Thiotepa‐based conditioning versus total body irradiation as myeloablative conditioning prior to allogeneic stem cell transplantation for acute lymphoblastic leukemia: A matched‐pair analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

The optimal conditioning regimen to employ before hematopoietic stem cell transplantation in acute lymphoblastic leukemia (ALL) is still undecided, and while cyclophosphamide/total body irradiation (Cy/TBI) is the most commonly used myeloablative regimen, there are concerns regarding long‐term toxicity for patients conditioned with this regimen. Thiotepa‐based conditioning is an emerging radiation‐free regimen with recent publications indicative of comparable clinical outcomes to TBI‐based conditioning. In this analysis of the acute leukemia working party of the EBMT, we performed a retrospective matched‐pair analysis, evaluating the outcome of adult patients with ALL who received thiotepa‐based conditioning (n = 180) with those receiving Cy/TBI conditioning (n = 540). The 2‐year leukemia‐free survival and overall survival (OS) rates of both conditioning regimens were comparable, 33% for thiotepa [95% confidence interval (CI): 26.4‐42.8] versus 39% for Cy/TBI (95% CI: 34.8‐44.5] (P = .33) and 46.5% [95% CI: 38.6‐56.1] versus 48.8% [95% CI: 44.2‐54] (P = .9), respectively. There was no significant difference between the two regimens in the incidence of either acute graft versus host disease (GVHD) or chronic GVHD. Multivariate analysis demonstrated increased relapse incidence for thiotepa conditioning compared to Cy/TBI (HR = 1.78, 95% CI, 1.07‐2.95; P = .03) which did not affect OS. Our results indicate that thiotepa‐based conditioning may not be inferior to Cy/TBI for adult patients with ALL.     

Thiotepa‐based conditioning for allogeneic stem cell transplantation in acute lymphoblastic leukemia—A survey from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

In this study, we analyzed a thiotepa‐based conditioning regimen for allogeneic stem cell transplantation in adults with acute lymphoblastic leukemia, using the EBMT database. A total of 323 patients were identified. The median age was 43 years. Disease status at transplant was first complete remission (CR1) in 48.9%, CR2 in 21.7%, CR3 in 6.2%, while 23.2% of the patients had an active disease at the time of transplant. This was performed from a HLA‐matched sibling (49.8%) or a matched‐unrelated donor (51.2%). The incidence of acute graft‐vs.‐host disease (GvHD) (grade > II) was 26.6%, while chronic GvHD occurred in 35.9% of the patients at 1 year (24.6% with extensive disease). With a median follow‐up of 16.8 months, the nonrelapse mortality was 12.4 and 25.3% at 100 days and 1 year, respectively. The relapse incidence at 1 year was 33.3% with no difference for patients in CR1 (27%). The one‐year leukemia‐free survival (LFS) and overall survival (OS) were 57 and 66%, respectively for the entire cohort and 50 and 66%, respectively in patients in CR1. Thiotepa/busulfan ± melphalan (n = 213) in comparison to thiotepa/other (n = 110) conditioning regimen resulted in higher relapse incidence at 1 year (34.9 vs. 30.3%, P = 0.016) and lower LFS (38.8 vs. 45.9%, P = 0.0203), while nonrelapse mortality (23.8 vs. 26.3%, n.s.) and OS (59.6 vs. 51.1%, P = 0.109) did not differ. This large study suggests that a thiotepa‐based conditioning for allogeneic transplantation in acute lymphoblastic leukemia is feasible and effective, with the main outcomes being comparable to those achieved with other regimens. Am. J. Hematol. 92:18–22, 2017. © 2016 Wiley Periodicals, Inc.     

