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Highlights • Azacitidine post-transplant maintenance may promote a graft-versus-leukemia effect and reduce GVHD. • Extended oral CC-486 dosing may prolong epigenetic regulation post-allograft. • CC-486 post-transplant maintenance was associated with low rates of relapse and GVHD. • One-year relapse- and progression-free survival rate was 72% with 14-day CC-486 dosing. • Recommended dose is 200 mg daily for 14 days per 28-day cycle. Abstract Relapse is the main cause of treatment failure after allogeneic stem cell transplant (alloSCT) in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Injectable azacitidine can improve post-transplant outcomes but presents challenges with exposure and compliance. Oral CC-486 allows extended dosing to prolong azacitidine activity. We investigated use of CC-486 maintenance therapy after alloSCT. Adults with MDS or AML in morphologic complete remission at CC-486 initiation (42 to 84 days after alloSCT) were included. Patients received 1 of 4 CC-486 dosing schedules per 28-day cycle for up to 12 cycles. Endpoints included safety, pharmacokinetics, graft-versus-host disease (GVHD) incidence, relapse/progression rate, and survival. Of 30 patients, 7 received CC-486 once daily for 7 days per cycle (200 mg, n = 3; 300 mg, n = 4) and 23 for 14 days per cycle (150 mg, n = 4; 200 mg, n = 19 [expansion cohort]). Grades 3 to 4 adverse events were infrequent and occurred with similar frequency across regimens. Standard concomitant medications did not alter CC-486 pharmacokinetic parameters. Three patients (10%) experienced grade III acute GVHD and 9 experienced chronic GVHD. Of 28 evaluable patients, 6 (21%) relapsed or had progressive disease: 3 of 7 patients (43%) who had received 7-day dosing and 3 of 23 (13%) who had received 14-day dosing. Transplant-related mortality was 3%. At 19 months of follow-up, median overall survival was not reached. Estimated 1-year survival rates were 86% and 81% in the 7-day and 14-day dosing cohorts, respectively. CC-486 maintenance was generally well tolerated, with low rates of relapse, disease progression, and GVHD. CC-486 maintenance may permit epigenetic manipulation of the alloreactive response postallograft. Findings require confirmation in randomized trials. (ClinicalTrials.gov NCT01835587.) [ABSTRACT FROM AUTHOR]

In this study, we compared transplantation outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with advanced myelodysplastic syndrome (MDS) who received a CD34 + cell-selected and those who received an unmodified allograft. This analysis initially included 181 patients, 60 who received a CD34 + cell-selected transplant and 121 who received an unmodified transplant. Owing to significant differences in disease characteristics, the analysis was limited to patients with <10% blasts before HSCT (n = 145). Two groups were defined: low risk, with low- and intermediate-risk cytogenetics (CD34 + , n = 39; unmodified, n = 46), and high risk: poor and very poor risk cytogenetics (CD34 + , n = 19; unmodified, n = 41). In the low-risk group, the incidence of grade II-IV acute graft-versus-host disease (aGVHD) at 1 year post-transplantation was 18% in the CD34 + subgroup versus 41.3% in the unmodified subgroup ( P  = .015). There were no differences between the subgroups in the incidence of grade III-IV aGVHD. The incidence of chronic graft-versus-host disease (cGVHD) at 3 years in the 2 subgroups was 5.3% and 56%, respectively ( P  < .001). At 3 years post-transplantation, relapse, overall survival (OS), and relapse-free survival (RFS) were similar in the CD34 + and unmodified subgroups: 8.1% versus 19.4% ( P  = .187), 58.5% versus 53.7% ( P  = .51), and 59.5% versus 52.4% ( P  = .448). However, the composite outcome combining extensive cGVHD-free status and relapse-free status (CRFS) at 3 years was 59.5% in the CD34 + group versus 19.2% in the unmodified group ( P  < .001). In the high-risk group, grade II-IV aGVHD at 1 year was 31.6% in the CD34 + subgroup versus 24.4% in the unmodified subgroup ( P  = .752). There were no differences between the subgroups in the incidence of grade III-IV aGVHD. The incidence of cGVHD at 3 years in the 2 subgroups was 0% versus 27.6% ( P  = .013). At 3 years post-transplantation, relapse, OS, RFS, and CRFS in the 2 subgroups were 31.6% versus 69.3% ( P  = .007), 35.5% versus 14.5% ( P  = .068), 31.6% versus 10.7% ( P  = .045), and 31.6% versus 6.1% ( P  = .001), respectively. Cytogenetic abnormalities at diagnosis and transplant type had significant univariate associations with RFS in the high-risk cohort. Only cytogenetics ( P  = .03) remained associated with this outcome in a multivariate model. OS was similar in the 2 transplant groups; however, CRFS was superior in the CD34 + cell-selected transplant group. [ABSTRACT FROM AUTHOR]

We investigated the impact of patient and disease characteristics, including cytogenetics, previous therapy, and depth of response, on the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) for patients with myelodysplastic syndrome (MDS). We analyzed 256 MDS patients who underwent transplantation from a matched related (n = 133) or matched unrelated (n = 123) donor after 2001. Of the 256, 78 (30.5%) did not receive cytoreductive therapy before HSCT; 40 (15.6%) received chemotherapy, 122 (47.7%) received hypomethylating agents (HMA), and 16 (6.2%) received both (chemo+HMA). Disease status at HSCT defined by International Working Criteria was complete remission in 46 (18%) patients. There were significant differences between therapy groups: there were more therapy-related MDS and higher use of matched related donor in the untreated group. The chemotherapy group had higher serum ferritin levels at HSCT. Patients were older and had more high-risk disease by revised International Prognostic Scoring in the HMA group. Despite those differences, transplantation outcomes were similar in patients who were untreated and who received cytoreductive therapy before HSCT. Three-year event-free survival (EFS) was 44.2%, 30.6%, 34.2%, and 32.8% for untreated, chemotherapy, HMA, and chemo+HMA groups, respectively ( P = .50). Multivariate analyses revealed that older age (hazard ratio [HR], 1.3; P = .001); high-risk histologic subtypes, including refractory anemia with excess blasts (HR, 1.5; P = .05) and chronic myelomonocytic leukemia (HR, 2.1; P = .03), high-risk cytogenetics with monosomal karyotype (MK) (HR, 4.0; P < .0001) and high serum ferritin level at HSCT (HR, 1.8; P = .002) were poor prognostic factors for EFS. Bone marrow blast count 5% or higher at HSCT (HR, 1.6; P = .01) and MK (HR, 4.2; P < .0001) were the only prognostic factors for increased relapse incidence after HSCT. Patients with MK represented a poor prognostic group, with 3-year EFS of 11.4% and relapse incidence of 60.9%. In this analysis, various therapy approaches before HSCT did not lead to different transplantation outcomes. Cytogenetics defined by MK was able to identify a very poor prognostic groups that innovative transplantation approaches to improve outcomes are urgently needed. [ABSTRACT FROM AUTHOR]

Abstract: Risk stratification is important to identify patients with acute myelogenous leukemia (AML) who might benefit from allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission. We retrospectively studied 150 patients with AML and diagnostic cytogenetic abnormalities who underwent myeloablative allo-HSCT while in first complete remission to evaluate the prognostic impact of persistent cytogenetic abnormalities at allo-HSCT. Three risk groups were identified. Patients with favorable/intermediate cytogenetics at diagnosis (n = 49) and patients with unfavorable cytogenetics at diagnosis but without a persistent abnormal clone at allo-HSCT (n = 83) had a similar 3-year leukemia-free survival of 58%-60% despite the higher 3-year relapse incidence (RI) in the latter group (32.3%, versus 16.8% in the former group). A third group of patients with unfavorable cytogenetics at diagnosis and a persistent abnormal clone at allo-HSCT (n = 15) had the worst prognosis, with a 3-year RI of 57.5% and 3-year leukemia-free survival of only 29.2%. These data suggest that patients with AML and unfavorable cytogenetics at diagnosis and a persistent abnormal clone at allo-HSCT are at high risk for relapse after allo-HSCT. These patients should be considered for clinical trials designed to optimize conditioning regimens and/or to use preemptive strategies in the posttransplantion setting aimed at decreasing RI. [Copyright &y& Elsevier]

