REVIEW URRENT C OPINION
Allogeneic haematopoietic stem cell transplantation in myelodysplastic syndromes Emily Bart-Smith and Ghulam J. Mufti
Purpose of review Allogeneic haematopoietic stem cell transplantation remains the only curative treatment for myelodysplastic syndrome. We highlight the various issues to consider in the pretransplant, transplant and posttransplant periods with emphasis on the management of relapse following transplant. Recent findings Cytogenetic and molecular characteristics are becoming more important in predicting transplant outcome. Hypomethylating agents are effective in the pretransplant setting to reduce disease burden. Haploidentical and umbilical cord blood donations may be valid transplant options for patients without human leukocyte antigen-identical sibling or match unrelated donor options. A preemptive management approach to patients at high risk of relapse is more effective. Adjusting the timing and dose of donor lymphocyte infusion reduces the risk of graft-versus-host disease without jeopardizing the graft-versus-leukaemia effect of donor lymphocyte infusion. Summary Allogeneic haematopoietic stem cell transplantation is curative in up to 40% of myelodysplastic syndrome patients. Appropriate patient selection, modification of conditioning regimes and donor selection should be considered carefully. A preemptive approach for the management of patients at high risk of relapse should be employed following transplant, with the use of immune modulating therapies such as donor lymphocyte infusion and azacitidine. Keywords allogeneic haematopoietic stem cell, donor lymphocyte infusion, graft-versus-host disease, graft versus leukaemia, human leukocyte antigen
INTRODUCTION Myelodysplastic syndromes (MDS) comprise a group of heteregeneous diseases, characterized by a clonal abnormality of haematopoietic stem cells resulting in peripheral blood cytopenias, increase in bone marrow blast percentage and risk of transformation into acute myeloid leukaemia (AML). MDS is predominantly a disease of the elderly with more than 80% of patients aged over 60 years. The only curative treatment for MDS is allogeneic haematopoietic stem cell transplantation (AHSCT) historically limited to young patients [1–3]. The number of transplants performed for MDS/AML continues to increase, as recently described by the European Group for Blood and Marrow Transplantation, rising from 2 to 14% from 2001 to 2010, respectively. The introduction of reduced intensity conditioning (RIC) and nonmyeloablative (NMA) regimens, as well as improved supportive care has undoubtedly driven this increase. Despite these advances, a number of questions remain unanswered in the www.co-oncology.com
pre-HSCT, HSCT and post-HSCT setting. Patients who relapse following transplant are particularly difficult to manage, and a number of novel approaches are suggested. Please see Fig. 1.
PRETRANSPLANT CONSIDERATIONS Before considering transplant as a treatment option for MDS, there are a number of disease, patient and chemotherapy-related factors which must be considered.
Department of Haematology, King’s College Hospital, Denmark Hill, London, UK Correspondence to Dr Emily Bart-Smith, MD, Department of Haematology, King’s College Hospital, Denmark Hill, London, SW6 9RS, UK. Tel: +44 020 3299 9000 x33080; fax: +44 020 3299 4980; e-mail: [email protected] Curr Opin Oncol 2014, 26:642–649 DOI:10.1097/CCO.0000000000000137 Volume 26 Number 6 November 2014
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Allogeneic HSCT in myelodysplastic syndromes Bart-Smith and Mufti
For patients with MDS, survival can vary from a few months to several years. Anticipating where a patient lies between these two extremes is important when considering treatment options, which range from supportive therapy to the intensive and potentially curative approach of AHSCT. A number of prognostic scores are used to accurately classify disease risk with the most recent being the Revised International Prognostic Scoring System
(IPSS-R) [4,5]. Current guidelines advise an upfront discussion regarding AHSCT with both high-risk and low-risk disease patients, however early transplantation in high-risk disease is emphasized. This stems from Cutler et al.’s [6] retrospective analysis of MDS patients who received human leukocyte antigen (HLA)-identical sibling transplants after myeloablative conditioning. Analysis according to the previously used IPSS demonstrated that early HSCT in intermediate-2 and high-risk disease achieved a survival advantage; conversely, delaying transplant until disease progression in patients with lower risk disease provided maximal survival [6]. This study did not represent the majority of patients being transplanted for MDS, as it did not reflect elderly patients, those receiving NMA or RIC protocols and those receiving an unrelated donor transplant. Attempts to overcome these shortcomings were made via using the Markov model of 92 patients with de-novo MDS undergoing RIC HSCT, with the similar conclusion that immediate transplantation did not improve outcome in elderly patients with intermediate-1/low-risk disease [7]. Conversely, de Witte et al. [8] reviewed 374 patients and demonstrated an improved outcome for low-risk patients when the time from diagnosis to transplantation was shorter. Care must be taken in selecting appropriate patients for early transplant, but equally important is the issue of excluding ‘low-risk’ patients with compatible sibling or unrelated donor options from an early transplant. We favour current guidelines which recommend considering early transplant in
Pre-HSCT
Post HSCT
KEY POINTS Cytogenetics (monosomal karyotype) and molecular characteristics (TP53, ETV6, RUNX1, ASXL1, EZH2 and SF3B1) play an increasingly important role in risk-stratifying patients prior to transplantation. Haploidentical and umbilical cord blood donors may be valid options for those patients without HLA-identical sibling or matched unrelated donors; however, more research regarding the safety and efficacy of these alternative donor options is required. The outcome for patients who relapse following AHSCT is dismal and a preemptive management approach is suggested, particularly in patients with high-risk disease. Adjusting the timing and dose of DLI in relation to the patient’s disease, form of T-cell depletion, degree of donor–recipient HLA mismatch and degree of donor chimerism at the time of DLI may limit the amount of GVHD without jeopardizing the GVL effect required to prevent disease relapse.
