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Several prognostic factors for the outcome after allogeneic hematopoietic stem-cell transplant (HSCT) from matched unrelated donors have been postulated from registry data; however, data from randomized trials are lacking. We present analyses on the effects of patient-related, donor-related, and treatment-related prognostic factors on acute GVHD (aGVHD), chronic GVHD (cGVHD), relapse, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS) in a randomized, multicenter, open-label, phase III trial comparing standard graft-versus-host-disease (GVHD) prophylaxis with and without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before HSCT from HLA-A, HLA-B antigen, HLA-DRB1, HLA-DQB1 allele matched unrelated donors. High-resolution testing (allele) of HLA-A, HLA-B, and HLA-C were obtained after study closure, and the impact of an HLA 10/10 4-digit mismatch on outcome and on the treatment effect of ATG-F versus control investigated. Advanced disease was a negative factor for relapse, DFS, and OS. Donor age ≥40 adversely affected the risk of aGVHD III-IV, extensive cGVHD, and OS. Younger donors are to be preferred in unrelated donor transplantation. Advanced disease patients need special precautions to improve outcome. The degree of mismatch had no major influence on the positive effect of ATG-F on the reduction of aGVHD and cGVHD. [ABSTRACT FROM AUTHOR]

• Relapse- and immunosuppression-free survival were novel endpoints after transplant. • These endpoints were formulated and statistically analyzed by multistate methodology and resampling. • A randomized clinical trial was conducted on GVHD prophylaxis. • The difference between treatment groups was estimated as approximately 30% over 8 years. • An R code was provided to promote our methods to the transplant community. In most clinical oncology trials, time-to-first-event analyses are used for efficacy assessment, which often do not capture the entire disease process. Instead, the focus may be on more complex time-to-event endpoints, such as the course of disease after the first event or endpoints occurring after randomization. We propose "relapse- and immunosuppression-free survival" (RIFS) as an innovative and clinically relevant outcome measure for assessing treatment success after hematopoietic stem cell transplant (SCT). To capture the time-dynamic relationship of multiple episodes of immunosuppressive therapy during follow-up, relapse, and nonrelapse mortality, a multistate model was developed. The statistical complexity is that the probability of RIFS is nonmonotonic over time; thus, standard time-to-first-event methodology is inappropriate for formal treatment comparisons. Instead, a generalization of the Kaplan-Meier method was used for probability estimation, and simulation-based resampling was suggested as a strategy for statistical inference. We reanalyzed data from a recently published phase III trial in 201 leukemia patients after SCT. The study evaluated long-term treatment success of standard graft-versus-host disease prophylaxis plus a pretransplant antihuman T-lymphocyte immunoglobulin compared with standard prophylaxis alone. Results suggested that treatment increased the long-term probability of RIFS by approximately 30% during the entire follow-up period, which complements the original findings. This article highlights the importance of complex endpoints in oncology, which provide deeper insight into the treatment and disease process over time. Multistate models combined with resampling are highlighted as a promising tool to evaluate treatment success beyond standard endpoints. An example code is provided in the Supplementary Materials. [ABSTRACT FROM AUTHOR]

• Allotransplant for myelodysplastic syndrome is limited by high nonrelapse mortality. • Comorbidities assessed by the original Sorror score impact mortality negatively. • Chronological age also continues to play an independent prognostic role on mortality. • Both age and comorbidities should be integrated in the allotransplant decision process. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only potentially curative option for myelodysplastic syndromes (MDSs) but is severely limited by nonrelapse mortality (NRM), especially in this mostly older population. Comorbidity assessment is crucial to predict NRM and often assessed with the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI). Moreover, the impact of age on NRM still remains a matter of debate. In recent years, the age at which transplants are made has been progressively increasing, and patients with comorbidities have become more common. Extricating the respective roles of age and comorbidities in toxic mortality is all the more important. This study by the European Group for Blood and Marrow Transplantation registry included 1245 adult patients who underwent a first allogeneic stem cell transplantation for MDSs between 2003 and 2014. Overall, 4-year NRM and overall survival were 32% and 47%, respectively. When considered as continuous predictors, HCT-CI score and age were associated with an increased hazard ratio (HR) for NRM. In multivariate analysis, age band (HR, 1.13; 95% CI, 1.02 to 1.25; P =.016), HCT-CI ≥3 (HR, 1.34; 95% CI, 1.04 to 1.73; P =.022), and Karnofsky Performance Status ≤80 (HR, 2.03; 95% CI, 1.52 to 2.73; P <.0001) were significantly predictive of a worse NRM. In our large cohort, both comorbidities, evaluated by the original HCT-CI score, and chronological age significantly affected NRM. Thus, age should be part of the transplant decision-making process and should be integrated in future scoring systems predicting outcomes of HSCT in MDSs. [ABSTRACT FROM AUTHOR]

Standard first-line therapy for older patients with high-risk myelodysplastic syndrome (MDS) includes hypomethylating agents, such as azacitidine (AZA). However, the only approach with curative potential remains allogeneic hematopoietic cell transplantation (HCT). To date, no direct comparison of both strategies has been reported. The outcomes of 2 well-balanced cohorts of patients with high-risk MDS defined by age (60-70 years), performance status (Eastern Cooperative Oncology Group score ≤2), and donor availability (yes/no) were compared, including 103 patients undergoing HCT and 75 patients without this option who received AZA. The estimated 2-year overall survival after the start of treatment was 39% (95% confidence interval, 30%-50%) for the patients undergoing HCT and 23% (95% confidence interval, 14%-40%) for the patients receiving AZA therapy. In a multivariate Cox regression analysis of all patients (n = 178), Eastern Cooperative Oncology Group score (0 versus 1 versus 2; hazard ratio [HR], 2.9/3.9; P <  .001), cytogenetics (good versus intermediate versus poor; HR, 1.2/1.7; P = .026), and treatment (HCT versus AZA; HR, 0.3; P = .007) were associated with overall survival. This retrospective cohort analysis suggests a survival advantage for allogeneic HCT compared with AZA therapy in medically fit patients with high-risk MDS age 60-70 years. Prospective controlled studies are warranted. [ABSTRACT FROM AUTHOR]

Chronic graft-versus-host disease (cGVHD) frequently involves oral tissues. Although the mucosal changes may be painful and impair oral function, there is currently no topical therapy available for oral cGVHD that has been proven to work in an evidence-based manner. The aims of this study were to (1) assess the response of patients with oral cGVHD to various doses of a new topical budesonide formulation; (2) evaluate the efficacy and safety of the new topical budesonide formulation in these patients. An open, randomized, multicenter phase II pilot study with 4 treatment arms differing in application frequency and duration was performed. Response to treatment was scored by the clinician and patient using several scales. Oral cGVHD improved in all patients, with a median reduction of 70%. Pain reduction was similar in all study arms. The rate of objective improvement (defined as ≥50%) was not significantly different among the 4 study arms. The safety profile was satisfactory. Topical budesonide mouthwash (3 mg/10 mL) improved oral cGVHD in all patients when applied for 5 or 10 minutes, 2 or 3 times daily. The response was similar in all treatment arms. Safety analysis supported a dosing schedule of 3 mg of budesonide 3 times a day for 10 minutes. [ABSTRACT FROM AUTHOR]

