Lower Risk Of Non-relapse Mortality Research Articles

Late events after anti-CD19 CAR T-cell therapy for relapsed/refractory B-cell non-Hodgkin lymphoma.

The short-term complications from chimeric antigen receptor T-cell therapy (CART) are well characterized, but the long-term complications still need to be further investigated. Therefore, herein, we will review the currently available literature published on the late adverse events following CART. We reviewed published data available from pivotal trials and real-world experiences with anti-CD19 CART (CART19) for adults with lymphoma. We defined late events as occurring or persisting beyond 1 month after CART infusion. We focused our literature review on the following late-event outcomes post-CART19: cytopenia, immune reconstitution, infections, and subsequent malignancies. Grade 3-4 cytopenia beyond 30 days occurs in 30%-40% of patients and beyond 90 days in 3%-22% of patients and is usually managed with growth-factor and transfusion support, along with neutropenic prophylaxis. B-cell aplasia and hypogammaglobulinemia are expected on-target off-tumor effects of CART19, 44%-53% of patients have IgG < 400 mg/dL, and approximately 27%-38% of patients receive intravenous immunoglobulin (IVIG) replacement. Infections beyond the initial month from CART19 are not frequent and rarely severe, but they are more prevalent and severe when patients receive subsequent therapies post-CART19 for their underlying disease. Late neurotoxicity and neurocognitive impairment are uncommon, and other causes should be considered. T-cell lymphoma (TCL) after CART is an extremely rare event and not necessarily related to CAR transgene. Myeloid neoplasm is not rare post-CART, but unclear causality given heavily pretreated patient population is already at risk for therapy-related myeloid neoplasm. CART19 is associated with clinically significant long-term effects such as prolonged cytopenia, hypogammaglobulinemia, and infections that warrant clinical surveillance, but they are mostly manageable with a low risk of non-relapse mortality. The risk of subsequent malignancies post-CART19 seems low, and the relationship with CART19 and/or prior therapies is unclear; but regardless of the possible causality, this should not impact the current benefit-risk ratio of CART19 for relapsed/refractory B-cell non-Hodgkin lymphoma (NHL).

Pretransplant Blinatumomab Improves Outcomes in B Cell Acute Lymphoblastic Leukemia Patients Who Undergo Allogeneic Hematopoietic Cell Transplantation

BackgroundBlinatumomab, a bispecific monoclonal antibody, effectively controls refractory B cell acute lymphoblastic leukemia (ALL) and promotes measurable residual disease (MRD) negativity. This study investigated the impact of pretransplant blinatumomab on allogeneic hematopoietic cell transplantation (HCT) outcomes in B cell ALL patients. MethodsWe analyzed the effect of pretransplant blinatumomab on transplant outcomes of 117 adults undergoing allogeneic HCT for B cell ALL at Princess Margaret Hospital, Toronto, between 2010 and 2021. Outcomes assessed included overall survival (OS), graft-versus-host disease and relapse-free survival (GRFS), cumulative incidences of relapse (CIR), and nonrelapse mortality (NRM). ResultsThe median follow-up was 36 months. Thirty-one participants (26.5%) received blinatumomab. Blinatumomab group had higher proportions of individuals with high disease risk index, primary induction failure and was more likely to receive dual T cell depletion with antithymocyte globulin and post-transplant cyclophosphamide. Two-year OS, GRFS, NRM, and CIR in the blinatumomab and nonblinatumomab groups were, respectively: 65.4% versus 45.6% (P = .05), 42.2% versus 17.3% (P = .01), 3.2% versus 43.0% (P = .007) and 34.4% versus 14.4% (P = .02). Blinatumomab was associated with a lower incidence of day-100 grade 2 to 4 and grade 3 to 4 acute graft-versus-host disease (aGVHD): 27.5% versus 56.7% (P = .009), and 10.9% versus 34.7% (P = .04), respectively. Multivariate analysis confirmed the association between pretransplant blinatumomab and improved OS and NRM. ConclusionsPretransplant blinatumomab is associated with improved OS and lower risk of NRM in B cell ALL patients undergoing allogeneic HCT, likely reflecting lower burden of treatment-related toxicity in this population. Larger prospective trials are warranted to validate our findings.

Impact of rabbit anti-thymocyte globulin (ATG) exposure on outcomes after ex vivo T-cell–depleted hematopoietic cell transplantation in pediatric and young adult patients

Background aimsTraditional weight-based dosing of rabbit anti-thymocyte globulin (rATG) used in allogeneic hematopoietic cell transplantation (HCT) to prevent graft-versus-host disease (GVHD) and graft rejection leads to variable exposures. High exposures induce delayed CD4+immune reconstitution (CD4+IR) and greater mortality. We sought to determine the impact of rATG exposure in children and young adults receiving various types of EX-VIVO T-cell–depleted (EX-VIVO-TCD) HCT. MethodsPatients receiving their first EX-VIVO-TCD HCT (CliniMACS CD34+, Isolex or soybean lectin agglutination), with removal of residual T cells by E-rosette depletion (E-) between 2008 and 2018 at Memorial Sloan Kettering Cancer Center were retrospectively analyzed. rATG exposure post-HCT was estimated (AU*d/L) using a validated population pharmacokinetic model. Previously defined rATG-exposures, <30, 30–55, ≥55 AU*d/L, were related with outcomes of interest. Cox proportional hazard and cause-specific models were used for analyses. ResultsIn total, 180 patients (median age 11 years; range 0.1–44 years) were included, malignant 124 (69%) and nonmalignant 56 (31%). Median post-HCT rATG exposure was 32 (0–104) AU*d/L. Exposure <30 AU*d/L was associated with a 3-fold greater probability of CD4+IR (P < 0.001); 2- to 4-fold lower risk of death (P = 0.002); and 3- to 4-fold lower risk of non-relapse mortality (NRM) (P = 0.02). Cumulative incidence of NRM was 8-fold lower in patients who attained CD4+IR compared with those who did not (P < 0.0001). There was no relation between rATG exposure and aGVHD (P = 0.33) or relapse (P = 0.23). Effect of rATG exposure on outcomes was similar in three EX-VIVO-TCD methods. ConclusionsIndividualizing rATG dosing to target a low rATG exposure post-HCT while maintaining total cumulative exposure may better predict CD4+IR, reduce NRM and increase overall survival, independent of the EX-VIVO-TCD method.

