H e m a t o lo g y E d u c a t io n - European Hematology Association

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P. Krishnamurthy 1 G.J. Mufti 1,2 1 Department of Haematological Medicine, King’s College London, Rayne Institute, London; 2 Department of Haematological Medicine, King’s College Hospital, London, United Kingdom Hematology Education: the education program for the annual congress of the European Hematology Association 2011;5:235-243 Myelodysplasic syndromes Issues in allogeneic hematopoietic stem cell transplantation in myelodysplastic syndromes Patient selection for hematopoietic stem cell transplantation Recipient age MDS is predominantly a disease of the older person, with the median age at diagnosis around 70 years of age. 3 The majority of data relating to outcomes of HSCT in MDS patients is derived from retrospective studies, with a paucity of randomized controlled clinical trials performed in this area. Those patients considered suitable for HSCT, who eventually undergo the procedure and are reported in any clinical trials of HSCT, may not be representative of the cohort of MDS patients as a whole, since in many cases, patients older than 60 years are excluded from such trials. The decision to proceed to HSCT for MDS patients is influenced by a number of factors, including disease stage (discussed below), donor availability, patient, and physician choice, but the over-riding factors within the patient are recipient age and the increasing frequency of comorbidities in older patients. Since the feasibility of HSCT for younger patients is established, the major interest in HSCT for MDS focuses on the older age groups. However, even here the boundaries between “younger” and “older” are blurred, with “older” often defined as 40 years onwards. The development of reduced intensity conditioning (RIC) regimens (Figure 1) for HSCT in MDS has enabled this procedure to be offered to older patients; 4-6 however, this is clearly a heterogeneous cohort and the decision to proceed to HSCT must be considered on a case-by-case basis, with the risks and benefits clearly outlined to the patient. A B S T R A C T Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment option for myelodysplastic syndrome (MDS). Whilst there has been considerable interest regarding the use of new therapeutic agents for the treatment of MDS, the ability to achieve long-term disease eradication with demethylating or immunomodulatory drugs remains elusive. 1,2 However, HSCT may not be the most appropriate treatment for all patients with MDS, and the decision to proceed with transplantation should not be taken without due consideration of the probability of long-term benefit to the patient versus the inherent complications associated with the procedure. No prospective randomized controlled trials have directly compared non-transplant therapies with HSCT for MDS. Although the curative potential of allogeneic HSCT is recognized, certain controversies exist surrounding patient selection for such therapy, the optimal timing and the type of HSCT, and the use of chemotherapeutic agents to reduce the disease burden pre-transplant. This review will focus on the most recent data relating to these issues. Previous (mainly registry) studies of HSCT in older patients with MDS have shown that advanced age is significantly correlated with a higher risk of non-relapse mortality (NRM). 7-9 The majority of such data comes from standard myeloablative conditioning (SMC) HSCT, with the “oldest” patients being up to around 60 years of age. The increasing use of RIC regimens and unrelated donors has extended the use of HSCT to older patients and as such, the effect of age on outcomes for HSCT in MDS has needed to be re-appraised. Two recent reports have specifically addressed the influence of age on outcomes for HSCT in MDS (Table 1). A retrospective multicentre analysis by the European Group for Blood and Marrow Transplantation reported on the outcomes of 1,333 patients over 50 years of age transplanted for MDS between 1998 and 2006. 10 Patients were grouped into those aged 50–60 years and those over 60 years. The median age overall was 56 (and 63 in the over 60 age group). Sixty-seven percent of patients underwent a matched sibling allograft (33% unrelated donor source). Thirty-eight of patients underwent SMC, whereas 62% underwent RIC; of note, 60% of patients receiving SMC had more advanced disease at diagnosis and transplantation, compared with 49% of those receiving RIC HSCT. Four-year overall survival (OS) was 34% in those aged 50–60 years and 27% in those over 60 (p=0.23, HR=0.87). Estimated 4-year NRM was 36% in those aged 50–60 years versus 39% in the over 60s (p=0.39, HR 1.11). Patients receiving RIC HSCT (despite having less advanced stage disease at transplantation) and those Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 235 |
16 th Congress of the European Hematology Association Table 1. Major findings of three recent retrospective studies of RIC and SMC HSCT for MDS; see also. 58 patients over 60 years of age had higher rates of relapse at 4 years: relapse rate 41% versus 33% for RIC versus SMC (HR 1.39 and p65y) Transfusion dependent 34% > 60y 40–78 (MDS, 10% >65y) 21–72 (49) 18–65 (48) Disease stage (FAB), N,% RA/RARS 313 (24%) Not reported RAEB 471 (35%) RAEB-t 215 (16%) sAML 334 (25%) Disease stage (WHO), N,% RA/RARS/MDS with del 5q31 – 23 (7%) RCMD/RS – 61 (17%) RAEB-1 – 53 (15%) RAEB-2 – 107 (30%) MDS-AML – 113 (31%) Conditioning, N, % SMC 500 (38%) No SMC: all RIC/NMA 217 (61%) RIC 833 (62%) 141 (39%) Comments 4y OS 31% a No effect of age on NRM, DFS, OS Transfusion dependency independently or relapse at multivariate analysis b associated with inferior NRM and OS c a No difference in OS for those aged 50–60y versus those aged >60y; use of RIC and advanced stage disease at transplant associated with inferior RFS. b Adverse cytogenetics associated with inferior DFS and OS (AML) and inferior DFS (MDS). c High pre-HSCT ferritin predictive of worse OS and NRM; adverse impact of transfusion dependency restricted to SMC HSCT. RA=Refractory anemia, RARS=RA with ring sideroblasts, RCMD=Refractory cytopenia with multilineage dysplasia, RAEB=Refractory anemia with excess of blasts, RAEBt=RAEB in transformation, sAML=secondary AML. N=Number of patients.
