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. 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.
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. 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, 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.
Following a risk analysis study, an International Prognostic Scoring System (IPSS) was published in 1997 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). 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%. 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). 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.
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. 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%. 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). T-cell depletion of the allograft, although decreasing the risk of GVHD, results in higher rates of graft failure and relapse.
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. 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. 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.
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 as well as a European group 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. 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%. 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 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.
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. 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, 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. 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, 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.
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.
1. Greenberg PL: Myelodysplastic syndrome, in Hoffman R, Benz EJ Jr, Shattil SJ, et al (eds): Hematology: Basic Principles and Practice, 3rd ed, pp 1106-1129. Philadelphia, Churchill Livingstone, 2000.
2. Greenberg P, Cox C, Le Beau M, et al: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079-2083, 1997.
3. Bennett JM, Catovsky D, Daniel MT, et al: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51:189-199, 1982.
4. Third MIC Cooperative Study Group: Recommendations for a morphologic, immunologic, and cytogenetic (MIC) working classification of the primary and therapy-related myelodysplastic disorders. Report of the workshop held in Scottsdale, Arizona, USA, on February 23-25, 1987. Cancer Genet Cytogenet 32:1-10, 1988.
5. Jaffe ES, Harris NL, Stein H, et al: World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France, IARC Press, 2001.
6. Germing U, Gattermann N, Strupp C, et al: Validation of the WHO proposals for a new classification of primary myelodysplastic syndromes: A retrospective analysis of 1600 patients. Leuk Res 24:983-992, 2000.
7. Kurzrock R, Albitar M, Cortes JE, et al: Phase II study of R115777, a farnesyl transferase inhibitor, in myelodysplastic syndrome. J Clin Oncol 22:1287-1292, 2004.
8. Silverman LR, Demakos EP, Peterson BL, et al: Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: A study of the Cancer and Leukemia Group B. J Clin Oncol 20:2429-2440, 2002.
9. Deeg HJ, Gotlib J, Beckham C, et al: Soluble TNF receptor fusion protein (etanercept) for the treatment of myelodysplastic syndrome: A pilot study. Leukemia 16:162-164, 2002.
10. Raza A, Meyer P, Dutt D, et al: Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes. Blood 98:958-965, 2001.
11. Greenberg PL, Baer M, Bennett JM, et al: The NCCN myelodysplastic syndromes clinical practice guidelines in oncology, version 1.2005. National Comprehensive Cancer Network. Available at www.nccn.org. Accessed March 7, 2005.
12. Estey E, Thall P, Beran M, et al: Effect of diagnosis (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia [AML]) on outcome of AML-type chemotherapy. Blood 90:2969-2977, 1997.
13. Appelbaum FR, Anderson J: Allogeneic bone marrow transplantation for myelodysplastic syndrome: Outcomes analysis according to IPSS score. Leukemia 12:S25-29, 1998.
14. Runde V, de Witte T, Arnold R, et al: Bone marrow transplantation from HLA-identical siblings as first-line treatment in patients with myelodysplastic syndromes: Early transplantation is associated with improved outcome. Chronic leukemia working party of the European group for blood and marrow transplantation. Bone Marrow Transplant 21:255- 261, 1998.
15. de Witte T, Suciu S, Verhoef G, et al: Intensive chemotherapy followed by allogeneic or autologous stem cell transplantation for patients with myelodysplastic syndromes (MDSs) and acute myeloid leukemia following MDS. Blood 98:2326-2331, 2001.
16. Guardiola P, Runde V, Bacigalupo A, et al: Retrospective comparison of bone marrow and granulocyte colony-stimulating factor- mobilized peripheral blood progenitor cells for allogeneic stem cell transplantation using HLA identical sibling donors in myelodysplastic syndromes. Blood 99:4370-4378, 2002.
17. Sierra J, Perez WS, Rozman C, et al: Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia. Blood 100:1997-2004, 2002.
18. de Witte T, Hermans J, Vossen J, et al: Haematopoietic stem cell transplantation for patients with myelodysplastic syndromes and secondary acute myeloid leukaemias: A report on behalf of the chronic leukemia working party of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol 110:620-630, 2000.
