Reduced-intensity Conditioning Hematopoietic Cell Transplantation Research Articles

The role and novel use of natural killer cells in graft-versus-leukemia reactions after allogeneic transplantation

Allogeneic hematopoietic cell transplantation (HCT) has transformed over the past several decades through enhanced supportive care, reduced intensity conditioning (RIC), improved human leukocyte antigen (HLA) typing, and novel graft-versus-host disease (GVHD)-prevention and treatment strategies. Most notably, the implementation of post-transplantation cyclophosphamide (PTCy) has dramatically increased the safety and availability of this life-saving therapy. Given reductions in nonrelapse mortality (NRM) with these advances, the HCT community has placed even greater emphasis on developing ways to reduce relapse - the leading cause of death after HCT. When using RIC HCT, protection from relapse relies predominantly on graft-versus-leukemia (GVL) reactions. Donor lymphocyte infusion (DLI), adoptive cellular therapy, checkpoint inhibition, and post-HCT maintenance strategies represent approaches under study that aim to augment or synergize with the GVL effects of HCT. Optimizing donor selection algorithms to leverage GVL represents another active area of research. Many of these strategies seek to harness the effects of T cells, which for decades were felt to be the primary mediators of GVL and the focus of investigation in relapse reduction. However, there is growing interest in capitalizing on the ability of natural killer (NK) cells to yield potent anti-tumor effects. A potential advantage of NK cell-based approaches over T cell-mediated is the potential to reduce NRM in addition to relapse. By decreasing infection, without increasing the risk of GVHD, NK cells may mitigate NRM, while still yielding relapse reduction through identification and clearance of cancer cells. Most T cell-focused relapse-prevention strategies must weigh the benefits of relapse reduction against the increased risk of NRM from GVHD. In contrast, NK cells have the potential to reduce both, potentially tipping the scales significantly in favor of survival. Here, we will review the role of NK cells in GVL, optimization of NK cell match or mismatch, and burgeoning areas of research in NK cell therapy such as adoptive transfer and chimeric antigen receptor (CAR) NK cells.

Role of Splenic Irradiation Prior to Transplant for Myelofibrosis: A Global Collaboration

JAK inhibitors and novel agents have shown promising reduction of spleen size in newly diagnosed myelofibrosis. However, not all patients will respond or they eventually progress at some point. Despite hematopoietic cell transplantation (HCT) being the only curative treatment option to date, splenomegaly prior to HCT remains a particular challenge. On the other hand, numbers of patients eligible for HCT continue to increase worldwide, and thus management of splenomegaly becomes more and more relevant. One approach to reduce spleen size prior to HCT could be splenic irradiation. However, evidence on its role remains scarce. We took advantage of a global collaboration between European, US, and Latin American centers to investigate the role of splenic irradiation as part of the HCT platform for patients with myelofibrosis. Radiation therapy had to be given within 3 months prior to or be part of conditioning therapy for HSCT. Detailed information on irradiation as well as post-HCT safety profiles was collected in addition to usual patient-, disease-, and transplant-related variables. This global collaborative study included 52 patients, of whom 71% had primary myelofibrosis, 17% post polycythemia vera and 12% post essential thrombocythemia myelofibrosis. Median age at HCT was 60 years (range, 32-76). Risk category according to DIPSS prior to irradiation was intermediate-1 in 20%, intermediate-2 in 52%, and high in 28%. Driver mutation status was JAK2 in 44%, CALR in 40%, MPL in 4%, and triple negative in 12%. Four patients had portal vein thrombosis before irradiation. Ruxolitinib before irradiation was received by 76% and 4% received fedratinib. Reduced intensity conditioning HCT was received by 73% and 85% were matched related or matched unrelated donor transplants. Median time from irradiation to HCT was 2 weeks (range, 0.9-12 weeks) and median spleen size prior to irradiation was 23 cm (range, 14-35). Spleen size was measured by ultrasound in 70%, CT scan in 20%, and physical examination in 10%. Median total irradiation dose was 7 Gy (range, 3-12), fractionated in a median of 5 administrations (range, 2-12). Splenic irradiation resulted in a significant spleen reduction prior to HCT but was also associated with significant reduction in platelet and leukocyte counts ( Table). Spleen size did not correlate with blood counts prior or after irradiation. Higher platelet count prior to irradiation correlated with higher counts after irradiation (r=0.83; P<0.001). There was no correlation between irradiation dose and post-irradiation hematological toxicities. Only 1 patient had non-hematological adverse events (tumor lysis syndrome). Neutrophil engraftment was achieved by 90% within a median of 18 days after HCT and platelet engraftment was achieved by 81% within a median of 38 days. Median follow-up of the total cohort was 2.7 years and 3-year overall survival was 66% (95% CI, 52-80%; Figure). Non-relapse mortality was 27% (95% CI, 15-39%) and cumulative incidence of relapse was 11% (95% CI, 2-20%; Figure). Incidence of acute GVHD grade II-IV and chronic GVHD was 25% and 38%, respectively. Increased spleen size (as continuous variable) prior to irradiation was associated with worse outcome (P=0.05), showing 3-year survival of 73% for spleen ≤25cm vs 42% for >25cm, and non-relapse mortality of 58% vs 14%, respectively (P=0.02). No effect of spleen size after irradiation on outcomes was observed. All 4 patients with portal vein thrombosis died (2-year survival 25%). A multivariable model showed that larger spleen size before irradiation, lower hemoglobin levels, CALR/MPL-unmuated driver mutation genotype, and presence of portal vein thrombosis were significantly associated with worse survival ( Table). This first international and largest study to date on splenic irradiation as part of the HCT algorithm for patients with myelofibrosis and splenomegaly showed a significant impact of spleen size on overall survival and non-relapse mortality, while relapse rates were low. In addition, lower hemoglobin levels and presence of portal vein thrombosis at time of irradiation predicted worse outcomes.