Abstract: Polyclonal anti-T-lymphocyte globulins (ATG) are used in allogeneic stem cell transplantation (SCT) for the prophylaxis of graft versus host disease (GVHD) by in vivo T cell depletion. In this study we investigated the complement independent induction of apoptosis by rabbit ATG in peripheral blood mononuclear cell (PBMNC) compartments and hematopoetic stem cells (HSC). We also detected antileukemic activity of ATG by measuring apoptosis in myeloid and lymphatic leukemia cell lines and primary leukemia cells. We found ATG to induce apoptosis in T-lymphocytes (CD4+, CD8+), B-lymphocytes (CD20+), natural killer (NK)-cells (CD56+), and monocytes (CD14+). HSC, in contrast, were apoptosis resistant and could be growth stimulated by low-dose ATG in the presence of bystander cells. The human leukemia cell lines Jurkat, Daudi, DG-75 (lymphoblastic), and K562, HL-60, KG1, and U937 (myeloblastic) underwent ATG-induced apoptosis, whereas the NK-cell line YT was resistant. Primary leukemia cells from 6 investigated patients with acute lymphoblastic leukemia, 9 of 10 patients with chronic lymphocytic leukemia, and 4 of 8 patients with acute myeloblastic leukemia underwent ATG-induced apoptosis. We conclude apoptosis induction in all PBMNC compartments contributes to GVHD prophylaxis. ATG might support engraftment. Finally, antileukemic activity of ATG could positively influence the transplantation outcome. [Copyright &y& Elsevier]

• FLAMSA (fludarabine, Ara-C, and amsacrine) sequential chemotherapy followed by total body irradiation (TBI)-based reduced-intensity conditioning (RIC) and myeloablative conditioning (MAC) led to similar transplantation outcomes in relapsed/refractory active acute myeloid leukemia. • FLAMSA sequential chemotherapy followed by TBI-free RIC was associated with lower nonrelapse mortality resulting in increased overall survival. • There were no significant differences in relapse incidence between FLAMSA sequential chemotherapy followed by RIC and MAC. The use of myeloablative conditioning (MAC) in the setting of active relapsed/refractory (R/R) acute myeloid leukemia (AML) has been hindered by high historical rates of nonrelapse mortality (NRM). FLAMSA (fludarabine, Ara-C, and amsacrine) chemotherapy (CT) followed by reduced-intensity conditioning (RIC) has been proposed as an effective and potentially safer alternative in this scenario. As improvements in supportive care have contributed to decreasing NRM rates after MAC, a comparative reassessment of these two strategies was performed. This was a registry-based analysis by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Eligibility criteria included age 18 to 50 years, primary refractory, first or second relapsed active AML, first allogeneic stem cell transplantation from a matched sibling donor (MSD) or an unrelated donor (UD) performed between 2005 and 2018, MAC or FLAMSA-RIC. A total of 1018 patients were included. The median patient age was 39 years (range, 18 to 50). Two hundred and fifty-eight patients received busulfan (Bu)/cyclophosphamide (Cy), 314 received Cy/total body irradiation (TBI), 318 received FLAMSA-TBI, and 128 received FLAMSA-CT. The median duration of follow-up was 50 months. In univariate analysis, the 2-year relapse incidence (RI) (54%; 95% confidence interval (CI), 50%-57%), leukemia-free survival (LFS) (30%; 95% CI, 27%-33%), and refined graft-versus-host disease-free, relapse-free survival (GRFS) (21%; 95% CI, 18%-24%) were not significantly different between cohorts. Lower 2-year NRM was observed in the FLAMSA-CT group (7% versus 16% in Bu/Cy, 19% in Cy/TBI, and 18% in FLAMSA-TBI; P =.04), as well as increased 2-year overall survival (OS) (50% versus 33% in Bu/Cy, 34% in Cy/TBI, and 36% in FLAMSA-TBI; P =.03). These results were maintained in the multivariate analysis (hazard ratio [HR] for NRM:.40, P =.01; HR for OS:.65, P =.01; Bu/Cy as reference). These data suggest that FLAMSA-CT may be a preferred conditioning regimen in patients with active R/R AML due to lower NRM. Yet, the high relapse rates observed in our analyses emphasize the need for novel therapeutic strategies in this clinical setting. [ABSTRACT FROM AUTHOR]

• In this largest cohort of myelofibrosis transplants analyzed to date, no significant difference in 5-year probabilities of overall survival (OS) was noted between those undergoing myeloablative conditioning (MAC) (53.0%; 95% confidence interval [CI], 49.1% to 56.9%) and reduced-intensity conditioning (RIC) (51.0%; 95% CI, 48.3% to 53.7%); P =.78. • Graft failure rates appeared higher in those undergoing RIC protocols compared with MAC protocols. • MAC platforms demonstrated a trend toward less relapse and significantly improved graft-versus-host disease-free/relapse-free survival, although this requires validation. This retrospective study by the European Society for Blood and Marrow Transplantation analyzed the outcome of 2224 patients with myelofibrosis (MF) who underwent allogeneic stem cell transplantation (allo-SCT) between 2000 and 2014; 781 (35%) underwent myeloablative conditioning (MAC) and 1443 (65%) reduced-intensity conditioning (RIC). Median patient age was 52.9 years (range, 18 to 74 years) and 57.5 years (range, 21 to 76 years) in the MAC and RIC cohorts, respectively. Donor type was similar: matched sibling donors (MAC, 317 [41%]; RIC, 552 [38%]) and unrelated donors (MAC, 464 [59%]; RIC, 891 [62%]). Median time to both neutrophil and platelet (>20 × 109/L) engraftment did not differ between cohorts. Rates of grade II to IV acute GVHD were 28% (MAC) and 31% (RIC; P = NS). Cumulative chronic GVHD rates (limited/extensive) were 22%/27% (MAC) and 19%/31% (RIC; P =.10). Cumulative incidences of nonrelapse mortality (NRM) at 1, 3, and 5 years were 25.5%, 32.2%, and 34.6% (MAC) and 26.3%, 32.8%, and 34.4% (RIC), respectively. There was a trend toward a higher relapse rate with RIC regimens compared with MAC (P =.08); rates at 1, 3, and 5 years were 10.9%, 17.2%, and 20.1% (MAC) and 14%, 19.7%, and 23.2% (RIC), respectively. No significant difference in 5-year probabilities of overall survival (OS) was noted: MAC (53.0%; 95% confidence interval [CI], 49.1% to 56.9%) and RIC (51.0%; 95% CI, 48.3% to 53.7%); P =.78. Regarding the composite end point of GVHD-free/relapse-free survival (GRFS), the unadjusted Kaplan-Meier estimate of 5-year GRFS was 32.4% (95% CI, 29.0% to 36.1%) in the MAC group and 26.1% (95% CI, 23.9% to 28.2%) in the RIC group (P =.001). In the MAC cohort, multivariable analysis confirmed worse OS and NRM with older age (>50 years), using an unrelated donor and a Karnofsky Performance Status of 80 or less. For the RIC cohort, worse OS and NRM were associated with age 60 to 70 years compared with younger recipients, use of a mismatched donor, and poor performance status. In conclusion, although similar OS rates existed for both cohorts overall, this study suggests that MAC should still be used for younger individuals suitable for such an approach due to a trend toward less relapse and an overall suggested advantage of improved GRFS, albeit this should be examined in a more homogeneous cohort. RIC allo-SCT still offers significant survival advantage in the older, fitter MF allograft patient, and optimization to reduce significant relapse and NRM rates is required. [ABSTRACT FROM AUTHOR]