Disease risk and timing of transplant
HSCT
•
Disease risk of HSCT
•
•
Cytogenetics molecular markers
•
•
Age
•
HCT-CI Modifiable comorbidities − ferritin
•
Donor (type/ age /matching) Stem cell source (PB/BM)
• •
GVHD Weaning IST
• •
Monitoring disease Relapse management DLI (proph vs therapy)
•
Conditioning
•
T cell purging
Chemotherapy
•
CMV status
Second transplant
(MA/NMA/RIC)
•
Remission status
Adoptive immuneTx
•
Bridging therapy
Tumour vaccination
There are a multitude of factors that physicians must be satisfied of before considering transplant as a valid treatment. These can be divided into questions related to the patient and the disease in the pre-transplant setting; conditioning and donor selection in the transplant setting; and management of complications, disease monitoring and relapse in the posttransplant setting
FIGURE 1. Important factors when considering transplant as a treatment option for myelodysplastic syndromes. BM, bone marrow; CMV, cytomegalovirus; DLI, donor lymphocyte infusion; HCT-CI, haematopoietic cell transplant-comorbidity index; HSCT, haematopoietic stem cell transplantation; IST, immune suppression therapy; MA, myeloablative; NMA, nonmyeloablative; PB, peripheral blood; RIC, reduced intensity conditioning. 1040-8746 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
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Hematologic malignancies Table 1. Prognostic group according to cytogenetics in myelodysplastic syndromes Prognostic group
Proportion of patients
Cytogenetics
Median OS, years
AML evolution, 25%, yearsa
Very good
Del(11q),-Y
4%
5.4
NR
Good
Normal, del(5q), del(12p), del(20q), double including del(5q)
72%
4.8
9.4
Intermediate
Del(7q), þ8, þ19, i(17q), any other single or double independent clones
13%
2.7
2.5
Poor
-7, inv(3)/t(3q)/del(3q), double incl -7/del(7q), complex: 3 abn
4%
1.5
1.7
Very poor
Complex: >3 abn
7%
0.7
0.7
AML, acute myeloid leukaemia; OS, overall survival. a median time for 25% of patients to develop AML.
IPSS-R-labelled ‘low-risk’ patients, especially when in patients presenting with other poor risk factors, such as blood or platelets transfusion dependence, or severe cytopenias refractory to growth factor therapy [9].
Cytogenetics and molecular markers Cytogenetics plays a major role in the current IPSS-R and is highly predictive of outcome after AHSCT. Specifically, it includes the new and comprehensive cytogenetic scoring system defined by Schanz et al. based on analysis of 2801 untreated de-novo MDS patients, which defines 19 categories into five prognostic subgroups [10–12,13 ]. Specifically, the presence of a monosomal karyotype is associated with an extremely poor outcome in MDS patients and is also associated with higher rates of relapse and nonrelapse mortality in AHSCT [12] (see Table 1). Our understanding of the molecular pathogenesis of MDS has improved considerably in recent years with the emergence of genomic technologies, such as next-generation sequencing and highdensity single nucleotide polymorphism karyotyping. Identification of mutations, such as TP53, ETV6, RUNX1, ASXL1, EZH2 and SF3B1, has been shown to influence survival in the nontransplant setting, and it is anticipated that they may influence the patient selection for AHSCT in the future [14,15]. A recent study at our institute of 389 patients assessed the impact of TP53 mutation in MDS and demonstrated that patients with mutant TP53 had worse overall survival (OS) (9 versus 66 months) and that a reduction of the mutant clone correlated with response to azacitidine [16 ]. Such studies contribute to our improved understanding of the molecular basis of MDS and will have a significant practical impact on risk-stratifying patients in the pretransplant setting. &
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Age and comorbidities Age has traditionally been a limiting factor when considering AHSCT. This is especially relevant to MDS patients aged above 55 years and, therefore, deemed ‘old’ in the context of transplantation. However, the decision to exclude older patients from AHSCT has evolved from studies using predominantly myeloablative conditioning [2]. Two recent trials have been important in altering the emphasis of age as a major prognostic indicator [17,18]. The Center for International Blood and Marrow Transplantation reviewed 1080 patients above 40 years old with MDS or AML in complete remission following RIC or NMA HSCT and did not demonstrate a difference in overall outcomes [17]. Similarly, analysis of 1333 MDS patients aged at least 50 years receiving an AHSCT by the European Group for Blood and Marrow Transplantation demonstrated no statistical difference between the 50–60 group and the more than 60 group for nonrelapse mortality (NRM) at 4 years or OS. This finding is perhaps made more significant by the fact that a large number of patients received myeloablative conditioning despite their advanced age [18]. Interpretation of these findings must be countered by acknowledgement of the heterogeneity and inherent selection bias which confounds retrospective analysis. We propose that recipients’ age alone should not be considered a contraindication for AHSCT. Patients’ comorbid health is perhaps more predictive of risk-assessing NRM following HSCT [17]. Several retrospective studies have demonstrated that a higher haematopoietic cell transplant-comorbidity index (HCT-CI) score equates to higher NRM and lower OS [19–22]. One such study by Sorror et al. [22] stratified patients according to HCT-CI and disease stage, demonstrating that patients with higher HCT-CI score and also high-risk disease Volume 26 Number 6 November 2014
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Allogeneic HSCT in myelodysplastic syndromes Bart-Smith and Mufti
had worse survival rates (29% OS at 2 years, compared to 70% in patients with low HCT-CI score and low-risk disease). There was no difference between NMA and myeloablative conditioning for patients in this poor-risk group because the lower NRM in the RIC-treated patients was offset by a higher risk of relapse. These findings have also been confirmed in a recent prospective study using HCT-CI to stratify patients undergoing transplant for haematological malignancies including MDS, although further studies are required to clarify the issue fully [23].
‘Modifiable’ comorbidities Several patient factors have been identified as contributing to comorbidity, but which can be corrected prior to transplant. These include anaemia, recurrent infection as well as iron overload. The latter has been shown to influence survival after transplantation, with higher rates of bacterial and fungal infections, sinusoidal obstruction syndrome and other regimen-related toxicities [24]. Serum ferritin is traditionally used to assess iron status, with studies demonstrating higher NRM and worse OS in patients with a ferritin level of at least 1500 mcg/l prior to myeloablative as well as RIC AHSCT [25]. Whether this observation is solely related to iron overload is unlikely, as hyperferritinaemia can be indicative of an acute phase reaction as well as cellular apoptosis. Pretransplant iron chelation may improve ferritin levels, but evidence does not exist that confirms an improvement in transplantation outcomes. A recent retrospective study has suggested that MRI techniques are more effective in assessing systemic iron status and that liver iron content is an independent negative prognostic indicator for posttransplant outcome [26]. Prospective studies should include assessment of iron overload through MRI techniques and measurement of labile plasma iron to assess whether correction of this ‘modifiable’ comorbidity leads to improved transplant outcomes.