Pilot Study of Donor-Engrafted Clonal Hematopoiesis Evolution and Clinical Outcomes in Allogeneic Hematopoietic Cell Transplantation Recipients Using a National Registry

Improved treatment options, such as reduced-intensity conditioning (RIC), enable older patients to receive potentially curative allogeneic hematopoietic cell transplantation (HCT). This progress has led to increased use of older HLA-matched sibling donors. An unintended potential risk associated with older donors is transplantation of donor cells with clonal hematopoiesis (CH) into patients. We aimed to determine the prevalence of CH in older HLA-matched sibling donors pretransplantation and to assess the clinical impact of donor-engrafted CH on HCT outcomes. This was an observational study using donor peripheral blood samples from the Center for International Blood and Marrow Transplant Research repository, linked with corresponding recipient outcomes. To explore engraftment efficiency and evolution of CH mutations following HCT, recipient follow-up samples available through the Bone Marrow Transplant Clinical Trials Network (Protocol 1202) were included. Older donors and patients (both ≥55 years) receiving first RIC HCT for myeloid malignancies were eligible. DNA from archived donor blood samples was used for targeted deep sequencing to identify CH. The associations between donor CH status and recipient outcomes, including acute graft-versus-host disease (aGVHD), chronic GVHD (cGVHD), overall survival, relapse, nonrelapse mortality, disease-free survival, composite GVHD-free and relapse-free survival, and cGVHD-free and relapse-free survival, were analyzed. A total of 299 donors were successfully sequenced to detect CH. At a variant allele frequency (VAF) ≥2%, there were 44 CH mutations in 13.7% (41 of 299) of HLA-matched sibling donors. CH mostly involved DNMT3A (n=27; 61.4%) and TET2 (n= 9; 20.5%). Post-HCT samples from 13 recipients were also sequenced, of whom 7 had CH+ donors. All of the donor CH mutations (n=7/7; 100%) were detected in recipients at day 56 or day 90 post-HCT. Overall, mutation VAFs remained relatively constant up to day 90 post-HCT (median change, .005; range, -.008 to .024). Doubling time analysis of recipient day 56 and day 90 data showed that donor-engrafted CH mutations initially expand then decrease to a stable VAF; germline mutations had longer doubling times than CH mutations. The cumulative incidence of grade II-IV aGVHD at day 100 was higher in HCT recipients with CH+ donors (37.5% versus 25.1%); however, the risk for aGVHD by donor CH status did not reach statistical significance (hazard ratio, 1.35; 95% confidence interval, .61 to 3.01; P=.47). There were no statistically significant differences in the cumulative incidence of cGVHD or any secondary outcomes by donor CH status. In subset analysis, the incidence of cGVHD was lower in recipients of grafts from DNMT3A CH+ donors versus donors without DNMT3A CH (34.4% versus 57%; P=.035). Donor cell leukemia was not reported in any donor-recipient pairs. CH in older HLA-matched sibling donors is relatively common and successfully engrafts and persists in recipients. In a homogenous population (myeloid malignancies, older donors and recipients, RICr, non-cyclophosphamide-containing GVHD prophylaxis), we did not detect a difference in cGVHD risk or other secondary outcomes by donor CH status. Subgroup analyses suggest potential differential effects by clinical characteristics and CH mutations. Larger prospective studies are needed to robustly determine which subsets of patients and CH mutations elicit meaningful impacts on clinical outcomes.