When an HLA-identical sibling is unavailable in a patient who needs allogeneic transplant, physicians are faced with the choice of several alternative donor types: matched unrelated donors, mismatched unrelated donors, and single- or double-unit umbilical cord (UCB) blood grafts. UCB transplant is a viable alternative for many patients, though adolescents and adults are limited to double-unit grafts due to dose limitations. Double-unit UCB transplants after myeloablative conditioning regimens have been linked with lower relapse rates than other donor types, though they are also associated with longer time to hematopoietic engraftment and subsequent higher rates of non-relapse mortality. The role of double-unit UCB transplants in reducing relapse incidence is less clear with reduced-intensity conditioning regimens. [Copyright &y& Elsevier]

Reduced-intensity conditioning (RIC) umbilical cord blood (UCB) transplantation is increasingly used in hematopoietic stem cell transplantation (HCT) for older and medically unfit patients. Data on the efficacy of HCT after RIC relative to myeloablative conditioning (MAC) are limited. We compared the outcomes of acute myeloid leukemia (AML) patients >18 yrs who received UCB grafts after either RIC or MAC. One hundred nineteen adult patients with AML in complete remission (CR) underwent an UCB transplant after RIC (n =74, 62%) or MAC (n = 45, 38%) between January 2001 and December 2009. Conditioning was either reduced intensity and consisted of cyclophosphamide 50 mg/kg, fludarabine 200 mg/m2, and total-body irradiation (TBI) 200 cGy or myelablative and consisted for cyclophosphamide 120 mg/kg, fludarabine 75 mg/m2, and TBI 1200-1320 cGy. All patients received cyclosporine (day −3 to day +180) and mycophenolate mofetil (day −3 to day +45) post-HCT immunosuppression and hematopoietic growth factor. Use of RIC was reserved for patients >45 years (n = 66, 89%) or preexisting severe comorbidities (n = 8, 11%). The 2 groups were similar except for preceding myelodysplastic syndrome (RIC = 28% versus MAC = 4%, P < .01) and age that was dictated by the treatment protocols (median, RIC = 55 years versus MAC = 33years; P < .01). The incidence of neutrophil recovery at day +42 was higher with RIC (94% versus MAC = 82%, P < .1), whereas platelet recovery at the sixth month was similar (RIC = 68% versus MAC = 67%, P = .30). Incidence of grade II-IV acute graft-versus-host disease (aGVHD) (RIC = 47% versus MAC = 67%, P < .01) was decreased with similar incidence of chronic GVHD (cGVHD) (RIC = 30% versus MAC = 34%, P = .43). Median follow-up for survivors was 3.8 and 4.5 years for RIC and MAC, respectively (P = .4). Using RIC, 3-year leukemia-free survival (LFS) was decreased (31% versus MAC = 55%, P = .02) and 3-year relapse incidence was increased (43% versus MAC = 9%, P < .01). Two-year transplant-related mortality (TRM) was similar (RIC = 19% versus MAC = 27%; P = .55). In multivariate analysis, RIC recipients and those in CR2 with CR1 duration <1 year had higher risk of relapse and poorer LFS with no independent predictors of TRM. UCB with RIC extends the use of allogeneic HCT for older and frail patients without excessive TRM with greater benefit for patients in CR1 and CR2 with longer CR1. [Copyright &y& Elsevier]

We studied cytogenetic risk grouping schemes to stratify patients with acute myelogenous leukemia (AML) (n = 212) into prognostically distinct subgroups for relapse incidence (RI), progression-free survival (PFS), and overall survival (OS) after allogeneic hematopoietic stem cell transplantation (HSCT). Patients were divided according to cytogenetic abnormalities based on the Medical Research Council, Southwest Oncology Group, Cancer and Leukemia Group B (CALGB), Dana-Farber, and recently described monosomal karyotype (MK) classification schemes and analyzed separately for first complete remission (CR1; n = 134) and beyond (CR2+; n = 78). Multivariate analysis was performed after adjusting for age, conditioning intensity, donor type, and cytomegalovirus serology status. Although none of the covariates was associated with OS in CR1, the presence of MK (MK+) was associated with worse RI and PFS (hazard ratio [HR], 3.3, P = .01 and HR, 2.0, P = .05, respectively). No other classification scheme was predictive of outcomes in CR1. In CR2+, for RI, only MK+ was predictive of poor outcome (HR, 3.7; P = .03). For PFS, all 5 classification schemes were predictive, and for OS, both the MK+ and CALGB adverse karyotypes were predictive. In addition to cytogenetics, nonmyeloablative conditioning was associated with decreased PFS and OS in patients in CR2+ in all models. Our results indicate that among all classification schemes, MK classification can identify a subgroup with very poor prognosis in patients with AML after allogeneic HSCT. [Copyright &y& Elsevier]

Abstract: Transplant-associated microangiopathy (TAM) is a life-threatening complication after allogeneic HSCT, particularly with the use of calcineurin inhibitors as post-transplantation immunosuppressive therapy. We report our experience with TAM after HSCT with tacrolimus-based GVHD prophylaxis in a single-center study. Sixty-six of 1219 transplant recipients developed TAM with a cumulative incidence of 5.9%. Risk factors for TAM were female gender, lymphoid malignancy, receipt of a matched unrelated donor, and grade II-IV aGVHD. Most patients had infection and/or active GVHD at the diagnosis of TAM (82%). In the absence of renal dysfunction or encephalopathy, tacrolimus was generally continued, maintaining blood levels within the lower therapeutic range. Sixty-three patients were treated with plasma exchange. The cumulative incidence of response of TAM was 60%. Only 1 patient had a response of TAM without resolution of concomitant infections or GVHD. Six-month survivals were 0% and 50% for TAM nonresponders and responders, respectively. In conclusion, TAM is a common, life-threatening complication of allogeneic hematopoietic transplantation using tacrolimus prophylaxis. Control of TAM generally requires response of associated infections and GVHD. TMA response may occur despite continuation of tacrolimus treatment. [Copyright &y& Elsevier]

Abstract: Reduced-intensity conditioning has extended the use of allogeneic hematopoietic stem cell transplantation (HSCT) to patients otherwise not eligible for this treatment due to older age or frailty. One hundred twelve acute myelogenous leukemia/myelodysplastic syndromes patients received fludarabine and melphalan (FM) conditioning with allogeneic HSCT. Most patients (73%) were not in remission. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and mini-methotrexate. Median age was 55 years (range, 22-74). Donors were related (53%) and unrelated (47%). Median follow-up of surviving patients (n = 43) was 29.4 months (range, 13.1-87.7). The complete remission (CR) rate was 82%. Estimates of 2-year survival were 66%, 40%, and 23% for patients in CR, with active disease without and with circulating blasts at HSCT, respectively. In multivariate analysis, survival was negatively influenced by active disease at HSCT and development of grade II-IV acute GVHD. Presence of circulating blasts at HSCT negatively influenced freedom from disease progression. Incidence of nonrelapse mortality (NRM) was significantly higher for patients with active disease, but was not influenced by patient age. Patients in CR had a day-100 and 2-year NRM of 0% and 20%, respectively. Use of unrelated donors increased the risk of NRM only among patients with active disease. FM and HSCT elicited long-term disease control in a significant fraction of this high-risk cohort. [Copyright &y& Elsevier]

Abstract The outcome of persons > 65 years with acute myeloid leukemia (AML) is poor. A transplant from an HLA-identical sibling or an HLA-matched unrelated donor can cure some of these patients but is associated with a substantial transplant-related mortality and a high relapse risk. We analyzed 185 subjects > 65 years with high-risk AML receiving conventional (n = 42) or reduced-intensity (n = 143) pretransplant conditioning and a transplant from an HLA-identical sibling (n = 66) or a 10/10 loci HLA-matched unrelated donor (n = 119). Two-year survival was 37%. Subjects with serious adverse events during before chemotherapy for their leukemia had a poor outcome after stem cell transplantation. Patients who had active leukemia or measurable residual disease (MRD) before transplantation had a worse outcome. Delayed hematologic recovery after induction or consolidation chemotherapy, high-risk AML genetics, donor–recipient HLA-DRβ3/4/5-DP mismatches, and history of cardiovascular disease were also correlated with survival in multivariate analyses. The 57 MRD-negative patients with few other adverse prognostic factors had an excellent outcome (2-year overall survival, 76%), whereas the 58 patients with detectable leukemia and more than 1 other additional factor fared poorly (2-year overall survival, 8%). These data indicate it is possible to identify persons > 65 years with high-risk AML likely to benefit from an allotransplant. Validation of this prediction is needed. [ABSTRACT FROM AUTHOR]

