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Reduced intensity conditioning (RIC) transplantation is increasingly offered to older patients with acute myeloblastic leukemia. We have previously shown that a RIC allograft, particularly from a sibling donor, is beneficial in intermediate-risk patients aged 35-65 years. We here present analyses from the NCRI AML16 trial extending this experience to older patients aged 60-70 inclusive lacking favorable-risk cytogenetics. Nine hundred thirty-two patients were studied, with RIC transplant in first remission given to 144 (sibling n=52, matched unrelated donor n=92) with a median follow-up for survival from complete remission of 60 months. Comparisons of outcomes of patients transplanted versus those not were carried out using Mantel-Byar analysis. Among the 144 allografted patients, 93 had intermediate-risk cytogenetics, 18 had adverse risk and cytogenetic risk group was unknown for 33. In transplanted patients survival was 37% at 5 years, and while the survival for recipients of grafts from siblings (44%) was better than that for recipients of grafts from matched unrelated donors (34%), this difference was not statistically significant (P=0.2). When comparing RIC versus chemotherapy, survival of patients treated with the former was significantly improved (37% versus 20%, hazard ratio = 0.67 [0.53-0.84]; P

Microbiota injury occurs in many patients undergoing allogeneic hematopoietic cell transplantation, likely as a consequence of conditioning regimens involving chemo- and radiotherapy, the widespread use of both prophylactic and therapeutic antibiotics, and profound dietary changes during the peri-transplant period. Peri-transplant dysbiosis is characterized by a decrease in bacterial diversity, loss of commensal bacteria and single-taxon domination (e.g., with Enterococcal strains). Clinically, deviation of the post-transplant microbiota from a normal, high-diversity, healthy state has been associated with increased risk of bacteremia, development of graft-versus-host disease and decreases in overall survival. A number of recent clinical trials have attempted to target the microbiota in allogeneic hematopoietic cell transplantation patients via dietary interventions, selection of therapeutic antibiotics, administration of pre- or pro-biotics, or by performing fecal microbiota transplantation. These strategies have yielded promising results but the mechanisms by which these interventions influence transplant-related complications remain largely unknown. In this review we summarize the current approaches to targeting the microbiota, discuss potential underlying mechanisms and highlight the key outstanding areas that require further investigation in order to advance microbiota- targeting therapies.

Allogeneic hematopoietic stem-cell transplantation is a potentially curative therapy for various hematologic diseases. An essential component of this procedure is the pre-transplant conditioning regimen, which should facilitate engraftment and reduce or eliminate tumor cells. The recognition of the substantial association of a graft-versus- tumor effect and the high toxicity of the commonly used conditioning regimen led to the introduction of more differentiated intensity strategies, with the aim of making hematopoietic stem-cell transplantation less toxic and safer, and thus more applicable to broader populations such as older or unfit patients. In general, prospective and retrospective studies suggest a correlation between increasing intensity and nonrelapse mortality and an inverse correlation with relapse incidence. In this review, we will summarize traditional and updated definitions for conditioning intensity strategies and the landscape of comparative prospective and retrospective studies, which may help to find the balance between the risk of non-relapse mortality and relapse. We will try to underscore the caveats regarding these definitions and analyses, by missing complex differences between intensity and toxicity as well as the broad influences of other factors in the transplantation procedure. We will summarize evidence regarding several confounders which may influence decisions when selecting the intensity of the conditioning regimen for any given patient, according to the individual risk of relapse and non-relapse mortality.

With limited data comparing hematopoietic cell transplant outcomes between myeloablative total body irradiation (TBI) containing and non-TBI regimens in children with de novo acute myeloid leukemia, the aim of this study was to compare transplant-outcomes between these regimens. Cox regression models were used to compare transplant-outcomes after TBI and non-TBI regimens in 624 children transplanted between 2008 and 2016. Thirty two percent (n=199) received TBI regimens whereas 68% (n=425) received non-TBI regimens. Five-year non-relapse mortality was higher with TBI regimens (22% vs. 11%, P

