, we are faced with a lack of effective, nontoxic therapies that can be employed when aggressive therapy is desired. While allogeneic HSCT is the only treatment known to potentially result in long-term disease-free survival, this approach carries the highest rate of treatment-related mortality. Moreover, patients who do best with allogeneic transplantation (young, RA, RARS, normal cytogenetics) are also those who are most likely to do well without transplantation. However, since the median age of patients with MDS is over 60 years, most patients are not candidates for this procedure. Therefore, supportive care remains the mainstay of care for the disease. As we learn more about the biology of MDS, new approaches and agents are being studied for treatment. The optimal role of these agents in the treatment paradigm is unclear; they may work alone or in combination as alternatives to transplant, or they may function as long-term maintenance agents. Although it is clear that young patients with HLA-identical siblings who have an increased number of blasts should undergo allogeneic HSCT as soon as possible, there are still many unanswered questions regarding HSCT in MDS. The role of pretransplant therapy is not clear. In the absence of an HLA-identical donor, the best alternative donor choice-whether mismatched related, unrelated, or autologous-is not clear. In patients with low-risk disease, the role of HSCT is not as well defined. This is because of the potential prolonged survival of these patients with supportive care alone and the high morbidity and mortality associated with standard allogeneic transplantation. Furthermore, although it appears that it is not detrimental to wait several years prior to transplant in patients with low-risk disease, survival rates posttransplant decrease if the transplant is performed once the disease has become more aggressive or has transformed to acute leukemia. Given the lack of markers that reliably predict for disease progression, it is therefore not possible to choose the optimal time for transplant. More recently, in an attempt to decrease the toxicity of allogeneic transplantation, several reduced-intensity conditioning regimens have been developed. These allow the patient to benefit from the allogeneic GVT effect without the complications of standard myeloablative regimens, thereby enabling patients who may not otherwise be eligible for standard allogeneic HSCT to undergo transplant. Although preliminary results are encouraging in terms of both response and toxicity, there remain significant toxicities secondary to infection and organ toxicity. Furthermore, longterm results of this approach are as yet unknown. While HSCT should always be considered considered in the management of a patient with myelodysplastic syndrome, many uncertainties remain. Patients should be enrolled in appropriate clinical trials whenever possible, hopefully allowing us to improve upon these techniques by developing ways to increase efficacy while decreasing toxicity.

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

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