Interest of Cytoreductive Therapy before Allogenic Hematopoietic Stem Cell Transplantation in Childhood Myelodysplastic Syndromes: A Retrospective Study on Behalf of the Société Francophone De Greffe De Moelle Et De Thérapie Cellulaire (SFGM-TC)

Background: Pediatric myelodysplastic syndromes (cMDS) are rare and biologically different from that seen in adults. In addition to a specific genomic landscape, they are characterized by the high frequency of hypoplastic forms, and the recurrent association with germline predispositions (Khoury et al. 2022; Locatelli et Strahm 2018). For most patients, allogenic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option. In case of cMDS with increased blasts (cMDS-IB), pre-tranplant cytoreductive chemotherapy may be considered, but remains controversial (Strahm et al. 2011). Methods This multicenter retrospective study included all cMDS patients (&amp;lt;18y.o.) reported to the SFGM-TC registry who underwent an allo-HSCT between 2000 and 2020. Data have been obtained through ProMISe (internet-based system shared by all EBMT transplantation centers). All patients have given signed informed consent. Results Eighty-four cMDS patients from 17 centers were included. Median age at transplant was 10.2 years (IQR: 7.2, 14.2). Fifty-two percent of patients presented with increased blasts at diagnosis. Germline predispositions were known in 24% of patients. GATA 2 mutations were the most frequent (14%). Eighty-two percent of patients presented with hematologic cytogenetic abnormalities, including 64% of monosomy 7. Myeloablative conditioning was used in most of cases (91%). Busulfan/melphalan was the most frequent conditioning regimen (58%). HSCT were performed from sibling donors in 29% of the cases, matched unrelated donors (MUD) in 44%, umbilical cord blood (UCB) in 21% and haploidentical in 6%. Stem cell source was bone marrow in 68% of the cases. Considering the whole cohort, 5y overall survival (OS) and disease-free survival (DFS) were 67% (IC95% 57-78%) and 63% (IC95% 54-74%) respectively (Figure 1). Five years cumulative incidences of non-relapse mortality (NRM) and relapse were 26% (IC95% 17-35%) and 12% (IC95% 5.6-20%) respectively. Of the 21 cases of reported toxic death, 15 were related to acute GVH (aGVHD). Six months cumulative incidences of grade II-IV and III-IV acute graft vs host disease were 46 % and 24 % respectively. In univariate analysis, patients under 12 years (p=0,018) or who received a BuCyMel conditioning (p=0,004) or a graft from a MUD (p=0,030) had worst 5y OS and PFS. As expected, OS increased with time (p=0,014) reflecting improvements in supportive care and HSCT procedures (Figure 2A). These results were confirmed in multivariate analysis, except for MUD. Twenty-four patients received pre-transplant cytoreductive therapy, most often intensive chemotherapy (20/24). In the overall population, pre-transplant cytoreduction was not associated with an improved survival. However, subgroup analysis of the 40 patients with cMDS-IB showed a significant improvement of the OS probability (HR 0.18 [0.04-0.83], p=0.014) in patients who received a pre-transplant cytoreductive therapy in univariate analysis (Figure 2B). Cytoreductive therapy did not appear to be associated with a reduced risk of relapse, but with a lower risk of NRM. Although not statistically significant, the incidence of aGVHD was higher in patients who did not receive any cytoreductive therapy (HR 0.60 [0.09-3.85]). Conclusion: This retrospective study reports the outcomes of 84 patients who underwent allo-HCT for childhoodMDS. This study seems to show a benefit associated with the pre-transplant cytoreduction therapy in the subgroup of patients with cMDS-IB, notably through a reduction of aGVHD and NRM occurrence. BuCyMel conditioning, currently recommended for cMDS-IB, appears here, to be associated with excess of toxic mortality. This study also confirms the high aGVH-related toxic mortality rates already reported in cMDS (Strahm et al. 2011). Recent retrospective data have shown a benefit of post-transplantation cyclophosphamide (PTCy) in GATA2 patients transplanted with sibling or matched unrelated donors (Nichols-Vinueza et al. 2022). Prospective data on the use of PTCy in cMDS are therefore needed. Acknowledgment: This research is funded by the non-profit organization Etoile de Martin/SFCE.

Comparison of Two Reduced Intensity Conditioning Regimens (Baltimore with Clofarabine vs Thiotepa-Busulfan-Fludarabine) in Adults Receiving Peripheral Blood Stem Cell Haploidentical Transplantation for Myeloid Malignancies: A Retrospective Study of the SFGM-TC

Background: Haploidentical transplantation (haploT) has become a routine practice in many centers but the optimal conditioning regimen has yet to be determined. Indeed, the historic Baltimore reduced intensity conditioning (RIC) regimen has been associated with poor outcomes in myeloid malignancies. Two alternative RIC regimens have recently demonstrated promising results in this setting. One of them replaces fludarabine with second-generation nucleoside analogue clofarabine (Clo-Baltimore regimen [CloB], Chevallier et al., Oncotarget 2018) and the other combines thiotepa-busulfan-fludarabine (TBF, Duléry et al., BBMT 2019). Here we compared outcomes in order to determine if one of these two regimens was superior for the treatment of myeloid malignancies. Methods: This was a multicenter retrospective study conducted by the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC). All consecutive adults having received a haploT after a CloB or a TBF RIC regimen for a myeloid malignancy between September 2013 and May 2023 were eligible. Patients data were extracted from the PROMISE database. CloB consisted of clofarabine 30 mg/m²/day (d) 5 d, cyclophosphamide (Cy) 14.5mg/kg/d 2 d, and 2-Gy TBI on d-2. TBF consisted of thiotepa 5mg/kg 1 d, busulfan 3.2 mg/kg 2 d, a fludarabine total dose of 120 to 150 mg/m². Graft-versus-host disease (GVHD) prophylaxis consisted of post-transplant Cy (2 doses of 50mg/kg), followed by cyclosporine A and mycophenolate mofetil starting on d+5. Some patients received antithymocyte globulin (ATG) 2.5mg/kg/d on d-2. Graft source was exclusively peripheral blood stem cells (PBSC). To minimize bias between the CloB and the TBF groups, a propensity score matching (PSM) was constructed using a logistic regression model that included age, donor and recipient sex, hematopoietic cell transplantation-specific comorbidity index (HCT-CI), disease, cytogenetic risk (European LeukemiaNet [ELN] 2022), previous transplant, use of ATG, and cytomegalovirus (CMV) status, with the nearest-neighbor algorithm, and strict matching of key factors. Matched groups were then compared for time to engraftment (absolute neutrophil count &amp;gt; 0.5 x 10 9/L) and platelet (PLT) recuperation (&amp;gt;50 x 10 9/L), overall survival (OS), progression-free survival (PFS), GVHD-free, progression-free survival (GRFS), non-relapse mortality (NRM), and incidences of relapse as well as acute and chronic GVHD. Results: A total of 329 patients from 25 centers were included, 267 (81%) receiving TBF and 62 (19%) CloB. After PSM, 51 patients remained in each group, with comparable baseline characteristics except for the proportion of previous allotransplants ( Table). Median age was 60 years, and median HCT-CI score was 2. Main diagnoses comprised acute myeloblastic leukemia (AML, n=72 [71%]), including 42% with adverse genetic risk, and myelodysplastic syndrome (MDS, n=22 [22%]), including 25% with high or very high Revised International Prognostic Scoring System (R-IPSS). Thirty-eight (37%) patients received ATG. Time to engraftment was equivalent after both TBF and CloB (19 d vs 19.5 d, respectively, p=0.70), but TBF patients achieved PLT recuperation faster (27 d vs 31 d, p=0.03). Median follow-up was 24 months. Two-year OS, PFS and GRFS were 55% vs 60% (p=0.19), 52% vs 60% (p=0.25), and 37% vs 50% (p=0.15) for TBF and CloB patients, respectively. No differences were observed in terms of grade 3-4 acute GVHD at 3 months (18 vs 20%, p=0.86) nor two-year extensive chronic GVHD (16% vs 8.3%, p=0.25). However, two-year NRM was significantly higher after TBF (41% vs 16%, p=0.003), while relapse incidence was lower (7.1% vs 24%, p=0.02, Figure). In multivariate analysis, CloB was associated with a lower risk of NRM (hazard ratio [HR] 0.31, 95%CI: 0.1-0.7, p=0.008) and a higher risk of relapse (HR 4.03, 95%CI: 1.2-13.9, p=0.03). Finally, in patients aged &amp;gt;60y, two-year OS was significantly lower for those receiving TBF conditioning (39% vs 61%, p=0.02, Figure) due to higher NRM (56% vs 23%, p=0.005). Conclusions: In this retrospective study, a TBF RIC regimen used for PBSC haploT in adults with myeloid malignancies appeared substantially more toxic than a CloB RIC regimen. However, its enhanced anti-leukemic effect suggests that it should be offered to younger patients with no comorbidities or to those with high-risk disease. Conversely, CloB should be proposed for older or frail patients.