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H e m a t o l o g y E d u c a t i o
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Copyright Information ©2011 by Eur
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Editorial Board Education Book Edit
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Acute lymphoblastic leukemia 1-8 Th
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S. Schnell P. Van Vlierberghe A. Fe
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lineage cells, and in differentiati
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FLT3 mutations The FMS-like tyrosin
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44. Bar-Eli M, Ahuja H, Foti A, Cli
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J.M. Rowe 1,2 C. Ganzel 1 1 Shaare
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treated on the MRC UKALL XII/ECOG29
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asparaginase (PEG), where the Esche
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or higher. It is, however, importan
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25. Bruggemann M, Schrauder A, Raff
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lymphoblastic leukemia: prospective
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such as high white blood cell count
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doxorubicine, there was a trend tow
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of the aging process with respect t
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K.L. Rice 1 M. Buzzai 2 J. Altman 1
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ing FLT3-ITD, wild-type NPM1, or bo
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ciated with gene activation, via th
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leukemia with inv(16) and t(8;21):
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99. Parsons DW, Jones S, Zhang X, e
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abnormalities, some of which are al
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file. 27,31 Thus, the double gene-m
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karyotype represents a distinct gen
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Table 1. Meta-analysis of 23 random
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A recent study by the Center for In
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Patients with HLA-matched related o
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After allogeneic HSCT, an autologou
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A. Bacigalupo Ospedale San Martino,
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Table 2. The effect of HLA mismatch
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References 1. Petersdorf EW, Malkki
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neutrophil and platelet recovery an
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Figure 2. One Year-Overall Survival
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infused on day 21. No serious adver
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W, et al. Effect of graft source on
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TRM was higher for patients who rec
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following a myeloablative preparati
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effect. Surprisingly, none of the p
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nancies. Bone Marrow Transplant. 20
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J.G. Gilles Center for Molecular an
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14C12 was humanized by grafting VH
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Table 1. VWD Classification. VWD Su
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Figure 1. Missense mutations found
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associated with an increased bleedi
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49. Brown SA, Eldridge A, Collins P
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leed. These issues are especially i
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estored function. 43,44 A phase I t
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years’ experience of prophylactic
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J.A. Burger Department of Leukemia,
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chemotaxis, migration across vascul
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Regulatory T cells (T reg), identif
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16. Burger JA, Ghia P, Rosenwald A,
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TE, Nowakowski GS, et al. CD49d exp
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andomized trial demonstrating impro
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Conclusions Chemoimmunotherapy has
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with multiple comorbidities (≥ 2)
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ment was finished in all 100 patien
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Table 2. Treatment recommendation f
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34. Ferrajoli A. The combination of
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to be the source of additional gene
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potential to prevent LSCs from acce
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ABL1 confirms that eradication of d
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65. Fiskus W, Pranpat M, Balasis M,
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alive after 10 years. 11 Hence, CCy
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each arm). A minimal change in myel
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Any discussion about the definition
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H. Kantarjian J. Cortes Leukemia De
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59%; the CCyR rate was 44%. Among p
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ern era of BCR-ABL1 tyrosine kinase
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the hematopoietic system, 10 nor in
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over the period of 6 weeks, demonst
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Data on clonal changes in the blood
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2006 Feb 1;107(3):924-30. 41. Liang
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demonstrated that changes in osteob
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“Mafia” transgenic mice in whic
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68. Coetzee T, Fujita N, Dupree J,
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ization. In WASP deficiency, lympho
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Currently the epistatic relationshi
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R. Küppers Institute of Cell Biolo
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Figure 1. TNFAIP3 mutation in HL ce
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Figure 2. HRS cells and their precu
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Hansmann ML, et al. Detection of cl
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fying patients for whom different a