Abstract: The role consolidation chemotherapy prior to reduced-intensity (RIC) HCT is unclear. We reviewed 60 consecutive patients with AML in CR1 undergoing RIC HCT at the University of Minnesota and evaluated outcomes based on exposure to pre-transplant consolidation chemotherapy. The two year incidence of relapse and the probability of overall survival were similar between those who did and did not receive consolidation chemotherapy. The 2 year incidence of transplant-related mortality was slightly higher in those who did not receive consolidation and correlated with a higher HCT comorbidity index (HCT-CI) in that cohort. Our data suggest that exposure to consolidation chemotherapy prior to RIC HCT may not improve post-transplant outcomes for patients with AML in CR1. [Copyright &y& Elsevier]

• Clonal cytogenetic abnormalities (CCA) in donor cells after stem cell transplant (SCT) can be seen in donor-derived cells. • CCA may reflect a constitutional abnormality in a donor or may be present in a recipient with or without overt neoplasia. • In our cohort, ~1% of the patients had CCA in donor-derived cells. • Loss of 7q is the most common somatic CCA, in donor derived cells. • Presence of del(7q) in cases without an overt neoplasia appears to be an adverse prognostic factor. Clonal cytogenetic abnormalities (CCA) in donor-derived cells after stem cell transplant (SCT) are typically reported in donor-derived cell neoplasms, but CCA also may reflect a constitutional abnormality in the donor or may be present in a recipient without overt hematological malignancy. We reviewed 8515 tests on 2035 patients, who had allogenic sex mismatched SCT and underwent serial cytogenetic analysis between 2006 and 2020 in our institution. A constitutional CCA was observed in 3 patients: inv(10), t (1;5), and t (13;14). A somatic CCA without overt neoplasia was detected in 12 patients: del(7q) (n = 6), del(20q) (n = 3), der(11) t (11;11) (n = 1), t (1;9) (n = 1), dup(6p)(n = 1). In this group, four patients with cytopenia had del(7q), and an association between del(7q) and an adverse overall survival (OS) was observed [HR:5.99; 95%CI 1.23–29.92). Four patients had a donor-derived cell neoplasm: myelodysplastic syndrome (n = 3) and acute myeloid leukemia (n = 1), and all four neoplasms had loss of 7q. In our cohort, ∼1% of the patients (19/2,035) had CCA in donor-derived cells. Balanced constitutional CCA can pose a reproductive risk to donor. Loss of 7q is the most common somatic CCA, in donor-derived cells. [ABSTRACT FROM AUTHOR]

• Myeloablative pharmacokinetic-guided i.v. busulfan is safe in older myelofibrosis patients. • It reduced relapse without increasing NRM even in older patients. • Intermediate 2 DIPSS-plus risk has better outcomes than high-risk disease. Optimal conditioning regimens for older patients with myelofibrosis undergoing allogeneic hematopoietic cell transplant are not known. Likewise, the role of dose intensity is not clear. We conducted a nonrandomized, prospective, phase II trial using low-dose, later escalated to high-dose (myeloablative conditioning), busulfan with fludarabine (Bu-Flu) in myelofibrosis patients up to age 74 years. The first 15 patients received i.v. busulfan 130 mg/m2/day on days –3 and –2 ("low dose"); 31 patients received high-dose conditioning, either 100 mg/m2/day (days –5 to –2; n = 4) or pharmacokinetic-guided area under the curve of 4000 μmol/min (days –5 to –2; n = 27). The primary endpoint was day 100 nonrelapse mortality (NRM). Median age was 58 years (interquartile range [IQR], 53-63). Dynamic international prognostic scoring system-plus was intermediate (n = 28) or high (n = 18). Donors were related (n = 19) or unrelated (n = 27). Cumulative incidence of NRM was 9.7% (95% confidence interval [CI], 0-20.3) at day 100 and at 3 years in the high-dose group and 0% in the low-dose group at day 100, which increased to 20% (95% CI, 0-41.9) at 3 years. With a median follow-up of 5.1 years (IQR, 3.8-6), 3-year relapse was 32.3% (95% CI, 15.4-49.1) in high dose versus 53.3% (95% CI, 26.6-80.1) in low dose. Event-free survival was 58% (95% CI, 43-78) versus 27% (95% CI, 12-62), and overall survival was 74% (95% CI, 60-91) versus 60% (95% CI, 40-91). In multivariate analysis, high-dose busulfan had a trend toward lower relapse (hazard ratio,.44; 95% CI,.18-1.07; P =.07), with no impact on NRM. Intensifying the Bu-Flu regimen using pharmacokinetic-monitoring appears to be promising in reducing relapse without increasing NRM. [ABSTRACT FROM AUTHOR]

• This retrospective analysis evaluated the impact of ATG on viral infections and survival in HCT. • ATG use increased post-HCT viral EOD and viral-related hospitalizations. • OS and RFS at the final time point were inferior in those who received ATG. • Rigorous viral preemptive monitoring may reduce risk of viral EOD with ATG use. Antithymocyte globulin (ATG) has been shown to reduce the incidence of graft-versus-host-disease (GVHD) after matched related donor (MRD) and matched unrelated donor (MUD) hematopoietic stem cell transplantation (HCT); however, because of increased risks of infection and relapse, this use has not translated into a significant improvement in post-transplant survival. The goal of this single-center, retrospective cohort analysis was to quantify the incidence of viral reactivation and viral end-organ disease (EOD) within the first 100 days after MUD HCT with ATG-based conditioning compared with MRD HCT without ATG. Fifty-nine adult patients underwent ATG-based MUD HCT compared with 64 patients receiving MRD HCT without ATG. Cytomegalovirus reactivation was the most frequent event in both groups (65% MUD versus 61% MRD), followed by BK virus reactivation (26% versus 24%) and Epstein-Barr virus reactivation (20% versus 9%). A higher percentage of MUD patients experienced viral EOD by day +100 when compared with MRD patients (34% versus 16%, P =.022). This was most notable for EOD involving BK virus (15% versus 6%, P =.14) and Epstein-Barr virus (7% versus 0%, P =.050). Correspondingly, more patients in the MUD group experienced virus-related complications, including hospitalization (24% versus 3%, P <.001), intensive care unit admission (10% versus 6%, P =.19), and mortality (8% versus 4%, P =.44). There were no significant differences in either relapse-free survival (RFS; 62% versus 78%, P =.07) or overall survival (OS; 72% versus 86%, P =.07) at 6 months post-HCT. However, when using the final time point of 21 months in the MUD/ATG group and 23 months in the MRD/no ATG group, MUD patients who received ATG had inferior survival (OS: 27% versus 77%, P =.009; RFS: 40% versus 59%, P =.042). Our results add to and further quantify the infectious risks associated with the use of ATG in MUD transplants and promote the implementation of more intensive preemptive viral monitoring practices in patients receiving ATG-based MUD transplants. [ABSTRACT FROM AUTHOR]

Although bortezomib and rituximab have synergistic activity in patients with lymphoma and both can attenuate graft-versus-host disease (GVHD), the drugs have not been used together in patients undergoing allogeneic stem cell transplantation (alloSCT). In this phase I/II trial, we assessed the safety and activity of bortezomib added to the rituximab (R) plus BEAM (carmustine, etoposide, cytarabine, melphalan) regimen in patients with relapsed lymphoma undergoing alloSCT. Primary GVHD prophylaxis consisted of tacrolimus and methotrexate. Bortezomib (1 to 1.3 mg/m2 per dose) was administered i.v. on days –13, –6, –1, and +2. We performed inverse probability weighting analysis to compare GVHD and survival results with an historical control group that received R-BEAM without bortezomib. Thirty-nine patients were assessable for toxic effects and response. The median age was 54 years. The most common diagnosis was diffuse large B cell lymphoma (41%). Twenty-two patients (56%) and 17 patients (44%) received their transplants from matched related and matched unrelated donors, respectively. The maximum tolerated bortezomib dose was 1 mg/m2. The weighted cumulative incidences of grades II to IV and III or IV acute GVHD were 50% and 34%, respectively; these incidences and survival rates were not significantly different from those of the control group. Median survival was not reached in patients age ≤ 50 years and with a long follow-up time of 60.7 months. The R-BEAM regimen has a survival benefit in lymphoma patients age ≤ 50 years undergoing alloSCT. The addition of bortezomib has no impact on survival or incidence of GVHD. [ABSTRACT FROM AUTHOR]