Graft-versus-host disease (GvHD) prophylaxis for unmanipulated haploidentical hematopoietic cell transplantation includes posttransplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG). Utilizing data in the European Society for Blood and Marrow Transplantation registry, we compared ATG- versus PTCy-based GvHD prophylaxis in 434 adults with acute lymphoblastic leukemia undergoing haploidentical hematopoietic cell transplantation. Of the 434 patients included in this study, ATG was used in 98 and PTCy in 336.. The median follow-up was approximately 2 years. The baseline characteristics of the patients were similar between the groups except that the ATG group was more likely to have had relapsed/refractory acute lymphoblastic leukemia (P=0.008), had conditioning not including total body irradiation (P

Core binding factor acute myeloid leukemia (AML) comprises two subtypes with distinct cytogenetic abnormalities of either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22). Since longterm response to chemotherapy in these leukemias is relatively good, allogeneic hematopoietic stem cell transplantation is considered in patients who relapse and achieve second complete remission. To evaluate the outcomes of allogeneic transplantation in this indication, we studied 631 patients reported to the European Society for Blood and Marrow Transplantation Registry between the years 2000 and 2014. Leukemia-free survival probabilities at two and five years were 59.1% and 54.1%, while overall survival probabilities were 65% and 58.2%, respectively. The incidence of relapse and risk of non-relapse mortality at the same time points were 19.8% and 22.5% for relapse and 20.9% and 23.3% for non-relapse mortality, respectively. The most important adverse factors influencing leukemia-free and overall survival were: leukemia with t(8;21), presence of three or more additional chromosomal abnormalities, and Karnofsky performance score

Outcomes of patients with persistent high-risk leukemia or myelodysplasia prior to allogeneic hematopoietic cell transplantation are dismal. We therefore conducted a phase I trial evaluating the use of CD45-targeted radiotherapy preceding hematopoietic cell transplantation with the goal of improving outcomes for this high-risk scenario. Fifteen patients, median age 62 (range 37-76) years, were treated: ten with advanced acute myeloid leukemia, five with high-risk myelodysplastic syndrome. All patients had evidence of disease prior to treatment including nine with marrow blast counts ranging from 7-84% and six with minimal residual disease. Patients received escalating doses of yttrium-90-labeled anti-CD45 antibody followed by fludarabine and 2 Gy total body irradiation prior to human leukocyte antigen-matched, related or unrelated hematopoietic cell transplantation. Although a maximum dose of 30 Gy was delivered to the liver, no dose-limiting toxicity was observed. Therefore, the maximum-tolerated dose could not be estimated. Treatment led to complete remission in 13 patients (87%). All patients engrafted by day 28. Six patients relapsed, median of 59 (range 6-351) days, after transplantation. The 1-year estimate of relapse was 41%. Eight patients (53%) are surviving with median follow up of 1.8 (range 0.9-5.9) years. Estimated overall survival at one and two years was 66% and 46%, respectively, with progression-free survival estimated to be 46% at each time point. In conclusion, the combination of 90Y-DOTA-BC8 with an allogeneic hematopoietic cell transplantation regimen was feasible and tolerable. This approach appears promising in this high-risk leukemia/myelodysplasia patient population with active disease. (Trial registered at clinicaltrials.gov identifier: NCT01300572).

We sought to study whether survival after haploidentical transplantation is comparable to that after matched unrelated donor transplantation for 822 patients aged 50-75 years with acute myeloid leukemia in first or second complete remission. One hundred and ninety-two patients received grafts from haploidentical donors (sibling 25%; offspring 75%) and 631 patients from matched unrelated donors aged 18-40 years. Patients' and disease characteristics of the two groups were similar except that recipients of matched unrelated donor transplantation were more likely to have poor risk cytogenetics and more likely to receive myeloablative conditioning regimens. Time from documented remission to transplant did not differ by donor type. Five-year overall survival was 32% and 42% after haploidentical and matched unrelated donor transplant, respectively (P=0.04). Multivariable analysis showed higher mortality (hazard ratio 1.27, P=0.04) and relapse (hazard ratio 1.32, P=0.04) after haploidentical transplantation, with similar non-relapse mortality risks. Chronic graft-versus-host disease was higher after matched unrelated donor compared to haploidentical transplantation when bone marrow was the graft (hazard ratio 3.12, P

