Allogeneic hematopoietic stem cell transplantation for aggressive lymphomas

DCTH - 2 2014-73-85 REVIEW Allogeneic hematopoietic stem cell transplantation for aggressive lymphomas Maurizio Musso, Renato Scalone, Alessandra Crescimanno, Ferdinando Porretto, Vita Polizzi, Vincenza Bonanno, Ignazio Abbene U.O. Oncoematologia e TMO, Dipartimento Oncologico La Maddalena, Palermo, Italy SUMMARY The heterogeneity of lymphomas results in a wide therapeutic options including both autologous and allogeneic hematopoietic stem cell transplantation (allo-hsct). We reviewed the role of allo-hsct in a high-risk group of aggressive non-hodgkin lymphoma patients such as those with relapsed or refractory disease, especially after autologous HSCT. Moreover, we have analyzed the different modalities of conditioning with myeloablative, reduced-intensity or non-myeloablative regimens, considering their pro and contra, in order to highlight the best approach with allo-hsct for different scenarios. INTRODUCTION Non-Hodgkin lymphomas (NHL) are a heterogeneous group of hematologic malignancies with varied aggressiveness. High-dose chemotherapy (HDcht) and autologous hematopoietic stem cell transplantation (auto-hsct) is the standard care for patients with relapsed chemosensitive diffuse large Key words: aggressive non-hodgkin lymphomas, allogeneic hematopoietic stem-cell transplantation. Correspondence: Maurizio Musso U.O. Oncoematologia e TMO, Dipartimento Oncologico La Maddalena Via San Lorenzo Colli, 312/D 90146 Palermo, Italy E-mail: mamusso@libero.it B-cell lymphoma (DLBCL) with a significant percentage of durable responses (1). Relapsed NHL patients with other aggressive histology, including transformed B-cell lymphoma, mantle cell lymphoma (MCL), Burkitt lymphoma (BL) and peripheral T-cell lymphoma (PTCL), or refractory aggressive NHL patients, generally do not achieve a durable response after auto-hsct (2-4) and are considered hard to treat lymphomas with a very poor prognosis. Allogeneic hematopoietic stem cell transplantation (allo-hsct) is a potentially curative procedure as the advantages of an allogeneic graft are a tumor-free graft and a potential immune-mediated graft-versus-lymphoma (GVL) effect. Nevertheless the high rate of non-relapse mortality (NRM) associated with

74 M. Musso, et al. myeloablative (MA) conditioning regimens often offsets any potential curative benefits. Reduced-intensity conditioning (RIC) and non-myeloablative (NMA) conditioning regimens are being used increasingly in patients with NHL for their lower NRM making the allo-hsct a feasible therapeutic option also for older patients with comorbidities. On the other hand, a high relapse rate was reported with RIC and NMA with respect to MA conditioning regimens. We review here the role of allo-hsct in the treatment of relapsed or refractory aggressive lymphomas and the different conditioning regimens used, MA versus RIC or NMA. DIFFUSE LARGE B-CELL LYMPHOMA One-third of all NHL cases are DLB- CL. The evolution of the first-line modern therapy, combining anthracycline-based chemotherapy with rituximab, together with an ameliorated supportive care, has improved the outcome of patients with DLBCL, and about 60% of these patients can now expect to be cured (5). Patients whose response is suboptimal or who relapse can be salvaged by HD-cht followed by auto-hsct with response rate of 40% to 50% in chemosensitive disease (1, 6). However, a poor prognosis group of patients with adverse risk at the relapse, such as advanced stage, chemorefractory disease, a short interval between remission and relapse, or a relapse after HD-cht and auto-hsct, have limited options for curative treatment (7-9). Allo-HSCT could be a feasible option. Lazarus et al. (10) retrospectively analyzed the outcomes of relapsed DL- BCL patients undergoing first autologous (n=837) or HLA-identical sibling MA allogeneic HSCT (n=79) reported to Center for International Bone Marrow Transplantation Research (CIBM- TR) between 1995 and 2003. Allo-HSCT group had a similar risk of relapse with respect to autologous group (5-years relapse: 33% versus 40%, P=0.59) despite having more patients with an intermediate-high or high International Prognostic Index score, extranodal involvement, B symptoms, more prior chemotherapy regimens, and more resistant disease. However, allo-hsct was associated with a higher treatment-related mortality (TRM) and a lower overall survival (OS) with respect to auto-hsct (1-5-years NRM: 41%-45% versus 12%-18%, P<0.0001; 1-5-years OS: 30%-22% versus 66%-49%, P<0.0001) that greatly limited the potential benefit of this approach. Given