• Haploidentical transplants with post-transplantation cyclophosphamide have similar long-term survival as seen with HLA-matched donor transplants. • The FM100 regimen is associated with similar survival as the FM140 regimen for patients with lymphoma, although it is used primarily in older patients. We analyzed 186 patients with lymphoma who underwent allogeneic stem cell transplantation (ASCT) with fludarabine-melphalan (FM) conditioning and different types of donors (25 haploidentical [HD], 98 matched unrelated [MUD], and 63 matched related [MRD]) at our institution between September 2009 and January 2018. Patients received fludarabine 160 mg/m2 (40 mg/m2/day for 4 days) in combination with 1 dose of melphalan 140 mg/m2 (FM140) or 100 mg/m2 (FM100). Engraftment was similar among the 3 groups (92%, 89%, and 98%, respectively; P =.7). The 6-month cumulative incidence of grade III-IV acute graft-versus-host disease (GVHD) was 4% in the HD group, 14% in the MUD group, and 8% in the MRD group (P not significant), and the respective 3-year cumulative incidence of chronic GVHD was 5%, 16%, and 26% (P not significant). The respective 3-year nonrelapse mortality and relapse rates were 31%, 32%, and 10% (HD versus MUD, P =.9; HD versus MRD, P =.02) and 15%, 21%, and 39% (HD versus MUD, P =.4; HD versus MRD, P =.04). At 3 years, progression-free survival (PFS) was 59%, 44%, and 46% (P not significant); overall survival (OS) was 52%, 54%, and 67% (P not significant); and GVHD-free, relapse-free survival was 39%, 31%, and 24% (P not significant). No differences in the 3-year PFS (57% versus 43%; P =.3) and OS (64% versus 58%; P =.7) were seen between patients receiving FM100 and those receiving FM140. Our data demonstrate that in patients with lymphoma, ASCT with HD transplants have similar outcomes as ASCT with HLA-matched transplants, and the FM100 conditioning regimen appears to be at least as effective as the FM140 regimen. [ABSTRACT FROM AUTHOR]

Abstract HLA-DP mismatched allogeneic hematopoietic stem cell transplantation (allo-HCT) is associated with increased risk of aGVHD and decreased risk of relapse with no effects on overall survival (OS). It has been proposed that CMV-reactivation induces expression of HLA-DP molecules on GVHD target tissues by releasing inflammatory cytokines. We hypothesized that the increased GVHD incidence in HLA-DP mismatched allo-SCTs correlates with recipient CMV serostatus or CMV reactivation. In addition, CMV reactivation is associated with increased risk of GVHD with an unknown mechanism. Here, we analyzed the association between HLA-DPB1 and CMV reactivation on cumulative incidence of aGVHD and relapse as well as OS in 613 patients with AML and MDS who underwent matched related or unrelated allo-HCT at MD Anderson Cancer Center from 2005 to 2011. In multivariable analysis, HLA-DPB1 mismatching was associated with increased risk of aGVHD (hazard ratio (HR): 1.53, P < 0.001) independent of CMV serostatus and CMV reactivation. Additionally, HLA-DPB1 mismatching was associated with decreased risk of relapse and no effect on OS. CMV reactivation increased risks of aGVHD (HR: 5.82, P < 0.001) independent of HLA-DP mismatching with no effect on relapse or OS. In conclusion, our data suggests that HLA-DPB1 mismatching and CMV reactivation increase risk of aGVHD independently. [ABSTRACT FROM AUTHOR]

Fluid overload (FO) commonly occurs during hospitalization for allogeneic hematopoietic stem cell transplantation. We hypothesized that FO is associated with transplantation outcomes and evaluated this complication in 2 cohorts of patients. FO was graded based on post-transplantation weight gain, symptoms, and need for treatment, scored in real time by an independent team. The first cohort (study cohort; n = 145) underwent haploidentical transplantation for hematologic malignancies following a melphalan-based conditioning regimen. In univariate analysis, factors associated with day +100 nonrelapse mortality (NRM) were FO grade ≥2 (hazard ratio [HR], 15; 95% confidence interval [CI], 4.2 to 55; P  < .001), creatinine >1 mg/dL (HR, 4.7; 95% CI, 1.6 to 14; P  = .005), and age >55 years (HR, 4.5; 95% CI, 1.5 to 13; P  = .008). In multivariate analysis, factors associated with day +100 NRM were FO grade ≥2 (HR, 13.1; 95% CI, 3.4 to 50; P  < .001) and serum creatinine level >1 mg/dL at transplantation admission (HR, 3.5; 95% CI, 1.1 to 11; P  = .03). These findings were verified in a separate cohort (validation cohort) of patients with acute myelogenous leukemia/myelodysplastic syndrome who underwent HLA-matched transplantation with busulfan-based conditioning (n = 449). In multivariate analysis, factors associated with day +100 NRM were FO grade ≥2 (HR, 34; 95% CI, 7.2 to 158; P  < .001) and, in patients with FO grade <2, advanced disease status (HR, 5; 95% CI, 1.1 to 22; P  = .03). A higher NRM translated to significantly poorer 1-year overall survival rates for patients with FO ≥2 than for patients without FO (70% versus 42%, P  < .001 in the study cohort and 64% versus 38%, P  < .001 in the validation cohort). In conclusion, FO grade ≥2 is strongly associated with higher NRM and shorter survival and should be considered an important prognostic factor in transplantation. [ABSTRACT FROM AUTHOR]

We previously showed the safety of using cord blood (CB) expanded ex vivo in cocultures with allogeneic mesenchymal precursor cells (MPC) after myeloablative conditioning with faster recovery of neutrophils and platelets compared with historical controls. Herein, we report the transplantation outcomes of 27 patients with hematologic cancers who received 1 CB unit expanded ex vivo with MPCs in addition to an unmanipulated CB (MPC group) after reduced-intensity conditioning (RIC). The results in this group were compared with 51 historical controls who received 2 unmanipulated CB units (control group). The analyses were stratified for 2 RIC treatment groups: (1) total body irradiation 200 cGy + cyclophosphamide + fludarabine) (TCF), and (2) fludarabine + melphalan  (FM). Coculture of CB with MPCs led to an expansion of total nucleated cells by a median factor of 12 and of CD34 +  cells by a median factor of 49. In patients in whom engraftment occurred, the median time to neutrophil engraftment was 12 days in the MPC group, as compared with 16 days in controls ( P  = .02). The faster neutrophil engraftment was observed in both RIC groups. The cumulative incidence of neutrophil engraftment on day 26 was 75% with expansion versus 50% without expansion in patients who received FM as the RIC regimen ( P  = .03). Incidence of neutrophil engraftment was comparable in MPC and control groups if treated with TCF (82% versus 79%, P  = .40). Transplantation of CB units expanded with MPCs is safe and effective with faster neutrophil engraftment even after RIC regimens. [ABSTRACT FROM AUTHOR]