Remission: achieving it and keeping it Several recent studies have indicated that high pretransplant disease burden equates to poor posttransplant outcome [27–29]. Warlick et al. published a study of 84 patients which demonstrated the following point exactly: a 1-year relapse rate of 35% in patients with a blast count of above 5% going into transplant, compared with 18% in patients in complete remission at time of transplant [27–29]. This practice is far from being established however, with several studies being unable to demonstrate the
benefit of bulk reduction before transplantation [30,31 ]. Newer therapeutic options, such as the hypomethylating agents, have potential value in the transplant management of MDS. Several studies have demonstrated these as feasible and effective treatment options, with potentially important roles in remission induction pre-AHSCT for patients previously considered not fit enough for such intensive management options [32–34]. The time to response is prolonged compared to conventional chemotherapy however, and it is a potential disadvantage. Whether there is an added advantage in using hypomethylating agents over conventional chemotherapy to achieve remission remains under debate; some investigators have postulated that there is an enhanced graft-versus-leukaemia (GVL) effect seen with these agents through the alteration of antigen recognition. A recent study at King’s College Hospital demonstrated that azacitidine has profound effects on CD4þ helper cells and induces FOXP3 and interleukin 17 secretion, which correlates with disease status and response to therapy. These findings provide further insights into the immune-modulatory effects of hypomethylating agents [35]. &
ALLOGENEIC HAEMATOPOIETIC STEM CELL TRANSPLANT: DONOR AND CONDITIONING OPTIONS The choice between a well matched unrelated donor versus a HLA-identical sibling donor for MDS patients remains under debate, with comparable outcomes being demonstrated for both donor options [36–38]. Management of patients without such choices is more challenging. A number of recent studies have suggested that umbilical cord blood transplantation (UBCT) is comparable to sibling donor transplantation. Specifically, Majhail et al. [39] demonstrated OS at 3 years of 31 and 37% in the UBCT and sibling donor groups respectively, concluding that UBCT was a feasible option for patients without HLA-matched sibling donors. An important limitation to UBCT must be highlighted however, and that is the inability to obtain subsequent donor collections. Donor lymphocyte infusion (DLI) is, therefore, not possible, which can pose significant problems in the posttransplant setting. This is especially relevant in our elderly patients who are more likely to undergo a RIC AHSCT, and therefore have an increased risk of relapse [39,40]. Analysis of data from our institution has revealed that UBCT can be particularly challenging in patients over 55 years old, and therefore caution must be expressed [41].
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Hematologic malignancies
Haploidentical donors have the advantage of immediate availability (of initial stem cells as well as donor lymphocytes for immune therapy in the event of relapse) and lower cost compared with UBCT. Although data regarding these easily accessible donors in MDS is minimal, and confounded by inherent heterogeneity, initial studies suggest that haploidentical transplants are at least comparable to UBCT [42,43]. Higher rates of relapse have been identified as a potential concern following transplant, however more research is required to establish whether this a viable donor option for patients lacking sibling or volunteer unrelated donors [44].
Conditioning regimes The principle that RIC and NMA conditioning regimens achieve the GVL effect of transplantation whilst simultaneously limiting the toxicity associated with standard myeloablative conditioning regimens has undoubtedly broadened the scope for AHSCT in MDS. The benefit of reduced toxicity and resultant survival benefit from a lower transplant-related mortality associated with RIC/NMA conditioning, however, is offset by an increase in the risk of relapse [45]. The Center for International Blood and Marrow Transplantation compared outcomes in patients with AML/MDS who received AHSCT either after RIC or NMA or standard myeloablative conditioning, with no difference being identified in the RIC and myeloablative groups; however, inferior disease-free survival was demonstrated after NMA conditioning [46]. Heterogeneity and selection bias which confounds such studies makes it difficult to interpret these findings. The much anticipated prospective study by the EBMT comparing RIC versus myeloablative conditioning will help find the best way to tailor conditioning regimens to individual patients (#NCT00682396).
T-cell purging Both T-cell-replete (TCR) and T cell-deplete (TCD) protocols have demonstrated success, with lower rates of chronic graft-versus-host disease (GVHD) being seen in the latter. Prevention of chronic GVHD is unquestionably important, but must be weighed against the decreased GVL effect and resultant higher relapse rate following T-cell depletion. One argument in favour of T-cell depletion is that it achieves a base on which to build, in the form of DLI, hypomethylating agents and vaccine and other immunotherapeutic modulations. However, in the absence of a randomized, prospective study aimed at answering this question, management is invariably 646
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guided by local policy. The prevention of the often devastating effects of GVHD is something which holds a similar level of importance as relapse, and this balance is often difficult to achieve.
POSTALLOGENEIC HAEMATOPOIETIC STEM CELL TRANSPLANT ISSUES Salvage treatment options for MDS patients who have relapsed following HSCT are limited. Relapse in MDS may present indolently and physicians rely on evidence of minimal residual disease as a marker of relapse, typically in the form of chimerism analysis and Wilms tumor gene (WT1) expression [47,48]. Traditional management has been to treat patients at time of relapse; however, current evidence indicates that achieving a good outcome following relapse is very small. A more preemptive approach to managing relapse is, therefore, of paramount importance.
Anticipating and preventing relapse The hypomethylating agent azacitidine has a potential role in both prevention and treatment of relapse. A recent dose finding study treated 45 high-risk, heavily pretreated AML/MDS patients with azacitidine maintenance after AHSCT for at least four cycles. The study demonstrated an impressive 1-year OS and event-free survival (EFS) of 77 and 58%, respectively, and suggested that more cycles may be associated with greater benefit [49]. The benefit of preemptive azacitidine has also been demonstrated in a further trial in which 20 patients were given four cycles of azacitidine if their CD34 donor chimerism was less than 80%, but with complete haematological remission. Sixteen patients (80%) responded with improved/stabilized chimerism, and although 13 patients (65%) went on ultimately to relapse, this was delayed until 231 days. The authors concluded that preemptive azacitidine was well tolerated and may have a role in preventing or delaying haematologic relapse [50]. DLIs are similarly used in the relapse setting as they may enhance a GVL effect. The major complication of this treatment modality is GVHD reported to varying degrees in many studies [51–53]. A recent analysis at our institution involved 113 MDS patients following RIC T-cell depletion AHSCT treated with DLI preemptively (pDLI) to improve donor chimerisms and prevent relapse, or therapeutically (tDLI) after disease recurrence. Impressive 5-year OS rates were demonstrated particularly in the pDLI group compared to the tDLI group (80 and 40%, respectively), without excess GVHD or GVHD-related mortality [51]. The risk of GVHD is Volume 26 Number 6 November 2014
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Allogeneic HSCT in myelodysplastic syndromes Bart-Smith and Mufti
No TCD
Ex-vivo TCD
In-vivo TCD
High (>50% risk of GvHD)
Degree of HLA mismatch
T cell dose of DLI (cells/kg)
1 × 108
1 ×107
Medium (25%–50% risk of GvHD) X
1 ×106
Low (12
6
3
0
Timing of DLI following HSCT (months)
FIGURE 2. The ’sweet spot’ for DLI following transplant for myelodysplastic syndromes. DLI, donor lymphocyte infusion; GVHD, graft-versus-host disease; HLA, human leukocyte antigen; TCD, T-cell deplete. Published with permission from [54 ]. &
significant in other studies with reasons likely reflecting different conditioning, timing and dose schedules. Yun and Walker [54 ] have postulated that there is a so-called ‘sweet spot’ for DLI based on the method of TCD (in vivo or ex vivo), the timing of DLI, the degree of HLA mismatch and the T-cell dose of DLI. Adapting timing and dose according to the other predetermined variables may help physicians use DLI to its maximum benefit of enhancing GVL without the consequences of GVHD [54 ]. Please see Fig. 2. The concomitant use of DLI with azacitidine has been postulated to limit GVHD in this setting through expansion of cells with a regulatory phenotype. Initial studies have demonstrated encouraging results; however, more work is required to assess whether this combination can improve the safety and antitumour effect of DLI [55,56 ]. &
further clinical research into this novel treatment approach [58,59]. gd T cells have also been shown to demonstrate antitumour activity in a number of malignancies, including AML [60]. It is postulated that engineered gd-TCR-expressing effector cells will have a role in immunotherapy and may have a role in the management of MDS in elderly patients.