• Marked improvement has been achieved in recent years in stem cell transplantation (SCT) from unrelated donors. • Long-term outcome is equivalent after SCT from unrelated and sibling donors. • Patients who are leukemia-free 2 years after SCT can expect a favorable outcome. Allogeneic stem cell transplantation (SCT) is potentially curative therapy in acute myeloid leukemia (AML). Marked improvement has been achieved with SCT from matched unrelated donors (MUDs) in recent years. However, there are limited data comparing the long-term outcomes (beyond 10 years) after SCT from sibling donors and MUDs in older patients with AML. We analyzed these outcomes in a large cohort of patients with AML (n = 1134), age ≥50 years, who were alive and leukemia-free 2 years after SCT from matched siblings (n = 848) or MUDs (n = 286), with a median follow-up of 8.9 years. The median age was 56 and 58 years after SCT from siblings and MUDs, respectively (P =.005). In the sibling group, 77%, 12%, and 11% were in first complete remission (CR1), second complete remission (CR2), and active leukemia at SCT compared with 50%, 25%, and 25% in the MUD group, respectively (P <.001). Sixty-one percent of siblings and 62% of MUDs had reduced-intensity conditioning (P =.78). The 10-year leukemia-free survival (LFS) of patients surviving leukemia-free 2 years after SCT was 72% and 62%, respectively (P =.30). Multivariate analysis identified active leukemia at SCT (hazard ratio [HR], 1.86; P =.0001) or CR2 (HR, 1.51; P =.02) compared with CR1, female recipients (HR, 0.71; P =.006), adverse cytogenetics (HR, 2.52; P =.01), and prior graft-versus-host disease (HR, 1.31; P =.04) as independent factors predicting LFS. Donor and conditioning type were not significant. The cumulative incidence was 15% and 17% (P =.97) for late relapse mortality and 13% and 21% for late nonrelapse mortality, respectively (P =.15). In conclusion, long-term LFS is similar, and patients who are leukemia-free 2 years after SCT can expect favorable outcomes with both donor types. [ABSTRACT FROM AUTHOR]

Introduction Recurrent disease is the major cause of treatment failure after allogeneic stem cell transplantation (SCT) in patients with AML. Second SCT (SCT2) is a valid treatment option in this setting but outcome is relatively poor. Haplo-identical (haplo) SCT is increasingly used over the last decade due to the introduction of non T-depleted methods. Prior studies have shown similar outcome when using the same or different HLA-matched donor for SCT2. However, there is relatively limited data on the use of haplo-donors in this setting. Methods and Results The study included 556 patients with AML relapsing after a first allogeneic SCT (SCT1) given in CR1 from sibling (sib, n= 294) or unrelated donor (UD, n=262) and given SCT2 during the years 2006-2016. The median age at SCT2 was 46 years (20-73). 247 patients were in CR2 (45%) and 309 had active leukemia (55%) at SCT2. The conditioning regimen for SCT1 was myeloablative (MAC, 66%) or reduced-intensity (RIC, 34%), and 41% and 59%, respectively for SCT2. Patients were divided into 3 groups based on the donor selected for SCT2; 1) same donor (n=163, sib/sib-112, UD/UD-51), 2) different matched donor (n=305, sib/different sib-44, sib/UD-93, UD/ different UD- 168), 3) haplo-donor (n=88, sib/haplo-45, UD/haplo-43). All haploSCT were non T-depleted. The 2-year leukemia-free survival (LFS) after SCT2 was 23.5%, 23.7% and 21.8%, respectively (unadjusted P=0.30). Multivariate analysis showed no effect of second donor type on subsequent relapse, hazard ratio (HR) 0.96 (P=0.83) and 1.20 (P=0.47) for different donor and haplo-donor compared to same donor, respectively. UD in SCT1, CR2 at SCT2 and chronic GVHD after SCT1 were associated with reduced relapse risk after SCT2, HR 0.70 (P=0.02), 0.60 (P=0.001) and 0.66 (P=0.03), respectively. Second donor type did predict for non-relapse mortality (NRM) after SCT2; HR 1.26 (P=0.41) and 2.18 (P=0.02) for different donor and haplo-donor compared to same donor, respectively. Advanced age and MAC in SCT1 also predicted for NRM, HR 1.40 (P<0.001) and 0.61 (P=0.04), respectively. The second donor predicted for LFS after SCT2; HR 1.05 (P=0.77) and 1.55 (P=0.03), respectively. Advanced age and SCT2 in CR2 predicted for LFS; HR 1.11 (P=0.06) and 0.66 (P=0.002), respectively. In all, there were no differences between same or different matched donors in SCT2 outcomes, but haploSCT2 was associated with higher NRM and lower LFS. The inferior outcome after SCT2 with haplo-donor was limited to patients given MAC in SCT1 and not observed in patients given RIC in SCT1. Conclusions Second SCT with the same donor or different matched donor is associated with similar outcomes in patients with relapsed AML after a first SCT. However, SCT2 with a haplo-donor is associated with higher NRM and lower LFS, mostly in patients given MAC in SCT1. Second haplo donor does not provide better GVL effect in this setting. [ABSTRACT FROM AUTHOR]

• Overall outcomes of patients allografted for BC CML remain poor in the TKI era. • Survival after alloSCT for BC CML depends on the pretransplant remission status. • Conventional prognostic factors remain outcome determinants for BC CML in remission. • UD transplant is associated with better LFS in patients with active BC at alloSCT. The prognosis of patients with blast crisis (BC) chronic myeloid leukemia (CML) is still dismal. Allogeneic stem cell transplantation represents the only curative treatment option, but data on transplant outcomes are scarce. We therefore conducted a retrospective, registry-based study of adult patients allografted for BC CML, focusing on patients with active disease at transplant and pretransplant prognostic factors. One hundred seventy patients allografted for BC CML after tyrosine kinase inhibitor pretreatment between 2004 and 2016 were analyzed. Before transplant, 95 patients were in remission, whereas 75 patients had active BC. In multivariable analysis of the entire cohort, active BC at transplant was the strongest factor associated with decreased overall survival (hazrd ratio, 1.87; P =.010) and shorter leukemia-free survival (LFS; hazard ratio, 1.69; P =.017). For patients with BC in remission at transplant, advanced age (≥45 years), lower performance status (≤80%), longer interval from diagnosis BC to transplant (>12 months), myeloablative conditioning, and unrelated donor (UD) transplant were risk factors for inferior survival. In patients with active BC, only UD transplant was significantly associated with prolonged LFS and trended toward improved overall survival. In summary, survival of patients allografted for BC CML was strongly dependent on pretransplant remission status. In patients with remission of BC, conventional prognostic factors remained the major determinants of outcome, whereas in those with active BC at transplant, UD transplant was associated with prolonged LFS in our study. [ABSTRACT FROM AUTHOR]