Donor Hematopoietic Cell Telomere Length and Magnitude of Post-HCT Shortening Predict Survival in Early Stage Leukemia and Myelodysplastic Syndrome

Introduction. Telomere length (TL) reflects cell replicative history and residual replicative potential. Telomeres in donated hematopoietic cells (HCs) shorten considerably after hematopoietic cell transplant (HCT) because of the extensive proliferation required to reconstitute the recipient hematopoietic system. Longer telomeres in donor HCs are associated with better survival post-HCT in patients with severe aplastic anemia (Gadalla et al., JAMA 2015; Blood 2018). However, it is unclear whether donor HC TL affects survival of patients receiving HCT for hematological malignancies. Methods. We identified 384 patients with leukemia or myelodysplastic neoplasms who received HCT between 2013 and 2016 at 1 st complete remission/early disease stage, and had post-HCT blood samples at day 90 (standard deviation: SD=14 days) in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) protocol 1202 repository. Pre-HCT matched donor samples were available at the Center for International Blood and Marrow Transplant Research (CIBMTR) biorepository. TL was measured by Southern blotting of the terminal restriction fragments. We used Cox proportional hazard models to evaluate the associations between HCT outcomes and (i) long donor HC telomeres (defined as ≥6.7 kb), and (ii) low post-HCT telomere shortening of donor HC TL (defined as &amp;lt;230 bp and calculated as the difference between pre-HCT donor HC TL and that in the recipient post-HCT). The telomere thresholds were determined by exploratory analyses relating HC TL parameters with recipients' outcomes. Study outcomes are 2-year overall survival (OS), relapse risk, and non-relapse mortality (NRM). We also calculated the adjusted cumulative risks of all-cause and cause-specific mortality associated with the two HC TL parameters using cause-specific competing risk methods. Follow-up started at day 100 post-HCT. Results. Patients' mean age was 49.6 years (SD=18) and that of the donors was 37.9 years (SD=15). About half (54.7%) of the patients received HCT from unrelated donors, and 9% from haplo-identical related donors. The 2- year OS probabilities were higher in patients receiving HCT from donors with HC TL ≥6.7 kb compared to those receiving HCT from donors with HC TL below this threshold (76% and 63%, respectively; p log-rank = 0.009). Similarly, recipients with telomere shortening of donated HCs ≥230 bp post-HCT compared with those below this threshold experienced better 2-year OS(78% and 62%, respectively; p=0.003). These associations remained significant after adjusting for donor age and predictive clinical factors (HR= 0.60, p = 0.03 for donor HC TL ≥ vs. &amp;lt; 6.7 kb; and HR = 1.95, p = 0.003 for donated HC telomere shortening post-HCT below vs. ≥ 230 bp). The leading cause of excess mortality differed by HC TL parameters. Donor HC TL of ≥6.7 kb was associated with lower risk of NRM (HR= 0.45, 95% CI = 0.22 - 0.93, p = 0.03; 2-year NRM risk of 9.0% vs. 15%). However, post-HCT telomere shortening of &amp;lt;230 bp was associated with higher risk of relapse (HR=1.82, 95% CI = 1.11 - 1.82, p=0.02; 2-year relapse-mortality risk of 28% vs. 12%) (Figure 1A). When considering the combined effect of donor HC TL and magnitude of TL shortening in recipient, the adjusted cumulative risk of all-cause mortality dropped in half (from 41% in patients with donor HC TL &amp;lt;6.7 kb and telomere shortening &amp;lt;230 bp to 21% in those with donor HC TL ≥6.7 kb and telomere shortening ≥230 bp (Figure 1B) Conclusions. Short telomeres in donated HCs and their limited telomere shortening after HCT are associated with poor survival in patients receiving HCT for hematological malignancies at 1st complete remission/early disease stage. The study suggests that TL in donors prior to HCT may be a useful marker for improved donor selection independent of age. Less HC telomere shortening in the recipients during the first 90 days might identify patients at higher risk for relapse of hematological malignancies.

Novel risk assessment for the intensity of conditioning regimen inolder patients.

Reduced-intensity conditioning (RIC) regimens have long-term outcomes that are generally comparable with those of myeloablative conditioning (MAC) because of a lower risk of nonrelapse mortality (NRM) but a higher risk of relapse. However, it is unclear how we should select the conditioning intensity in individual cases. We propose the risk assessment for the intensity of conditioning regimen in elderly patients (RICE) score. We retrospectively analyzed 6147 recipients aged 50 to 69 years using a Japanese registry database. Based on the interaction analyses, advanced age (≥60 years), hematopoietic cell transplantation-specific comorbidity index (≥2), and umbilical cord blood were used to design a scoring system to predict the difference in an individual patient's risk of NRM between MAC and RIC: the RICE score, which is the sum of the 3 factors. Zero or 1 implies low RICE score and 2or 3, high RICE score. In multivariate analyses, RIC was significantly associated with a decreased risk of NRM in patients with a high RICE score (training cohort: hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.60-0.90; P= .003; validation cohort: HR, 0.57; 95% CI, 0.43-0.77; P< .001). In contrast, we found no significant differences in NRM between MAC and RIC in patients with a low RICE score (training cohort: HR, 0.99; 95% CI, 0.85-1.15; P=.860; validation cohort: HR, 0.81; 95% CI, 0.66-1.01; P= .061). In summary, a new and simple scoring system, the RICE score, appears to be useful for personalizing the conditioning intensity and could improve transplant outcomes in older patients.