the high TRM/NRM associated with MA conditioning, the use of RIC and NMA regimens has increased for allo-hsct in DLBCL. Sirvent et al. (11) reported the experience of the French Society of Bone Marrow Transplant on 68 patients, 79% of whom had received a prior auto-hsct, undergoing RIC allo-hsct, 82% of whom with HLA-identical sibling donor. At the time of transplantation 53% had not achieved complete remission (CR). With a median follow-up of 49 months, the 1-year cumulative incidence (CI) of NRM was 23%; the 2-years OS, progression-free survival (PFS), and the CI of relapse were 49%, 44%, and 41%, respectively. According to multivariate analysis, the patients in CR at transplantation had a significant longer PFS and lower CI of relapse than those transplanted in par-

Allogeneic hematopoietic stem cell transplantation for aggressive lymphomas 75 tial remission (PR) or stable disease (SD) or progressive disease (PD), 59% versus 30%, P=0.01, and 20% versus 61%, P=0.009, respectively. Similar results were reported by Rezvani et al. (12) with NMA regimens adopted for transplantation of 32 relapsed patients (31 DLBCL, 1 BL) with related (66%) or unrelated (34%) donor. Seventy-five percent of patients had undergone previous auto-hsct and 72% had chemosensitive disease at transplantation. With a median follow-up of 45 months, the 3-years CI of NRM and relapse were 25% and 41%, respectively; the 3-years OS and PFS were 45% and 35%, respectively. In multivariate models, chemosensitive disease was associated with a better outcome (3-years OS and PFS: 56% and 43%, respectively). Bacher et al. (13) analyzed the outcomes of 396 patients undergone allo-hsct for relapsed/refractory DLB- CL, who received MA (n=165) or RIC (n=143) or NMA (n=88) conditioning regimens, reported to CIBMTR between 2000 and 2009. RIC and NMA conditioning recipients were older, and they were more likely to have received prior auto-hsct, prior radiation, and more prior chemotherapy lines than MA conditioning recipients. The 5-years CI of NRM was significantly higher in the MA group (56%) than in the RIC (47%) and NMA (36%) group. On the opposite, the 5-years CI of relapse/progression was significantly lower in the MA group (26%) than in the RIC (38%) and NMA (40%) group. The respective 5-years OS (18%, 20% and 26%) and PFS (18%, 15%, 25%) did not differ significantly. In a poor-risk population like that including DLBCL patients with relapsed/ refractory disease after auto-hsct, allo-hsct has been used as salvage strategy with encouraging results. van Kampen et al. (14) analyzed retrospectively 101 patients undergone allo-hsct with an HLA-identical related (71%) or unrelated (29%) donor and receiving a MA (37%) or a RIC (63%) regimen between 1997 and 2006, captured from database of the European Group for Blood and Marrow Transplantation (EBMT). The 3-years CI of NRM and relapse were 28% and 30%, respectively; the 3-years OS and PFS were 54% and 42%, respectively. In multivariate analysis, time to relapse after auto-hsct <12 months was associated with a higher risk of NRM and shorter OS and PFS, chemorefractory disease was associated with a higher risk of relapse. A similar study was conducted by Rigacci et al. (15) on behalf of the Gruppo Italiano Trapianto di Midollo Osseo. From 1995 to 2008, 884 patients relapsed or progressed after auto-hsct were identified, 165 of whom were treated with allo-hsct. A related donor was available in 108 cases, a RIC regimen was used in 116. With a median follow-up of 24 months (range, 2-144), OS and PFS were 39% and 32%, respectively. The TRM was 28%. The only parameter affecting either OS or PFS was the response status at the time of allo-hsct. Concluding, it is not still clear which conditioning regimen to use in allo-hsct for DLBCL. In general, for younger and fit patients, with high-risk of relapse (not in CR at transplant), MA regimens should be preferred. For older patients, those with comorbid conditions, those with prior auto-hsct, RIC or NMA regimens should be the better