Testosterone is an important determinant of endothelial function and vascular health in men. As both factors play a role in mortality after allogeneic stem cell transplantation (alloSCT), we retrospectively evaluated the impact of pre-transplant testosterone levels on outcome in male patients undergoing alloSCT. In the discovery cohort (n=346), an impact on outcome was observed only in the subgroup of patients allografted for acute myeloid leukemia (AML) (n=176, hereafter termed 'training cohort'). In the training cohort, lower pre-transplant testosterone levels were significantly associated with shorter overall survival (OS) [hazard ratio (HR) for a decrease of 100 ng/dL: 1.11, P=0.045]. This was based on a higher hazard of non-relapse mortality (NRM) (cause-specific HR: 1.25, P=0.013), but not relapse (cause-specific HR: 1.06, P=0.277) in the multivariable models. These findings were replicated in a confirmation cohort of 168 male patients allografted for AML in a different center (OS, HR: 1.15, P=0.012 and NRM, cause-specific HR: 1.23; P=0.008). Next, an optimized cut-off point for pre-transplant testosterone was derived from the training set and evaluated in the confirmation cohort. In multivariable models, low pre-transplant testosterone status (

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a curative option for severe aplastic anemia (SAA), and transplantation from identical sibling donors (ISD) has been recommended as a first-line treatment. Haploidentical donor (HID) transplantation for SAA has made great advances; thus, an increased role of HID-SCT in SAA should be considered. We performed a national registry-based analysis comparing long-term outcomes in the upfront HID or upfront ISD SCT setting. A total of 342 SAA patients were enrolled, with 183 patients receiving HID SCT and 159 receiving ISD SCT. The estimated 9-year overall survival and failure-free survival were 87.1±2.5% and 89.3±3.7% (P=0.173) and 86.5±2.6% versus 88.1±3.8% (P=0.257) for patients in the HID and ISD SCT groups, respectively. Transplantation from HID or ISD SCT has greatly improved quality of life (QoL) levels post-HSCT compared to pre-HSCT. The occurrence of chronic graft-versus-host disease was the only identified adverse factor affecting each subscale of QoL. Physical and mental component summaries in adults as well as physical, mental, social, and role well-being in children were all similar between HID and ISD SCT at 5-year time points. At the last follow-up, the proportion of returning to society was comparable between the HID and ISD groups, showing 78.0% versus 84.6% among children and 74.6% versus 81.2% among adults. These data suggest that haploidentical transplant can be considered a potential therapeutic option in the upfront setting for SAA patients in the absence of an HLA-identical related or unrelated donor.

Advances in understanding the pathogenesis and molecular landscape of myelofibrosis have occurred over the last decade. Treating physicians now have access to an ever-evolving armamentarium of novel agents to treat patients, although allogeneic hematopoietic stem cell transplantation remains the only curative approach. Improvements in donor selection, conditioning regimens, disease monitoring and supportive care have led to augmented survival after transplantation. Nowadays, there are comprehensive guidelines concerning allogeneic hematopoietic stem cell transplantation for patients with myelofibrosis. However, it commonly remains difficult for both physicians and patients alike to weigh up the risk-benefit ratio of transplantation given the inherent heterogeneity regarding both clinical course and therapeutic response. In this timely review, we provide an up-to-date synopsis of current transplantation recommendations, discuss usage of JAK inhibitors before and after transplantation, examine donor selection and compare conditioning platforms. Moreover, we discuss emerging data concerning the impact of the myelofibrosis mutational landscape on transplantation outcome, peritransplant management of splenomegaly, poor graft function and prevention/management of relapse.

The use of antihuman T-lymphocyte immunoglobulin in the setting of transplantation from an HLA-matched related donor is still much debated. Acute and chronic graft-versus-host disease are the main causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis. The aim of this study was to evaluate the effect of antihuman T-lymphocyte immunoglobulin in a large cohort of patients with myelofibrosis (n=287). The cumulative incidences of grade II-IV acute graft-versus-host disease among patients who were or were not given antihuman T-lymphocyte immunoglobulin were 26% and 41%, respectively. The corresponding incidences of chronic graft-versus-host disease were 52% and 55%, respectively. Non-adjusted overall survival, disease-free survival and non-relapse mortality rates were 55% versus 53%, 49% versus 45%, and 32% versus 31%, respectively, among the patients who were or were not given antihuman T-lymphocyte immunoglobulin. An adjusted model confirmed that the risk of acute graft-versus-host disease was lower following antihuman T-lymphocyte immunoglobulin (hazard ratio, 0.54; P=0.010) while it did not decrease the risk of chronic graft-versus-host disease. The hazard ratios for overall survival and non-relapse mortality were 0.66 and 0.64, with P-values of 0.05 and 0.09, respectively. Antihuman T-lymphocyte immunoglobulin did not influence disease-free survival, graft-versus-host disease, relapse-free survival or relapse risk. In conclusion, in the setting of matched related transplantation in myelofibrosis patients, this study demonstrates that antihuman T-lymphocyte immunoglobulin decreases the risk of acute graft-versus-host disease without increasing the risk of relapse. ispartof: HAEMATOLOGICA vol:104 issue:6 pages:1230-1236 ispartof: location:Italy status: published