Prophylactic Donor Lymphocyte Infusion in Patients after Allogeneic Stem Cell Transplantation with Post-Transplant Cyclophosphamide Is Associated with Low Relapse Risk and Excellent Survival in Patients below 65 Years with Acute Myeloid Leukemia and High-Risk Myelodysplasia

BackgroundPost-transplant cyclophosphamide (PTCy) effectively prevents graft-versus-host-disease (GVHD) in allogeneic stem cell transplantation (alloSCT) with matched related and matched unrelated donors resulting in low risk of non-relapse mortality (NRM) (<10%). However, PTCy-alloSCT is associated with high relapse rates of approximately 20-30% after 1 year and 30-40% after 2 years (Gooptu et al. Blood 2021, Ruggeri et al. J Hemat Oncol 2018). Prophylactic donor lymphocyte infusion (DLI) may reduce relapse, although it may increase the risk of GVHD. AimTo provide evidence for reduction of relapse and improvement of survival by combining allogeneic SCT with PTCy and subsequent standardized prophylactic donor lymphocyte infusions (DLI) in a cohort of patients with acute myeloid leukemia (AML) and high risk myelodysplasia (MDS). Patients and MethodsSixty-five patients with AML (n=50) or high risk MDS (n=15) received myeloablative (n=15) or reduced-intensity (n=50) alloSCT with a matched related (n=8) or 9/10 (n=19) or 10/10 (n=38) matched unrelated donor. Based on modified ELN criteria, 10 AML patients were intermediate risk and 40 poor risk. GVHD prophylaxis consisted of PTCy, mycophenolate until day +30, and tacrolimus tapered from +70 (related or 10/10 unrelated) or day +90 (9/10 unrelated). All patients were planned to receive DLI at 6 months after transplantation at a dose of 3 x 10^6 CD3+ cells/kg in related and 1.5 x 10^6 CD3+ cells/kg in unrelated alloSCT. In poor risk patients (poor risk AML and high risk MDS) additional low dose DLI (0.3 or 0.15 x 10^6 CD3+ cells/kg in related and unrelated alloSCT, respectively) was planned one month after tacrolimus tapering (i.e. 3-4 months after alloSCT). In poor risk patients with a sensitive molecular or immunophenotypical minimal residual disease (MRD) marker (<0.1%) low dose DLI was not administered but MRD monitored; only in case of MRD positivity at 2 or 4 months additional low dose DLI was given. ResultsOf the 65 patients, 49 received standard dose DLI at 6 months after alloSCT (75%), either as a first dose at 6 months (40%), or as a second DLI after a low dose DLI at 3-4 months after alloSCT (35%). Reasons for not receiving standard dose DLI were NRM (5%), GVHD (9%), relapse (9%) and donor-related (2%). Of the 22 poor risk patients with a sensitive MRD marker, 15 received the first DLI at 6 months; 6 received both low dose DLI and 6 month DLI because of MRD positivity at 2 or 4 months after alloSCT; one patient did not receive prophylactic DLI because of systemic relapse at day 105. With a median follow up of 400 days (range 183-814), 12 patients developed systemic relapse. Most relapses (67%) occurred very early after transplant (median 110 days, range 63 to 165 days), before low dose DLI could be effectively given. These early relapses occurred significantly more in patients >= 65 years (88%) than <65 years (p=0.01 Fisher's exact). Overall survival at 1 year was 95% (95% CI 89-100%) in patients <65 (n=42), significantly higher than the 68% (95% CI 49-95%) in patients >=65 (n=23) (p=0.01). Relapse rate at 1 year was 5% (95% CI 1-15%) in patients <65, significantly lower than the 37% (95% CI 25-58%) in patients >=65 (p=0.001). Grade 2-4 acute and chronic GVHD incidence at 1 year was low (6% (95% CI 2-14%) and 11% (2.5-25%), respectively). Survival at 1 year was similar (p=0.35) in poor risk patients without MRD marker (80%, 95% CI 67-96%), poor risk with MRD marker (95%, 95% CI 87-100%) and intermediate risk (86%, 95% CI 63-100%). For these groups relapse risk was also similar: 18% (95% CI 7-33%), 16% (95% CI 3-36%) and 11% (95% CI 5-41%), respectively. ConclusionsThis study is the first to demonstrate feasibility of prophylactic DLI after PTCy-alloSCT with a low associated risk of GVHD. The observed low incidence of relapse at 1 year after transplantation (5%) of patients aged <65 years appears to be substantially less than the reported risk without pre-planned DLI (20-30%). Although the value of early DLI administration (around 3-4 months) is still unclear, standard dose DLI administration at 6 months appears feasible in intermediate risk patients and poor risk patients with sensitive MRD markers. Early relapses after alloSCT, at a time point before early DLI could be effective, caused the inferior survival of patients aged >= 65 years. The results of this study can serve as a reference for designing future prophylactic cellular interventions in the PTCy-alloSCT setting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Post-Transplantation Cyclophosphamide Versus Tacrolimus and Methotrexate Graft-Versus-Host Disease Prophylaxis for HLA-Matched Donor Transplantation

The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis is increasing in patients undergoing HLA-matched sibling (MSD) or unrelated (MUD) donor hematopoietic cell transplantation (HCT), but data about its comparative efficacy against the traditional GVHD prophylaxis are scarce. Two broad questions assessed in this study were (a) comparison of PTCy-based GVHD prophylaxis versus Tac/MTX (without ATG) in the MSD and (b) comparison of PTCy-based GVHD prophylaxis versus Tac/MTX (with ATG) in the MUD group. This retrospective single-center study analyzed the outcomes of 964 patients who received Tac/MTX (n=578) versus PTCy-based (n=386) GVHD prophylaxis. All MUD recipients in the Tac/MTX group also received ATG; thus separate analyses were conducted for MSD (n=412) and MUD (n=552) cohorts. In the MUD cohort, 306 patients received Tac/MTX/ATG and 246 received PTCy-based GVHD prophylaxis. In the MSD cohort, 272 received Tac/MTX and 140 received PTCy-based prophylaxis. Both PTCy groups included somewhat older patients than the Tac/MTX groups and more patients had myeloid malignancy (85%-90% versus 59%-64%, respectively). A majority of patients in all groups received myeloablative conditioning and peripheral blood graft. Both PTCy groups had a significantly delayed neutrophil engraftment, higher risk of hemorrhagic cystitis, and higher risk of bacterial infections than the Tac/MTX groups. The risks of viral infections and related deaths were significantly higher in Tac/MTX group in the MUD cohort. In multivariate analysis, the risk of grade III-IV acute GVHD was similar in PTCy and Tac/MTX groups in both MSD and MUD cohorts, but the risk of chronic GVHD was significantly lower with PTCy in the MSD cohort. PTCy was associated with a significantly lower risk of non-relapse mortality and better progression-free survival in the MUD. PTCy was associated with improved GVHD-free relapse-free survival in both MSD and MUD groups. Our data suggest a benefit of using PTCy-based GVHD prophylaxis in both MSD (versus Tac/MTX) and MUD (versus Tac/MTX/ATG) HCT.