We investigated the long-term safety and disease control data obtained with i.v. busulfan (Bu) combined with clofarabine (Clo) in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT). A total of 107 patients, median age 38 years (range, 19 to 64 years) received a matched sibling donor (n = 52) or matched unrelated donor (n = 55) transplant for ALL in first complete remission (n = 62), second complete remission (n = 28), or more advanced disease (n = 17). Nearly one-half of the patients had a high-risk cytogenetic profile as defined by the presence of t(9;22) (n = 34), t(4;11) (n = 4), or complex cytogenetics (n = 7). Clo 40 mg/m 2 was given once daily, with each dose followed by pharmacokinetically dosed Bu infused over 3 hours daily for 4 days, followed by hematopoietic cell infusion after 2 days of rest. The Bu dose was based on the drug clearance as determined by a test Bu dose of 32 mg/m 2 . The target daily area under the curve was 5500 µmol/min for patients aged <60 years and 4000 µmol/min for patients aged >59 years. With a median follow-up of 3.3 years among surviving patients (range, 1 to 5.8 years), the 2-year progression-free survival (PFS) for patients undergoing HSCT in first complete remission (CR1), second complete remission (CR2), or more advanced disease was 62%, 34%, and 35%, respectively. The regimen was well tolerated, with nonrelapse mortality (NRM) of 10% at 100 days and 31% at 2 years post-HSCT. The incidence of grade II-IV and III-IV acute graft-versus-host disease (GVHD) was 35% and 10%, respectively; 18% patients developed extensive chronic GVHD. The 2-year overall survival (OS) for patients undergoing HSCT in CR1, CR2, or more advanced disease was 70%, 57%, and 35%, respectively. Among 11 patients aged >59 years treated with reduced-dose Bu in CR1 (n = 7) or CR2 (n = 4), 4 remain alive and disease-free, with a median follow-up of 2.6 years (range, 2 to 4.7 years). Only the presence of minimal residual disease at the time of transplantation was associated with significantly worse PFS and OS in multivariate analysis. Our data indicate that the Clo-Bu combination provides effective disease control while maintaining a favorable safety profile. OS and NRM rates compare favorably with those for traditional myeloablative total body irradiation-based conditioning regimens. [ABSTRACT FROM AUTHOR]

In major ABO-mismatched allogeneic hematopoietic stem cell transplantation (HSCT) persistence of antidonor isohemagglutinins leads to pure red cell aplasia (PRCA). To investigate severe pancytopenia noted in a previous study of PRCA, we analyzed all major ABO-mismatched HSCT between January 2003 and December 2012. Of 83 PRCA patients, 13 (16%) had severe pancytopenia. Severe pancytopenia was defined as an absolute neutrophil count (ANC) < 1.5 K/μL or requiring granulocyte colony-stimulating factor, platelets < 50 K/μL or transfusion dependent, and PRCA with RBC transfusion dependence at post-transplant day 90. In 6 patients (46%) severe pancytopenia resolved after PRCA resolution. Two patients (15%) received a second transplant because of persistent pancytopenia/secondary graft failure, 1 (8%) died from secondary graft failure despite a stem cell boost, 1 (8%) did not recover his platelet counts despite RBC/ANC recovery, and 3 patients (23%) died from disease relapse. We found that severe pancytopenia is frequently associated with PRCA in 16% of major ABO-incompatible HSCT with a higher incidence in males and pancytopenia resolved with resolution of PRCA in 46% of patients. [ABSTRACT FROM AUTHOR]

The treatment of patients with chronic myelomonocytic leukemia (CMML) with transplant has not been optimized. We retrospectively reviewed the data for 83 consecutive patients with CMML (47 with CMML-1/2 and 36 with CMML progressed to acute myeloid leukemia) who received an allogeneic stem cell transplant (allo-SCT) at our institution between April 1991 and December 2013 to identify factors associated with improved survival and determine whether treatment with hypomethylating agents before transplant improves progression-free survival (PFS). The median age of the cohort was 57 years. Seventy-eight patients received induction treatment before transplant, with 37 receiving hypomethylating agents and 41 receiving cytotoxic chemotherapy. Patients treated with a hypomethylating agent had a significantly lower cumulative incidence of relapse at 3 years post-transplant (22%) than those treated with other agents (35%; P = .03), whereas treatment-related mortality at 1 year post-transplant did not significantly differ between the groups (27% and 30%, respectively; P = .84). The lower relapse rate resulted in a significantly higher 3-year PFS rate in patients treated with a hypomethylating agent (43%) than in those treated with other agents (27%; P = .04). Our data support the use of hypomethylating agents before allo-SCT for patients with CMML to achieve morphologic remission and improve PFS of these patients. Future studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Chimerism testing after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) represents a promising tool for predicting disease relapse, although its precise role in this setting remains unclear. We investigated the predictive value of T lymphocyte chimerism analysis at 90 to 120 days after allo-HSCT in 378 patients with AML/MDS who underwent busulfan/fludarabine-based myeloablative preparative regimens. Of 265 (70%) patients with available T lymphocyte chimerism data, 43% of patients in first or second complete remission (CR1/CR2) at the time of transplantation had complete (100%) donor T lymphocytes at day +90 to +120 compared with 60% of patients in the non-CR1/CR2 cohort ( P = .005). In CR1/CR2 patients, donor T lymphocyte chimerism ≤ 85% at day +90 to +120 was associated with a higher frequency of 3-year disease progression (29%; 95% confidence interval [CI], 18% to 46% versus 15%; 95% CI, 9% to 23%; hazard ratio [HR], 2.1; P = .04). However, in the more advanced, non-CR1/CR2 cohort, mixed T lymphocyte chimerism was not associated with relapse (37%; 95% CI, 20% to 66% versus 34%; 95% CI, 25% to 47%; HR, 1.3; P = .60). These findings demonstrate that early T lymphocyte chimerism testing at day +90 to +120 is a useful approach for predicting AML/MDS disease recurrence in patients in CR1/CR2 at the time of transplantation. [ABSTRACT FROM AUTHOR]

Cord blood transplantation (CBT) is curative for many patients with hematologic malignancies but is associated with delayed immune recovery and an increased risk of viral infections compared with HLA-matched bone marrow or peripheral blood progenitor cell transplantation. In this study we evaluated the significance of lymphocyte recovery in 125 consecutive patients with hematologic malignancies who underwent double-unit CBT (DUCBT) with an antithymocyte globulin–containing regimen at our institution. A subset of 65 patients was prospectively evaluated for recovery of T, natural killer (NK), and B cells, and in 46 patients we also examined viral-specific T cell recovery against adenovirus, Epstein-Barr virus, cytomegalovirus, BK virus, respiratory syncytial virus, and influenza antigen. Our results indicate that in recipients of DUCBT, the day 30 absolute lymphocyte count is highly predictive of nonrelapse mortality and overall survival. Immune recovery post-DUCBT was characterized by prolonged CD8 + and CD4 + T lymphopenia associated with preferential expansion of B and NK cells. We also observed profound delays in quantitative and functional recovery of viral-specific CD4 + and CD8 + T cell responses for the first year post-CBT. Taken together, our data support efforts aimed at optimizing viral-specific T cell recovery to improve outcomes post-CBT. [ABSTRACT FROM AUTHOR]

Graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (CY) after ablative HLA-matched bone marrow (BM) transplantation has been reported to have comparable rates of acute GVHD with an apparent reduction in chronic GVHD and infections when compared to historical prophylaxis with a calcineurin-inhibitor (CNI) and methotrexate (MTX). We conducted a phase II trial of post-transplantation CY (post-CY) after reduced-intensity conditioning (RIC) using intravenous busulfan (area under the curve of 4000 micromolar minute), fludarabine (40 mg/m 2 ) for 4 days, and CY 50 mg/kg on days +3 and +4 after BM or peripheral blood (PB) transplantations from matched related (MRD) or unrelated donors (MUD). MUD recipients received antithymocyte globulin (ATG); however, a later amendment removed ATG. Forty-nine patients were treated (acute myeloid leukemia/myelodysplastic syndrome, 82%). Median age was 62 years (range, 39 to 72). Fifteen patients received an MRD (9 PB/6 BM); 34 had a MUD (2 PB/32 BM). The cumulative incidence of grade II to IV acute GVHD, III to IV acute GVHD, and chronic GVHD was 58%, 22%, and 18%, respectively. A matched cohort analysis compared outcomes to tacrolimus/methotrexate GVHD prophylaxis and indicated higher rates of acute GVHD grade II to IV (46% versus 19%; hazard ratio [HR], 2.8; P = .02) and treatment-related mortality (HR, 3.3; P = .035) and worse overall survival (HR, 1.9; P = .04) with post-CY. The incidence of chronic GVHD and CMV reactivation did not differ. This study suggests that post-CY should not be used as sole GVHD prophylaxis after a RIC transplantation from HLA-matched donors. [ABSTRACT FROM AUTHOR]