• The DIPSS was not predictive of survival in myelofibrosis secondary to essential thrombocythemia or polycythemia vera after stem cell transplantation. • The MYSEC-PM predicted survival and showed improved prognostic ability. • Although performance of the MYSEC-PM was still moderate, risk stratification may be improved by incorporating clinical, mutational, and transplant-related factors. We aimed to validate the MYelofibrosis SECondary to PV and ET prognostic model (MYSEC-PM) in 159 patients with myelofibrosis secondary to polycythemia vera (PV) and essential thrombocythemia (ET) from the European Society for Blood and Marrow Transplantation registry undergoing transplantation from matched siblings or unrelated donors. Furthermore, we aimed to test its prognostic performance in comparison with the Dynamic International Prognostic Scoring System (DIPSS). Score performance was analyzed using the concordance index (C): the probability that a patient who experienced an event had a higher risk score than a patient who did not (C >.5 suggesting predictive ability). Median follow-up of the total cohort was 41 months (range, 34 to 54), 45 months in post-PV and 38 months in post-ET myelofibrosis. Survival at 1, 2, and 4 years was 70% (95% CI, 63% to 77%), 61% (95% CI, 53% to 69%), and 52% (95% CI, 43% to 61%) for the total cohort; 70% (95% CI, 59% to 80%), 61% (95% CI, 49% to 73%), and 51% (95% CI, 38% to 64%) for post-PV; and 71% (95% CI, 61% to 81%), 61% (95% CI, 50% to 72%), and 54% (95% CI, 42% to 66%) for post-ET myelofibrosis (P =.78). Overall, the DIPSS was not significantly predictive of outcome (P =.28). With respect to the MYSEC-PM, overall survival at 4 years was 69% for the low-risk, 55% for the intermediate 1-risk, 47% for the intermediate 2-risk, and 22% (0% to 45%) for the high-risk groups. The prognostic model was predictive of survival overall (P =.05), whereas groups with intermediate 2 and high risk showed no significant difference (P =.44). Assessment of prognostic utility yielded a C-index of.575 (95% CI,.502 to.648) for the DIPSS, whereas assessment of the MYSEC-PM resulted in a C-statistics of.636 (95% CI,.563 to.708), indicating improvement in prediction of post-transplant survival using the new MYSEC-PM. In addition, transplantations from an unrelated donor in comparison with an HLA-identical sibling showed worse outcome (P =.04), and transplant recipients seropositive for cytomegalovirus in comparison with seronegative recipients (P =.01) showed worse survival. In conclusion, incorporating transplant-specific and clinical and mutational information together with the MYSEC-PM may enhance risk stratification. [ABSTRACT FROM AUTHOR]

Highlights • Major mechanisms of relapse include HLA loss, HLA down-regulation, and expression of coinhibitory ligands. • Combination of donor lymphocyte infusion with immunomodulating agents and tyrosine kinase inhibitors may enhance the graft-versus-leukemia (GVL) effect. • Immune checkpoint inhibitors can induce a significant GVL effect, but toxicity is high. ABSTRACT The curative potential of allogeneic hematopoietic cell transplantation (allo-HCT) in the treatment of acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) relies mainly on the graft-versus-leukemia effect. Relapse after allo-HCT occurs in a considerable proportion of patients and has a dismal prognosis, with still very limited curative potential. This review provides an overview of the established and evolving approaches to preventing or treating relapse of AML and MDS after allo-HCT, in the context of novel insight into the biology of relapse. Established prophylactic measures to prevent relapse include optimized conditioning and graft-versus-host disease (GVHD) prophylaxis, as well as donor lymphocyte infusion (DLI) for high-risk patients; novel immunomodulatory interventions and maintenance approaches are still experimental. Improved diagnostics can detect persistent or recurring disease at a molecular level, enabling early preemptive interventions. Established options include hypomethylating agents and DLI. Standard treatments for hematologic relapse include chemotherapy, cessation of immunosuppressive treatment, and DLI. Experimental approaches include molecular targeted therapies, novel immunomodulatory treatments, and second allo-HCT. For all interventions, the potential risks, including occurrence of GVHD, must be weighed against the benefits individually in each patient. Concurrently, prevention and treatment of relapse after allo-HCT remain challenging and unmet medical needs. [ABSTRACT FROM AUTHOR]

Highlights • Overall survival, progression-free survival, and nonrelapse mortality were better in haploidentical than in cord blood donors. • Nonrelapse mortality was not significantly different between haploidentical and mismatched unrelated donor. • Relapse risk was not influenced by the type of donor. • Acute graft-versus-host disease risk was lower with haploidentical or cord blood donors than with mismatched unrelated donors. • Chronic graft-versus-host disease was not influenced by the type of donor. Abstract Recently, haploidentical transplantation (haplo) using post-transplant cyclophosphamide (PTCy) has been reported to give very encouraging results in patients with hematological malignancies. Patients who have no HLA-matched donor currently have the choice between a mismatched unrelated donor, an unrelated cord blood (CB) donor, and a haploidentical related donor. The aim of our study is to compare the outcome of patients with myelodysplastic syndrome (MDS) who have been transplanted from a haploidentical donor using PTCy, an HLA-mismatched unrelated donor (marrow or peripheral blood stem cells), or an unrelated mismatched CB donor. A total of 833 MDS patients from the European Group for Blood and Marrow Transplantation (EBMT) registry, transplanted between 2011 and 2016, were identified. The potential benefit of haplo was compared with mismatched unrelated and CB donors in an adjusted and weighted model taking into account potential confounders and other prognostic variables. Haplo was at lower risk of acute graft-versus-host disease (GVHD) than mismatched unrelated donor (P =.010) but at similar risk than CB. Progression-free survival was better after haplo (versus mismatched unrelated, P =.056; versus CB, P =.003) and overall survival tended to be superior after haplo (versus mismatched unrelated, P =.082; versus CB, P =.002). Nonrelapse mortality was not significantly different between haplo and mismatched unrelated donors. Relapse risk was not influenced by the type of donor. In conclusion, patients with MDS from the EBMT registry receiving hematopoietic stem cell transplantation from a haplo donor have significantly better outcome than those receiving hematopoietic stem cell transplantation from a CB donor and at least similar or better outcome than with a mismatched unrelated donor. Prospective studies comparing the type of donors will be needed to confirm this assumption. [ABSTRACT FROM AUTHOR]

Highlights • The impact of donor age and sex but not CMV matching is comparable with that of single HLA disparity on survival after HSCT. • Similar survival after matched unrelated and related donor HSCT for AML or MDS reflects lower NRM but higher relapse risks in the latter. Abstract Increasing donor–recipient HLA disparity is associated with negative outcomes of allogeneic hematopoietic stem cell transplantation (HSCT), but its comparative relevance amid non-HLA donor characteristics is not well established. We addressed this question in 3215 HSCTs performed between 2005 and 2013 in Germany for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Donors were HLA-matched related (MRD; n = 872) or unrelated (10/10 MUD, n = 1553) or HLA-mismatched unrelated (<10/10 MMUD, n = 790). Overall survival (OS) was similar after MRD compared with 10/10 MUD HSCT, reflecting opposing hazards of relapse (hazard ratio [HR], 1.32; P <.002) and nonrelapse mortality (HR,.63; P <.001). After UD HSCT, increasing HLA disparity was associated with inferior OS (HR, 1.21 [ P <.02] and HR, 1.57 [ P <.001] for 9/10 and ≤8/10 MMUD, respectively, compared with 10/10 MUD). Among non-HLA donor characteristics, age, sex mismatching (male recipient–female donor), and cytomegalovirus (CMV) mismatching (positive recipient–negative donor) impacted OS. Multivariate subgroup analysis showed that OS was similar after HSCT from the youngest 9/10 MMUD (<30 years) compared with the oldest 10/10 MUD (>40 years) (HR, 1.18; P =.25) and also in male patients transplanted from female 10/10 MUD compared with male 9/10 MMUD (HR,.89; P =.46). In contrast, OS of CMV-positive patients tended to be better with CMV-negative 10/10 MUDs compared with CMV-positive 9/10 MMUDs (HR, 1.31; P =.04). Because of low patient numbers in subgroups, definite conclusions and establishment of a hierarchy among HLA matching and non-HLA donor characteristics could not be made. Our data suggest that the impact of donor age and sex mismatch but not CMV mismatch on outcome of allogeneic HSCT may be comparable with that of single HLA disparity. [ABSTRACT FROM AUTHOR]