76 M. Musso, et al. option. For patients in CR at transplant, RIC or NMA regimens should be preferred also for younger, fit patient (16). TRANSFORMED B-CELL LYMPHOMA Transformation into aggressive-histology lymphoma is a recognized event in the natural history of follicular non-hodgkin lymphoma and outcome of this group of patients is poor (17, 18). There is no standard treatment for patients with transformed follicular lymphoma. The majority receives conventional chemotherapy, whereas selected patients are treated with HD-cht followed by auto-hsct or allo-hsct. It is unknown if any of these approaches are more effective than others, due to the lack of comparative data in literature (19-21), as well as, it is not clearly defined the role of rituximab in the treatment of patients with transformed lymphoma (22). To determine if auto-hsct or allo-hsct improves outcome in patients with transformed follicular lymphoma compared with rituximab-containing chemotherapy alone, Villa et al. (23) analyzed retrospectively a large series of 172 patients coming from 14 Canadian institutions, 13% treated with allo-hsct using MA regimens, 56% with auto-hsct, 31% with rituximab-containing chemotherapy. Five-years OS were 46% for patients treated with allo-hsct, 65% with auto-hsct, and 61% with rituximab-containing chemotherapy. Five-years PFS were 46% for patients treated with allo-hsct, 55% with auto-hsct, and 40% with rituximab-containing chemotherapy. In multivariate analysis, patients treated with auto-hsct had improved OS compared with those who received rituximab-containing chemotherapy. On the other hand, there was no OS difference between those treated with allo-hsct and rituximab-containing chemotherapy. Similar treatment effects were observed for PFS. Fiveyears TRM was clearly higher in the allogeneic group (23%) with respect to autologous (5%). In summary, in this large series of transformed lymphoma patients, an improvement in their outcome, even if modest, was given by auto-hsct, while the higher TRM offsets any potential benefit of allo-hsct. MANTLE CELL LYMPHOMA MCL accounts for 6% of NHL and typically presents as advanced stage disease with bone marrow, peripheral blood, and extranodal sites involvement (24). Over the last decade, strategies with multiagent immunochemotherapy, including rituximab and high-dose of methotrexate/cytarabine, alone or as induction for auto-hsct, have produced higher response rate and improved the PFS (25-27). Nevertheless, the disease course remains characterized by frequent relapse. After first relapse, the prognosis is poor, with a median survival of 1-2 years, especially for patients with refractory disease, where the results of auto-hsct have been uniformly disappointing, or relapsed after auto-hsct (28-30). Despite the higher risk of TRM, allo-hsct can be offered to select relapsed MCL patients, especially those with chemosensitive disease. MA conditioning regimens were adopted in allo-hsct for MCL with TRM ranging from 19% to 29% and 5-years

Allogeneic hematopoietic stem cell transplantation for aggressive lymphomas 77 relapse rate, PFS, and OS of 21%, 44-50%, and 49% respectively (31, 32). Because median age at time of diagnosis of MCL is 65-68 years, most patients are not eligible for MA allo-hsct. Therefore, RIC and NMA are the conditioning regimens of choice for the relapsed MCL patient candidate to allo-hsct. In 2004, Maris et al. (33) published their experience on 33 MCL patients with relapsed or refractory disease undergone NMA allo-hsct with HLAmatched related (n=16) or unrelated (n=17) donor. The median number of previous chemotherapy lines received was 4 (range, 1-10); 14 patients (42%) had failed a prior auto-hsct; 13 (39%) had chemorefractory disease. With a median follow-up of 24.6 months, the 2-years CI of NRM and relapse were 24% and 16%, respectively. None of the patients transplanted in CR had a relapse. The 2-years OS and PFS were 65% (56% for recipients of related donor grafts, 74% for recipients of unrelated donor grafts) and 60% (56% for recipients of related donor grafts, 66% for recipients of unrelated donor grafts), respectively. More recently, Tam et al. (34) published mature results on NMA allo-hsct in 35 patients with relapsed and refractory MCL. The median number of previous chemotherapy lines received was 3 (range, 1-10); 6 patients (17%) had failed a prior auto-hsct; 6 (17%) had chemorefractory disease. Only 3 patients died within 1 year from transplantation, thus the 1-year TRM was 9%. With a very long median follow-up of 56 months (range, 19-110), the 6-years OS and PFS were 53% and 46%, respectively. Importantly, plateaus in the survival curves were observed for both OS and PFS, with no relapses or deaths occurring in 9 patients followed between 63 and 110 months. These data support the GVL effect. In a study of the CIBMTR, Fenske et al. (35) analyzed the outcome of 519 patients with chemosensitive MCL who received a first transplantation, auto-hsct (n=381) or NMA/RIC allo-hsct (n=138), at different times in the disease course, to establish the best time and modality of transplantation for MCL. In the early transplantation cohort, including the patients in first PR or CR with no more than two lines