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Tuning the Rigging before Sailing off into the Stormy Sea of Stem Cell Transplants for Patients with Myelodysplastic Syndromes

2012; Elsevier BV; Volume: 18; Issue: 8 Linguagem: Inglês

10.1016/j.bbmt.2012.05.004

1523-6536

David P. Steensma,

Acute Lymphoblastic Leukemia research

Wise mariners—veteran sailors who understand that waves are not measured in feet or in fathoms, but in increments of fear—always ensure that their vessels are fit before setting out on a long ocean voyage: hull sound, brightwork polished, adequate provisions laid down, lines and cordage clean, navigation equipment in good repair. Because the sea itself is beyond individual human influence, those who make their living by going down to the water have learned to control all those factors that are amenable to manipulation. Similarly, events after an allogeneic hematopoietic stem cell transplant (ASCT) procedure are as unpredictable as the weather of the notorious Southern Ocean, about which the old salts say, “Below 50 degrees South latitude there is no law; below 60 degrees, there is no God.” Wise physicians, therefore, ensure that their patients are always physiologically “ship-shape and Bristol fashion” before sending them off in search of the fabled Land of Cure, somewhere beyond the ASCT horizon. Despite the advent of effective drug therapies that can improve blood counts and extend the life of some patients who have myelodysplastic syndromes (MDS), ASCT remains the only definitive, potentially curative therapy for this difficult group of marrow failure syndromes [1Sekeres M.A. Are we nearer to curing patients with MDS?.Best Pract Res Clin Haematol. 2010; 23: 481-487Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar]. Unfortunately, because the median age of patients diagnosed with MDS is approximately 71 years, only a small subset of patients are eligible for ASCT, and even fewer (<5%) are referred to a transplantation center and actually undergo the procedure [2Sekeres M.A. Schoonen W.M. Kantarjian H. et al.Characteristics of US patients with myelodysplastic syndromes: results of six cross-sectional physician surveys.J Natl Cancer Inst. 2008; 100: 1542-1551Crossref PubMed Scopus (207) Google Scholar]. Each year, at least 25,000 people in the United States will learn that they have MDS [3Cogle C.R. Craig B.M. Rollison D.E. List A.F. Incidence of the myelodysplastic syndromes using a novel claims-based algorithm: high number of uncaptured cases by cancer registries.Blood. 2011; 117: 7121-7125Crossref PubMed Scopus (165) Google Scholar]. Yet according to data submitted to the Center for International Blood and Marrow Transplantation Research, fewer than 1000 patients underwent ASCT in the United States for MDS-related indications in 2011 [4Pasquini M, Wang Z. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2011. (See slide #8). Available at: http://www.cibmtr.org. 2011. Accessed June 6, 2012.Google Scholar]. Among those patients with MDS who do brave the deep waters of ASCT, most will receive reduced-intensity conditioning (RIC) before stem cell infusion, relying entirely upon the “graft-versus-leukemia” (GVL) immunological activity of the allograft to eradicate stubborn neoplastic MDS hematopoietic clones [5Parmar S. de Lima M. Deeg H.J. Champlin R. Hematopoietic stem cell transplantation for myelodysplastic syndrome: a review.Semin Oncol. 2011; 38: 693-704Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 6Martino R. Caballero M.D. Pérez-Simón J.A. et al.Evidence for a graft-versus-leukemia effect after allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning in acute myelogenous leukemia and myelodysplastic syndromes.Blood. 2002; 100: 2243-2245Crossref PubMed Scopus (155) Google Scholar]. It is now clear that long-term ASCT outcomes in MDS are comparable with traditional myeloablative and newer RIC conditioning [7Luger S.M. Ringdén O. Zhang M.J. et al.Similar outcomes using myeloablative vs reduced-intensity allogeneic transplant preparative regimens for AML or MDS.Bone Marrow Transplant. 2012; 47: 203-211Crossref PubMed Scopus (224) Google Scholar]. But a few retrospective studies have suggested that particularly with RIC ASCT, the less “clean-up work” that the graft has to do—that is to say, the fewer clonal cells that are present at the time of the transplantation and the lower the burden of residual disease—the more likely it is that the transplantation will be successful [8van Besien K. Artz A. Smith S. et al.Fludarabine, melphalan, and alemtuzumab conditioning in adults with standard-risk advanced acute myeloid leukemia and myelodysplastic syndrome.J Clin Oncol. 2005; 23: 5728-5738Crossref PubMed Scopus (120) Google Scholar, 9Kebriaei P. Kline J. Stock W. et al.Impact of disease burden at time of allogeneic stem cell transplantation in adults with acute myeloid leukemia and myelodysplastic syndromes.Bone Marrow Transplant. 