Alemtuzumab and CXCL9 levels predict likelihood of sustained engraftment after reduced-intensity conditioning HCT.

Overall survival after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) using alemtuzumab, fludarabine, and melphalan is associated with high rates of mixed chimerism (MC) and secondary graft failure (GF). We hypothesized that peritransplantation alemtuzumab levels or specific patterns of inflammation would predict these risks. We assessed samples from the Bone Marrow Transplant Clinical Trials Network 1204 (NCT01998633) to study the impact of alemtuzumab levels and cytokine patterns on MC and impending or established secondary GF (defined as donor chimerism <5% after initial engraftment and/or requirement of cellular intervention). Thirty-three patients with hemophagocytic lymphohistiocytosis (n= 25) and other IEIs (n= 8) who underwent HCTs with T-cell-replete grafts were included. Patients with day 0 alemtuzumab levels ≤0.32μg/mL had a markedly lower incidence of MC, 14.3%, vs 90.9% in patients with levels >0.32μg/mL (P= .008). Impending or established secondary GF was only observed in patients with day 0 alemtuzumab levels >0.32μg/mL (P= .08). Unexpectedly, patients with impending or established secondary GF had lower CXCL9 levels. The cumulative incidence of impending or established secondary GF in patients with a day 14+ CXCL9 level ≤2394 pg/mL (day 14+ median) was 73.6% vs 0% in patients with a level >2394 pg/mL (P= .002). CXCL9 levels inversely correlated with alemtuzumab levels. These data suggest a model in which higher levels of alemtuzumab at day 0 deplete donor T cells, inhibit the graft-versus-marrow reaction (thereby suppressing CXCL9 levels), and adversely affect sustained engraftment in the nonmyeloablative HCT setting. This trial was registered at www.clinicaltrials.gov as #NCT01998633.

Female Reproductive Health Outcomes after Hematopoietic Cell Transplantation for Sickle Cell Disease: Is Reduced Intensity Better Than Myeloablative Conditioning?

Curative therapy for sickle cell disease (SCD) through hematopoietic cell transplantation (HCT) is associated with a high level of risk for treatment-related gonadal dysfunction and future infertility. Both the myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) regimens used for SCD HCT are considered to carry a high risk for ovarian damage. Cyclophosphamide equivalent doses (CEDs) are thought to correlate with the degree of gonadal damage in pediatric oncology patients. We aimed to evaluate ovarian outcomes previously reported from our center, characterize the conditioning regimens as MAC or RIC, and calculate the CED for each regimen. The ovarian outcomes diminished ovarian reserve (DOR), as determined by an anti-Müllerian hormone (AMH) below the normal limits for age and assay or <5%, and premature ovarian insufficiency (POI), defined as a follicle-stimulating hormone (FSH) level >40 mIU/ML, are presented by conditioning regimen from 3 clinical studies from our center (2 published and 1 presented as an abstract in 2022). The studies were not mutually exclusive of patients. CEDs were calculated for each regimen. The CED ranged from 3388 to 9705 mg/m2 for MAC regimens and from 5600 to 18,750 mg/m2 for RIC regimens. DOR was observed in all regimens; however, in one study 2 patients had normal AMH levels after a fludarabine/melphalan regimen, and 1 patient had a normal AMH level after a fludarabine/melphalan/thiotepa regimen. Rates of POI were more variable and ranged from 40% to 100% after MAC regimens and from 0 to 100% after RIC regimens. Female patients with SCD who undergo HCT have very high rates of DOR after both MAC HCT and RIC HCT. Two of the 3 RIC regimens evaluated had higher CEDs than were seen in any of the MAC regimens evaluated. Rates of POI were more variable but may increase with time from transplantation. All SCD patients need to be counseled about the risk of infertility and provided information about fertility preservation.