A non-myeloablative regimen of fludarabine and 200 cGy total body irradiation combined with post-grafting immunosuppression with mycophenolate mofetil and a calcineurin inhibitor facilitates allogeneic hematopoietic cell transplantation from HLA-matched related or unrelated donors in older patients and/or those with comorbidities. However, outcomes of prior studies have been disappointing in patients with myelodysplastic syndromes or myeloproliferative neoplasms due to high incidences of progression or graft failure (together termed hematopoietic cell transplantation-failure). We hypothesized that escalating the total body irradiation dose may improve the outcomes and subsequently performed a phase II total body irradiation dose-escalation trial. Patients with median age 66 years were enrolled in two arms to receive non-myeloablative conditioning followed by hematopoietic cell transplantation with total body irradiation dose escalation for excessive hematopoietic cell transplantation-failure: Arm A: myeloproliferative neoplasm/myelodysplastic syndrome low risk (n=36); and Arm B: myelodysplastic syndrome high-risk/chronic myelomonocytic leukemia (n=41). Total body irradiation dose levels were: Level-1 (300 cGy), Level-2 (400 cGy), or Level-3 (450 cGy). Patients received intravenous fludarabine 30 mg/m2 for three days. Total body irradiation was administered on day 0 followed by infusion of peripheral blood stem cells from HLA-matched related (n=30) or unrelated (n=47) donors. Post-grafting immunosuppression with mycophenolate mofetil and cyclosporine was administered. The primary end point was day 200 hematopoietic cell transplant failure, with the objective of reducing the incidence to

Second allogeneic hematopoietic stem cell transplantation is a curative treatment option for patients with hematologic malignancies. However, it is unclear whether HLA discrepancy between graft and first donor has an impact on the outcome of second transplantation. We retrospectively analyzed 646 patients receiving second transplantation after an initial HLA mismatched transplantation. With regard to graft-versus-host, the one-allele mismatch (1 mismatch) group (SHR, 1.88; 95%CI: 0.79-4.45; P=0.163) and more than one-allele mismatch group (≥ 2 mismatch) (SHR, 1.84; 95%CI, 0.75–4.51; P=0.182) had higher risks of grade III–IV acute graft-versus-host disease (GvHD) compared to the HLA-matched (0 mismatch) group. In contrast, no difference in risk of acute GvHD was found among the 0, 1, and ≥ 2 mismatch group with respect to graft-versus-first donor. With regard to graft-versus-host, the ≥ 2 mismatch group showed a significantly higher risk of treatment-related mortality (SHR, 1.90; 95%CI, 1.04–3.50; P=0.038) compared to the 0 mismatch group, while the risk of relapse was slightly lower in the ≥ 2 mismatch group (SHR, 068; 95%CI, 0.44–1.06; P=0.086). In contrast, with regard to graft-versus-first donor, there were no significant differences in treatment-related mortality or relapse among the three groups. These findings suggested that HLA discrepancy between graft and host induces transplant-related immunological responses in second transplantation leading to an increase in treatment-related mortality, in contrast, the biological effects of HLA discrepancy between graft and first donor on outcome may be negligible.