CONCLUSION Transplantation remains the only cure for MDS and is now a valid option for many elderly patients who would previously have been excluded from this treatment modality. Physicians must weigh the balance between limiting the toxicity of transplantation and achieving a cure/preventing relapse. With our increasing knowledge of the molecular basis of MDS, we are now able to accurately assess an individual’s disease risk and make more informed decisions regarding a patient’s eligibility for transplantation. The use of RIC with T cell depleted HSCT as a base on which to preemptively add immunemodulating therapy may provide the balance required for cure without significant detrimental effects on quality of life. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
&
&
Other immune therapeutic approaches Recent advances for management of relapse include the development of vaccines for the purpose of immune modulation. Genetically modified leukaemia cells which express high levels of CD80 and interleukin 2 form the basis of a whole-cell leukaemia vaccination, for the purpose of T-cell activation. The combination of AHSCT with immunization aims to stimulate immune-mediated eradication of residual disease [57]. Peptide vaccination with leukaemia-associated antigens, such as WT1 and PR1, has demonstrated an immunological response and modest clinical response and we anticipate
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29. de Witte T, Hagemeijer A, Suciu S, et al. Value of allogeneic versus autologous stem cell transplantation and chemotherapy in patients with myelodysplastic syndromes and secondary acute myeloid leukemia. Final results of a prospective randomized European Intergroup Trial. Haematologica 2010; 95:1754–1761. 30. Scott BL, Storer B, Loken MR, et al. Pretransplantation induction chemotherapy and posttransplantation relapse in patients with advanced myelodysplastic syndrome. Biol Blood Marrow Transplant 2005; 11:65– 73. 31. Oran B, Kongtim P, Marcos de Lima MD, et al. Prior hypomethylating agents or & chemotherapy does not improve outcome of allogeneic hematopoietic transplantation for high risk MDS. Blood 2013; 21:731. Monosomal karyotype and histology were the only prognostic factors for EFS in MDS AHSCT patients; prior therapy and disease status at AHSCT were not found to be prognostic. The authors suggest that high-risk MDS patients should proceed with AHSCT without delay to achieve a better outcome. 32. Field T, Perkins J, Huang Y, et al. 5-azacitidine for myelodysplasia before allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 2010; 45:255–260. 33. Kim DY, Lee JH, Park YH, et al. Feasibility of hypomethylating agents followed by allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome. Bone Marrow Transplant 2012; 47:374– 379. 34. Gerds AT, Gooley TA, Estey EH, et al. Pretransplantation therapy with azacitidine vs induction chemotherapy and posttransplantation outcome in patients with MDS. Biol Blood Marrow Transplant 2012; 18:1211– 1218. 35. Constantini B, Kordasti SY, Kulasekararj AG, et al. The effects of 5-azacytidine on the function and number of regulatory T-cells and T effectors in myelodysplastic syndrome. Haematologica 2013; 98:1196–1205. 36. 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 2002; 99:1943–1951. 37. Kro¨ger N, Zabelina T, de Wreede L, et al. MDS subcommittee of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Allogeneic stem cell transplantation for older advanced MDS patients: improved survival with young unrelated donor in comparison with HLA-identical siblings. Leukemia 2013; 27:604–609. 38. Alousi AM, Le-Rademacher J, Saliba RM, et al. Who is the better donor for older hematopoietic transplant recipients: an older-aged sibling or a young, matched unrelated volunteer? Blood 2013; 121:2567–2573. 39. Majhail NS, Brunstein CG, Shanley R, et al. Reduced-intensity hematopoietic cell transplantation in older patients with AML/MDS: umbilical cord blood is a feasible option for patients without HLA-matched sibling donors. Bone Marrow Transplant 2012; 47:494–498. 40. Brunstein CG, Fuchs EJ, Carter SL, et al. Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood 2011; 118:282–288. 41. Ceesay MM, Lim ZY, Querol S, et al. Umbilical cord blood transplantation in adults with haematological malignancies - UK single centre pilot study. Bone Marrow Transplant 2010; 45:S161. 42. Chen Y, Liu K, Xu L, et al. HLA-mismatched hematopoietic SCT without in vitro T-cell depletion for myelodysplastic syndrome. Bone Marrow Transplant 2010; 45:1333–1339. 43. Raj K, Pagliuca A, Bradstock K, et al. Peripheral blood hematopoietic stem cells for transplantation of hematological diseases from related, haploidentical donors after reduced-intensity conditioning. Biol Blood Marrow Transplant 2014; 20:890–895. 44. Luznik L, O’Donnell PV, Symons HJ, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2008; 14:641–650. 45. Martino R, Iacobelli S, Brand R, et al. Myelodysplastic Syndrome Subcommittee of the Chronic Leukemia Working Party of the European Blood and Marrow Transplantation Group: retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes. Blood 2006; 108:836– 846. 46. Luger S, Ringden O, Zhang MJ, et al. Similar outcomes using myeloablative vs reduced-intensity allogeneic transplant preparative regimens for AML or MDS. Bone Marrow Transplant 2012; 47:203–221. 47. Wertheim GB, Bagg A. Minimal residual disease testing to predict relapse following transplant for AML and high-grade myelodysplastic syndromes. Expert Rev Mol Diagn 2011; 11:361–366. 48. Mohty M, Avinens O, Faucher C, et al. Predictive factors and impact of full donor T-cell chimerism after reduced-intensity conditioning allogeneic stem cell transplantation. Haematologica 2007; 92:1004–1006. 49. de Lima MD, Giralt S, Thall PF, 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; 116:5420–5431.