Comparison of reduced intensity and nonmyeloablative conditioning for adults with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation in first or second remission.

Reduced intensity conditioning (RIC) and nonmyeloablative (NMA) conditioning regimens have expanded use of allogeneic hematopoietic cell transplantation (HCT) in AML to include older and medically less-fit patients, but relative efficacies and toxicities remain poorly defined. Here, we analyzed outcomes from 343 adults transplanted in remission after RIC (n = 137) or NMA (n = 206) conditioning between 2006 and 2021. The characteristics of RIC and NMA HCT patients were similar except that RIC patients were younger and their time between most recent remission achievement and allografting was shorter. There were no significant differences in relapse risk, relapse-free survival (RFS), overall survival (OS), and non-relapse mortality (NRM) between RIC and NMA HCT patients, both overall (relapse: hazard ratio [HR] = 0.80, P = 0.27; RFS: HR = 0.93, P = 0.61; OS: HR = 0.93, P = 0.66; NRM: HR = 1.13, P = 0.59) and when patients were stratified by pre-HCT measurable residual disease (MRD) status. After multivariable adjustment, there was no statistically significant association between conditioning intensity and relapse (HR = 0.69, P = 0.088), RFS (HR = 0.86, P = 0.37), OS (HR = 0.89, P = 0.49), or NRM (HR = 1.37, P = 0.19). In this non-randomized cohort of adults undergoing allografting for AML in first or second remission at our center, we could not detect statistically significantdifferences in outcomes between those assigned to RIC and those assigned to NMA conditioning.

Myeloablative Vs Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation in Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia

Background: Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) has historically been associated with a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) is recommended in first complete remission (CR1). Strategies to decrease non-relapse mortality (NRM) and to increase the number of patients eligible to receive HCT have led to the utilization of reduced intensity conditioning (RIC) for patients unfit or too old for myeloablative conditioning (MAC), at the cost of a higher risk of relapse. Limited data exist comparing MAC vs. RIC HCT in Ph+ ALL. Here, we compared the outcomes of MAC- and RIC-HCT in Ph+ ALL. Methods: This was a single-center retrospective study examining patients with Ph+ ALL who underwent HCT from 2000-2019. The primary endpoint was progression free survival (PFS), while secondary endpoints include overall survival (OS), graft versus host disease free survival (GRFS), non-relapse mortality (NRM), and cumulative incidence of relapse (CIR), and GVHD. Survival estimates were calculated using the Kaplan-Meier method and differences were examined by the log-rank test. CIR and NRM were calculated using a competing risk analysis and differences were examined by Gray's test. Results: 185 patients were included, of whom, 131 (70.8%) underwent MAC, 128 (97.7%) of whom received total body irradiation (TBI)-based treatment, while 54 (29.2%) underwent RIC, 45 (83.3%) of whom received fludarabine plus melphalan (Flu/Mel). The median age (range) of the patients receiving MAC and RIC were 40 years (19-59) and 57 years (23-73), respectively. 66 (50.3%) vs 7 (13.0%) were ≤40 years in the MAC vs RIC groups (P<0.001). 66 (50.4%) vs 38 (70.4%) in the MAC vs RIC groups underwent HCT ≥2010. 115 (87.8%) vs 47 (87.0%) were in CR1 at the time of HCT in the MAC vs RIC groups (P=1.0), and 41 (31.3%) vs 16 (29.6) had measurable residual disease (MRD) by PCR at the time of HCT, although 34 (26.0%) vs 9 (16.7%) did not have a MRD pre-HCT report available (P=0.31), respectively. 110 (59.5%) received tyrosine kinase inhibitor (TKI) maintenance post-HCT, 73 (55.7%) in the MAC group vs 37 (68.5%) in the RIC group (P=0.14). The rest of their baseline characteristics are described in Table 1. In a sub-analysis of patients in MRD-negative CR1 at HCT, there was no statistically significant difference in 4-year PFS between MAC vs RIC, 71.1% vs 55.7% (P=0.12). PFS was similar in patients receiving TKI maintenance regardless of whether they received MAC vs RIC, hazard ratio 1.73 (95% confidence interval, 0.93-3.22; P=0.08). The 4-year NRM, CIR, and GVHD with MAC vs RIC were 25.6% vs 26.8% (P=0.50), 14.5% vs 21.4% (P=0.27), and 48.4% vs 46.3% (P=0.75), respectively. Conclusions: Patients with Ph+ ALL had similar PFS, OS, and GRFS when treated with MAC vs RIC. RIC-HCT is appropriate in those who would not be expected to tolerate MAC and may also be an acceptable strategy for younger patients when TKI maintenance post-HCT is administered. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Randomized Open Label Pilot Study of Clostridium Butyricum Miyairi 588 (CBM588) in Recipients of Allogeneic Hematopoietic Cell Transplantation