Cyclophosphamide versus etoposide in combination with total body irradiation as conditioning regimen for adult patients with Ph‐negative acute lymphoblastic leukemia undergoing allogeneic stem cell transplant: On behalf of the ALWP of the European Society for Blood and Marrow Transplantation

Allogeneic hematopoietic cell transplantation (alloHCT) with myeloablative conditioning based on total body irradiation (TBI) is widely used for the treatment of adults with acute lymphoblastic leukemia (ALL). TBI is most frequently administered in combination with either cyclophosphamide (Cy/TBI) or etoposide (Vp/TBI). The goal of this study was to retrospectively compare these two regimens. Adult patients with Ph‐negative ALL treated with alloHCT in first or second complete remission who received Cy/TBI (n = 1346) or Vp/TBI (n = 152) conditioning were included in the analysis. In a univariate analysis, as compared to Cy/TBI, the use of Vp/TBI was associated with reduced incidence of relapse (17% vs. 30% at 5 years, P = .007), increased rate of leukemia‐free survival (60% vs. 50%, P = .04), and improved “graft versus host disease (GVHD) and relapse‐free survival” (GRFS, 43% vs. 33%, P = .04). No significant effect could be observed in terms of the incidence of nonrelapse mortality or acute or chronic GVHD. In a multivariate model, the use of Vp/TBI was associated with reduced risk of relapse (HR = 0.62, P = .04) while the effect on other study end‐points was not significant. In conclusion, conditioning regimen based on Vp combined with TBI appears more effective for disease control than the combination of Cy with TBI for adult patients with Ph‐negative ALL treated with alloHCT.     

Mild chronic graft‐versus‐host disease may alleviate poor prognosis associated with FLT3 internal tandem duplication for adult acute myeloid leukemia following allogeneic stem cell transplantation with myeloablative conditioning in first complete remission: a retrospective study

Internal tandem duplication (ITD) of the FLT3 gene (Fms‐like tyrosine kinase 3) is the most commonly found mutation in acute myeloid leukemia (AML). The significance of FLT3‐ITD at diagnosis was retrospectively estimated for allo‐HSCT (allogeneic hematopoietic stem cell transplantation) outcomes in 140 patients, median age of 38, undergoing allo‐HSCT after myeloablative conditioning in first complete remission of AML. FLT3‐ITD was detected at AML diagnosis in 42/140 (30%) of included into this study patients. At 3 years, relapse incidence (RI) following allo‐HSCT in AML patients with intermediate or normal karyotype was significantly higher in those FLT3‐ITD positive than FLT3‐ITD negative [52.9 vs. 20.4%, P = 0.002]. Additionally, patients with mild chronic graft‐versus‐host disease (cGvHD) had significantly lower RI compared to patients with moderate or severe grade cGvHD or those not experiencing cGvHD, respectively, 4.8 vs. 36.0 vs. 27.8%, P = 0.032. FLT3‐ITD was harboring a poor prognosis in AML with intermediate or normal karyotype and significantly increased risk of relapse following allo‐HSCT. It appears that allo‐HSCT does not cure patients with FLT3‐ITD, unless they develop symptoms of mild cGvHD and graft versus leukemia, which may decrease RI.     

Centre characteristics and procedure‐related factors have an impact on outcomes of allogeneic transplantation for patients with CLL: a retrospective analysis from the European Society for Blood and Marrow Transplantation (EBMT)

The best approach for allogeneic haematopoietic stem cell transplantations (alloHCT) in patients with chronic lymphocytic leukaemia (CLL) is unknown. We therefore analysed the impact of procedure‐ and centre‐related factors on 5‐year event‐free survival (EFS) in a large retrospective study. Data of 684 CLL patients who received a first alloHCT between 2000 and 2011 were analysed by multivariable Cox proportional hazards models with a frailty component to investigate unexplained centre heterogeneity. Five‐year EFS of the whole cohort was 37% (95% confidence interval [CI], 34–42%). Larger numbers of CLL alloHCTs (hazard ratio [HR] 0·96, P = 0·002), certification of quality management (HR 0·7, P = 0·045) and a higher gross national income per capita (HR 0·4, P = 0·04) improved EFS. In vivo T‐cell depletion (TCD) with alemtuzumab compared to no TCD (HR 1·5, P = 0·03), and a female donor compared to a male donor for a male patient (HR 1·4, P = 0·02) had a negative impact on EFS, but not non‐myeloablative versus more intensive conditioning. After correcting for patient‐, procedure‐ and centre‐characteristics, significant variation in centre outcomes persisted. In conclusion, further research on the impact of centre and procedural characteristics is warranted. Non‐myeloablative conditioning appears to be the preferable approach for patients with CLL.     