Highlights • Incidence of BOS after reduced-intensity conditioning. • Mild small airway disease before transplantation predicts bronchiolitis obliterans. • Pulmonary cause of death is linked to pretransplantation severe small airway disease. • Mixed lung disease after transplantation is associated with non-relapse mortality Abstract Lung function deterioration contributes to treatment-related morbidity and mortality in patients after allogeneic hematopoietic cell transplantation (allo-HCT). Better understanding of impaired lung function including bronchiolitis obliterans syndrome (BOS) as chronic manifestation of graft-versus-host disease (GVHD) might improve outcomes of patients after allo-HCT. To detect early pulmonary function test abnormalities associated with BOS incidence and outcome after allo-HCT, we performed a retrospective analysis of homogenous-treated 445 patients (median age, 61.9 years; range, 19 to 76 years) with a reduced intensity/toxicity conditioning protocol. The cumulative incidence of BOS was 4.1% (95% confidence interval [CI], 2.6 to 6.4) at 1 year and 8.6% (95% CI, 6.3 to 11.6) at 5 years after allo-HCT with a median follow-up of 43.2 months (range, 3.3 to 209 months). In multivariate analysis, pre-existence of moderate small airway disease reflected by decreased midexpiratory flows before allo-HCT was associated with increased risk for BOS development. In addition, severe small airway disease before allo-HCT and combined restrictive/obstructive lung disease at day +100 after allo-HCT were associated with higher risk for nonrelapse mortality (NRM) due mainly to pulmonary cause of death. In summary, we identified novel pulmonary function test abnormalities prior and after allo-HCT associated with BOS development and NRM. These findings might help to identify a risk population and result in personalized GVHD prophylaxis and preventive or early therapeutic interventions. [ABSTRACT FROM AUTHOR]

Secondary acute myeloid leukemia (sAML) has been associated with inferior outcomes compared with de novo AML. Little is known about patient risk factors and outcomes in sAML after allogeneic hematopoietic stem cell transplantation (HCT); thus, this large systemic analysis of the European Society for Blood and Bone Marrow Transplantation registry was performed. This study included 4997 patients with sAML who received HCT from 2000 to 2016. In univariate analysis the 2-year cumulative incidence of chronic graft-versus-host disease (GVHD), relapse, and nonrelapse mortality (NRM) were 33.5% (95% confidence interval [CI], 32% to 34.9%), 33.7% (95% CI, 32.3% to 35.1%), and 27.5% (95% CI, 26.1% to 28.7%), respectively. Overall survival (OS), leukemia-free survival (LFS), and GVHD-free, relapse-free survival (GRFS) at 2 years were 44.5% (95% CI, 43% to 46%), 38.8% (95% CI, 37.4% to 40.3%), and 27.2% (95% CI, 25.9% to 28.6%), respectively. In multivariate analysis, patients receiving myeloablative regimens had decreased relapse (hazard ratio, .859; 95% CI, .761 to .97; P  = .01), higher NRM (hazard ratio, 1.175; 95% CI, 1.03 to 1.341; P  = .02), and no differences in OS, LFS, and GRFS compared with patients receiving reduced-intensity conditioning regimens. Active disease, adverse cytogenetics, older age, Karnofsky performance status (≤80%), ex vivo T cell depletion, other malignant hematologic diseases, and patient cytomegalovirus seropositivity were associated with inferior OS and LFS. These variables should be considered in patients with sAML in need of HCT, and further study regarding the impact of conditioning regimens on relapse is needed. [ABSTRACT FROM AUTHOR]

The deletion (5q) karyotype (del [5q]) in patients with myelodysplastic syndrome (MDS) is the most common karyotypic abnormality in de novo MDS. An increased number of blasts and additional karyotypic abnormalities (del [5q]+) are associated with a poor outcome. We analyzed the outcome of allogeneic hematopoietic cell transplants (HCT) in patients suffering from MDS with only del (5q) or del (5q)+ . A total of 162 patients, of median age 54 years (range, 9 to 73), having MDS and del (5q) abnormalities received HCT from identical siblings (n = 87) or unrelated donors (n = 75). The cumulative incidence of nonrelapse mortality and relapse incidence at 4 years was 29% (95% CI, 22 to 36) and 46% (95% CI, 38 to 54), whereas the estimated 4 year survival, relapse-free and overall, was 25% (95% CI, 18 to 33) and 30% (95% CI, 23 to 38), respectively. In a multivariate analysis patients with del (5q) and a blast excess displayed poorer survival (hazard ratio, 2.38; 95% CI, 1.44 to 3.93; P  < .001), whereas female recipient sex resulted in improved survival (hazard ratio, .61; 95% CI, .41 to .90; P  = .01). We conclude that allogeneic HCT can cure a subset of patients with MDS and a del (5q) abnormality. [ABSTRACT FROM AUTHOR]

In this retrospective analysis we evaluated the outcome of 313 patients aged ≥ 70 years in the registry of the European Group for Blood and Marrow Transplantation with myelodysplastic syndrome (MDS; n = 221) and secondary acute myeloid leukemia (n = 92) who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from related (n = 79) or unrelated (n = 234) donors. Median age at HSCT was 72 years (range, 70 to 78). Conditioning regimen was nonmyeloablative (n = 54), reduced intensity (n = 207), or standard intensity (n = 52). Allogeneic HSCT for MDS patients ≥ 70 years was increasingly performed over time. Although during 2000 to 2004 only 16 patients received HSCT, during 2011 to 2013 the number of transplantations increased to 181. The cumulative incidence of nonrelapse mortality at 1 year and relapse at 3 years was 32% and 28%, respectively, with a 3-year overall survival rate of 34%. Good performance, determined by Karnofsky performance status, and recipients' seronegativity for cytomegalovirus was associated with 3-year estimated overall survival rates of 43% ( P  = .01) and 46% ( P  = .002), respectively. Conditioning intensity did not impact survival. After careful patient selection, allogeneic HSCT can be offered to patients older than 70 years with MDS. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell transplantation (HSCT) remains the only curative treatment in patients with higher risk myelodysplastic syndrome (MDS), but the choice of the optimal alternative stem cell source is still a subject of debate in patients lacking an HLA-matched sibling donor. Here, we report on a large series of patients with MDS (N = 631) transplanted either with mobilized peripheral stem cells (PBs) from unrelated donors (n = 502) or with umbilical cord blood transplant (UCB, n = 129) as alternative grafts after reduced-intensity conditioning. Neutrophil engraftment was higher after PB (98% versus 78%, P < .0001). Acute graft-versus-host disease (GVHD) was similar after PB (31%) and UCB (29%), and chronic GVHD incidence was higher after PB (41% versus 23%). Two-year nonrelapse mortality was lower after PB (31% versus 42% P = .03). There was a better overall survival (OS) and disease-free survival (DFS) after PB (49% ± 2% versus 30% ± 4%, P < .0001 and 44% ± 2% versus 28% ± 4%, P < .0001). Multivariate analysis confirmed the advantage of PB for treatment-related mortality, OS, and DFS, whereas relative risk of chronic GVHD was similar. A multivariate analysis comparing PB from a 10/10 HLA-matched donor, PB from a 9/10 HLA-matched donor, and UCB showed an advantage on treatment-related mortality, DFS, and OS only in 10/10 PB. We conclude that in MDS patients lacking an HLA-matched sibling donor, PB from a 10/10 HLA-matched unrelated donor is the preferred source of hematopoietic stem cells. HLA-mismatched unrelated donor or cord blood seem to give similar inferior results except for neutrophil engraftment, which is delayed after UCB. [ABSTRACT FROM AUTHOR]