Poor graft function is a serious complication following allogeneic hematopoietic stem cell transplantation. Infusion of CD34+-selected stem cells without pre-conditioning has been used to correct poor graft function, but predictors of recovery are unclear. We report the outcome of 62 consecutive patients who had primary or secondary poor graft function who underwent a CD34+-selected stem cell infusion from the same donor without further conditioning. Forty-seven of 62 patients showed hematologic improvement and became permanently transfusion- and growth factorindependent. In multivariate analysis, parameters significantly associated with recovery were shared cytomegalovisur seronegative status of both the recipient and donor, the absence of active infection and matched recipientdonor sex. Recovery was similar in patients with mixed and full donor chimerism. Five-year overall survival rates were 74.4% (95% confidence interval [95% CI: 59-89]) in patients demonstrating complete recovery, 16.7% (95% CI: 3-46) in patients with partial recovery and 22.2% (CI 95% 5-47) in those who had no response. In patients with blood count recovery, those with poor graft function in one or two lineages had a better 5-year overall survival (93.8%, 95% CI: 82-99) than those with trilineage failure (53%, 95% CI: 34-88). New strategies including cytokine or agonist support, or a second transplant need to be investigated in patients whose blood counts do not recover.

After more than 60 years of research in allogeneic hematopoietic cell transplantation (HCT), this therapy has advanced from one that was declared dead in the 1960s to a standard treatment of otherwise fatal malignant and non-malignant blood diseases. To date, close to 1.5 million hematopoietic cell transplants have been performed in more than 1,500 transplantation centers worldwide. This review will highlight the enormous efforts by numerous investigators throughout the world who have brought the experimental field of HCT to clinical reality, examine ongoing challenges, and provide insights for the future.

The success of hematopoietic stem cell transplantation is determined by multiple factors. Additional complexity is conferred by covariables showing time-dependent effects. We evaluated the effect of predictors on competing-risk outcomes after hematopoietic stem cell transplantation in a time-dependent manner. We analyzed 14951 outcomes of adult patients with hematologic malignancies who underwent a first allogeneic transplant. We extended the combined endpoints of disease-free and overall survival to competing-risk settings: disease-free survival was split into relapse and non-relapse mortality. Overall survival was divided into transplant-related mortality, death from other causes and death from unknown causes. For time-dependent effects we computed estimators before and after a covariable-specific cut-point. Patients treated with reduced intensity conditioning had a constantly higher risk of relapse compared to patients treated with myeloablative conditioning. For non-relapse mortality, patients treated with reduced intensity conditioning had a reduced mortality risk but this effect was only seen in the first 4 months after transplantation (hazard ratio: 0.76, P

Mixed phenotype acute leukemias are infrequent and considered high risk. The optimal treatment approach and the role of allogeneic hematopoietic stem cell transplantation are not entirely clear. In this study, we investigated 519 patients with mixed phenotype acute leukemia in first complete remission who underwent allogeneic hematopoietic stem cell transplantation between 2000 and 2014, and who were reported to the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT). Median age was 38.1 years (range 18-75). Cytogenetics classified 49.3% as poor risk. At three years, relapse incidence was 31.4% (26.9-35.9), non-relapse mortality was 22.1% (18.4-26.1), the leukemia-free survival was 46.5% (41.7-51.4), and the overall survival was 56.3% (51.5-61.2). At six months, 32.5% had developed acute graft-versus-host disease, while at three years, 37.5% had developed chronic graft-versus-host disease (32.6-42.3). In a multivariate analysis, age and year of transplant had a strong impact on outcome. Myeloablative conditioning using total body irradiation correlated with a better leukemia-free survival. Our study suggests that mixed phenotype acute leukemia is potentially sensitive to graft-versus-leukemia and thus can benefit from allogeneic hematopoietic stem cell transplantation with a potential for cure.

Allogeneic hematopoietic stem cell transplantation has been well established for several decades as gene replacement therapy for patients with thalassemia major, and now offers very high rates of cure for patients who have access to this therapy. Outcomes have improved tremendously over the last decade, even in high-risk patients. The limited data available suggests that the long-term outcome is also excellent, with a >90% survival rate, but for the best results, hematopoietic stem cell transplantation should be offered early, before any end organ damage occurs. However, access to this therapy is limited in more than half the patients by the lack of suitable donors. Inadequate hematopoietic stem cell transplantation services and the high cost of therapy are other reasons for this limited access, particularly in those parts of the world which have a high prevalence of this condition. As a result, fewer than 10% of eligible patients are actually able to avail of this therapy. Other options for curative therapies are therefore needed. Recently, gene correction of autologous hematopoietic stem cells has been successfully established using lentiviral vectors, and several clinical trials have been initiated. A gene editing approach to correct the β-globin mutation or disrupt the BCL11A gene to increase fetal hemoglobin production has also been reported, and is expected to be introduced in clinical trials soon. Curative possibilities for the major hemoglobin disorders are expanding. Providing access to these therapies around the world will remain a challenge.