Similar outcome of allogeneic stem cell transplantation after myeloablative and sequential conditioning regimen in patients with refractory or relapsed acute myeloid leukemia: A study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire

Patients with acute myeloid leukemia (AML) in relapse or refractory to induction therapy have a dismal prognosis. Allogeneic hematopoietic stem cell transplantation is the only curative option. In these patients, we aimed to compare the results of a myeloablative transplant versus a sequential approach consisting in a cytoreductive chemotherapy followed by a reduced intensity conditioning regimen and prophylactic donor lymphocytes infusions. We retrospectively analyzed 99 patients aged 18‐50 years, transplanted for a refractory (52%) or a relapsed AML not in remission (48%). Fifty‐eight patients received a sequential approach and 41 patients a myeloablative conditioning regimen. Only 6 patients received prophylactic donor lymphocytes infusions. With a median follow‐up of 48 months, 2‐year overall survival was 39%, 95% confidence interval (CI) (24‐53) in the myeloablative group versus 33%, 95% CI (21‐45) in the sequential groups (P = .39), and 2‐year cumulative incidence of relapse (CIR) was 57% versus 50% respectively (P = .99). Nonrelapse mortality was not higher in the myeloablative group (17% versus 15%, P = .44). In multivariate analysis, overall survival, CIR and nonrelapse mortality remained similar between the two groups. However, in multivariate analysis, sequential conditioning led to fewer acute grade II‐IV graft versus host disease (GVHD) (HR for sequential approach = 0.37; 95% CI: 0.21‐0.65; P < .001) without a significant impact on chronic GVHD (all grades and extensive). In young patients with refractory or relapsed AML, myeloablative transplant and sequential approach offer similar outcomes except for a lower incidence of acute GvHD after a sequential transplant.     

Comparison of umbilical cord blood allogeneic stem cell transplantation vs. auto‐SCT for adult acute myeloid leukemia patients in second complete remission at transplant: a retrospective study on behalf of the SFGM‐TC

This retrospective study considered the outcomes of 181 patients with acute myeloid leukemia (AML) transplanted in second complete remission (CR2) between January 2005 and April 2012 and who received either a myeloablative autologous stem cell transplant (Auto‐SCT; n = 82; median age: 48 years; median follow‐up: 45 months) or an umbilical cord blood (UCB) allogeneic SCT (n = 99, median age: 46 years; median follow‐up: 36 months; conditioning regimens: myeloablative n = 21, reduced n = 78; single unit n = 37, double units n = 62). Although the Auto group showed a significant better prognostic profile at transplant, with longer median interval between diagnosis and time of graft, higher incidence of good‐risk cytogenetics and lower number of previously transplanted patients, 3‐year OS and LFS were similar between both groups (Auto: 59 ± 6% vs. 50 ± 6%, P = 0.45; and 57 ± 6% vs. 46 ± 6%, P = 0.37). In multivariate analysis, UCB allo‐SCT was associated with lower relapse incidence (HR: 0.3, 95% CI: 0.11–0.82, P = 0.02), but higher non‐relapse mortality (NRM) (HR: 4.16; 95% CI: 1.46–11.9, P = 0.008). Results from this large study suggest that UCB allo‐SCT provides better disease control than auto‐SCT, which is especially important in the setting of high‐risk disease. However, this disease control advantage is counterbalanced by higher toxicity, highlighting the need for novel approaches aiming to decrease NRM after UCB allo‐SCT.     