Total body irradiation has been the mainstay of conditioning since the inception of allogeneic hematopoietic cell transplantation, but toxicity often precludes its use. For less-fit patients with acute lymphoblastic leukemia and other hematologic malignancies frequently affecting the central nervous system, we designed a radiation-free regimen with fludarabine (25 mg/m2/day on days −6 to −4), carmustine (400 mg/m2 on day −6), and thiotepa (5 mg/kg twice daily on days −5 and −4), all of which readily penetrate the blood-brain barrier and have potent antileukemic and lymphotoxic activity. Here we present a series of 30 consecutive patients with high-risk or relapsed disease who underwent allogeneic hematopoietic cell transplantation with this protocol. The median patient age was 60 years (range, 42-70 years), and the median follow-up was 968 days (range, 58-1989 days). Graft-versus-host disease prophylaxis consisted of cyclosporine A and alemtuzumab (10-20 mg). At 2 years, overall survival was 52% (95% confidence interval [CI], 34%-71%), event-free survival was 39% (95% CI, 22%-57%), cumulative incidence of relapse/progression was 30% (95% CI, 17%-52%), and treatment-related mortality was 31% (95% CI, 18%-53%). Neurologic toxicity is a concern, especially in older and heavily pretreated patients. Our experience indicates the feasibility of this regimen as an alternative to total body irradiation and a potentially curative option for less-fit patients who need a highly central nervous system–active conditioning. [ABSTRACT FROM AUTHOR]

Peripheral blood stem cells (PBSCs) are increasingly used as the graft source in allogeneic hematopoietic cell transplantation. We compared long-term outcome after unrelated donor transplantation of 85 consecutive patients with acute myelogenous leukemia or myelodysplastic syndrome regarding disease status (early disease [CR1, refractory anemia); n = 25 and advanced/active disease [>CR1, >refractory anemia]; n = 60) who were treated with conventional conditioning regimens followed by bone marrow (BM) or PBSC grafts. Graft-versus-host disease prophylaxis consisted mainly of cyclosporine A, short-course methotrexate, and anti-T-lymphocyte globulin. After a median follow-up of 118 months (68-174), the 10-year event-free survival rate after peripheral blood stem cell transplantation (PBSCT) was 54.8% (95% confidence interval [CI], 39.7%-69.8%), and after bone marrow transplantation (BMT), it was 27.9% (14.5%-41.3%; P < .004). In the advanced/active disease group, the 10-year event-free survival rate after PBSCT was 50% (30.8%-69.2%), and after BMT, it was 23.5% (9.3%-37.8%; P < .007). Non relapse mortality was less after PBSCT than BMT (14.3% vs 30.2%), respectively. In multivariate Cox regression analysis, PBSCT showed a better overall survival (OS; hazard ratio [HR], 0.43; 95% CI, 0.23-0.79; P = .007) compared to BMT; unfavorable/unknown prognostic impact cytogenetic abnormalities were an adverse factor for all patients (HR, 2.202; 95% CI, 1.19-4.06; P = .011). In patients with advanced disease, the use of PBSCs showed a significant favorable outcome via multivariate analysis (HR, 0.49; 95% CI, 0.24-0.99; P = .046). Outcome of acute myelogenous leukemia/myelodysplastic syndrome after unrelated hematopoietic cell transplantation is adversely affected by cytogenetic abnormalities and state of remission at hematopoietic cell transplantation. PBSC as a graft source has a significant favorable influence on survival. [ABSTRACT FROM AUTHOR]

Cytogenetics play a major role in determining the prognosis of patients with acute myelogenous leukemia (AML). However, existing cytogenetics classifications were developed in chemotherapy-treated patients and might not be optimal for patients undergoing allogeneic hematopoietic cell transplantation (HCT). We studied 821 adult patients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) who underwent HCT for AML in first or second complete remission between 1999 and 2004. We compared the ability of the 6 existing classifications to stratify patients by overall survival. We then defined a new scheme specifically applicable to patients undergoing HCT using this patient cohort. Under this scheme, inv(16) is favorable, a complex karyotype (4 or more abnormalities) is adverse, and all other classified abnormalities are intermediate in predicting survival after HCT (5-year overall survival, 64%, 18%, and 50%, respectively; P = .0001). This scheme stratifies patients into 3 groups with similar nonrelapse mortality, but significantly different incidences of relapse, overall and leukemia-free survival. It applies to patients regardless of disease status (first or second complete remission), donor type (matched related or unrelated), or conditioning intensity (myeloablative or reduced intensity). This transplantation-specific classification could be adopted for prognostication purposes and to stratify patients with AML and karyotypic abnormalities entering HCT clinical trials. [ABSTRACT FROM AUTHOR]

Animal and human studies have shown that after allogeneic hematopoietic cell transplantation, epithelial cells containing donor-derived genome emerge. The mechanisms underlying this phenomenon are still unclear. We hypothesized that horizontal transfer of the hematopoietic donor-DNA to the host epithelium confers a possible operating mechanism. In an in vitro model mimicking the lymphocyte–epithelial interaction, we cocultivated keratinocyte HaCaT cells (Y-chromosome negative) with nonapoptotic or apoptotic, CMFDA, or BrdU-labeled hematopoietic Jurkat cells (Y+) and looked for the emergence of HaCaT cells bearing Jurkat genome. We found that DNA can be horizontally transferred from hematopoietic to epithelial cell lines through phagocytosis of apoptotic bodies. The ingested genomic material was also found within the nuclear compartment and in isolated chromosomes obtained from HaCaT metaphases. Both lysosomal inhibition in HaCaT cells and repetitive load of HaCaT cells with apoptotic bodies increased the intercellular and intranuclear DNA delivery. Although recipient cells remained viable and showed to express the foreign DNA, this expression was transient. Taking into consideration these findings of horizontal DNA transfer between hematopoietic and epithelial cells, we evaluated by quantitative microsatellite analysis the amount of donor DNA in 176 buccal swabs obtained from 71 patients after allogeneic transplantation. We found a high amount of donor-DNA (mean 26.6%) in the majority (89.7%) of them, although no donor hematopoietic cells were evident in the samples by immunofluorescence. We propose that the incessant charge of the transplant recipient with donor-DNA and its “inappropriate” intranuclear delivery in host epithelium may explain the emergence of epithelial cells with donor-derived genome. [Copyright &y& Elsevier]

Toxicity-reduced conditioning is a curative treatment option for medically compromised or elderly patients ineligible for myeloablative hematopoietic cell transplantation (HCT). The aim of this study was to detect prognostic factors for overall survival (OS) and to evaluate quality of life (QOL) in a large homogeneous cohort of 160 consecutive patients aged ≥60 years treated with allogeneic HCT. We evaluated age, sex, performance status, comorbidities, pulmonary function, lactic dehydrogenase concentration, type of donor, disease status, CD34+ cells transplanted, cytomegalovirus status, time from diagnosis to HCT, and the development of acute and chronic graft-versus-host disease (GVHD). All patients who survived for ≥6 months (n = 79) were asked to complete a QOL survey. All patients (median age, 64.7 years; range, 60.1-76 years) received pretransplantation conditioning with fludarabine, BCNU, and melphalan. With a median follow-up of 35 months, the 1-year OS was 62.4% and 3-year OS was 47.4%. Multivariate analysis revealed compromised performance status as the most significant negative prognostic parameter for OS (P < .003), whereas male donor (P = .008) and chronic GVHD (P = .024) were associated with better OS. The 89% of survivors who returned the QOL questionnaire rated their global QOL as good-to-excellent despite impaired functional capabilities and such symptoms as fatigue, dyspnea, and loss of appetite. The main prognostic factor was performance status, not age. Our data suggest that toxicity-reduced conditioning offers a chance for enhanced OS with an adequate QOL. [Copyright &y& Elsevier]