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prognosis HL, whilst those with res
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12. Noordijk EM, Carde P, Dupouy N,
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A. Sureda Consultant in Haematology
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Figure 1. Long-term outcome of pati
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from a MRD and 18 from MUDs. All pa
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Parker PM, Stein AS, et al. High-do
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R. Stasi Department of Haematology,
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common variants in the regulatory r
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against the TPO receptor (cMpl). 61
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W.B. Mitchell A.A. Miller J.B. Buss
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platelet counts and/or bleeding. Th
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Mpl. Cell. 1994;77(7):1117-24. 6. d
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Page 202 and 203: cation of molecularly distinct subg
Page 204 and 205: of cases) 46 and amplifications of
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Page 208 and 209: W. Wilson National Cancer Institute
Page 210 and 211: clear distinction among the lymphom
Page 212 and 213: Treatment strategies in germinal ce
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Page 220 and 221: Table 1. Diffuse Large B cell Lymph
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Page 226 and 227: A. Karsan Genome Sciences Centre an
Page 228 and 229: Balanced translocations In contrast
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Page 234 and 235: 38. Starczynowski DT, Morin R, McPh
Page 236 and 237: G. Garcia-Manero Department of Leuk
Page 238 and 239: trial evaluating different doses an
Page 240 and 241: acid. 62 The second was a large mul
Page 242 and 243: Borthakur G, et al. Cause of death
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Page 250 and 251: attainment of FDC post DLI. Interes
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Page 262 and 263: 72. Irandoust MI, Aarts LH, Roovers
Page 264 and 265: A.M. Vannucchi Section of Hematolog
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Page 268 and 269: tant use of aspirin should be caref
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Page 274 and 275: Table 1. Prognostic scoring systems
Page 276 and 277: Figure 1. Current inhibitors of JAK
Page 278 and 279: Table 4. A risk-based approach to d
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Page 282 and 283: A. Vacca 1 D. Ribatti 2 1 Departmen
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sone induction improves outcome of
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Table 1. Conventional chemotherapy
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Novel agents given as consolidation
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dence of peripheral neuropathy, gas
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31. Barlogie B, Tricot G, Anaissie
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Table 1. Major differences between
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first line therapy have shown survi
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transplantation, 7,91 and generally
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methylation characterizes juvenile
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Table 1. Clinical signs of possible
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Table 4. Distribution of CSF involv
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ently results in a less than 5% cum
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90. German-Austrian-Swiss ALL-BFM S
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U. Nowak-Göttl 1 R. Junker 1 A. Kr
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Based on the data obtained from the
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59. Male C, Chait P, Ginsberg JS, e
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Table 1. Characteristic features of
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Table 2. Mutational spectrum of CDA
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megarakaryoblastic leukemia (AMKL)
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R.E. Ware Professor and Vice-Chairm
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protein, cytokines, and soluble adh
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example, improving blood viscosity
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92(9):1266-7. 36. Bensinger TA, Gil
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London, United Kingdom, June 9-12,
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port have also been used. 5 Combina
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Wingard JR, Young J-AH, Boeckh MJ.
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K. Rezvani 1 J. Barrett 2 1 Haemato
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include the childhood infectious il
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Summary Patients undergoing hematop
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Table 1. Key issues. In a retrospec
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invasive method to assess iron over
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stitution but even with optimal sub
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T.M. Hackeng Department of Biochemi
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and inhibits FVIIa, and that the se
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Figure 4. Regulation of coagulation
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T. Baglin Department of Haematology
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Figure 1. Illustration of alternati
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compared with 3.5% in patients with
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49. Hron G, Kollars M, Binder BR, E
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Women receiving vitamin K antagonis
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molecular weight heparin as prophyl
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eral morbidity and mortality. 17-21
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the HOD construct. Furthermore, the
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Goals of future murine studies incl
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F. Noizat-Pirenne C. Tournamille Et
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phenotype. 26 In 2010, we investiga
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ody has been involved in DHTR. 37 T
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antigen. Cases can be encountered d
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S.R. Sloan Harvard Medical School &
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We also analyzed patient databases
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Index of authors Altman J. 27 Bacig
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Cornelissen J. Affiliations to disc
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GlaxoSmithKline (Research Support;
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