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Allogeneic HSCT in myelodysplastic syndromes Bart-Smith and Mufti 50. Platzbecker U, Wermke M, Radke J, et al. Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leukemia 2012; 26:381–389. 51. Krishnamurthy P, Potter VT, Barber LD, et al. Outcome of donor lymphocyte infusion after T cell-depleted allogeneic hematopoietic stem cell transplantation for acute myelogenous leukemia and myelodysplastic syndromes. Biol Blood Marrow Transplant 2013; 19:562–568. 52. Marks DI, Lush R, Cavenagh J, et al. The toxicity and efficacy of donor lymphocyte infusions given after reduced-intensity conditioning allogeneic stem cell transplantation. Blood 2002; 100:3108–3114. 53. Roddie C, Peggs KS. Donor lymphocyte infusion following allogeneic hematopoietic stem cell transplantation. Expert Opin Biol Ther 2011; 11:473–487. 54. Yun HD, Waller EK. Finding the sweet spot for donor lymphocyte infusions. & Biol Blood Marrow Transplant 2013; 19:507–508. Differences in the rate of GVHD following DLI between investigators is postulated. An optimum approach for each individual patient is influenced by intensity of conditioning regimen, in-vivo versus ex-vivo TCD, timing of DLI after AHSCT, T-cell subsets in DLI, degree of donor–recipient HLA mismatch, type and amount of residual cancer, intensity of posttransplantation immunosuppression and level of donor chimerism at the time of DLI. 55. Goodyear OC, Dennis M, Jilani NY, et al. Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML). Blood 2012; 119:3361–3369.
56. Schroeder T, Frobel J, Cadeddu RP, et al. Letter to Editor: salvage therapy with azacitidine increases regulatory T cells in peripheral blood of patients with AML or MDS and early relapse after allogeneic blood stem cell transplantation. Leukemia 2013; 1–4. Data supporting preliminary results that azacitidine increases circulating regulatory T cells especially in patients relapsing early after AHSCT. It is postulated that the lower rates of GVHD seen after DLI if given along with azacitidine are due to this increase in regulatory T cells. 57. Ingram W, Chan L, Guven H, et al. Human CD80/IL2 lentivirus-transduced acute myeloid leukaemia (AML) cells promote natural killer (NK) cell activation and cytolytic activity: implications for a phase I clinical study. Br J Haematol 2009; 145:749–760. 58. Keilholz U, Letsch A, Busse A, et al. A clinical and immunologic phase 2 trial of Wilms tumor gene product 1 (WT1) peptide vaccination in patients with AML and MDS. Blood 2009; 113:6541–6548. 59. Rezvani K, Yong AS, Mielke S, et al. Repeated PR1 and WT1 peptide vaccination in Montanide-adjuvant fails to induce sustained high-avidity, epitope-specific CD8 T cells in myeloid malignancies. Haematologica 2011; 96:432–440. 60. Aswald JM, Wang XH, Aswald S, et al. Flow cytometric assessment of autologous gammadelta T cells in patients with acute myeloid leukemia: potential effector cells for immunotherapy? Cytometry B Clin Cytom 2006; 70:379–390.
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Allogeneic haematopoietic stem cell transplantation in myelodysplastic syndromes Emily Bart-Smith and Ghulam J. Mufti
Purpose of review Allogeneic haematopoietic stem cell transplantation remains the only curative treatment for myelodysplastic syndrome. We highlight the various issues to consider in the pretransplant, transplant and posttransplant periods with emphasis on the management of relapse following transplant. Recent findings Cytogenetic and molecular characteristics are becoming more important in predicting transplant outcome. Hypomethylating agents are effective in the pretransplant setting to reduce disease burden. Haploidentical and umbilical cord blood donations may be valid transplant options for patients without human leukocyte antigen-identical sibling or match unrelated donor options. A preemptive management approach to patients at high risk of relapse is more effective. Adjusting the timing and dose of donor lymphocyte infusion reduces the risk of graft-versus-host disease without jeopardizing the graft-versus-leukaemia effect of donor lymphocyte infusion. Summary Allogeneic haematopoietic stem cell transplantation is curative in up to 40% of myelodysplastic syndrome patients. Appropriate patient selection, modification of conditioning regimes and donor selection should be considered carefully. A preemptive approach for the management of patients at high risk of relapse should be employed following transplant, with the use of immune modulating therapies such as donor lymphocyte infusion and azacitidine. Keywords allogeneic haematopoietic stem cell, donor lymphocyte infusion, graft-versus-host disease, graft versus leukaemia, human leukocyte antigen
INTRODUCTION Myelodysplastic syndromes (MDS) comprise a group of heteregeneous diseases, characterized by a clonal abnormality of haematopoietic stem cells resulting in peripheral blood cytopenias, increase in bone marrow blast percentage and risk of transformation into acute myeloid leukaemia (AML). MDS is predominantly a disease of the elderly with more than 80% of patients aged over 60 years. The only curative treatment for MDS is allogeneic haematopoietic stem cell transplantation (AHSCT) historically limited to young patients [1–3]. The number of transplants performed for MDS/AML continues to increase, as recently described by the European Group for Blood and Marrow Transplantation, rising from 2 to 14% from 2001 to 2010, respectively. The introduction of reduced intensity conditioning (RIC) and nonmyeloablative (NMA) regimens, as well as improved supportive care has undoubtedly driven this increase. Despite these advances, a number of questions remain unanswered in the www.co-oncology.com
pre-HSCT, HSCT and post-HSCT setting. Patients who relapse following transplant are particularly difficult to manage, and a number of novel approaches are suggested. Please see Fig. 1.
PRETRANSPLANT CONSIDERATIONS Before considering transplant as a treatment option for MDS, there are a number of disease, patient and chemotherapy-related factors which must be considered.