19. Anderson JE, Appelbaum FR, Schoch G, et al: Relapse after allogeneic bone marrow transplantation for refractory anemia is increased by shielding lungs and liver during total body irradiation. Biol Blood Marrow Transplant 7:163-170, 2001.
20. Deeg HJ, Storer B, Slattery JT, et al: Conditioning with targeted busulfan and cyclophosphamide for hemopoietic stem cell transplantation from related and unrelated donors in patients with myelodysplastic syndrome. Blood 100:1201-1207, 2002.
21. Deeg HJ, Shulman HM, Anderson JE, et al: Allogeneic and syngeneic marrow transplantation for myelodysplastic syndrome in patients 55 to 66 years of age. Blood 95:1188-1194, 2000.
22. Yakoub-Agha I, de La Salmoniere P, Ribaud P, et al: Allogeneic bone marrow transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia: A longterm study of 70 patients-report of the French Society of Bone Marrow Transplantation. J Clin Oncol 18:963-971, 2000.
23. Demuynck H, Verhoef GE, Zachee P, et al: Treatment of patients with myelodysplastic syndromes with allogeneic bone marrow transplantation from genotypically HLA-identical sibling and alternative donors. Bone Marrow Transplant 17:745-751, 1996.
24. Sutton L, Leblond V, Ribaud P, et al: Indications and timing of allogeneic bone marrow transplantation in myelodysplastic syndromes. Leuk Lymphoma 27:475-485, 1997.
25. Anderson JE, Gooley TA, Schoch G, et al: Stem cell transplantation for secondary acute myeloid leukemia: Evaluation of transplantation as initial therapy or following induction chemotherapy. Blood 89:2578-2585, 1997.
26. Cutler CS, Lee SJ, Greenberg P, et al: A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: Delayed transplantation for low risk myelodysplasia is associated with improved outcome. Blood 104:1224-1226, 2004.
27. Castro-Malaspina H, Harris RE, Gajewski J, et al: Unrelated donor marrow transplantation for myelodysplastic syndromes: Outcome analysis in 510 transplants facilitated by the National Marrow Donor Program. Blood 99:1943-1951, 2002.
28. Ooi J, Iseki T, Nagayama H, et al: Unrelated cord blood transplantation for adult patients with myelodysplastic syndrome-related secondary acute myeloid leukaemia. Br J Haematol 114:834-836, 2001.
29. Carella AM, Dejana A, Lerma E, et al: In vivo mobilization of karyotypically normal peripheral blood progenitor cells in high-risk MDS, secondary or therapy-related acute myelogenous leukaemia. Br J Haematol 95:127- 130, 1996.
30. Demuynck H, Delforge M, Verhoef GE, et al: Feasibility of peripheral blood progenitor cell harvest and transplantation in patients with poor-risk myelodysplastic syndromes. Br J Haematol 92:351-359, 1996.
31. Ashihara E, Shimazaki C, Okamoto A, et al: Successful peripheral blood stem cell transplantation for myelodysplastic syndrome. Bone Marrow Transplant 24:1343-1345, 1999.
32. de Witte T, van Biezen A, Hermans J, et al: Autologous bone marrow transplantation for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia following MDS. Blood 90:3853-3857, 1997.
33. Wattel E, Solary E, Leleu X, et al: A prospective study of autologous bone marrow or peripheral blood stem cell transplantation after intensive chemotherapy in myelodysplastic syndromes. Leukemia 13:524-529, 1999.
34. Oosterveld M, Muus P, Suciu S, et al: Chemotherapy only compared to chemotherapy followed by transplantation in high risk myelodysplastic syndrome and secondary acute myeloid leukemia; two parallel studies adjusted for various prognostic factors. Leukemia 16:1615-1621, 2002.
35. Martino R, Caballero MD, Perez Simon JA, 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 100:2243- 2245, 2002.
36. Martin PJ, Hansen JA, Buckner CD, et al: Effects of in vitro depletion of T cells in HLA-identical allogeneic marrow grafts. Blood 66:664-672, 1985.