HLA-matching with PTCy: a reanalysis of a CIBMTR dataset with propensity score matching and donor age

AbstractBlood or marrow transplantation (BMT) outcomes using haploidentical donors (Haplo) and posttransplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis compare favorably to HLA-matched donors using calcineurin inhibitor–based prophylaxis. A recent Center for International Blood and Marrow Transplant Research analysis of patients receiving homogenous PTCy-based prophylaxis found that, with reduced intensity conditioning, Haplo BMTs had worse outcomes than matched unrelated donor (MUD) BMTs. Due to significant differences between groups, we reanalyzed the dataset using propensity score matching and, additionally, added a donor age variable. After matching MUD BMTs to Haplo BMTs in a 1:5 ratio, no significant differences were found between groups across all measured baseline characteristics. Outcomes analyses demonstrated no significant differences in overall survival (hazard ratio [HR] of mortality with MUD vs Haplo [95% confidence interval], 0.95 [0.65-1.16], P = .75), disease-free survival (HR of relapse or death, 0.98 [0.73-1.18], P = .89), relapse rate (HR, 1.06 [0.77-1.38], P = .69), or nonrelapse mortality (NRM) (HR, 0.85 [0.42-1.13], P = .49) between groups. After stratification by conditioning intensity, MUD BMTs in the reduced-intensity cohort had lower risk of NRM (HR, 0.56 [0.14-0.99], P = .05), with no significant difference in other clinical outcomes. These results suggest the effect of HLA matching on BMT outcomes with PTCy is less meaningful than previously reported. Timely identification of a young, at least half-matched (related or unrelated) donor may be more important than finding a fully matched donor if the latter leads to a delay in BMT or use of an older donor.

Impact of donor-derived CD34 + infused cell dose on outcomes of patients undergoing allo-HCT following reduced intensity regimen for myelofibrosis: a study from the Chronic Malignancies Working Party of the EBMT.

The optimal CD34 + cell dose in the setting of RIC allo-HCT for myelofibrosis (MF) remains unknown. We retrospectively analyzed 657 patients with primary or secondary MF transplanted with use of peripheral blood (PB) stem cells after fludarabine/melphalan or fludarabine/busulfan RIC regimen. Median patient age was 58 (range, 22-76) years. Donors were HLA-identical sibling (MSD) or unrelated (UD). Median follow-up was 46 (2-194) months. Patients transplanted with higher doses of CD34 + cells (>7.0 × 106/kg), had an increased chance of achievement of both neutrophil (hazard ratio (HR), 1.46; P < 0.001) and platelet engraftment (HR, 1.43; P < 0.001). In a model with interaction, for patients transplanted from a MSD, higher CD34 + dose was associated with improved overall survival (HR, 0.63; P = 0.04) and relapse-free survival (HR, 0.61; P = 0.02), lower risk of non-relapse mortality (HR, 0.57; P = 0.04) and higher rate of platelet engraftment. The combined effect of higher cell dose and UD was apparent only for higher neutrophil and platelet recovery rate. We did not document any detrimental effect of high CD34 + dose on transplant outcomes. More bulky splenomegaly was an adverse factor for survival, engraftment and NRM. Our analysis suggests a potential benefit for MF patients undergoing RIC PB-allo-HCT receiving more than 7.0 × 106/kg CD34 + cells.

Antithymocyte globulin exposure in CD34+ T-cell–depleted allogeneic hematopoietic cell transplantation

AbstractTraditional weight-based dosing results in variable rabbit antithymocyte globulin (rATG) clearance that can delay CD4+ T-cell immune reconstitution (CD4+ IR) leading to higher mortality. In a retrospective pharmacokinetic/pharmacodynamic (PK/PD) analysis of patients undergoing their first CD34+ T-cell–depleted (TCD) allogeneic hematopoietic cell transplantation (HCT) after myeloablative conditioning with rATG, we estimated post-HCT rATG exposure as area under the curve (arbitrary unit per day/milliliter [AU × day/mL]) using a validated population PK model. We related rATG exposure to nonrelapse mortality (NRM), CD4+ IR (CD4+ ≥50 cells per µL at 2 consecutive measures within 100 days after HCT), overall survival, relapse, and acute graft-versus-host disease (aGVHD) to define an optimal rATG exposure. We used Cox proportional hazard models and multistate competing risk models for analysis. In all, 554 patients were included (age range, 0.1-73 years). Median post-HCT rATG exposure was 47 AU × day/mL (range, 0-101 AU × day/mL). Low post-HCT area under the curve (<30 AU × day/mL) was associated with lower risk of NRM (P < .01) and higher probability of achieving CD4+ IR (P < .001). Patients who attained CD4+ IR had a sevenfold lower 5-year NRM (P < .0001). The probability of achieving CD4+ IR was 2.5-fold higher in the <30 AU × day/mL group compared with 30-55 AU × day/mL and threefold higher in the <30 AU × day/mL group compared with the ≥55 AU × day/mL group. In multivariable analyses, post-HCT rATG exposure ≥55 AU × day/mL was associated with an increased risk of NRM (hazard ratio, 3.42; 95% confidence interval, 1.26-9.30). In the malignancy subgroup (n = 515), a tenfold increased NRM was observed in the ≥55 AU × day/mL group, and a sevenfold increased NRM was observed in the 30-55 AU × day/mL group compared with the <30 AU × day/mL group. Post-HCT rATG exposure ≥55 AU × day/mL was associated with higher risk of a GVHD (hazard ratio, 2.28; 95% confidence interval, 1.01-5.16). High post-HCT rATG exposure is associated with higher NRM secondary to poor CD4+ IR after TCD HCT. Using personalized PK-directed rATG dosing to achieve optimal exposure may improve survival after HCT.

Outcome of Children with Acute Leukemia Given Allogeneic HSCT Either from an Unrelated Donor or from an HLA-Partially Matched Relative after αβ-T Cell/B-Cell Depletion: A Multicenter, Retrospective, Comparative Analysis of the AIEOP Network