Department of Haematology, King’s College Hospital, Denmark Hill, London, UK Correspondence to Dr Emily Bart-Smith, MD, Department of Haematology, King’s College Hospital, Denmark Hill, London, SW6 9RS, UK. Tel: +44 020 3299 9000 x33080; fax: +44 020 3299 4980; e-mail: [email protected] Curr Opin Oncol 2014, 26:642–649 DOI:10.1097/CCO.0000000000000137 Volume 26 Number 6 November 2014
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Allogeneic HSCT in myelodysplastic syndromes Bart-Smith and Mufti
For patients with MDS, survival can vary from a few months to several years. Anticipating where a patient lies between these two extremes is important when considering treatment options, which range from supportive therapy to the intensive and potentially curative approach of AHSCT. A number of prognostic scores are used to accurately classify disease risk with the most recent being the Revised International Prognostic Scoring System
(IPSS-R) [4,5]. Current guidelines advise an upfront discussion regarding AHSCT with both high-risk and low-risk disease patients, however early transplantation in high-risk disease is emphasized. This stems from Cutler et al.’s [6] retrospective analysis of MDS patients who received human leukocyte antigen (HLA)-identical sibling transplants after myeloablative conditioning. Analysis according to the previously used IPSS demonstrated that early HSCT in intermediate-2 and high-risk disease achieved a survival advantage; conversely, delaying transplant until disease progression in patients with lower risk disease provided maximal survival [6]. This study did not represent the majority of patients being transplanted for MDS, as it did not reflect elderly patients, those receiving NMA or RIC protocols and those receiving an unrelated donor transplant. Attempts to overcome these shortcomings were made via using the Markov model of 92 patients with de-novo MDS undergoing RIC HSCT, with the similar conclusion that immediate transplantation did not improve outcome in elderly patients with intermediate-1/low-risk disease [7]. Conversely, de Witte et al. [8] reviewed 374 patients and demonstrated an improved outcome for low-risk patients when the time from diagnosis to transplantation was shorter. Care must be taken in selecting appropriate patients for early transplant, but equally important is the issue of excluding ‘low-risk’ patients with compatible sibling or unrelated donor options from an early transplant. We favour current guidelines which recommend considering early transplant in
Pre-HSCT
Post HSCT
KEY POINTS Cytogenetics (monosomal karyotype) and molecular characteristics (TP53, ETV6, RUNX1, ASXL1, EZH2 and SF3B1) play an increasingly important role in risk-stratifying patients prior to transplantation. Haploidentical and umbilical cord blood donors may be valid options for those patients without HLA-identical sibling or matched unrelated donors; however, more research regarding the safety and efficacy of these alternative donor options is required. The outcome for patients who relapse following AHSCT is dismal and a preemptive management approach is suggested, particularly in patients with high-risk disease. Adjusting the timing and dose of DLI in relation to the patient’s disease, form of T-cell depletion, degree of donor–recipient HLA mismatch and degree of donor chimerism at the time of DLI may limit the amount of GVHD without jeopardizing the GVL effect required to prevent disease relapse.
Disease risk and timing of transplant
HSCT
•
Disease risk of HSCT
•
•
Cytogenetics molecular markers
•
•
Age
•
HCT-CI Modifiable comorbidities − ferritin
•
Donor (type/ age /matching) Stem cell source (PB/BM)
• •
GVHD Weaning IST
• •
Monitoring disease Relapse management DLI (proph vs therapy)
•
Conditioning
•
T cell purging
Chemotherapy
•
CMV status
Second transplant
(MA/NMA/RIC)
•
Remission status
Adoptive immuneTx
•
Bridging therapy
Tumour vaccination
There are a multitude of factors that physicians must be satisfied of before considering transplant as a valid treatment. These can be divided into questions related to the patient and the disease in the pre-transplant setting; conditioning and donor selection in the transplant setting; and management of complications, disease monitoring and relapse in the posttransplant setting
FIGURE 1. Important factors when considering transplant as a treatment option for myelodysplastic syndromes. BM, bone marrow; CMV, cytomegalovirus; DLI, donor lymphocyte infusion; HCT-CI, haematopoietic cell transplant-comorbidity index; HSCT, haematopoietic stem cell transplantation; IST, immune suppression therapy; MA, myeloablative; NMA, nonmyeloablative; PB, peripheral blood; RIC, reduced intensity conditioning. 1040-8746 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
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Hematologic malignancies Table 1. Prognostic group according to cytogenetics in myelodysplastic syndromes Prognostic group
Proportion of patients
Cytogenetics
Median OS, years
AML evolution, 25%, yearsa
Very good
Del(11q),-Y
4%
5.4
NR
Good
Normal, del(5q), del(12p), del(20q), double including del(5q)
72%
4.8
9.4
Intermediate
Del(7q), þ8, þ19, i(17q), any other single or double independent clones
13%
2.7
2.5
Poor
-7, inv(3)/t(3q)/del(3q), double incl -7/del(7q), complex: 3 abn
4%
1.5
1.7
Very poor
Complex: >3 abn
7%
0.7
0.7
AML, acute myeloid leukaemia; OS, overall survival. a median time for 25% of patients to develop AML.
IPSS-R-labelled ‘low-risk’ patients, especially when in patients presenting with other poor risk factors, such as blood or platelets transfusion dependence, or severe cytopenias refractory to growth factor therapy [9].
Cytogenetics and molecular markers Cytogenetics plays a major role in the current IPSS-R and is highly predictive of outcome after AHSCT. Specifically, it includes the new and comprehensive cytogenetic scoring system defined by Schanz et al. based on analysis of 2801 untreated de-novo MDS patients, which defines 19 categories into five prognostic subgroups [10–12,13 ]. Specifically, the presence of a monosomal karyotype is associated with an extremely poor outcome in MDS patients and is also associated with higher rates of relapse and nonrelapse mortality in AHSCT [12] (see Table 1). Our understanding of the molecular pathogenesis of MDS has improved considerably in recent years with the emergence of genomic technologies, such as next-generation sequencing and highdensity single nucleotide polymorphism karyotyping. Identification of mutations, such as TP53, ETV6, RUNX1, ASXL1, EZH2 and SF3B1, has been shown to influence survival in the nontransplant setting, and it is anticipated that they may influence the patient selection for AHSCT in the future [14,15]. A recent study at our institute of 389 patients assessed the impact of TP53 mutation in MDS and demonstrated that patients with mutant TP53 had worse overall survival (OS) (9 versus 66 months) and that a reduction of the mutant clone correlated with response to azacitidine [16 ]. Such studies contribute to our improved understanding of the molecular basis of MDS and will have a significant practical impact on risk-stratifying patients in the pretransplant setting. &
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Age and comorbidities Age has traditionally been a limiting factor when considering AHSCT. This is especially relevant to MDS patients aged above 55 years and, therefore, deemed ‘old’ in the context of transplantation. However, the decision to exclude older patients from AHSCT has evolved from studies using predominantly myeloablative conditioning [2]. Two recent trials have been important in altering the emphasis of age as a major prognostic indicator [17,18]. The Center for International Blood and Marrow Transplantation reviewed 1080 patients above 40 years old with MDS or AML in complete remission following RIC or NMA HSCT and did not demonstrate a difference in overall outcomes [17]. Similarly, analysis of 1333 MDS patients aged at least 50 years receiving an AHSCT by the European Group for Blood and Marrow Transplantation demonstrated no statistical difference between the 50–60 group and the more than 60 group for nonrelapse mortality (NRM) at 4 years or OS. This finding is perhaps made more significant by the fact that a large number of patients received myeloablative conditioning despite their advanced age [18]. Interpretation of these findings must be countered by acknowledgement of the heterogeneity and inherent selection bias which confounds retrospective analysis. We propose that recipients’ age alone should not be considered a contraindication for AHSCT. Patients’ comorbid health is perhaps more predictive of risk-assessing NRM following HSCT [17]. Several retrospective studies have demonstrated that a higher haematopoietic cell transplant-comorbidity index (HCT-CI) score equates to higher NRM and lower OS [19–22]. One such study by Sorror et al. [22] stratified patients according to HCT-CI and disease stage, demonstrating that patients with higher HCT-CI score and also high-risk disease Volume 26 Number 6 November 2014
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Allogeneic HSCT in myelodysplastic syndromes Bart-Smith and Mufti
had worse survival rates (29% OS at 2 years, compared to 70% in patients with low HCT-CI score and low-risk disease). There was no difference between NMA and myeloablative conditioning for patients in this poor-risk group because the lower NRM in the RIC-treated patients was offset by a higher risk of relapse. These findings have also been confirmed in a recent prospective study using HCT-CI to stratify patients undergoing transplant for haematological malignancies including MDS, although further studies are required to clarify the issue fully [23].