Haematopoietic cell transplantation with and without sorafenib maintenance for patients with FLT3‐ITD acute myeloid leukaemia in first complete remission

We performed a retrospective study analysing the effect of sorafenib, an oral fms‐Like Tyrosine Kinase 3 (FLT3)/multikinase inhibitor, as post‐transplant maintenance in adult patients with FLT3‐internal tandem duplication (ITD) acute myeloid leukaemia (AML). We identified consecutive patients with FLT3‐ITD AML diagnosed between 2008 and 2014 who received haematopoietic cell transplantation (HCT) in first complete remission (CR1). Post‐HCT initiation of sorafenib (yes/no) was evaluated as a time‐varying covariate in the overall survival/progression‐free survival (OS/PFS) analysis and we performed a landmark analysis of controls alive without relapse at the median date of sorafenib initiation. We identified 26 sorafenib patients and 55 controls. Median follow‐up was 27·2 months post‐HCT for sorafenib survivors, and 38·4 months for controls (P = 0·021). The median time to initiating sorafenib was 68 days post‐HCT; 43 controls were alive without relapse at this cut‐off. Sorafenib patients had improved 2‐year OS in the d+68 landmark analysis (81% vs. 62%, P = 0·029). Sorafenib was associated with improved 2‐year PFS (82% vs. 53%, P = 0·0081) and lower 2‐year cumulative incidence of relapse (8·2% vs. 37·7%, P = 0·0077). In multivariate analysis, sorafenib significantly improved OS [Hazard ratio (HR) 0·26, P = 0·021] and PFS (HR 0·25, P = 0·016). There was no difference in 2‐year non‐relapse mortality (9·8% vs. 9·3%, P = 0·82) or 1‐year chronic graft‐versus‐host disease (55·5% vs. 37·2%, P = 0·28). These findings suggest potential benefit of post‐HCT sorafenib in FLT3‐ITD AML, and support further evaluation of post‐HCT FLT3 inhibition.     

GVHD prophylaxis using low‐dose cyclosporine improves survival in leukaemic recipients of HLA‐identical sibling transplants

Graft‐versus‐host disease (GVHD) prophylaxis of short duration (6 months) with low‐dose cyclosporine A (CsA) starting at 1 mg/kg per day i.v. and four doses of methotrexate (MTX) were given to 171 consecutive leukaemic recipients of HLA‐identical sibling transplants. In contrast, apart from MTX, retrospective controls received high‐dose CsA, starting at 5–7.5 mg/kg per day i.v. and discontinued 1 yr post‐transplant. In the low‐dose CsA group, the probability of acute GVHD grades I–II (70% vs. 53%, P < 0.01), and chronic GVHD were increased (58% vs. 25%, P < 0.01), whereas the incidences of acute GVHD grades III–IV (9% vs. 5%, P = 0.62), and non‐relapse mortality (20% vs. 22%, P = 0.58) were similar. Moreover, the probability of relapse was decreased (31% vs. 54%, P < 0.01), and both relapse‐free (56% vs. 38%, P = 0.04) and overall survival (61% vs. 40%, P = 0.04) were markedly improved using the low‐dose CsA regimen. In multivariate analyses, low‐dose CsA was strongly associated with chronic GVHD [relative hazard (RH) 2.56, P < 0.01], which decreased the risk of relapse (RH 0.46, P < 0.01) and improved the probability of survival (RH 1.84, P < 0.01). In conclusion, a low‐dose CsA regimen in leukaemic recipients of HLA‐identical sibling transplants increases the rate of chronic GVHD, which seems to attenuate the risk of relapse, thereby improving patient survival owing to enhanced graft‐versus‐leukaemia effect.     

High‐dose CD20‐targeted radioimmunotherapy‐based autologous transplantation improves outcomes for persistent mantle cell lymphoma

Autologous stem cell transplant (ASCT) can improve outcomes for mantle cell lymphoma (MCL) patients, yet relapses are frequent. We hypothesized that high‐dose anti‐CD20 radioimmunotherapy (RIT)‐based conditioning could improve results in this setting. We thus assessed 162 consecutive patients with MCL at our centre undergoing ASCT following high‐dose RIT‐based (n = 61) or standard (n = 101) conditioning. RIT patients were less likely to be in first remission (48% vs. 72%; P = 0·002), be in complete remission (CR) (26% vs. 61%; P < 0·001) and have chemosensitive disease (84% vs. 96%; P = 0·006). RIT‐based conditioning was associated with a reduced risk of treatment failure [hazard ratio (HR) 0·40; P = 0·001] and mortality (HR 0·49; P = 0·01) after adjusting for these imbalances. This difference increased as disease status worsened (from CR to partial remission to stable/progressive disease), with respective HRs of 1·14, 0·53 and 0·04 for mortality, and 0·66, 0·36 and 0·14 for treatment failure. RIT‐based conditioning appears to improve outcome following ASCT for MCL patients unable to achieve CR after controlling for imbalances in important risk factors. These data support the further study of RIT and radiation‐based strategies in a risk‐adapted approach to ASCT for persistent MCL.     