IntroductionFor patients in need of an allograft and lacking an HLA-identical sibling, hematopoietic stem cell transplantation (HSCT) from an unrelated donor (UD) is the standard of care. In the recent few years, αβ T-cell and B-cell depleted HLA-haploidentical HSCT (αβhaplo-HSCT) is becoming a widely employed alternative to UD-HSCT in patients with acute leukemia. We, thus, decided to conduct a retrospective analysis on the outcome of patients given either αβhaplo-HSCT or UD HSCT in the same time period, namely October 2010-December 2015, in one of the 13 centers affiliated with the Italian-HSCT pediatric network.Methods: Included in the study were 97 αβhaplo-HSCT recipients and 244 patients receiving UD-HSCT in the same period. Six centers performed both αβhaplo-HSCT and UD-HSCT, while only this latter procedure was performed in the remaining 7 centers. All children were transplanted in morphological complete remission (CR) after a fully myeloablative conditioning regimen. The UD was selected using high-resolution typing for the HLA-loci A, B, C, DRB1. The UD was 8/8 HLA-matched with the recipient in 52% of cases, while the remaining 48% of patients were transplanted from a donor with either 1 or 2 HLA-disparities. Details on patient characteristics of the 2 groups are shown in the Table; recipients of αβhaplo-HSCT were transplanted in more advanced phase and received more frequently a TBI-based regimen than UD-HSCT patients. Patients given αβhaplo-HSCT did not receive any post-transplantation pharmacological prophylaxis of graft-versus-host disease (GvHD), while the combination of anti-T lymphocyte globulin (ATLG), cyclosporine-A and short-term methotrexate was employed for preventing GvHD occurrence in all UD-HSCT recipients. ATLG was also infused before transplantation in all children treated with αβhaplo-HSCT to prevent both graft rejection and GvHD.Results: Two (2%) and 4 (2%) patients experienced graft failure in the αβhaplo-HSCT and UD-HSCT groups, respectively. Median time to neutrophil and platelet recovery was shorter in children given αβhaplo-HSCT (13 and 11 days vs. 19 and 23 days, respectively, P < 0.001 in both cases). The cumulative incidence (CI) of grade II-IV and grade III-IV acute GvHD in patients given αβhaplo-HSCT was 16% and 0%, as compared to 39% and 12% in UD-HSCT recipients (P < 0.001 and < 0.0005, respectively). Children treated with αβhaplo-HSCT benefited also from a lower incidence of both overall and extensive chronic GvHD (6% and 1%, respectively, vs 20% and 7% in UD-HSCT recipients, P < 0.01 and < 0.05, respectively), especially when compared with 7/8 and 6/8 UD-HSCT recipients. Forty-eight patients died for transplant-related complications: 9 (9%) and 40 (16%) in the αβhaplo-HSCT and UD-HSCT group, respectively, the CI of non-relapse- mortality (NRM) being 9% and 17% (P = N.S.). While the probability of NRM is superimposable in αβhaplo-HSCT and 8/8 UD-HSCT, 7/8 and 6/8 UD-HSCT had a higher risk of mortality (25% and 37%, respectively). Seventy-three children relapsed at a median time of 190 days (range 40-1603) after the allograft; no statistically significant difference for the CI of disease recurrence was observed between the 2 groups (25% vs 20%, respectively). With a median follow-up of 3.3 years (range 0.5-5 years for surviving patients) the 3-year probability of overall survival for patients given either αβhaplo-HSCT or UD-HSCT is 68% and 64%, respectively (P = N.S.), while that of event-free survival is 63% and 62%, respectively (P = N.S.). The 3-year chronic GvHD-free/relapse-free survival (GRFS) in the 2 groups is 59% and 48%, respectively (P = 0.03). GRFS of αβhaplo-HSCT or 8/8 UD-HSCT recipients was superimposable.Conclusions: Patients givenαβhaplo-HSCT had a faster ANC/PLT recovery and a lower probability of acute GvHD in comparison to children transplanted from an UD donor. Moreover, they also had a lower risk of NRM and better probability of GRFS in comparison to patients transplanted from an UD with 1 or 2 HLA-disparities. αβhaplo-HSCT is associated with a CI of disease recurrence comparable to that of children transplanted from an UD. Altogether, these data indicate that αβhaplo-HSCT is a competitive alternative to UD-HSCT, especially in the absence of a fully-matched donor. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Outcomes of Cord Blood Transplantation for Adult Patients with Hodgkin Lymphoma, a Eurocord and EBMT Lymphoma Working Party Study

Allogeneic stem cell transplantation represents an alternative for relapsed or refractory patients (pts) with Hodgkin Lymphoma (HL). In this setting, only limited data on unrelated umbilical cord blood transplantation (UCBT) are available. We analyzed 133 adult pts with HL who underwent UCBT in EBMT centers. Histological subtype was nodular sclerosis in 65% of the pts. Median age at UCBT was 29 (18-65) years. Median follow-up was 37 (2-119) months and median year of UCBT was 2010 (2003-2015). Ninety pts had received a previous autologous transplantation (ASCT), while 19 had received 2 ASCT before UCBT; median time from ASCT to UCBT was 15 (2-281) months. Disease status at UCBT was complete remission (CR) in 45%, partial remission (PR) in 28% and relapse or refractory disease in 27% of the pts. Sixty percent of pts were male and 54% had a positive cytomegalovirus serology. Fifty-one percent (n=68) received a single UCBT and 49% (n=65) a double UCBT; 58% of pts received a graft with 2 or more HLA mismatch. The majority of the pts (n=104, 77%) underwent a reduced intensity conditioning regimen, the most frequent conditioning regimen (n=69) being Cyclophosphamide + Fludarabine + Total Body Irradiation (TBI) (2 Gy). Forty percent (n=46) of pts received anti-thymocyte globulin and Cyclosporine A + mycophenolate mofetil prophylaxis was given to 60% (n=80) of the pts. Median total nucleated cell (TNC) dose at cryopreservation was 3.99 (1.5-12.2) x107/Kg.The cumulative incidence (CI) of neutrophil engraftment at 60 days was 87% (81%-93%). The 100-day CI of acute grade II-IV GVHD was 26% (19%-35%). At 3 years, chronic GVHD was 30% (21%-41%). Relapse incidence (RI) and non-relapse mortality (NRM) were 40% (32%-50%) and 30% (23%-40%) at 3 years, respectively. The overall survival (OS) was 48% (39%-57%) and progression free survival (PFS) was 28% (21%-37%) at 3 years. Sixty-nine patients died: 27 of relapse and 39 of transplant related causes (infections, n=13, GVHD, n=7, idiopathic pneumonia syndrome n=6, EBV-PTLD n=2, VOD n=2 and others causes, n=9). According to disease status at UCBT, OS at 3 years was 68% (55%-79%) for pts in CR, 31% (18%-50%) for pts in PR and 26% (14%-44%) for pts in relapsed or refractory disease.In multivariate analysis, adjusted for median year of UCBT, Cyclophosphamide + Fludarabine + low dose TBI conditioning regimen, disease status at UCBT, conditioning intensity and type of UCBT, none of these factors were found to be associated with acute or chronic GVHD. 3-year RI and NRM were higher for pts in relapse or refractory disease at UCBT compared to pts in CR (HR=2.62, 95%CI 1.12-6.11, p=0.03 and HR=3.66, 95%CI 1.52-8.80, p=0.004, respectively). The use of Cyclophosphamide + Fludarabine + low dose TBI conditioning regimen was associated with a lower risk of NRM (HR=0.38, 95%CI 0.15-0.95, p=0.04) and also with a better OS (HR=0.37, 95%CI 0.18-0.76, p=0.006). OS was significantly worse for pts who underwent UCBT in PR (HR=1.97, 95%CI 1.02-3.80, p=0.04) and for those in relapse or refractory disease at transplant (HR=2.86, 95%CI 1.41-5.81, p=0.004). Pts transplanted in relapse or refractory disease have also a lower PFS (HR=3.12, 95%CI 1.71-5.71, p<0.001).In conclusion, UCBT is feasible in heavily pretreated pts with HL, if there are no other alternative donors. Conditioning with Cyclophosphamide + Fludarabine + low dose TBI is associated with a better OS and NRM. However, outcomes are poor for patients not in CR at the time of UCBT and one might consider the use of new therapeutic agents earlier before UCBT in this setting. DisclosuresZuckerman:BioSight Ltd.: Consultancy. Snowden:Sanofi: Honoraria. Robinson:Gilead: Honoraria, Other: Travel Grants; Takeda: Consultancy, Honoraria, Other: Travel Grants; Roche: Honoraria, Other: Travel Grants; Riemser: Consultancy.