The mismatched minor histocompatibility antigens present on Y chromosome (H-Y) in male recipients receiving stem cells from female donors may contribute to the graft-versus-leukemia effect and results in a reduced relapse rate, especially in patients with high-risk disease. We retrospectively compared the outcomes of male patients with acute myeloid leukemia who received an allogeneic hematopoietic stem cell transplant (HSCT) from female donors (F-M) (174 patients) versus other gender combinations (667 patients). Median age was 50 years (range, 18 to 74 years). For the whole group, the 1-year cumulative incidence of relapse was significantly lower in F-M group (34.1% versus 41.3%, P = .044), whereas nonrelapse mortality (NRM) was higher (23.2% versus 15.7%, P = .004). For patients younger than 50 years beyond first complete remission, the F-M group was associated with lower relapse rate (42.5% versus 55.2%, P = .045) whereas NRM was not significantly different (35.8% versus 25.5%, P = .141). Although survival was not significantly improved, transplantation from a female donor for male recipient was associated with a lower relapse rate. When relapse is the most common concern for treatment failure, especially for younger patients, a female donor for a male recipient might be beneficial to decrease relapse rate after transplantation. Future studies are needed to explore how the H-Y mismatch may improve survival after transplantation. [ABSTRACT FROM AUTHOR]

Allogeneic stem cell transplantation for patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) has been performed primarily with an HLA-matched donor. Outcomes of haploidentical transplantation have recently improved, and a comparison between donor sources in a uniform cohort of patients has not been performed. We evaluated outcomes of 227 patients with AML/MDS treated with melphalan-based conditioning. Donors were matched related (MRD) (n = 87, 38%), matched unrelated (MUD) (n = 108, 48%), or haploidentical (n = 32, 14%). No significant differences were found between haploidentical and MUD transplantation outcomes; however, there was a trend for improved outcomes in the MRD group, with 3-year progression-free survival for patients in remission of 57%, 45%, and 41% for MRD, MUD, and haploidentical recipients, respectively ( P = .417). Recovery of T cell subsets was similar for all groups. These results suggest that haploidentical donors can safely extend transplantation for AML/MDS patients without an HLA-matched donor. Prospective studies comparing haploidentical and MUD transplantation are warranted. [ABSTRACT FROM AUTHOR]

Background aims. Umbilical cord blood (CB) is used with increasing frequency to restore hematopoiesis in patients with bone marrow transplant who lack a suitable human leukocyte antigen-matched donor. CB transplantation is limited by low cell doses and delays in neutrophil and platelet engraftment. CB progenitors expanded ex vivo before transplantation provide more rapid hematopoietic and immune reconstitution as well as less engraftment failure compared with unmanipulated CB. However, the safety of infusing double and ex iróo-expanded CB has not been systematically examined. Methods. We reviewed the immediate adverse events (AE) associated with the infusion of CB occurring within 24 hours in 137 patients enrolled in clinical CB transplant trials at the MD Anderson Cancer Center from February 2004 to May 2010. All patients received an unmanipulated CB unit followed by infusion of a second unmanipulated CB unit or a second CB unit expanded ex vivo with the use of cytokines in a liquid culture system or in mesenchymal stromal cell co-cultures. Results. A total of three grade 2 and two grade 3 infusion reactions occurred within 24 hours of CB transplantation. This resulted in an AE rate of 3.7%. The majority of AEs manifested as signs of hypertension. No association with patient age, sex, disease status, premedication, ABO compatibility or total infusion volume was observed. In summary, the incidence of infusion-related toxicities in patients who receive unmanipulated and ex iróo-expanded double CB transplantation is low. Conclusions. We conclude that the infusion of unmanipulated followed by expanded CB products is a safe procedure associated with a low probability of inducing severe reactions. [ABSTRACT FROM AUTHOR]

Abstract: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative treatment for multiple myeloma (MM); however, because of high treatment-related mortality (TRM), its role is not well defined. Patients with newly diagnosed, relapsed, or primary refractory myeloma were enrolled in a randomized phase II trial of 2 reduced-intensity conditioning regimens: fludarabine 120 mg/m2 + melphalan 100 mg/m2 (FM100) versus fludarabine 120 mg/m2 + melphalan 140 mg/m2 (FM140) before allo-HCT from related or unrelated donors. Fifty patients underwent allo-HCT using FM100 (n = 23) or FM140 (n = 27) conditioning between April 2002 and 2011. There were no significant differences between FM100 and FM140 in time to neutrophil engraftment (P = .21), acute grade II to IV graft-versus-host disease (GVHD) (P = 1.0), chronic GVHD (P = .24), response rate (P = 1.0), TRM (13% versus 15%, P = 1.0), median progression-free survival (PFS), 11.7 versus 8.4 months, P = .12, and median overall survival (OS), 35.1 versus 19.7 months, P = .38. Cumulative incidence of disease progression in FM100 and FM140 was 43% and 70%, respectively (P = .08). Recurrent disease was the most common cause of death for both FM100 (26%) and FM140 (44%), P = .24. On multivariate analysis, disease status at allo-HCT, complete response or very good partial response (VGPR) was significantly associated with longer PFS (15.6 versus 9.6 months in patients with

Reduced-intensity conditioning (RIC) extends the curative potential of allogeneic hematopoietic cell transplantation (HCT) to patients with hematologic malignancies unable to withstand myeloablative conditioning. We prospectively analyzed the outcomes of 123 patients (median age, 57 years; range, 23-70 years) with hematologic malignancies treated with a uniform RIC regimen of cyclophosphamide, fludarabine, and total-body irradiation (200 cGy) with or without antithymocyte globulin followed by related donor allogeneic HCT at the University of Minnesota between 2002 and 2008. The cohort included 45 patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), 27 with aggressive non-Hodgkin lymphoma (NHL), 8 with indolent NHL, 10 with Hodgkin lymphoma (HL), 10 with myeloma, and 23 with acute lymphocytic leukemia, chronic myelogenous leukemia, other leukemias, or myeloproliferative disorders. The probability of 4-year overall survival was 73% for patients with indolent NHL, 58% for those with aggressive NHL, 67% for those with HL, 30% for those with AML/MDS, and only 10% for those with myeloma. Corresponding outcomes for relapse in these patients were 0%, 32%, 50%, 33%, and 38%, and those for progression-free survival were 73%, 45%, 27%, 27%, and 10%. The incidence of treatment-related mortality was 14% at day +100 and 22% at 1 year. The incidence of grade II-IV acute graft-versus-host disease was 38% at day +100, and that of chronic graft-versus-host disease was 50% at 2 years. Multivariate analysis revealed superior overall survival and progression-free survival in patients with both indolent and aggressive NHL compared with those with AML/MDS, HL, or myeloma. Worse 1-year treatment-related mortality was observed in patients with a Hematopoietic Cell Transplantation Comorbidity Index score ≥3 and in cytomegalovirus-seropositive recipients. These results suggest that (1) RIC conditioning was well tolerated by an older, heavily pretreated population; (2) patients with indolent and aggressive NHL respond well to RIC conditioning, highlighting the importance of the graft-versus-lymphoma effect; and (3) additional peri-transplantation manipulations are needed to improve outcomes for patients with AML/MDS or myeloma receiving RIC conditioning before HCT. [Copyright &y& Elsevier]

Abstract: The purpose of this study was to determine the effect of alemtuzumab on treatment-related mortality (TRM), relapse, overall survival (OS), and disease-free survival (DSF) in patients with acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) undergoing reduced intensity conditioning (RIC). We compared the outcome of 95 patients treated at the University of Chicago with fludarabine melphalan (Flu + Mel) + alemtuzumab conditioning and 59 patients treated at the M.D. Anderson Cancer Center with Flu + Mel conditioning. Both groups had similar patient and donor characteristics. There were no significant differences in TRM, relapse, survival, and DFS between the 2 groups. The incidence of acute graft-versus-host disease (aGVHD) grade II-IV (relative risk [RR] 5.5, P < .01) and chronic GVHD (cGVHD) (RR 6.6, P < .01) were significantly lower in patients receiving alemtuzumab. The addition of alemtuzumab to an RIC regimen dramatically reduces the incidence of aGVHD and cGVHD in patients with AML and MDS undergoing allogeneic transplantation. TRM, relapse risk, OS and DFS are not affected. [Copyright &y& Elsevier]