Comparable long‐term outcomes after reduced‐intensity conditioning versus myeloablative conditioning allogeneic stem cell transplantation for adult high‐risk acute lymphoblastic leukemia in complete remission

The role of reduced‐intensity conditioning (RIC) in adult acute lymphoblastic leukemia (ALL) remains unclear because of the small sample size, short follow‐up duration, various regimens for conditioning and graft‐versus‐host disease (GVHD) prophylaxis, and the heterogeneity of selection criteria for transplantation. We compared long‐term outcomes of 60 consecutive RIC transplants (fludarabine plus melphalan) with 120 myeloablative conditioning (MAC) transplants (total body irradiation plus cyclophosphamide) for adult high‐risk ALL in first or second complete remission. All transplants received a uniform strategy of pretransplant chemotherapy and GVHD prophylaxis. Compared to MAC transplants, RIC transplants had older age (46 years vs. 33 years, P < 0.001) and higher proportions of transplantation using peripheral blood (93.3% vs. 13.3%; P < 0.001) but otherwise showed similar characteristics. After a median follow‐up of 67 months, RIC transplants showed comparable nonrelapse mortality (21.2% vs. 24.3%) and disease‐free survival (50.8% vs. 54.9%) to MAC transplants, although relapse risk was higher (34.2% vs. 26.4%; HR, 2.07; P = 0.019) in multivariate analysis. Other independent factors associated with better outcomes were the presence of chronic GVHD and transplantation in first complete remission. Interestingly, the negative impact of RIC on relapse risk was seen only for Philadelphia‐positive ALL transplants (32.7% vs. 19.6%; HR, 3.46; P = 0.020), while no difference was found between RIC and MAC for Philadelphia‐negative ALL transplants (35.0% vs. 32.1%; HR, 1.39; P = 0.429). RIC can be considered as a reasonable choice for providing a sufficient long‐term graft‐versus‐leukemia effect for adult high‐risk ALL patients ineligible for MAC. Am. J. Hematol. 88:634–641, 2013. © 2013 Wiley Periodicals, Inc.     

Long‐term follow‐up of patients receiving allogeneic stem cell transplant for chronic lymphocytic leukaemia: mixed T‐cell chimerism is associated with high relapse risk and inferior survival

There is limited information regarding the immunological predictors of post‐allogeneic stem cell transplant (alloSCT) outcome in chronic lymphocytic leukaemia (CLL), such as mixed T‐cell chimerism. We analysed 143 consecutive patients with relapsed/refractory CLL, transplanted between 2000 and 2012, to determine the prognostic relevance of mixed chimerism post‐alloSCT and the ability of post‐transplant immunomodulation to treat relapse. Mixed T‐cell chimerism occurred in 50% of patients at 3 months and 43% at 6 months post‐alloSCT; upon 3‐ and 6‐month landmark analysis, this was associated with inferior progression‐free survival (PFS) [Hazard ratio (HR) 1·93, P = 0·003 and HR 2·58, P < 0·001] and survival (HR 1·66, P = 0·05 and HR 2·17, P < 0·001), independent of baseline patient characteristics, and a lower rate of grade II–IV acute graft‐versus‐host disease (GHVD) (16% vs. 52%, P < 0·001). Thirty‐three patients were treated with immunomodulation for relapse post‐alloSCT (immunosuppression withdrawal, n = 6, donor lymphocyte infusion, n = 27); 17 achieved complete response (CR), which predicted superior PFS (53 months vs. 10 months, P < 0·001) and survival (117 months vs. 30 months, P = 0·006). Relapsed patients with mixed chimerism had inferior response to immunomodulation; conversion to full donor chimerism was highly correlated both with CR and with the development of severe acute GVHD, which was fatal in 3/8 patients. Novel therapeutic strategies are required for patients with mixed T‐cell chimerism post‐alloSCT for CLL.     