‘Modifiable’ comorbidities Several patient factors have been identified as contributing to comorbidity, but which can be corrected prior to transplant. These include anaemia, recurrent infection as well as iron overload. The latter has been shown to influence survival after transplantation, with higher rates of bacterial and fungal infections, sinusoidal obstruction syndrome and other regimen-related toxicities [24]. Serum ferritin is traditionally used to assess iron status, with studies demonstrating higher NRM and worse OS in patients with a ferritin level of at least 1500 mcg/l prior to myeloablative as well as RIC AHSCT [25]. Whether this observation is solely related to iron overload is unlikely, as hyperferritinaemia can be indicative of an acute phase reaction as well as cellular apoptosis. Pretransplant iron chelation may improve ferritin levels, but evidence does not exist that confirms an improvement in transplantation outcomes. A recent retrospective study has suggested that MRI techniques are more effective in assessing systemic iron status and that liver iron content is an independent negative prognostic indicator for posttransplant outcome [26]. Prospective studies should include assessment of iron overload through MRI techniques and measurement of labile plasma iron to assess whether correction of this ‘modifiable’ comorbidity leads to improved transplant outcomes.
Remission: achieving it and keeping it Several recent studies have indicated that high pretransplant disease burden equates to poor posttransplant outcome [27–29]. Warlick et al. published a study of 84 patients which demonstrated the following point exactly: a 1-year relapse rate of 35% in patients with a blast count of above 5% going into transplant, compared with 18% in patients in complete remission at time of transplant [27–29]. This practice is far from being established however, with several studies being unable to demonstrate the
benefit of bulk reduction before transplantation [30,31 ]. Newer therapeutic options, such as the hypomethylating agents, have potential value in the transplant management of MDS. Several studies have demonstrated these as feasible and effective treatment options, with potentially important roles in remission induction pre-AHSCT for patients previously considered not fit enough for such intensive management options [32–34]. The time to response is prolonged compared to conventional chemotherapy however, and it is a potential disadvantage. Whether there is an added advantage in using hypomethylating agents over conventional chemotherapy to achieve remission remains under debate; some investigators have postulated that there is an enhanced graft-versus-leukaemia (GVL) effect seen with these agents through the alteration of antigen recognition. A recent study at King’s College Hospital demonstrated that azacitidine has profound effects on CD4þ helper cells and induces FOXP3 and interleukin 17 secretion, which correlates with disease status and response to therapy. These findings provide further insights into the immune-modulatory effects of hypomethylating agents [35]. &
ALLOGENEIC HAEMATOPOIETIC STEM CELL TRANSPLANT: DONOR AND CONDITIONING OPTIONS The choice between a well matched unrelated donor versus a HLA-identical sibling donor for MDS patients remains under debate, with comparable outcomes being demonstrated for both donor options [36–38]. Management of patients without such choices is more challenging. A number of recent studies have suggested that umbilical cord blood transplantation (UBCT) is comparable to sibling donor transplantation. Specifically, Majhail et al. [39] demonstrated OS at 3 years of 31 and 37% in the UBCT and sibling donor groups respectively, concluding that UBCT was a feasible option for patients without HLA-matched sibling donors. An important limitation to UBCT must be highlighted however, and that is the inability to obtain subsequent donor collections. Donor lymphocyte infusion (DLI) is, therefore, not possible, which can pose significant problems in the posttransplant setting. This is especially relevant in our elderly patients who are more likely to undergo a RIC AHSCT, and therefore have an increased risk of relapse [39,40]. Analysis of data from our institution has revealed that UBCT can be particularly challenging in patients over 55 years old, and therefore caution must be expressed [41].
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Hematologic malignancies
Haploidentical donors have the advantage of immediate availability (of initial stem cells as well as donor lymphocytes for immune therapy in the event of relapse) and lower cost compared with UBCT. Although data regarding these easily accessible donors in MDS is minimal, and confounded by inherent heterogeneity, initial studies suggest that haploidentical transplants are at least comparable to UBCT [42,43]. Higher rates of relapse have been identified as a potential concern following transplant, however more research is required to establish whether this a viable donor option for patients lacking sibling or volunteer unrelated donors [44].
Conditioning regimes The principle that RIC and NMA conditioning regimens achieve the GVL effect of transplantation whilst simultaneously limiting the toxicity associated with standard myeloablative conditioning regimens has undoubtedly broadened the scope for AHSCT in MDS. The benefit of reduced toxicity and resultant survival benefit from a lower transplant-related mortality associated with RIC/NMA conditioning, however, is offset by an increase in the risk of relapse [45]. The Center for International Blood and Marrow Transplantation compared outcomes in patients with AML/MDS who received AHSCT either after RIC or NMA or standard myeloablative conditioning, with no difference being identified in the RIC and myeloablative groups; however, inferior disease-free survival was demonstrated after NMA conditioning [46]. Heterogeneity and selection bias which confounds such studies makes it difficult to interpret these findings. The much anticipated prospective study by the EBMT comparing RIC versus myeloablative conditioning will help find the best way to tailor conditioning regimens to individual patients (#NCT00682396).
T-cell purging Both T-cell-replete (TCR) and T cell-deplete (TCD) protocols have demonstrated success, with lower rates of chronic graft-versus-host disease (GVHD) being seen in the latter. Prevention of chronic GVHD is unquestionably important, but must be weighed against the decreased GVL effect and resultant higher relapse rate following T-cell depletion. One argument in favour of T-cell depletion is that it achieves a base on which to build, in the form of DLI, hypomethylating agents and vaccine and other immunotherapeutic modulations. However, in the absence of a randomized, prospective study aimed at answering this question, management is invariably 646
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guided by local policy. The prevention of the often devastating effects of GVHD is something which holds a similar level of importance as relapse, and this balance is often difficult to achieve.