Prevention of acute graft- versus -host disease (GvHD) after allogeneic hematopoietic cell transplantation (HCT) has long posed a major challenge for the field. In this issue, Koreth et al .[1][1] report results of a randomized three-arm phase II trial testing two different immunosuppressive

We compared severe graft-versus-host-disease (GvHD) free and relapse-free survival and other transplantation outcomes of acute myeloid leukemia (AML) patients given bone marrow (BM) without anti-thymocyte globulin (ATG) versus peripheral blood stem cells (PBSC) with ATG after myeloablative conditioning. In the cohort of patients receiving grafts from a human leukocyte antigen (HLA)-matched sibling donor, patients given PBSC with ATG (n=1,021) and those given BM without ATG (n=1,633) presented comparable severe GvHD-free relapse-free survival (GRSF)(hazard ratio [HR]=0.9, 95% confidence interval [CI]: 0.8-1.1, P=0.5) and overall survival (HR=1.0, 95% CI: 0.8-1.2, P=0.8). They had however, a lower incidence of chronic GvHD (cGvHD) (HR=0.7, 95% CI: 0.6-0.9, P=0.01). In the cohort of patients receiving grafts from HLA-matched unrelated donor , patients given PBSC with ATG (n=2,318) had better severe GvHD-free and relapse-free survival (GRFS) than those given BM without ATG (n=303) (HR=0.8, 95% CI: 0.6-0.9, P=0.001). They also had a lower incidence of cGvHD (HR=0.6, 95% CI: 0.5-0.8, P=0.0006) and better overall survival (HR=0.8, 95% CI: 0.6-1.0, P=0.04). In summary, these data suggest that PBSC with ATG results in comparable (in the case of sibling donor) or significantly better (in the case of unrelated donor) severe GRFS than BM without ATG in patients with AML in complete remission receiving grafts after myeloablative conditioning.

The prognosis of patients with acute myeloid leukemia in whom primary treatment fails remains very poor. In order to improve such patients' outcome, we conducted a phase 2, prospective, multicenter trial to test the feasibility of a new sequential regimen, combining a short course of intensive chemotherapy and a reduced intensity-conditioning regimen, before allogeneic stem-cell transplantation. Twenty-four patients (median age, 47 years) with acute myeloid leukemia in primary treatment failure were included. Cytogenetic risk was poor in 15 patients (62%) and intermediate in nine (38%). The sequential regimen consisted of clofarabine (30 mg/m2/day) and cytosine arabinoside (1 g/m2/day) for 5 days, followed, after a 3-day rest, by reduced-intensity conditioning and allogeneic stem-cell transplantation combining cyclophosphamide (60 mg/kg), intravenous busulfan (3.2 mg/kg/day) for 2 days and anti-thymocyte globulin (2.5 mg/kg/day) for 2 days. Patients in complete remission at day +120 received prophylactic donor lymphocyte infusion. Eighteen patients (75%) achieved complete remission. With a median follow-up of 24.6 months, the Kaplan-Meier estimate of overall survival was 54% (95% CI: 33-71) at 1 year and 38% (95% CI: 18-46) at 2 years. The Kaplan-Meier estimate of leukemia-free survival was 46% (95% CI: 26-64) at 1 year and 29% (95% CI: 13-48) at 2 years. The cumulative incidence of non-relapse mortality was 8% (95% CI: 1-24) at 1 year and 12% (95% CI: 3-19) at 2 years. Results from this phase 2 prospective multicenter trial endorsed the safety and efficacy of a clofarabine-based sequential reduced-toxicity conditioning regimen, which warrants further investigation. This study was registered at www.clinicaltrials.gov, identifier number: NCT01188174.