Leukaemia relapse after allogeneic transplants for acute myeloid leukaemia: predictive role of WT1 expression

We assessed WT1 expression (expressed as messenger copies/10⁴ ABL1) from marrow cells of 122 patients with acute myeloid leukaemia (AML), before and after an unmanipulated allogeneic haemopoietic stem cell transplant (HSCT). The median age was 44 years (15–69), 59% were in first remission, 74% received a myeloablative conditioning regimen and the median follow up was 865 d (34–2833). Relapse was higher in 67 patients with WT1 expression, at any time post‐HSCT, exceeding 100 copies (54%), as compared to 16%, for 55 patients with post‐HSCT WT1 expression <100 copies (P < 0·0001). Similarly, actuarial 5‐year survival (OS) was 40% vs. 63%, respectively (P = 0·03). In multivariate Cox analysis, WT1 expression post‐HSCT was the strongest predictor of relapse (Hazard Ratio [HR] 4·5, P = 0·0001), independent of disease phase (HR 2·3, P = 0·002). Donor lymphocyte infusions (DLI) were given to 17 patients because of increasing WT1 levels: their OS was 44%, vs. 14% for 21 patients with increasing WT1 expression who did not receive DLI (P = 0·004). In conclusion, WT1 expression post‐HSCT is a strong predictor of leukaemia relapse and survival in AML; WT1 may be used as a marker for early interventional therapy.     

Incidence and risk factors for cataract after haematopoietic stem cell transplantation for childhood leukaemia: an LEA study

Cataract was prospectively assessed by serial slip lamp tests in 271 patients included in the Leucémie Enfants Adolescents (LEA) programme, the French cohort of childhood leukaemia survivors. All had received haematopoietic stem cell transplantation (HSCT) after total body irradiation (TBI, n = 201) or busulfan‐based (n = 70) myeloablative conditioning regimen. TBI was fractionated in all but six patients. The mean duration of follow‐up from HSCT was 10·3 years. Cataract was observed in 113/271 patients (41·7%); 9/113 (8·1%) needed surgery. Cumulative incidence after TBI increased over time from 30% at 5 years to 70·8% and 78% at 15 and 20 years, respectively, without any plateau thereafter. The 15‐year cumulative incidence was 12·5% in the Busulfan group. A higher cumulative steroid dose appeared to be a cofactor of TBI for cataract risk, in both univariate and multivariate Cox analysis. In the multivariate analysis, cataract had an impact in two quality of life domains: ‘the role limitation due to physical problems’ and ‘the role limitation due to emotional problems’. These data suggest that with increasing follow‐up, nearly all patients who receive TBI, even when fractionated, will suffer from cataract that can impact on their quality of life and that high cumulative steroid dose is a cofactor.     

Next‐generation sequencing‐based detection of circulating tumour DNA After allogeneic stem cell transplantation for lymphoma

Next‐generation sequencing (NGS)‐based circulating tumour DNA (ctDNA) detection is a promising monitoring tool for lymphoid malignancies. We evaluated whether the presence of ctDNA was associated with outcome after allogeneic haematopoietic stem cell transplantation (HSCT) in lymphoma patients. We studied 88 patients drawn from a phase 3 clinical trial of reduced‐intensity conditioning HSCT in lymphoma. Conventional restaging and collection of peripheral blood samples occurred at pre‐specified time points before and after HSCT and were assayed for ctDNA by sequencing of the immunoglobulin or T‐cell receptor genes. Tumour clonotypes were identified in 87% of patients with adequate tumour samples. Sixteen of 19 (84%) patients with disease progression after HSCT had detectable ctDNA prior to progression at a median of 3·7 months prior to relapse/progression. Patients with detectable ctDNA 3 months after HSCT had inferior progression‐free survival (PFS) (2‐year PFS 58% vs. 84% in ctDNA‐negative patients, P = 0·033). In multivariate models, detectable ctDNA was associated with increased risk of progression/death (Hazard ratio 3·9, P = 0·003) and increased risk of relapse/progression (Hazard ratio 10·8, P = 0·0006). Detectable ctDNA is associated with an increased risk of relapse/progression, but further validation studies are necessary to confirm these findings and determine the clinical utility of NGS‐based minimal residual disease monitoring in lymphoma patients after HSCT.     