of chemotherapy, 249 received auto-hsct and 50 allo-hsct; in the late transplantation cohort, including all the other patients, 132 received auto-hsct and 88 allo-hsct. Auto-HSCT and allo-hsct resulted in similar OS and PFS for both early (5-years OS: 61% auto-hsct versus 62% allo-hsct, P=0.95; 5-years PFS: 52% auto-hsct versus 55% allo-hsct, P=0.75) and late cohort (5-years OS: 44% auto-hsct versus 31% allo-hsct, P=0.2; 5-years PFS: 29% auto-hsct versus 24% allo-hsct, P=0.55), even if the global outcome was significantly better in the early cohort for both auto-hsct and allo-hsct. The highest 5-year OS (75%) and PFS (70%) were reported for patients underwent auto-hsct in first CR. In both early and late transplantation cohorts, progression/relapse was lower and NRM was higher in the allo-hsct group, but the difference in progression/relapse between auto-hsct and allo-allo-hsct was less significant in the late cohort. The conclusions of the study were that the optimal timing for HSCT is early, preferring auto-hsct for patients in CR and allo-hsct for those not in CR with low comorbidities score. At the third

78 M. Musso, et al. line of therapy or beyond, allo-hsct should be the therapeutic choice for patients with chemosensitive or chemorefractory disease and low comorbidities score, auto-hsct only for patient with chemosensitive disease. A high-risk subgroup of MCL is that including patients with disease relapsed after auto-hsct. Le Gouill et al. (36) reported a multicenter retrospective analysis of 70 relapsed/refractory patients, coming from 12 centers of France and Germany, who received RIC/NMA allo-hsct between 1999 and 2008. The median number of previous therapeutic lines was 2 (range, 1-5) including auto-hsct in 47 cases (67%). At the transplant 15 patients (21%) had refractory disease. With a median follow-up of 24 months, the 2-years TRM in these heavily treated patients was 32%. The 2-years OS and event-free survival (EFS) were 53% and 50%, respectively. The number of lines of previous treatment had no impact on OS, EFS or TRM and the 3-years EFS for the 47 patients who relapsed after auto-hsct was 49%. Only disease status at the transplant reached statistical significance for OS and EFS (2-year OS: 62% for CR versus 31% for SD/PD; 2-year EFS: 62% for CR versus 11% for SD/PD). In the same setting of MCL patients relapsed after auto-hsct, Dietrich et al. (37), in a retrospective study of the EBMT, evaluated 360 patients, 80 of whom received NMA/RIC allo-hsct and 280 other therapies. Comparing the two subgroups of patients, the OS at 2-years were 46% for those receiving allo-hsct and 37% for those not receiving allo-hsct; the OS at 5-years was 34% and 16%, respectively. With a median follow-up of 32 months, in the allo-hsct, the 2-years CI of NRM and relapse were 30% and 33%, respectively. In multivariate analysis, time to relapse after auto-hsct <12 months and refractory disease affected the OS. In the subgroup of patients with relapse after auto-hsct >12 months and chemosensitive disease, the survival advantage given by allo-hsct was valuable at long-term, as probable GVL effect (2-years OS: 60% allo-hsct versus 82% other therapy; 5-years OS: 60% allo-hsct versus 29% other therapy). Patients with a refractory disease continue to have a bad prognosis, however, because the GVL effect can occur even in the absence of chemosensitivity, allo-hsct remains a therapeutic option also for this high-risk group of patients. Hamadani et al. (38) in an observational study of the CIBMTR reported outcomes of allo-hsct in refractory MCL patients relative to the intensity of pre-transplantation conditioning regimens. Between 1998 and 2010, 202 patients underwent allo-hsct receiving MA (n=74) or NMA/RIC (n=128) conditioning regimens. NMA/RIC group was older and more heavily treated; more patients had received auto-hsct, rituximab, and a graft from an unrelated donor. At 3 years post-transplantation, no significant between-group differences were seen in terms of NRM (47% in MA versus 43% in RIC/NMA; P=0.68), relapse/progression (33% in MA versus 32% in RIC/NMA; P=0.89), OS (25% in MA versus 30% in RIC/NMA; P=0.45) and PFS (20% in MA versus 25% in RIC/ NMA; P=0.68). These data highlight that, despite a refractory disease condition, about 25% of patients can attain durable remission after allo-hsct independently by conditioning reg-