2005; 35: 965-970Crossref PubMed Scopus (49) Google Scholar]. Just as for acute myelogenous leukemia, we now know from ongoing whole-genome sequencing efforts that ∼85% of the marrow cells in MDS are clonal and bear somatic mutations, even among the subset of patients with MDS who do not have excess blasts, highlighting both the danger in routinely relying on GVL and the widespread need for pre-ASCT cytoreduction [10Walter M.J. Shen D. Ding L. et al.Clonal architecture of secondary acute myeloid leukemia.N Engl J Med. 2012; 366: 1090-1098Crossref PubMed Scopus (611) Google Scholar]. The fact that most hematopoietic elements are clonal in MDS marrow raises the interesting possibility that all patients with MDS should undergo cytoreductive therapy before ASCT regardless of blast proportion, but such an approach is not uniformly practiced. Perhaps as a result, relapse (with subsequent complications of MDS-related cytopenias) remains the most frequent cause of death in patients with MDS who have undergone ASCT, and this sober fact is true regardless of how many blasts the patient had in the marrow before transplantation [11Lim Z. Brand R. Martino R. et al.Allogeneic hematopoietic stem-cell transplantation for patients 50 years or older with myelodysplastic syndromes or secondary acute myeloid leukemia.J Clin Oncol. 2010; 28: 405-411Crossref PubMed Scopus (237) Google Scholar]. Only prospective studies will establish the optimal pretransplantation approach in patients with <10% blasts. In the meantime, most patients with excess blasts do undergo cytoreductive therapy of one sort or another before ASCT, both to serve as a “bridge to transplantation” and to optimize the patient's marrow milieu. Unfortunately, traditional intensive chemotherapy (IC) cytoreductive strategies, such as the classic “3 & 7” anthracycline/cytarabine combination, are a tough upwind beat for many patients, and serious and durable adverse events from IC (or general disgust with the limitations of contemporary therapy, leading to a minimalist mindset) can prevent an otherwise suitable candidate from ever reaching ASCT [12Estey E. de Lima M. Tibes R. et al.Prospective feasibility analysis of reduced-intensity conditioning (RIC) regimens for hematopoietic stem cell transplantation (HSCT) in elderly patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS).Blood. 2007; 109: 1395-1400Crossref PubMed Scopus (207) Google Scholar]. In recent years, there has been great interest in effective pretransplantation therapies that are less toxic than IC but that might still achieve the same ends. Clinical practice is shifting toward the use of the hypomethylating agents (ie, DNA methyltransferase inhibitors), either azacitidine or its chemical cousin decitabine, for this purpose, and a number of small studies have demonstrated the feasibility of pre-ASCT hypomethylating agent therapy [13Kim D.Y. Lee J.H. Park Y.H. et al.Feasibility of hypomethylating agents followed by allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome.Bone Marrow Transplant. 2012; 47: 374-379Crossref PubMed Scopus (46) Google Scholar, 14Field T. Perkins J. Huang Y. et al.5-Azacitidine for myelodysplasia before allogeneic hematopoietic cell transplantation.Bone Marrow Transplant. 2010; 45: 255-260Crossref PubMed Scopus (121) Google Scholar, 15Cogle C.R. Imanirad I. Wiggins L.E. et al.Hypomethylating agent induction therapy followed by hematopoietic cell transplantation is feasible in patients with myelodysplastic syndromes.Clin Adv Hematol Oncol. 2010; 8: 40-46PubMed Google Scholar, 16De Padua Silva L. de Lima M. Kantarjian H. et al.Feasibility of allo-SCT after hypomethylating therapy with decitabine for myelodysplastic syndrome.Bone Marrow Transplant. 2009; 43: 839-843Crossref PubMed Scopus (72) Google Scholar, 17Lübbert M. Bertz H. Rüter B. et al.Non-intensive treatment with low-dose 5-aza-2'-deoxycytidine (DAC) prior to allogeneic blood SCT of older MDS/AML patients.Bone Marrow Transplant. 2009; 44: 585-588Crossref PubMed Scopus (89) Google Scholar]. Azacitidine and decitabine achieve cytoreduction less rapidly than IC, but it seems that with these agents, the marrow response rate is still high enough and on-treatment mortality is low enough to justify routine use. If hypomethylating agents are safer than and nearly as effective as IC, should they supplant IC as the preferred pre-ASCT cytoreductive therapy in patients with MDS? The only way to confirm the optimal preparatory regimen before ASCT in these patients would be to do a randomized prospective trial comparing no pretransplantation therapy with either azacitidine/decitabine or IC followed by ASCT, with stratification by baseline blast proportion and other known MDS-associated prognostic factors (the list of these is rapidly expanding) [18Bejar R. Stevenson K. Abdel-Wahab O. et al.Clinical effect of point mutations in myelodysplastic syndromes.N Engl J Med. 2011; 364: 2496-2506Crossref PubMed Scopus (1222) Google Scholar]. However, the number of study subjects required to detect the probable small mortality difference between these 3 conditioning approaches would be quite large—several hundred patients at least, depending on how pessimistic the biostatistical assumptions are about the proportion of randomized patients who would stay on such a study long enough to undergo ASCT. Such prospective transplantation trials are notoriously difficult to conduct. Perhaps the Germans could complete such a study, as German hematological malignancy study groups have proved in recent years that they can accomplish almost anything, including an ongoing randomized trial of azacitidine as primary therapy versus azacitidine followed by ASCT in MDS (http://clinicaltrials.gov/ct2/show/NCT01404741). But a 3-arm trial along the lines of that described that is large enough to answer the question of the optimal ASCT preconditioning preparatory regimen seems unlikely to occur. We are left, then, with retrospective comparisons between IC and other preconditioning cytoreductive approaches, such as the new analysis by Aaron Gerds et al. [19Gerds A.T. Gooley T.A. Estey E.H. Appelbaum F.R. Deeg H.J. Scott B.L. Pretransplantation therapy with azacitidine vs induction chemotherapy and posttransplantation outcome in patients with MDS.Biol Blood Marrow Transplant. 