Post‐transplantation cyclophosphamide versus conventional graft‐versus‐host disease prophylaxis in mismatched unrelated donor haematopoietic cell transplantation

Post‐transplantation cyclophosphamide (PTCy) is an effective strategy to prevent graft‐versus‐host disease (GVHD) after haploidentical haematopoietic cell transplantation (HCT). We determined the efficacy of PTCy‐based GVHD prophylaxis in human leucocyte antigen (HLA)‐mismatched unrelated donor (MMUD) HCT. We analysed 113 adult patients with high‐risk haematological malignancies who underwent one‐antigen MMUD transplantation between 2009 and 2013. Of these, 41 patients received PTCy, tacrolimus and mycophenolate mofetil (MMF) for GVHD prophylaxis; 72 patients received conventional prophylaxis with anti‐thymocyte globulin, tacrolimus and methotrexate. Graft source was primarily bone marrow (83% PTCy vs. 63% conventional group). Incidence of grade II–IV (37% vs. 36%, P = 0·8) and grade III–IV (17% vs. 12%, P = 0·5) acute GVHD was similar at day 100. However, the incidence of grade II‐IV acute GVHD by day 30 was significantly lower in the PTCy group (0% vs. 15%, P = 0·01). Median time to neutrophil (18 days vs. 12 days, P < 0·001) and platelet (25·5 days vs. 18 days, P = 0·05) engraftment was prolonged in PTCy group. Rates of graft failure, chronic GVHD, 2‐year non‐relapse mortality, relapse, progression‐free survival or overall survival were similar. Our results demonstrate that PTCy, tacrolimus and MMF for GVHD prophylaxis is safe and produced similar results as conventional prophylaxis in patients with one antigen HLA‐MMUD HCT.     

Inhibitory killer cell immunoglobulin‐like receptor (iKIR) mismatches improve survival after T‐cell‐repleted haploidentical transplantation

Alloreactivity triggered by interaction between killer cell immunoglobulin‐like receptors (KIRs) and natural killer (NK) cells plays a role in the graft‐versus‐tumor effect after hematopoietic stem cell transplantation (SCT). Our aim in this study was to evaluate this role in the setting of T‐cell‐repleted haploidentical SCT with postinfusion high‐dose cyclophosphamide (PT‐Cy). We included 33 patients. Among patient–donor pairs with at least 1 inhibitory KIR (iKIR) gene mismatch, event‐free survival (EFS) and cumulative incidence of relapse 1 year after transplant were significantly better (85% vs. 37% [P = 0.008] and 18% vs. 46% [P = 0.041], respectively). A subanalysis in 12 patients with Hodgkin's lymphoma (HL) showed an improvement in EFS 1 year after transplant in those patients with KIR ligand mismatch (100% vs. 25%, P = 0.012), although overall survival (OS) was not affected (85% vs. 80%, P = 0.2). Eight of 12 patient–donors pairs presented iKIR mismatches. Of note, this outcome was better in the small subgroup, both for EFS (100% vs. 25%, P = 0.012) and for OS (100% vs. 37%, P = 0.004). Our data suggest that in the setting of T‐cell‐repleted haploidentical SCT with PT‐Cy, iKIR mismatch is associated with improved survival, with particularly good results for both iKIR and KIR ligand mismatches in patients with HL.     