The prognosis after hematopoietic cell transplantation (HCT) for the treatment of leukemia or lymphoma in humans is influenced by donor-derived natural killer (NK) cells, which enhance the graft-versus-leukemia (GVL) effect. Such alloreactive killer cells can be generated in vivo after HCT if the donor expresses killer cell immunoglobulin-like receptors (KIRs), such as KIR2DL1, KIR2DL2/3, or KIR3DL1, for which the recipient lacks HLA class I ligands. We studied effector cells from 22 KIR/HLA-ligand mismatched and 14 KIR/HLA-ligand matched, primarily HLA-matched patient-donor pairs after allogeneic HCT. A novel 8-color flow cytometry panel allowed us to characterize effector-cell populations without “broadly reactive” inhibitory receptors such as CD94/NKG2A or LIR1. The numbers of such NKG2A– LIR1– NK cells increased following HCT in patients transplanted by KIR/HLA-ligand mismatched grafts, compared to KIR/HLA-ligand matched grafts, and in patients transplanted from donors of the A/B, compared to A/A, KIR haplotypes. NKG2A–LIR1– NK cells expressing only those inhibitory KIRs for which the patient had no HLA class I ligands could be stimulated by HLA class I-deficient cells to express CD107a. Thus, NKG2A–LIR1– NK cells may be important GVL effector cells following HCT, even in patients transplanted from HLA-matched donors. [Copyright &y& Elsevier]

Prophylaxis of acute graft-versus-host disease (aGVHD), while maintaining the graft-versus-leukemia (GVL)/lymphoma effect and preventing severe infectious diseases, remains the main challenge in allogeneic hematopoetic cell transplantation (allo-HCT). To evaluate this, we examined the feasibility of deescalating the dose of alemtuzumab (MabCampath™) in combination with cyclosporine (CsA) as the sole GVHD-prophylaxis in patients after fludarabine (Flu)-based reduced-intensity conditioning (RIC) in an observational cohort study. We included 127 consecutive patients (median age 63 years) with an unrelated (UD; n=69) or related donor (SIB; n=58) after their first transplantation, mostly presenting with advanced disease. The first 30 patients received 20 mg/day on day −2 and −1 (40 mg), the following 48 patients 10 mg/day on day −2 and −1 (20 mg), and the last 49 patients 10 mg on day −1 (10 mg) alemtuzumab intravenous (i.v.) prior to transplant. We observed no statistical differences comparing the 40 mg, 20 mg, or 10 mg dose groups, in terms of cumulative incidences of aGVHD grade III-IV 7% (confidence interval [CI] 95%; 1-51), 12% (1-40), 6% (1-40), extensive chronic GVHD (cGVHD) 24.4% (3.3-55.8), 17% (2.5-42), and 14.2% (1.5-41.5) and of aGVHD grade II-IV 7 % (0-51.5), 29% (11.9-49.1), 21% (15.3-43.1), respectively. The difference between the 20-mg and 40-mg groups was significant for aGVHD grade II-IV(P < .05). In conclusion, we demonstrate the feasibility of reducing the dose of alemtuzumab as GVHD-prophylaxis to 10 mg absolute in combination with CsA only for UD transplantation in particular. [Copyright &y& Elsevier]

Abstract: Development of severe steroid-resistant acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) is associated with poor outcome. The humanized monoclonal antibody alemtuzumab was shown to be effective in GVHD prophylaxis in conditioning regimens before allogeneic HCT. We evaluated the efficacy and safety of alemtuzumab in 20 patients with histologically confirmed steroid refractory grade III and IV intestinal GVHD after related and unrelated HCT. Overall response rate was 70%, with complete response in 35%. Despite the severe grade of GVHD in our patients, the median survival of 280 days and 1-year overall survival (OS) of 50% were superior or comparable to those associated with other treatment options. Cytomegalovirus (CMV) reactivation, bacterial infection, and invasive aspergillosis were frequent complications; however, infection was not a significant predictor for survival. These data suggest that treatment with alemtuzumab has favorable activity in severe intestinal GVHD after allogeneic HCT, but emphasize the importance of careful monitoring and anti-infectious supportive care. [Copyright &y& Elsevier]

Abstract: Buccal administration of budesonide (mouthwash) may be effective as a topical add-on therapy in patients with oral chronic graft-versus-host disease (cGVHD). Safety of approved oral budesonide is based on high intestinal and hepatic extraction by cytochrome P450 3A (CYP3A) enzymes. The purpose of this study was to evaluate the presystemic extraction and pharmacodynamic action of buccal budesonide. Oral budesonide (3 mg) was taken as reference to which various single and multiple dose regimens of buccal budesonide were compared. Budesonide and the 2 main CYP3A-dependent metabolites (6β-hydroxybudesonide, 16α-hydroxyprednisolone) were analyzed in blood and urine along with the drug''s effect on endogenous cortisol in 12 healthy subjects and 7 patients with oral cGVHD. We assessed CYP3A-dependent metabolites in both healthy subjects and patients after buccal budesonide. Whereas systemic exposure to budesonide was markedly lower in healthy subjects after the mouthwash compared to oral dosing (mean relative bioavailability 18%–36%), the systemic concentrations thereafter in patients were as high as those after the identical dose of oral budesonide. Reduced buccal CYP3A activity (lower inactivation of budesonide) in patients contributed to this remarkable difference. Endogenous cortisol was suppressed in some patients during 1 week of continuous treatment with buccal budesonide (3 × 3 mg per day). We are the first to report the biotransformation of budesonide via CYP3A enzymes after buccal drug administration. Only 2% of a buccal dose of budesonide achieves systemic circulation in healthy individuals; that fraction is 10% in patients with oral cGVHD, probably because of alterations in drug uptake and metabolization. [Copyright &y& Elsevier]

Acute myeloid leukemia bearing a RUNX1 gene mutation (RUNX1 + AML) has been proposed as a provisional entity in the 2016 WHO classification. Clinically, it has been associated with inferior response rates and outcome after conventional chemotherapy. Accordingly, RUNX1 + AML is allocated in the unfavorable prognostic category of the 2017 European Leukemia Net classification. Following allogeneic stem cell transplantation (alloSCT), RUNX1 was an unfavorable factor in one study in MDS/secondary AML, while data in de novo AML are scarce. Here, we present a retrospective study by the EBMT Acute Leukemia Working Party, aiming to elucidate the prognostic value of RUNX1 mutation in patients undergoing alloSCT for AML in first complete remission (CR1). Adults undergoing alloSCT for AML in CR1 from matched related or unrelated donors between 2013 and 2018 with complete information on conventional cytogenetics and RUNX1 mutational status were selected from the EBMT registry. Variables of interest were overall and leukemia-free survival (OS/LFS), GvHD/relapse free survival (GRFS), cumulative relapse incidence (RI), non-relapse mortality (NRM) and GvHD. Log rank test, Gray test and Cox regression models were used. 128 RUNX+ and 388 RUNX- patients were identified, >80% of both subgroups presenting as de novo AML. As expected, RUNX1+ patients rarely had co-mutations in NPM1 (6% vs. 26%, p=10−3), and showed a positive correlation with ASXL1 mutations (50% vs. 16%, p=10−4). Cytogenetic categories and other mutations (FLT3 -ITD, CEBPA) were equally distributed between the two groups, as were age, donor and graft type, CMV, conditioning and T cell depletion (TCD). Median follow-up was 16.4 (RUNX+) and 19.8 (RUNX-) months. 2y OS/LFS of the entire cohort were 64% [59-69]/57% [52-62], with no difference between RUNX1 + and RUNX1 - patients either in univariate or multivariate analysis (2y OS: 67.9% [57.3-78.5] vs. 63.1%v[57.4-68.7]p=0.15; 2y LFS: 57.6% [46.4-68.7] vs. 57% [51.4-62.6], p=0.38], figure 1). RUNX1 mutation neither had any impact among patients with normal karyotype (figure 2). Similarly, no other outcome parameter was influenced by RUNX1 mutational status. Instead, multivariate analysis revealed age and donor type as risk factors for OS, LFS and NRM. Poor cytogenetic was associated with higher RI and inferior LFS/GRFS, in vivo TCD with a lower rate of aGvHD II-IV, cGvHD, and better GRFS. Among patients with available information, FLT3 -ITD was an independent risk factor for relapse, LFS and GRFS. RUNX1 did not modify the role of FLT3 -ITD. Within the limits of a retrospective registry analysis, we could not find a negative influence of RUNX1 mutation on outcome after allogeneic SCT in CR1. Hence, transplantation in CR1 might overcome the unfavorable prognostic value of RUNX1 mutation and can be recommended as consolidation treatment in this entity. [ABSTRACT FROM AUTHOR]