Most hematological malignancies occur in older patients. Until recently these patients and those with comorbidities were not candidates for treatment with allogeneic hematopoietic transplantation because they were unable to tolerate the heretofore used high-dose conditioning regimens. The finding that many of the cures achieved with allogeneic hematopoietic transplantation were due to graft-versus-tumor effects led to the development of less toxic and well-tolerated reduced intensity and nonmyeloablative regimens. These regimens enabled allogeneic engraftment, thereby setting the stage for graft-versus-tumor effects. This review summarizes the encouraging early results seen with the new regimens and discusses the two hurdles that need to be overcome for achieving even greater success, disease relapse and graft-versus-host disease.

The outcome of patients undergoing HLA-matched unrelated donor allogeneic hematopoietic cell transplantation following reduced-intensity conditioning or myeloablative regimens is reported to be equivalent; however, it is not known if the intensity of the conditioning impacts outcomes after mismatched unrelated donor transplantation for acute myeloid leukemia. Eight hundred and eighty three patients receiving reduced-intensity conditioning were compared with 1041 myeloablative conditioning regimen recipients in the setting of mismatched unrelated donor transplantation. The donor graft was HLA-matched at 9/10 in 872 (83.8%) and at 8/10 in 169 (16.2%) myeloablative conditioning recipients, while in the reduced-intensity conditioning cohort, 754 (85.4%) and 129 (14.6%) were matched at 9/10 and 8/10 loci, respectively. Myeloablative conditioning regimen recipients were younger, 70% being

Allogeneic bone marrow transplantation is an essential therapy for acquired aplastic anemia and prognosis has recently improved. However, engraftment failure and graft-versus-host disease are potential fatal complications. Various risk factors for poor prognosis have been identified, such as patient age and human-leukocyte antigen disparity, but the relationship between donor age and prognosis is still unknown. Therefore, we performed a cohort study to compare the prognosis of unrelated bone marrow transplantation from younger and older donors using the registry database in Japan. We evaluated 427 patients (age 16–72 years) with aplastic anemia who underwent bone marrow transplantation from younger (≤39 years, n=281) or older (≥40 years, n=146) unrelated donors. Overall survival of the older donor group was significantly inferior to that of the younger donor group (adjusted hazard ratio 1.64; 95% confidence interval 1.15–2.35; P

In the field of hematopoietic stem cell transplantation, the common approach is to focus outcome analyses on time to relapse and death, without assessing the impact of post-transplant interventions. We investigated whether a multi-state model would give insight into the events after transplantation in a cohort of patients who were transplanted using a strategy including scheduled donor lymphocyte infusions. Seventy-eight consecutive patients who underwent myeloablative T-cell depleted allogeneic stem cell transplantation for acute myeloid leukemia or myelodysplastic syndrome were studied. We constructed a multi-state model to analyze the impact of donor lymphocyte infusion and graft-versus-host disease on the probabilities of relapse and non-relapse mortality over time. Based on this model we introduced a new measure for outcome after transplantation which we called ‘treatment success’: being alive without relapse and immunosuppression for graft-versus-host disease. All relevant clinical events were implemented into the multi-state model and were denoted treatment success or failure (either transient or permanent). Both relapse and non-relapse mortality were causes of failure of comparable magnitude. Whereas relapse was the dominant cause of failure from the transplantation state, its rate was reduced after graft-versus-host disease, and especially after donor lymphocyte infusion. The long-term probability of treatment success was approximately 40%. This probability was increased after donor lymphocyte infusion. Our multi-state model helps to interpret the impact of post-transplantation interventions and clinical events on failure and treatment success, thus extracting more information from observational data.

Primary refractory acute myeloid leukemia (AML) is associated with a dismal prognosis. The FLAMSA-reduced intensity conditioning protocol (total body irradiation or treosulfan-based) has been described as an effective approach in patients with refractory leukemia undergoing allogeneic hematopoietic cell transplantation. A modified protocol (without amsacrine) has also recently been used. We retrospectively analyzed the transplantation characteristics and outcomes of all consecutive patients between the years 2003 and 2017 (n=51) diagnosed with primary refractory AML who underwent transplantation at the University of Cologne and the Tel Aviv Medical Center. Median age was 54 years and median follow up was 37 months. Median time to neutrophil and platelet engraftment was 13 (range, 8-19) and 13 (range, 7-30) days, respectively. None of the patients had primary graft failure. Incidences of grade 2-4 and grade 3-4 acute graft-versus-host disease (GvHD), overall and moderate-severe chronic GvHD were 50% (95%CI: 41-67%), 12% (95%CI: 3-25%), 61% (95%CI: 47-72%), and 42% (95%CI: 34-51%), respectively. Anti-thymocyte globulin administration was associated with lower incidence of acute GvHD (HR: 0.327; P=0.02). Non-relapse mortality at three months and three years were 6% and 16%, respectively. Relapse incidences were 6% and 29%, respectively. Overall survival rates at three months, three and five years were 90%, 61%, and 53%, respectively. Chronic GvHD disease was associated with a decreased mortality rate (HR: 0.397; P=0.045). We conclude that sequential therapy in patients with primary refractory acute myeloid leukemia is safe and provides a remarkable anti-leukemic effect with durable survival and should be considered for every patient with primary refractory disease.