Improved prognosis with additional medium‐dose VP16 to CY/TBI in allogeneic transplantation for high risk ALL in adults

Allogeneic hematopoietic stem cell transplantation (HSCT) with the conventional cyclophosphamide and total body irradiation (CY/TBI) regimen is an essential therapeutic strategy for acute lymphoblastic leukemia (ALL) in adults. Medium‐dose etoposide (VP16, 30‐40 mg/kg) can be added to intensify this CY/TBI regimen and reduce relapse; however, differences in prognosis between the VP16/CY/TBI and CY/TBI regimens have not yet been fully analyzed. We conducted a retrospective cohort study using a Japanese transplant registry database to compare the prognosis between the VP16/CY/TBI (VP16, total 30‐40 mg/kg) (N = 376) and CY/TBI (N = 1178) regimens in adult patients with ALL transplanted at complete remission (CR) between January 1, 2000 and December 31, 2014. Our analyses indicated that VP16/CY/TBI significantly reduced relapse compared with CY/TBI (risk ratio, 0.75; 95% confidence interval [CI], 0.56‐1.00; P = .05) with a corresponding improvement in leukemia‐free survival (hazard ratio [HR], 0.76; 95%CI, 0.62‐0.93; P = .01), particularly in patients transplanted at CR1 with advanced‐risk (positive minimal residual disease, presence of poor‐risk cytogenetics, or an initial elevated leukocyte count) (HR, 0.75; 95%CI, 0.56‐1.00; P = .05) or those transplanted beyond CR2 (HR, 0.58; 95%CI, 0.39‐0.88; P = .01). The addition of VP16 did not increase post‐transplant complications or nonrelapse mortality (HR, 0.88; 95%CI, 0.65‐1.18; P = .38). This study is the first to reveal the efficacy of the addition of medium‐dose VP16 to CY/TBI in high‐risk ALL. To establish new myeloablative conditioning regimens including VP16, a large‐scale prospective study is necessary.     

Outcome for children and young people with Early T‐cell precursor acute lymphoblastic leukaemia treated on a contemporary protocol,UKALL 2003

We investigated the outcome for children and young people with Early T‐precursor acute lymphoblastic leukaemia (ETP‐ALL), a recently described poor prognosis sub‐group of T‐ALL, treated on a contemporary protocol, UKALL 2003. After a median follow‐up of 4 years and 10 months, the ETP sub‐group, representing 16% of T‐ALL patients, had non‐significantly inferior 5‐year event‐free survival (76·7% vs. 84·6%, P = 0·2) and overall survival (82·4% vs. 90·9%, P = 0·1), and a higher relapse rate (18·6% vs. 9·6%, P = 0·1) compared to typical T‐ALL. ETP‐ALL has an intermediate risk outcome, which does not warrant experimental treatment or first remission allogeneic transplant for the group universally.     

Impact of total body irradiation- vs chemotherapy-based myeloablative conditioning on outcomes of haploidentical hematopoietic cell transplantation for acute myelogenous leukemia

The optimal myeloablative conditioning (MAC) for patients undergoing haploidentical hematopoietic cell transplantation (haplo-HCT) is unknown. We studied the outcomes of total body irradiation (TBI) vs chemotherapy (CT) based MAC regimens in acute myeloid leukemia (AML) patients. The study included 1008 patients who underwent first haplo-HCT with post-transplant cyclophosphamide, following TBI (N = 89, 9%) or CT (n = 919, 91%) based MAC. Patients in the TBI cohort were younger (median age, 38 vs 47 years, P < .01) and more likely to receive BM graft (57% vs 43%, P = .01). Two-year overall chronic GVHD (cGVHD) incidence was 42% vs 27% (P < .01) and extensive cGVHD incidence was 9% vs 12% (P = .33) in TBI and CT cohorts, respectively. Graft failure was reported in two (2%) TBI- and 65 (7%) CT-MAC recipients (P = .08). Death from veno-occlusive disease was reported in one (3%) TBI and 11 (3%) CT patients who died during the study period. In the multivariate analysis, TBI was associated with increased risk for overall cGVHD (hazard ratio = 1.95, 95% confidence interval:1.2-3.1, P < .01) compared to CT-based MAC. The choice of conditioning regimen did not impact relapse incidence, leukemia-free survival, non-relapse mortality, overall survival or GVHD-relapse-free survival in multivariate analysis. In conclusion, major transplant outcomes were not statistically different between TBI-based MAC and CT-based MAC in patients with AML after haplo-HCT/PTCy.