Abstract: Despite gratifying cure rates in germ cell tumors, conventional-dose chemotherapy achieves long-term remissions in less than 50% of patients at high risk. High-dose chemotherapy followed by autologous (auto) peripheral blood stem cell transplantation (PBSCT) has shown impressive remission rates in high-risk and relapsed germ cell tumors. We report on 64 consecutive patients with high- (n = 39), intermediate- (n = 18), and refractory or relapsed low- (n = 7) risk germ cell tumors who underwent auto-PBSCT between January 1993 and February 2003. PBSCTs were performed as a single (n = 40) or repeated (n = 24) transplantation using either etoposide, ifosfamide, and carboplatin (n = 80) or related protocols (paclitaxel, ifosfamide, carboplatin, etoposide [n = 7]; carboplatin, etoposide, thiotepa [n = 4]). With a median follow-up of 6 years, estimated 2- and 5-year overall survivals were 77.2% (95% confidence interval [CI] 66.7-87.7) and 73.1% (95% CI 61.7-84.5), respectively. We observed unfavorable results in those patients showing refractoriness to cisplatin (hazard ratio 20.36; 95% CI 6.64-62.47) or no response to induction chemotherapy (hazard ratio 10.67; 95% CI 1.37-83.37). Auto-PBSCT was well tolerated, showed objective antitumor activity, and achieved long-term survival in patients at high risk and with relapse. Our data suggest that auto-PBSCT can increase response rates and may improve the outcome in these patients. [Copyright &y& Elsevier]

Data on outcome of allogeneic transplantation (HSCT) from mismatched unrelated donors (MMUD) (≤6/8) in leukemic patients (pts) are limited. We assess HSCT results in pts with AML/ALL in CR transplanted between 2000 and 2017 from ≤6/8 MMUD (2-4 HLA mismatches at the allelic level at loci A, B, C and DR) reported to the EBMT. A total of 465 pts were allocated, AML-320 and ALL-145. Median age was 50.2 years (range, 18-71.8) and 34.8 years (range, 18.2-62.9); 54% and 64% were males, respectively. Median F/U was 63 and 75 months, respectively. 69% and 66% were in CR1, while 31% and 34% were in CR2. 40% of AML pts had intermediate risk cytogenetics, 10% poor risk and 5% good risk (missing 45%),respectively. 37% of ALL pts were Ph positive, 22% Ph negative and 18% T ALL (17% B ALL with no Ph data,6% missing data). The number of HLA mismatches (HLAMM) was 6/8 - in 82% and 85%,5/8- in 11.5% and 12% and 3-4 in 6% and 3% of AML and ALL pts, respectively. 85% of AML pts and 77% of ALL pts received PBSC graft. Conditioning regimen was myeloablative in the majority of pts (89% of AML and 61% of ALL pts). 82% and 77% underwent in vivo TCD, respectively. GVHD prophylaxis was CSA/MTX in 51% and 67% and CSA/MMF in 21% and 10% of AML and ALL pts, respectively. Engraftment was achieved in 97% and 95% of pts, respectively. The incidence of acute (a) GVHD grade (Gr) II-IV and Gr III-IV was 34% and 41% and 14% and 21% for AML and ALL pts, respectively. Total and extensive chronic(c) GVHD rates at 2y were 38% and 38% and 23% and 14%, respectively. The main causes of death were disease recurrence (37% in both), GVHD (29% and 22%) and infections (22% and 26%).The 2 and 5y outcomes in the entire population were: RI-28% and 33%, NRM-28% and 30%; LFS-44% and 37%, OS- 50% and 41% and GRFS- 33% and 27%, respectively. More than 2 HLA mismatches were associated with a higher incidence of aGVHD Gr II-IV (29% vs 15%, respectively).In MVA, RI was lower for ALL vs AML HR (95% CI) 0.60, p=0.02. Disease status (CR2 vs CR1) was poor prognostic factor for RI, LFS and OS. Age was prognostic factor for NRM, LFS and OS. HLA mismatch at locus DR was poor prognostic factor, giving increased NRM: HR (95% CI) 1.68, p=0.02, and lower LFS: HR (95% CI), 1.42, p= 0.03and OS HR (95% CI) 1.46, p= 0.03and higher GVHD Gr II-IV HR (95% CI) 1.48, p= 0.048. Results of MVA in AML pts in CR1 were similar. GVHD prophylaxis CSA/MMF in comparison to CSA/MTX resulted in higher NRM HR (95% CI) 2.2,p= 0.005 and lower GRFS HR (95% CI) 1.58, p= 0.02.Notably, in 154 pts with AML in CR1 transplanted from ≤6/8 UD with T cell depletion c mismatches was associated with higher incidence of cGVHD HR (95% CI) 2.52, p=0.002. HSCT from ≤6/8 MMUD transplantation can provide 40% 5y OS, 37% LFS and GRFS of 27% in leukemic pts. DR mismatch is a poor prognostic factor. cGVHD incidence at 5y is 41% with 21% being severe and is associated in AML pts with HLA C mismatches. CSA and MTX is the preferred GVHD prophylaxis. [ABSTRACT FROM AUTHOR]

Molecular pathogenesis of relapse after allogeneic hematopoietic cell transplantation is poorly understood. Data regarding relapse mechanisms after transplantation is scarcely available. We investigated genomic aberrations (GAs) in 21 patients undergoing related and unrelated HLA-matched transplantation in leukemic blasts before transplant and at relapse after transplantation. We found a higher number of GAs after transplantation, suggesting increased genomic instability during relapse. Two of 21 patients showed a large homozygous region spanning the whole HLA-locus on chromosome 6p in the relapse sample. In both patients sequence-based HLA typing of the blasts revealed a loss of the patient-specific allele at the mismatched locus leading to homozygosity for the HLA haplotype shared by the patient and the donor. In addition, GAs were found in critical regions such as 12p13, 13q12.2, and 17p13. Our results suggest that escape from immunologic surveillance may be a relevant mechanism of relapse after transplantation in patients with GAs on chromosome 6p. A combination of continuous immunologic pressure mediated by donor T cells and clonal evolution of myeloid leukemia may result in acquired GAs after transplantation. [Copyright &y& Elsevier]