Outcomes Associated With Thiotepa-Based Conditioning in Patients With Primary Central Nervous System Lymphoma After Autologous Hematopoietic Cell Transplant

Primary central nervous system lymphoma (PCNSL) requires induction and consolidation to achieve potential cure. High-dose therapy and autologous hematopoietic cell transplant (AHCT) is an accepted and effective consolidation strategy for PCNSL, but no consensus exists on the optimal conditioning regimens. To assess the outcomes in patients with PCNSL undergoing AHCT with the 3 most commonly used conditioning regimens: thiotepa/busulfan/cyclophosphamide (TBC), thiotepa/carmustine (TT-BCNU), and carmustine/etoposide/cytarabine/melphalan (BEAM). This observational cohort study used registry data from the Center for International Blood and Marrow Transplant Research registry. The Center is a working group of more than 380 transplantation centers worldwide that contributed detailed data on HCT to a statistical center at the Medical College of Wisconsin, Milwaukee. The participant data were from 603 adult patients with PCNSL who underwent AHCT as initial, or subsequent, consolidation between January 2010 and December 2018. Patients were excluded if they had a non-Hodgkin lymphoma subtype other than diffuse large B-cell lymphoma, systemic non-Hodgkin lymphoma, or HIV; received an uncommon conditioning regimen; or were not in partial remission or complete remission prior to AHCT. Statistical analysis was performed from July 5, 2020, to March 1, 2021. Patients received 1 of 3 conditioning regimens: TBC (n = 263), TT-BCNU (n = 275), and BEAM (n = 65). The primary outcome was progression-free survival. Secondary outcomes included hematopoietic recovery, incidence of relapse, nonrelapse mortality, and overall survival. Of 603 patients, the mean age was 57 (range, 19-77) years and 318 (53%) were male. The 3-year adjusted progression-free survival rates were higher in the TBC cohort (75%) and TT-BCNU cohort (76%) compared with the BEAM cohort (58%) (P = .03) owing to a higher relapse risk in the BEAM cohort (hazard ratio [HR], 4.34; 95% CI, 2.45-7.70; P < .001). In a multivariable regression analysis, compared with the TBC cohort, patients who received TT-BCNU had a higher relapse risk (HR, 1.79; 95% CI, 1.07-2.98; P = .03), lower risk of nonrelapse mortality (NRM) (HR, 0.50; 95% CI, 0.29-0.87; P = .01), and similar risk of all-cause mortality more than 6 months after HCT (HR, 1.54; 95% CI, 0.93-2.55; P = .10). Age of 60 years or older, Karnofsky performance status less than 90, and an HCT-comorbidity index greater than or equal to 3 were associated with lower rates of survival across all 3 cohorts. Subgroup analyses demonstrated that patients aged 60 years and older had considerably higher NRM with TBC. In this cohort study, thiotepa-based conditioning regimen was associated with higher rates of survival compared with BEAM, despite higher rates of early toxic effects and NRM; these findings may assist clinicians in choosing between TBC or TT-BCNU based on patient and disease characteristics.

Recipient and donor genetic variants associated with mortality after allogeneic hematopoietic cell transplantation

AbstractMany studies have suggested that genetic variants in donors and recipients are associated with survival-related outcomes after allogeneic hematopoietic cell transplantation (HCT), but these results have not been confirmed. Therefore, the utility of testing genetic variants in donors and recipients for risk stratification or understanding mechanisms leading to mortality after HCT has not been established. We tested 122 recipient and donor candidate variants for association with nonrelapse mortality (NRM) and relapse mortality (RM) in a cohort of 2560 HCT recipients of European ancestry with related or unrelated donors. Associations discovered in this cohort were tested for replication in a separate cohort of 1710 HCT recipients. We found that the donor rs1051792 A allele in MICA was associated with a lower risk of NRM. Donor and recipient rs1051792 genotypes were highly correlated, making it statistically impossible to determine whether the donor or recipient genotype accounted for the association. Risks of grade 3 to 4 graft-versus-host disease (GVHD) and NRM in patients with grades 3 to 4 GVHD were lower with donor MICA-129Met but not with MICA-129Val, implicating MICA-129Met in the donor as an explanation for the decreased risk of NRM after HCT. Our analysis of candidate variants did not show any other association with NRM or RM. A genome-wide association study did not identify any other variants associated with NRM or RM.

Impact of Donor-Derived CD34+ Infused Cell Dose on Outcomes of Patients Undergoing Allo-HCT Following Reduced Intensity Regimen for Myelofibrosis:a Study from the Chronic Malignancies Working Party of the EBMT

Introduction: Cellular composition of grafts is believed to be one of the significant determinants of outcomes of reduced-intensity conditioning (RIC) allogenic hematopoietic cell transplantation (allo-HCT). However, inconsistent results of the influence of CD34+ cells dose on the incidence of graft-versus-host disease (GVHD), disease control and survival have been reported in studies published thus far. Allo-HCT remains the only potentially curative treatment modality for eligible patients with myelofibrosis (MF). As patients with this diagnosis were underrepresented or not included in the above mentioned analyses, this EBMT registry study aimed to determine impact of CD34+ cell counts on allo-HCT results in this population. Methods: Six hundred and fifty seven patients with primary or secondary MF transplanted with use of peripheral blood (PB) as a source of stem cells after RIC regimen (Fludarabine/Melphalan, N=536 (82%); Fludarabine/Busulphan, N=121 (18%)) between 2000 and 2016 were included. Stem cell donor type was HLA-identical sibling (MSD; N=249, 38%) or unrelated (UD; N=408, 62%). Use of ex vivo T-cell depletion and post-transplant cyclophosphamide to prevent GVHD were the exclusion criteria. Median patient age was 58 (range, 22-76) years. In-vivo T-cell depletion was used in 526 (80%) of cases. Median transplanted CD34+ dose was 6.6 (2-29) x 10^6 per kg of recipient body weight. Median follow-up was 46 (2-194) months. Patient and transplant characteristics are summarized in Table 1. Results: We did not observe any impact of CD34+ cells dose on outcome variables in the whole study group. However, in an analysis adjusted for donor type, among patients transplanted from a MSD, the 2yr overall survival (OS) probability was 77% for those transplanted with higher doses of CD34+ cells (defined as &gt;7.0 x 10^6/kg) compared to 60% for lower CD34+ counts (below 7.0 x 10^6/kg), P=0.007 (Figure 1). The corresponding probabilities of 2yr non-relapse mortality (NRM) were 16% and 29% (P=0.04), respectively (Figure 2). In multivariate analysis, for patients transplanted from a MSD, higher CD34+ dose was an independent predictor for better survival (HR 0.56; P=0.01) and lower risk of NRM (HR 0.54; P=0.02). We did not find any association between CD34+ counts with probability of engraftment, the incidence of acute (aGVHD) and chronic (cGVHD) nor disease relapse. The effect of cell dose was not seen in the UD cohort. Factors associated independently with an unfavorable outcome in the whole study group were: older patient age and transplantation from CMV seronegative donors to seropositive recipients for OS and NRM and use of an UD and female donor for NRM. Allo-HCT from UD was also an independent predictor for higher incidence of aGVHD and lower probability of engraftment. Use of in vivo T-cell depletion was a protective factor for aGVHD. It was in turn associated with higher risk of relapse. Conclusions: Our analysis suggests a potential survival benefit for MF patients treated with RIC PB-allo-HCT from MSD with higher doses of CD34+ cells (threshold &gt; 7.0 x 10^6/kg). We suggest that this factor should be taken into consideration when planning and performing hematopoietic cell apheresis. Disclosures Kröger: Celgene: Honoraria, Research Funding; DKMS: Research Funding; JAZZ: Honoraria; Medac: Honoraria; Neovii: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Riemser: Research Funding; Sanofi-Aventis: Research Funding. Robin:Novartis Neovii: Research Funding. Chevallier:Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Incyte: Consultancy, Honoraria. Mielke:Bellicum: Consultancy, Honoraria, Other: Travel (via institution); EBMT/EHA: Other: Travel support; Miltenyi: Consultancy, Honoraria, Other: Travel and speakers fee (via institution), Speakers Bureau; IACH: Other: Travel support; Jazz Pharma: Honoraria, Other: Travel support, Speakers Bureau; ISCT: Other: Travel support; GILEAD: Consultancy, Honoraria, Other: travel (via institution), Speakers Bureau; Celgene: Honoraria, Other: Travel support (via institution), Speakers Bureau; DGHO: Other: Travel support; Kiadis Pharma: Consultancy, Honoraria, Other: Travel support (via institution), Speakers Bureau. Snowden:Janssen: Honoraria; Mallinckrodt: Honoraria; Kiadis: Membership on an entity's Board of Directors or advisory committees; IDMC: Honoraria; Jazz: Honoraria; Gilead: Honoraria. Blaise:Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria. Hernandez Boluda:Incyte: Other: Travel expenses paid. McLornan:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Novartis: Honoraria.