We previously reported that conditioning with Bu-Mel results in significantly longer PFS compared to Mel alone in patients with newly diagnosed multiple myeloma ([NDMM] Lancet Haematol 2019). Here we report the outcomes of the high-risk patients (based on chromosomal abnormalities as defined by IMWG) enrolled in this trial. The primary objective was to compare PFS in NDMM patients who undergo auto-HCT with Bu-Mel versus Mel conditioning. Transplant eligible patients were randomly assigned (1:1) to treatment. Patients in Bu-Mel arm received test dose Bu 32 mg/m2 followed by PK adjusted Bu to achieve a target AUC of 5000 microMol-minute (days -7 to -4) and Mel 70 mg/m2 on days -2 and -1. Patients in Mel arm received Mel 200 mg/m2 on day -2. Sixty-two patients (Bu-Mel, n=32; Mel, n=30) were identified. Median age at transplant was 61 yrs in the Bu-Mel and 60 yrs in the Mel arm. Sixteen (50%) and 18 (60%) patients were male in the Bu-Mel and the Mel arm, respectively. The R-ISS stage was I in 6 (22%), II in 17 (63%), and III in 4 (15%) of 27 patients in the Bu-Mel arm versus I in 8 (38%), II in 9 (43%), and III in 4 (19%) of 21 patients in the Mel arm, p=0.39. There was no significant difference in the HCT-CI score, induction therapy, response to induction, number of patients receiving maintenance therapy, and other patients, disease, or treatment characteristics between the two treatment groups. The median time to neutrophil engraftment (ANC ≥500) was 11 days and 12 days in the Bu-Mel and Mel arms, respectively, p=0.002. The median time to platelet engraftment (platelet count ≥20K without transfusion support) was 10 days and 12.5 days in the Bu-Mel and Mel arms, respectively, p<0.001. There was no 100-day treatment-related mortality in either arm. Grade II-IV mucositis was seen in 24 (76%) patients in the Bu-Mel and 5 (17%) in the Mel arm, p<0.001. Grade III neutropenic fever was seen in 22 (69%) patients in the Bu-Mel and 9 (30%) in the Mel arm, p=0.005. There was no grade IV toxicity in either arm. The overall response rate (PR or better) at day 90 after auto-HCT was 100% (sCR/CR=34%) in the Bu-Mel arm and 93% (sCR/CR=37%) in the Mel arm, p=0.23. The median follow-up was 41.3 months in the Bu-Mel arm and 36.5 months in the Mel arm. The median PFS was 44.7 months versus 25.7 months in the Bu-Mel and Mel arms, respectively, p=0.044 (Figure 1). The median overall survival (OS) was not reached in either arm, p=0.51 (Figure 2). The three-year PFS & OS rates in the Bu-Mel and Mel arm were 69% & 90%, and 41% & 87%, respectively. In a fitted Bayesian piecewise exponential regression model, treatment with Bu-Mel was associated with superior PFS. Conditioning therapy with Bu-Mel before auto-HCT yields significantly longer PFS in high-risk myeloma patients compared with Mel alone. Longer follow-up is needed to characterize any OS benefit. [ABSTRACT FROM AUTHOR]

Traditionally, pre-transplant conditioning regimen is given over 4-6 days before hematopoietic cell transplant (HCT). Delivering higher dose chemotherapy preparative regimen over a longer time period has not been tested previously. We hypothesized that the delivery of myeloablative dose of busulfan over a 3-week period may reduce toxicity and non-relapse mortality (NRM), without affecting relapse, and tested this in a prospective phase II study. Patients between 18 and 70 years of age with hematological malignancies and adequate organ function, with 8/8-HLA matched related or unrelated donor were eligible. They received a fixed dose of busulfan 80mg/m2 as outpatient on days -20 and -13. Then, fludarabine 40mg/m2 was given on days -6 to -2 followed by busulfan dosed to achieve target area under the curve (AUC) of 20,000 mol/min for the whole course based on pharmacokinetic studies. GVHD prophylaxis was cyclophosphamide (PTCy) 50mg/kg on days 3 and 4 and tacrolimus. Mycophenolate mofetil (MMF) was added to later unrelated donor recipients. All patients received standard supportive care. The primary endpoint was day 100 NRM. We enrolled 52 patients with a median age of 62 (range, 39-69) years. Almost half (n=25, 48%) had AML or MDS and the other half (n=26, 50%) had had CML or MPD; 1 (2%) had multiple myeloma. Low, intermediate, high and very-high disease risk index (DRI) was present in 3 (6%), 34 (65%), 14 (27%) and 1 (2%). HCT-comorbidity index was ≥3 in 23 (44%) and 1-2 (n=23, 44%). A majority (n=32, 62%) had an unrelated donor. With a median follow up of 14 months (range, 3-23), NRM at day 100 was 1.9% (n=1) and 8% (95% CI, 0-15) at 1 year. Overall survival, progression-free survival and relapse at 1-year were 83% (95% CI, 73-95%), 78% (95% CI, 67-91%), and 14% (95% CI, 4-24%), respectively [Table]. There were no graft failures. The median time to neutrophil engraftment was 17 days (range, 13-33) and that of platelets (≥ 20K/µL, n=45) was 24 days (range, 9-266). Day 100 grade II-IV and III-IV acute GVHD rates were 37% (95% CI, 23-50%) and 6% (95% CI, 0-12%), respectively; 1-year chronic GVHD and extensive chronic GVHD rates were 9% (95% CI, 0-17%) and 7% (95% CI, 0-14%), respectively. Overall survival at 1-year differed significantly among patients with low/intermediate DRI (94%; 87-100%) and those with high/very high DRI (53%; 31-91%), P=0.001. Myeloablative fractionated busulfan regimen with PTCy GVHD prophylaxis is feasible in older patients, has low incidence of severe acute GVHD, chronic GVHD, and NRM and results in promising overall survival. [ABSTRACT FROM AUTHOR]

Background Our group previously reported a 16% incidence of HC after hematopoietic cell transplantation (HCT) involving mostly matched unrelated donors (85%) and ATG-containing regimens (80%) (Silva, Haematologica 2010). PT-Cy is an effective GVHD prophylaxis in haplo- or matched unrelated transplants. There is a paucity of information about the risk of HC in this setting. Objective To retrospectively assess the incidence and clinical factors associated with HC in alloHCT recipients receiving PTCy as GVHD prophylaxis. Methods A retrospective analysis of patients (pts.) who underwent HCT with PT-Cy at our center between 2012-2018 was performed. We stratified the study cohort (N=478) into HC (N=193, 40%) and Non-HC (N=285, 60%) to compare their characteristics and outcome. Association between HC and clinical variables was assessed using logistic regression modeling. Results Pt's age, HCT-CI, # prior therapies, disease type and status were not statistically different between the 2 groups. However, the HC group pts. were more likely to have received more intense conditioning (Busulfan/Fludarabine(BF) +/- Clofarabine, or Thio; F/Melphalan (FM) 140+/-Thio or TBI vs. FM 100+/-TBI) (p=0.018), had haplo-transplants (p=0.018), BM as graft (p=0.021), and tacrolimus+mycophenolate mofetil (MMF) (p=0.043). Delayed ANC engraftment (p=0.032) and time to achieve an absolute lymphocyte count >500 was noted in HC group (p=0.014). 54% of HC pts. had grade 2-4 cystitis and BK virus was isolated in 87% of cases. CMV viremia was higher in HC group compared to Non-HC group (p<0.001). HC pts. experienced a higher # of hospitalizations (p=0.012) and longer hospital stay (p=0.06) days compared to Non-HC pts. Additionally, HC pts. were more likely to experience grade II-IV aGVHD compared to Non-HC pts (p=0.005). In multivariable analysis, conditioning intensity remained significant [HR 2.27 (95% CI: 1.28, 4.01); p=0.005]. Conclusion Our study showed a 40% incidence of HC after HCT recipients receiving PT-Cy. The intensity of the conditioning regimen is an independent predictive factor for developing HC. A formal comparison to ATG-containing regimens is in progress. [ABSTRACT FROM AUTHOR]