Allogeneic hematopoietic stem cell transplantation for aggressive lymphomas 79 imen adopted, suggesting that GVL effect might be more important than conditioning intensity in long-term disease control. BURKITT LYMPHOMA Sporadic variant of BL accounts for 1-2% of adult NHL (39). Actually, the modern immunochemotherapy (R-CODOX-M/R-IVAC or R-Hyper- CVAD/R-MA), plus central nervous system (CNS) prophylaxis has resulted in dramatic improvement, with reported 3-years survival close to 90% (40-42), similar to those obtained with less intensive induction chemotherapy plus auto-hsct as consolidation. Therefore, there has been a progressive reduction in the use of auto-hsct as consolidative therapy in first CR. Nevertheless, patient with poor-risk factors (elevated lactate dehydrogenase, bulky disease, involvement of bone marrow or CNS), or with relapsed/refractory disease, have an unfavorable outcome. Both autologous and allogeneic HSCT have been used in an attempt to improve survival with allo-hsct preferred for advanced stages and relapsed/refractory disease. Recently, Maramattom et al. (43) published the results of a retrospective study of the CIBMTR, about the employment of auto-hsct or allo-hsct for BL between 1985 and 2007. Of the 241 patients, 113 (47%) received auto-hsct, 128 (53%) received allo-hsct, the majority with a MA regimen, 80 from a related donor, 48 from an unrelated. A substantial decline in the numbers of auto-hsct performed in recent years has been confirmed (only 19% after 2000). In the auto-hsct group, 42% was transplanted in first CR; in the allo-hsct group, 23% was transplanted in first CR, 30% in second or beyond CR. The 5-years CI of NRM was 8% for auto-hsct and 30% for allo-hsct. The 5-years CI of relapse/progression was similar between auto-hsct and allo-hsct, 44% and 42-48% (related-unrelated), respectively. The 5-years OS and PFS were 54% and 48%, respectively, for auto-hsct; 32-23% and 30-22%, respectively, for allo-hsct (related-unrelated). Significant higher progression/relapse rates and lower OS and PFS rates were reported for both auto-hsct and allo-hsct, when BL patients were transplanted beyond first CR, or not in CR. PERIPHERAL T-CELL LYMPHOMA PTCLs constitute a rare and very heterogeneous group of NHL that accounts for 10-15% of NHL, but with a great geographic variation around the world (44). Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large-cell lymphoma (ALCL), account for 75-80% of all PTCLs in western countries. Compared to the corresponding aggressive B-cell lymphomas, with the exception of ALCL ALK+, PTCLs have a poor prognosis after first-line conventional chemotherapy, with 5-years EFS and OS of 33% and 41%, respectively (45, 46). For small size of patient population in clinical trials and heterogeneity of PTCLs, the exact role of auto-hsct remains undefined and also the timing is still a matter of debate. Few prospective studies have evaluated up-front autograft as consolidation of response (47-49). Only patients achieving first CR appear to benefit from auto-hsct.

80 M. Musso, et al. However, patients receiving auto-hsct in second remission or with refractory disease have a poor outcome with OS and PFS ranging from 40% to 30% and from 20% to 0%, respectively (50, 51). Most reports on allo-hsct focus on the three most frequent sub-entities (PT- CL-NOS, AITL, ALCL ALK-) and, important to note, deal with patients transplanted for very advanced and often refractory disease. Corradini et al. (52) published the first prospective report on allo-hsct for relapsed/refractory PTCL in 2004. Seventeen patients with relapsed (n=15) or refractory (n=2) PTCL (PTCL-NOS, AITL, ALCL ALK-) undergone RIC allo-hsct with graft from related donor were described. Eight patients (47%) had failed a previous up-front auto-hsct. With a median follow-up of 28 months, an excellent 3-year OS and PFS (81% and 64%, respectively) and a very low 2-year CI of NRM and relapse (6% and 12%, respectively) were reported. More recently, the same group of investigators published mature data on a larger series of 52 patients with relapsed PTCL, including all major T-cell subtypes plus 9 cases with rare histology, undergone RIC allo-hsct (53). Twenty-five percent had refractory disease; 52% had failed a prior auto-hsct. Thirty-three patients received graft from matched related donors, 19 from alternative donors. With a very long follow-up (56 months), the 5-year OS and PFS were 50% and 40%, respectively, with no significant differences among the various histotypes. At 5-year NRM was low (12%), but the CI of relapse was high (49%), influenced by disease status at transplantation and number of treatment lines. Le Gouill et al. (54) reported the French experience especially on MA allo-hsct. Seventy-seven patients with various PTCL subtypes were transplanted mostly from matched related donors (78%) and received a MA