Transplant outcomes for patients with therapy-related acute myeloid leukemia with prior lymphoid malignancy: an ALWP of EBMT study.

Allogeneic hematopoietic cell transplant (HCT) is a curative therapy for patients with secondary acute myeloid leukemia (sAML), though the impact of conditioning regimens on HCT outcomes for patients with antecedent lymphoid malignancy is largely unknown. This multicenter, retrospective registry study of the ALWP of the EBMT assessed HCT outcomes in this population. In all, 549 patients ≥18 years with sAML following an antecedent lymphoid malignancy treated with first allograft between 2000-2016 were included. Myeloablative (MAC) and reduced intensity conditioning (RIC) was given in 258 (47%) and 291 (53%), respectively. At 2 years, leukemia-free survival (LFS) was 31.7% (95% CI, 27.5-35.9), overall survival (OS) was 37.4% (95% CI, 33-41.8), nonrelapse mortality (NRM) was 28.9% (95% CI, 25-33), and GVHD-free, relapse-free survival (GRFS) was 22.8% (95% CI, 19-26.6). In multivariate analysis, patients receiving RIC regimens had lower risk of NRM (HR: 0.58, CI: 0.40-0.83, p = 0.003), and improved LFS (HR: 0.67, CI: 0.52-0.85, p = 0.001). Patients with prior autologous HCT had inferior LFS (HR: 1.30, CI: 1.01-1.67, p = 0.01). This study demonstrates that sAML patients following prior lymphoid malignancy treated with RIC regimens have a lower risk of NRM and improved LFS, OS, and GFRS. Other variables associated with inferior outcomes include older age, active disease, adverse cytogenetics, and prior auto-HCT.

Risk Factors Influencing Outcome of Acute Leukemia Patients Who Experience Relapse After Allogeneic Hematopoietic Stem-Cell Transplantation

BackgroundPrognosis of acute leukemia patients who experience relapse after hematopoietic stem-cell transplantation (HSCT) remains poor. Identifying risk factors influencing outcome of these patients is essential. Patients and MethodsFollow-up of 234 acute leukemia patients who underwent allogeneic HSCT from matched related donor was performed for occurrence of posttransplantation relapse. Statuses of remission and survival were assessed at 6 months after treatment of relapse. Analysis of risk factors influencing postrelapse overall survival (prOS), complete remission (CR), and nonrelapse mortality (NRM) was carried out. ResultsPosttransplantation relapse occurred in 43 patients (17.9%). After treatment, 11 patients (25.6%) experienced postrelapse remission, the prOS rate was 20.9% (9 patients), and the NRM rate was 25.6% (11 patients). Older age (P = .007) and failure to experience remission after relapse treatment (P = .027) were associated with lower prOS in multivariate analysis. Female sex (P = .027), posttransplantation extramedullary relapse (P = .001), and absence of postrelapse graft-versus-host disease P = .025) were associated with lower CR rate. Also, presence of extramedullary relapse (P = .011) was associated with lower risk of NRM whereas treatment of posttransplantation relapse with donor lymphocyte infusion with or without chemotherapy (P = .002) and occurrence of postrelapse graft-versus-host disease (P = .025) were associated with higher risk of NRM. ConclusionSurvival of acute leukemia patients who experience relapse after allogeneic HSCT is poor, especially in elderly patients and those who do not experience remission after relapse treatment.

Factors associated with allogeneic hematopoietic stem cell transplantation (HSCT) outcomes in patients (pts) with relapsed/refractory acute lymphoblastic leukemia (R/R ALL) treated with inotuzumab ozogamicin (InO) versus (v) conventional chemotherapy (C).

7007 Background: InO therapy in R/R ALL resulted in superior complete remission (CR)/CR with incomplete hematologic recovery (CRi) rates v C in the Phase 3 INO-VATE trial (NCT01564784; Kantarjian NEJM 2016). More InO v C pts proceeded to HSCT (41% [45/109] v 11% [12/109]; P&lt;0.001). Factors associated with outcomes after HSCT are described. Methods: Full details have been published. Multivariate analyses (MVA) using Cox regression modeling were conducted to determine predictors of non-relapse mortality (NRM) and overall survival (OS). Results: As of 3/8/16, 108/326 pts underwent allogeneic HSCT (InO n=77; C n=31). Baseline characteristics were generally similar, except baseline platelet values were lower in InO v C pts. More InO v C pts achieved minimal residual disease negativity (MRDneg [best status]; 71% v 26%; P&lt;0.0001). Less InO v C pts received additional therapy before HSCT (14% v 55%, P&lt;0.0001). NRM rates were higher in InO v C pts at 1 year (yr; 36% [95% CI 26–47] v 20% [8–36]) and 2 yrs (39% [27–51] v 31% [13–51]), but relapse rates were lower (1 yr, 23% [15–33] v 29% [13–48]; 2 yrs, 33% [22–44] v 46% [24–65]). No significant difference in post-HSCT survival was detected in InO v C pts; however, visual inspection of the curve suggested the survival probability varied before and after 15 months post-HSCT (1 yr, 44% [95% CI 33–55] v 65% [44–79]; 2 yr, 39% [28–50] v 34% [15–54]). Fatal veno-occlusive disease (VOD) was observed in 5 InO pts (all during the first 100 days from the date of HSCT) and no C pts. MVA showed that conditioning regimens without dual alkylators and thiotepa were associated (2-sided; P&lt;0.05) with lower risk of NRM and post-HSCT survival, respectively. Conclusions: Compared with C, InO permitted more pts with R/R ALL to proceed to HSCT in CR/CRi with MRDneg (best status). Despite increased NRM and fatal VOD, long-term survival was attainable in InO pts. In pts previously treated with InO, interventions to reduce NRM and improve OS after HSCT include avoiding dual alkylator conditioning regimens, especially those containing thiotepa. Funding: Pfizer Clinical trial information: NCT01564784.