37. Maraninchi D, Gluckman E, Blaise D, et al: Impact of T-cell depletion on outcome of allogeneic bone-marrow transplantation for standard-risk leukaemias. Lancet 2:175-178, 1987.
38. Gale RP, Horowitz MM, Ash RC, et al: Identical-twin bone marrow transplants for leukemia. Ann Intern Med 120:646-652, 1994.
39. Porter DL, Roth MS, McGarigle C, et al: Induction of graft-versus-host disease as immunotherapy for relapsed chronic myeloid leukemia. N Engl J Med 330:100-106, 1994.
40. Chakraverty R, Peggs K, Chopra R, et al: Limiting transplantation-related mortality following unrelated donor stem cell transplantation by using a nonmyeloablative conditioning regimen. Blood 99:1071-1078, 2002.
41. Giralt S, Estey E, Albitar M, et al: Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: Harnessing graft-versus-leukemia without myeloablative therapy. Blood 89:4531- 4536, 1997.
42. Slavin S, Nagler A, Naparstek E, et al: Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 91:756-763, 1998.
43. Storb R, Yu C, Wagner JL, et al: Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation. Blood 89:3048-3054, 1997.
44. Junghanss C, Boeckh M, Carter RA, et al: Incidence and outcome of cytomegalovirus infections following nonmyeloablative compared with myeloablative allogeneic stem cell transplantation, a matched control study. Blood 99:1978-1985, 2002.
45. Childs R, Clave E, Contentin N, et al: Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: Full donor T-cell chimerism precedes alloimmune responses. Blood 94:3234-3241, 1999.
46. Antin JH, Childs R, Filipovich AH, et al: Establishment of complete and mixed donor chimerism after allogeneic lymphohematopoietic transplantation: Recommendations from a workshop at the 2001 Tandem Meetings of the International Bone Marrow Transplant Registry and the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant 7:473-485, 2001.
47. Castagna L, El Weshi A, Bourhis JH, et al: Successful donor lymphocyte infusion (DLI) in a patient with myelodysplastic syndrome (MDS) after failure of T-cell-depleted bone marrow transplantation (TD-BMT). Br J Haematol 103:284-285, 1998.
48. Kroger N, Schetelig J, Zabelina T, et al: A fludarabine-based dose-reduced conditioning regimen followed by allogeneic stem cell transplantation from related or unrelated donors in patients with myelodysplastic syndrome. Bone Marrow Transplant 28:643-647, 2001.
49. Parker JE, Shafi T, Pagliuca A, et al: Allogeneic stem cell transplantation in the myelodysplastic syndromes: Interim results of outcome following reduced-intensity conditioning compared with standard preparative regimens. Br J Haematol 119:144-154, 2002.
50. Bressoud A, Chapuis B, Roux E, et al: Donor lymphocyte infusion for a patient with relapsing myelodysplastic syndrome after allogeneic bone marrow transplantation. Blood 88:1902-1903, 1996.
51. Okumura H, Takamatsu H, Yoshida T: Donor leucocyte transfusions for relapse in myelodysplastic syndrome after allogeneic bone marrow transplantation. Br J Haematol 93:386- 388, 1996.
52. Nagler A, Ackerstein A, Or R, et al: Adoptive immunotherapy with haploidentical allogeneic peripheral blood lymphocytes following autologous bone marrow transplantation. Exp Hematol 28:1225-1231, 2000.
53. Matthews DC: Immunotherapy in acute myelogenous leukemia and myelodysplastic syndrome. Leukemia 12 (suppl 1):S33-S36, 1998.
54. Roberts TF, Foss F, Schenkein D, et al: A novel preparatory regimen associated with reduced morbidity and mortality following allogeneic bone marrow transplantation. Blood 96:781a, 2000.
55. Chan GW, Foss FM, Klein AK, et al: Reduced-intensity transplantation for patients with myelodysplastic syndrome achieves durable remission with less graft-versus-host disease. Biol Blood Marrow Transplant 9:753-759, 2003.
56. Rezvani K, Lalancette M, Szydlo R, et al: Nonmyeloablative stem cell transplant (NMSCT) in AML, ALL and MDS: Disappointing outcome for patients with advanced phase disease. Blood 96(11):479a, 2000.