POSTALLOGENEIC HAEMATOPOIETIC STEM CELL TRANSPLANT ISSUES Salvage treatment options for MDS patients who have relapsed following HSCT are limited. Relapse in MDS may present indolently and physicians rely on evidence of minimal residual disease as a marker of relapse, typically in the form of chimerism analysis and Wilms tumor gene (WT1) expression [47,48]. Traditional management has been to treat patients at time of relapse; however, current evidence indicates that achieving a good outcome following relapse is very small. A more preemptive approach to managing relapse is, therefore, of paramount importance.
Anticipating and preventing relapse The hypomethylating agent azacitidine has a potential role in both prevention and treatment of relapse. A recent dose finding study treated 45 high-risk, heavily pretreated AML/MDS patients with azacitidine maintenance after AHSCT for at least four cycles. The study demonstrated an impressive 1-year OS and event-free survival (EFS) of 77 and 58%, respectively, and suggested that more cycles may be associated with greater benefit [49]. The benefit of preemptive azacitidine has also been demonstrated in a further trial in which 20 patients were given four cycles of azacitidine if their CD34 donor chimerism was less than 80%, but with complete haematological remission. Sixteen patients (80%) responded with improved/stabilized chimerism, and although 13 patients (65%) went on ultimately to relapse, this was delayed until 231 days. The authors concluded that preemptive azacitidine was well tolerated and may have a role in preventing or delaying haematologic relapse [50]. DLIs are similarly used in the relapse setting as they may enhance a GVL effect. The major complication of this treatment modality is GVHD reported to varying degrees in many studies [51–53]. A recent analysis at our institution involved 113 MDS patients following RIC T-cell depletion AHSCT treated with DLI preemptively (pDLI) to improve donor chimerisms and prevent relapse, or therapeutically (tDLI) after disease recurrence. Impressive 5-year OS rates were demonstrated particularly in the pDLI group compared to the tDLI group (80 and 40%, respectively), without excess GVHD or GVHD-related mortality [51]. The risk of GVHD is Volume 26 Number 6 November 2014
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Allogeneic HSCT in myelodysplastic syndromes Bart-Smith and Mufti
No TCD
Ex-vivo TCD
In-vivo TCD
High (>50% risk of GvHD)
Degree of HLA mismatch
T cell dose of DLI (cells/kg)
1 × 108
1 ×107
Medium (25%–50% risk of GvHD) X
1 ×106
Low (12
6
3
0
Timing of DLI following HSCT (months)
FIGURE 2. The ’sweet spot’ for DLI following transplant for myelodysplastic syndromes. DLI, donor lymphocyte infusion; GVHD, graft-versus-host disease; HLA, human leukocyte antigen; TCD, T-cell deplete. Published with permission from [54 ]. &
significant in other studies with reasons likely reflecting different conditioning, timing and dose schedules. Yun and Walker [54 ] have postulated that there is a so-called ‘sweet spot’ for DLI based on the method of TCD (in vivo or ex vivo), the timing of DLI, the degree of HLA mismatch and the T-cell dose of DLI. Adapting timing and dose according to the other predetermined variables may help physicians use DLI to its maximum benefit of enhancing GVL without the consequences of GVHD [54 ]. Please see Fig. 2. The concomitant use of DLI with azacitidine has been postulated to limit GVHD in this setting through expansion of cells with a regulatory phenotype. Initial studies have demonstrated encouraging results; however, more work is required to assess whether this combination can improve the safety and antitumour effect of DLI [55,56 ]. &
further clinical research into this novel treatment approach [58,59]. gd T cells have also been shown to demonstrate antitumour activity in a number of malignancies, including AML [60]. It is postulated that engineered gd-TCR-expressing effector cells will have a role in immunotherapy and may have a role in the management of MDS in elderly patients.
CONCLUSION Transplantation remains the only cure for MDS and is now a valid option for many elderly patients who would previously have been excluded from this treatment modality. Physicians must weigh the balance between limiting the toxicity of transplantation and achieving a cure/preventing relapse. With our increasing knowledge of the molecular basis of MDS, we are now able to accurately assess an individual’s disease risk and make more informed decisions regarding a patient’s eligibility for transplantation. The use of RIC with T cell depleted HSCT as a base on which to preemptively add immunemodulating therapy may provide the balance required for cure without significant detrimental effects on quality of life. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
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Other immune therapeutic approaches Recent advances for management of relapse include the development of vaccines for the purpose of immune modulation. Genetically modified leukaemia cells which express high levels of CD80 and interleukin 2 form the basis of a whole-cell leukaemia vaccination, for the purpose of T-cell activation. The combination of AHSCT with immunization aims to stimulate immune-mediated eradication of residual disease [57]. Peptide vaccination with leukaemia-associated antigens, such as WT1 and PR1, has demonstrated an immunological response and modest clinical response and we anticipate
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Allogeneic HSCT in myelodysplastic syndromes Bart-Smith and Mufti 50. Platzbecker U, Wermke M, Radke J, et al. Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leukemia 2012; 26:381–389. 51. Krishnamurthy P, Potter VT, Barber LD, et al. Outcome of donor lymphocyte infusion after T cell-depleted allogeneic hematopoietic stem cell transplantation for acute myelogenous leukemia and myelodysplastic syndromes. Biol Blood Marrow Transplant 2013; 19:562–568. 52. Marks DI, Lush R, Cavenagh J, et al. The toxicity and efficacy of donor lymphocyte infusions given after reduced-intensity conditioning allogeneic stem cell transplantation. Blood 2002; 100:3108–3114. 53. Roddie C, Peggs KS. Donor lymphocyte infusion following allogeneic hematopoietic stem cell transplantation. Expert Opin Biol Ther 2011; 11:473–487. 54. Yun HD, Waller EK. Finding the sweet spot for donor lymphocyte infusions. & Biol Blood Marrow Transplant 2013; 19:507–508. Differences in the rate of GVHD following DLI between investigators is postulated. An optimum approach for each individual patient is influenced by intensity of conditioning regimen, in-vivo versus ex-vivo TCD, timing of DLI after AHSCT, T-cell subsets in DLI, degree of donor–recipient HLA mismatch, type and amount of residual cancer, intensity of posttransplantation immunosuppression and level of donor chimerism at the time of DLI. 55. Goodyear OC, Dennis M, Jilani NY, et al. Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML). Blood 2012; 119:3361–3369.
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