Background At our center, we observed a series of patients who developed transudative refractory ascites secondary to non-cirrhotic non-veno-occlusive disease (NC-nVOD) portal hypertension after allogeneic transplant (allo-SCT). The natural history, pathogenesis and etiology of this phenomenon is not well characterized nor well studied in the literature. Objectives To study and analyze the clinical characteristics and outcome of myeloid and lymphoid malignancy patients who developed IPHRA post allo-HCT. Methods In this retrospective study, we analyzed age>18 myeloid and lymphoid malignancy patients who developed IPHRA post allo-HCT. IPHRA was defined as NC-nVOD intrahepatic portal hypertension (serum ascites albumin gradient ≥ 1.1 or hepatic venous pressure gradient (HVPG) >5) and related refractory ascites in the absence of pre and post-hepatic etiologies of portal hypertension. Results We identified 24 patients who developed IPHRA post allo-HCT from our database. Median age at the time of allo-HCT was 52 yrs (range, 23-67). 23/24 did not have elevated LFT (Transaminases> 2.5 ULN/Bilirubin>1.5 ULN) before allo-HCT. Median time to development of IPHRA after allo-HCT was 95 days (range, 21-576 days). A median number of paracentesis that these patients had was 2 (range, 1-11); 5 had an intraperitoneal catheter placed, and 2 had TIPS to decrease the portal pressure. Portal pressures were measured in 15 patients, 9 had moderate portal hypertension (HVPG 5-10), and 6 had severe portal hypertension (HVPG >10). Liver biopsy was done in 20 patients, and for 3 patients we had autopsy results available. None of the patients met either the histological or clinical criteria of VOD or cirrhosis. 19 patients (79 %) died, and the median survival after development of IPHRA was 5.2 months (range, 0.7-49). The most common cause of death were complications of ascites/liver failure (n=7, 37%), and infectious causes (n=7, 37%). Conclusion IPHRA is an unrecognized fatal entity post-allo-HCT and has a high mortality rate. Further investigation is necessary to establish prognostic criteria for patients at risk of this serious complication. [ABSTRACT FROM AUTHOR]

Background Myeloablative conditioning (MA) reduces relapse as compared to reduced intensity (RIC), [Scott BL JCO 2017]. But it is avoided in older patients and those with comorbidities due to high non-relapse mortality (NRM), whose outcomes remain dismal. A CIBMTR study of AML patients ≥60 years (100% CR1) showed NRM of 32-34%, relapse rate of 33-37%, progression free survival (PFS) of 31-34% and overall survival (OS) of 34-36% at 2 years. [McClune. JCO 2010] A prospective trial in AML (≥60 years, 100% CR1) showed better 2-year PFS (42%) and OS (48%). [Devine. JCO 2015] Herein, we report the results of MA HCT using timed-sequential (TS) busulfan (Bu) in 71 AML patients up to age 73. Methods Patients received intravenous Bu in TS manner targeted to achieve an area under the curve of 16,000-20,000 μmol.min, with fludarabine (flu) 40 mg/m2 intravenously for four days. Results Median age was 64 years (range, 29-73). Donor was HLA matched unrelated (n=45, 63%) or related (n=26, 27%). Most received peripheral blood graft (n=46, 65%). Only 26% (n=18) had MRD-negative CR1/2 at HCT; others had MRD-positive CR1/2 (13%, n=9), primary induction failure (PIF; 45%, n=32) or relapsed disease (16%, n=11). Nearly half (47%) had the European LeukemiaNet (ELN) adverse risk disease. More than half (55%) had HCT-CI ≥ 3. Median follow-up was 40 months (range, 21-63). The cumulative incidences of grade II-IV and III-IV acute GVHD at day 100 were 39% (95% CI, 28-51%) and 10% (95% CI, 3-17%), respectively and extensive chronic GVHD at 1 year was 20% (95% CI, 10-29%). NRM was 6% (95% CI, 0-11%) at day 100 and 24% (95% CI, 14-34%) at 2 years. At 2 years, relapse was 28% (95% CI, 3-53%) in the CR/MRD-negative group vs 48% (95% CI, 34-62%) in others; progression-free survival (PFS) was 78% (95% CI, 61-99.6%) vs 25% (95% CI, 16-40%) and overall survival (OS) was 78% (95% CI, 61-99.6%) vs 33% (95% CI, 22-48%), respectively. [Fig 1a] Two year OS was was 67% (95% CI 51-87%) in the CR group, irrespective of MRD [Fig 1b]. In multivariate analysis (MVA) adjusted for covariates higher dose Bu vs lower dose [HR 0.39, 95% CI 0.18-0.85, p=0.02] was the only significant predictor of lower relapse risk. In MVA adjusted for age, Bu dose and ELN risk, not being in CR/MRD-negative state was the only predictor of significantly inferior PFS [HR 3.2, 95% CI, 1.3-8.2, p=0.01]. For OS, MVA adjusted for age, Bu dose and ELN risk, HCT-CI ≥3 [HR 1.98, 95% CI, 1-3.9, p=0.05] and not being in CR/MRD-negative state [HR, 2.7, 95% CI 0.98-7.2, p=0.05] were associated with higher mortality. Conclusion Our outcomes of MA HCT in an extremely high risk older population are promising especially in CR patients, whose outcomes approach that of younger patients. This was achieved by delivering Bu in TS manner which minimized toxicity and potentially increased efficacy. This approach warrants further investigation. [ABSTRACT FROM AUTHOR]

Background Post transplant cyclophosphamide (PTCy), tacrolimus, and MMF GvHD prophylaxis makes transplantation from haploidentical donors feasible without T cell depletion. In matched donor transplant recipients, cumulative incidences of grades II-IV acute, grades III-IV acute, and chronic GVHD were 51%, 15%, and 14%, respectively when single agent PTCy was used (Kanakry et al JCO 2014 32:3497-3505). However; as a single agent it was inferior to tacrolimus and methotrexate in another study (Alousi etal BBMT 2015, 906-912). We therefore hypothesized that addition of tacrolimus to PTCy may be needed to prevent severe acute GVHD and improve transplant outcomes. Methods All patients with AML undergoing first allogeneic transplant from matched sibling or at least 9/10 matched unrelated donor between 1/1/2011 to 4/30/2018 were eligible for this retrospective study if they received a melphalan or timed sequential busulfan (course AUC 20,000 umol/min) based conditioning regimen. GVHD prophylaxis consisted of tacrolimus and methotrexate 5mg/m2 on day 1, 3, 6, and 11 in the Tac/MTX cohort (n=140); and cyclophosphamide 50mg/kg given on days 3 and 4 and tacrolimus in the PTCy cohort (n=76). Results Patient characteristics were similar in both cohorts except that patients in PTCy cohort were younger with a median age of 59 years versus 63.5 years (P<0.001) and more likely to be in CR-57% v/s 41% (P=0.03). Outcomes and results of univariate analysis are summarized in Table1. Conclusion Tacrolimus and PostCy based GVHD prophylaxis reduces severe GVHD and improves survival. [ABSTRACT FROM AUTHOR]

Haploidentical (Haplo) HCT using post-transplantation cyclophosphamide (PT-Cy) has improved donor availability. However, a matched sibling donor (MSD) is still considered the optimal donor. Using the CIBMTR database, we compared outcomes after MSD HCT vs. PT-Cy-based Haplo-HCT in AML patients in CR1. Data from 1,205 adult CR1 AML patients (PT-Cy-based Haplo-HCT: 336, MSD with calcineurin inhibitor-based GVHD prophylaxis: 869) (2008-2015) were analyzed. The Haplo group included more reduced-intensity conditioning (65% vs. 30%) and bone marrow grafts (62% vs. 7%), consistent with current practice (Table 1). In univariate analysis, the Haplo group had less chronic GVHD (26 [21-31]% vs. 56 [53-60]% at 3 years, p<0.001), lower OS (48 [42-54]% vs. 55 [52-59]% at 3 years, p=0.03), and a trend for higher NRM (19 [15-24]% vs. 14 [12-17]% at 3 years, p=0.06), but similar grade II-IV acute GVHD (p=0.98), relapse (p=0.90), and LFS (p=0.11). In multivariable analysis (Figure 1), Haplo vs. MSD groups were not different in OS (p=0.15), LFS (p=0.50), or grade II-IV acute GVHD (p=0.98). However, the Haplo group had a lower rate of chronic GVHD (HR [95%CI]: 0.38 [0.30-0.48], p<0.001). Results of subgroup analyses by era or conditioning intensity were consistent with the main analysis. Our results suggest similar outcomes after current standard practices of PT-Cy-based Haplo-HCT using mostly bone marrow vs. MSD HCT using mostly peripheral blood, except for less cGVHD after Haplo-HCT. Although the groups were balanced for many important variables, the tight relationship of donor type with graft source and conditioning intensity may have influenced our findings. [ABSTRACT FROM AUTHOR]