regimen in 74% of cases. With a median follow-up of 43 months, the 5-years OS and EFS were 57% and 53%, respectively. As expected there was an higher TRM and lower relapse rate (at 5 years: 34% and 13%, respectively. There was a trend for better outcome for AITL. This latter result was confirmed in a successive EMBT study conducted by Kyriakou et al. (55) on 45 AITL, with a 3 years OS, PFS and relapse rate of 64%, 54% and 20%, respectively. Shustov et al. (56) published their results with NMA allo-hsct. Seventeen PTCL patients with relapsed/refractory (n=14) or very poor-risk newly diagnosed (n=3) disease received graft from matched related or unrelated donor. Median number of prior treatments was 3 (range, 1-7), 35% had failed auto-hsct, 29% was refractory at transplantation. After a median follow-up of 3.3 years, the 3-years NRM, relapse rate, OS and PFS were 19%, 26%, 59% and 53%, respectively. Of note, one patient with NK-leukemia/ lymphoma and one patient with adult T-cell leukaemia/lymphoma (ATLL) were alive and in CR after 50 and 25 months, respectively. Recently, Smith et al. (57) published on behalf of the CIBMTR an overview on their experience with auto and allo-hsct that has given interesting results. Two hundred forty-one PTCL patients were analyzed. Histotypes were PTCL-NOS, ALCL, and AITL. Between 1996 and 2006, 115 received auto-hsct, 126 MA or NMA/RIC allo-hsct. The auto-hsct group had more favor-

Allogeneic hematopoietic stem cell transplantation for aggressive lymphomas 81 able characteristics as more patients in first CR. As expected, the best outcome was reported for patients who received auto-hsct in first CR. Excluding patients in first CR, relapse was lower allo-hsct group, but OS and PFS were similar for both transplantation groups. Moreover, in the allo-hsct group, regimen intensity did not have an impact on NRM, relapse, OS and PFS. In multivariate analysis, chemorefractory disease and higher number of chemotherapy lines were the only negative prognostic factors of survival. Many issues suggest employing allo-hsct in first CR: the condition of CR itself, the low burden of chemotherapy received and the risk of chemo-resistance at the relapse. Kanakry et al. (58) retrospectively observed a trend toward better PFS for allo-hsct in first remission versus beyond first remission (2-years PFS: 53% versus 29%, P=0.08). Corradini et al. (59) published the results of a phase II study where patients could receive allo-hsct or auto-hsct in first remission according to the donor availability. At a median follow-up of 40 months, 4-years OS and PFS for patients receiving allo-hsct were 69% each. About allo-hsct for the rare PTCL histotypes, the two largest series published regard mycosis fungoides/sèzary syndrome (MF/SS) and ATLL. Duarte et al. (60) analyzed retrospectively on behalf of EBMT 60 patients with relapsed/ refractory MF/SS who received MA/RIC allo-hsct from matched related/unrelated donors. Median number of prior therapy lines was 4 (range, 1-10); 47% was chemorefractory. For these heavily treated patients, after a median follow-up of 36 months, 2-years NRM was 22%; 3-year CI of relapse, OS and PFS were 47%, 53% and 34%, respectively. Hishizawa et al. (61) reported 386 patients with ATLL receiving allo-hsct. At 3-years, the TRM and OS, for these very poor-risk patients, were 37% and 33%, respectively. Patients with human T-lymphotropic virus-1-seropositive donor had a higher risk of relapse. Except for 28 patients affected by NK-cell neoplasms, described by Murashige et al. (62), that at 2 years from MA allo-hsct had an OS and PFS of 40% and 34%, respectively, only case-reports exist on allo-hsct for the other histologies. CONCLUSIONS Allo-HSCT remains the sole curative modality for high-risk aggressive NHL patients, especially for those with refractory disease with a very dismal prognosis. In the modern era of transplantation, NRM rates over 30% even following MA regimens are unacceptably high. NMA/RIC conditioning regimens are an attractive modality that has shown impressively low NRM rate without compromising efficacy. It is certain that with the introduction of target-agents like PI3-kinase, bruton tyrosin-kinase, histone deacetylase, or immunomodulators the role and timing of allo-hsct will become even more complex. Incorporating these agents as a maintenance strategy after allo-hsct could be an attractive strategy. In the future, clinical trials should aim to consider also these novel agents in the peri-transplant and post-transplant period. Contributions: the authors contributed equally.

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