We previously reported initial results in 102 multiple myeloma (MM) patients treated with sequential high-dose melphalan and autologous hematopoietic cell transplantation followed by 200 cGy total body irradiation with or without fludarabine 90 mg/m2 and allogeneic hematopoietic cell transplantation. Here we present long-term clinical outcomes among the 102 initial patients and among 142 additional patients, with a median follow up of 8.3 (range 1.0-18.1) years. Donors included human leukocyte antigen identical siblings (n=179) and HLA-matched unrelated donors (n=65). A total of 209 patients (86%) received tandem autologous-allogeneic upfront, while thirty-five patients (14%) had failed a previous autologous hematopoietic cell transplantation before the planned autologous-allogeneic transplantation. Thirty-one patients received maintenance treatment at a median of 86 days (range, 61-150) after allogeneic transplantation. Five-year rates of overall survival (OS) and progression-free survival (PFS) were 54% and 31%, respectively. Ten-year OS and PFS were 41% and 19%, respectively. Overall non-relapse mortality was 2% at 100 days and 14% at five years. Patients with induction-refractory disease and those with high-risk biological features experienced shorter OS and PFS. A total of 152 patients experienced disease relapse and 117 of those received salvage treatment. Eighty-three of the 117 patients achieved a clinical response, and for those, the median duration of survival after relapse was 7.8 years. Moreover, a subset of patients who became negative for minimal residual disease (MRD) by flow cytometry experienced a significantly lower relapse rate as compared with MRD-positive patients (P=0.03). Our study showed that the graft-versus-myeloma effect after non-myeloablative allografting allowed long-term disease control in standard and high-risk patient subsets. Ultra-high-risk patients did not appear to benefit from tandem autologous/allogeneic hematopoietic cell transplantation because of early disease relapse. Incorporation of newer anti-MM agents into the initial induction treatments before tandem hematopoietic cell transplantation and during maintenance might improve outcomes of ultra-high-risk patients. Clinical trials included in this study are registered at: clinicaltrials.gov identifiers: 00075478, 00005799, 01251575, 00078858, 00105001, 00027820, 00089011, 00003196, 00006251, 00793572, 00054353, 00014235, 00003954.

Diffuse alveolar hemorrhage after hematopoietic stem cell transplantation is a frequently fatal complication with no standard therapy. Although significant changes in supportive and intensive care measures for patients undergoing hematopoietic stem cell transplantation have been made over the past decades, the impact of these changes on the incidence and outcome of patients with diffuse alveolar hemorrhage has not been examined. We analyzed 1228 patients who underwent allogeneic hematopoietic stem cell transplantation between 2008-2015 at the University of Minnesota to study the incidence, risk factors, and outcomes of diffuse alveolar hemorrhage. Diffuse alveolar hemorrhage developed in 5% of allogeneic hematopoietic stem cell transplant recipients, at a median of 30 days (range +3 to +168 days) after transplantation. The incidence of diffuse alveolar hemorrhage was significantly greater in recipients of umbilical cord blood than peripheral blood or bone marrow grafts (HR: 2.08, 95% CI: 1.16-3.74; P=0.01). In multivariate analysis, delayed neutrophil engraftment or primary graft failure was a risk factor for diffuse alveolar hemorrhage following peripheral blood or bone marrow hematopoietic stem cell transplants (HR: 5.51, 95% CI: 1.26-24; P=0.02) and delayed platelet engraftment was associated with significantly increased diffuse alveolar hemorrhage in umbilical cord blood transplant recipients (HR: 6.96, 95% CI: 2.39-20.29; P