2012; 18: 1211-1218Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar] from the Fred Hutchinson Cancer Research Center (FHCRC) in Seattle that publishes in this issue of Biology of Blood and Marrow Transplantation. The FHCRC investigators compared 35 patients with MDS who underwent azacitidine therapy before ASCT from 2004 to 2010 with 33 patients with MDS who received IC before ASCT between 1992 and 2002. All of the patients undergoing IC received a myeloablative ASCT, whereas 60% of those in the azacitidine cohort underwent RIC ASCT. Once disease-associated prognostic markers were accounted for, the FHCRC investigators observed no differences between the 2 cohorts in overall survival, relapse mortality, or nonrelapse mortality, confirming the feasibility of either preconditioning approach. Although these retrospective data are all we have to work with, they are difficult to draw general conclusions from, because the patients were treated in different eras on a wide variety of distinct ASCT protocols. The FHCRC MDS ASCT experience is large compared to other centers, but as the investigators acknowledge, this study was powered such that only a dramatic difference in outcomes between azacitidine and IC could have been observed. Of note, the older age of patients taking azacitidine in the series (median of 60 years versus 47 for IC) would suggest a trend for the azacitidine-treated patients to have poorer outcomes, but the opposite was true—a point in favor of azacitidine. As a practical matter, azanucleoside therapy offers the attraction of a relatively nontoxic outpatient bridge to ASCT, and hematology-oncology clinicians are already showing that they believe by using azacitidine and decitabine widely in this role outside the context of a clinical study. Even when a patient is recognized as an excellent transplantation candidate from the day of MDS diagnosis and promptly referred for a transplantation consultation, and even when the patient comes to the initial consultation accompanied by a cluster of healthy siblings the size of an America's Cup crew, all eager to be tissue typed immediately, ASCT does not happen overnight. There is certain activation energy: A suitable donor must be identified, insurers may need some persuasion to pay for the procedure, and pretransplantation screening tests must be completed. While all this is ongoing, azanucleosides can keep the patient's disease temporarily becalmed. Azacitidine and decitabine are thought to exert their clinical activity by altering epigenetic patterns and consequently reactivating aberrantly silenced tumor suppressor genes [20Issa J.P. Epigenetic changes in the myelodysplastic syndrome.Hematol Oncol Clin North Am. 2010; 24: 317-330Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar]. However, recently, hypomethylating agents have also been found to modulate the number and activity of T cell subsets, including immunomodulatory regulatory T cells, by up-regulating tumor-associated antigen expression in post-ASCT patients [21Goodyear O.C. Dennis M. Jilani N.Y. et al.Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML).Blood. 2012; 119: 3361-3369Crossref PubMed Scopus (297) Google Scholar]. Refinement of such a strategy might finally help cut GVL free from where it has been stubbornly fouled on the snag of graft-versus-host disease, thereby improving ASCT outcomes. Posttreatment hypomethylating agent therapy might also directly act on persistent neoplastic clones that escape GVL, delaying relapse [22de Lima M. Giralt S. Thall P.F. et al.Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome: a dose and schedule finding study.Cancer. 2010; 116: 5420-5431Crossref PubMed Scopus (356) Google Scholar]. Experienced seamen have learned that the sea is a relentless test proctor, eventually detecting every ship and sailor's failings, probing for anywhere preparation was skimped. Before bidding bon voyage to our patients with MDS on their ASCT cruise, we too owe it to them to ensure that they are as prepared as they can be for a safe and successful journey. For now, the study of Gerds et al. [19Gerds A.T. Gooley T.A. Estey E.H. Appelbaum F.R. Deeg H.J. Scott B.L. Pretransplantation therapy with azacitidine vs induction chemotherapy and posttransplantation outcome in patients with MDS.Biol Blood Marrow Transplant. 2012; 18: 1211-1218Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar] indicates that azacitidine cytoreduction could be an important part of these plans for send-off, but more data are needed. Financial disclosure: The author has nothing to disclose.