A Randomized Open Label Pilot Study of Clostridium Butyricum Miyairi 588 (CBM588) in Recipients of Allogeneic Hematopoietic Cell Transplantation

Similar Event-Free Survival but Higher Incidence of Mixed T Cell Chimerism after Hematopoietic Cell Transplantation for Sickle Cell Disease Using Rabbit Versus Horse ATG: a Study from the Sickle Transplant Alliance for Research (STAR)

▪Background: Myeloablative HLA-matched sibling donor hematopoietic cell transplantation (HCT) is highly curative for children and young adults with sickle cell disease (SCD). The most common regimen used worldwide has been Busulfan, Cyclophosphamide and anti-thymocyte globulin (ATG). The optimal type of ATG for this approach remains unclear.Objective: To compare HCT outcomes of horse ATG (hATG) versus rabbit ATG (rATG) in patients with SCD undergoing HCT.Methods: Multicenter retrospective data from patients with SCD undergoing HCT were abstracted from the Sickle Transplant Alliance for Research (STAR) database. Patients undergoing myeloablative and reduced intensity conditioning HCT with matched related donors where the conditioning regimen included ATG were included in the analysis. Baseline characteristics were compared between the groups using chi-square and Wilcoxon Rank-Sum tests. Kaplan-Meier curves were used to assess time-to-event outcomes, such as overall and event free survival (EFS), and compared with log-rank tests. Death, disease recurrence (acute sickle cell symptoms/HbS >50%) and graft failure (whole blood or myeloid chimerism < 5%) were considered events for EFS. Full donor chimerism was defined as ≥95% donor. P-values less than 0.05 were considered statistically significant.Results: 103 patients (hATG = 78, rATG = 25) from 7 U.S. centers and one Canadian site were available in the database for analysis. Median age at HCT (8.1 years vs 7.6 years, p = 0.866) and gender distribution (55.1% vs 56.0% male, p = 0.939) was similar between the cohorts. Sickle cell genotype was 97.4% vs. 84% HbSS, 1.3% vs. 12.0% HbSBetazero, 1.3% vs. 0% HbSC, and 0% vs.4% other. Pre-transplant disease acute symptoms were similar between the groups. Myeloablative conditioning was used in 92.3% and 96.0% in the hATG group versus the rATG group (p=1) and the most common conditioning regimen was Busulfan and Cyclophosphamide +/- Fludarabine in both groups (93.2%). Donor age and source of graft were similar between the two groups. Median follow-up for hATG and rATG groups were 3.0 and 3.6 years respectively. The year of transplant for the two groups ranged from 1993 to 2015 (hATG) and 2003 to 2014 (rATG). Three-year OS for the entire group was 92.6% (95% CI: 87.4-98.0), with 90.1% (95% CI: 83.4-97.4) in the hATG group and 100% (95% CI: 100-100) in the rATG group (p = 0.122) (Figure 1). Three-year EFS was 90% vs. 96% (p=0.415) in hATG vs. rATG group with 2-year graft failure incidence of 0% vs. 4% (p =0.085) respectively. Limiting the analysis to transplants performed after 2000 did not materially alter the analyses for OS and EFS. Causes of death were GVHD related (n=5) and infection/sepsis (n=3) in the hATG group versus no deaths in rATG group. Six month incidence of acute grade III-IV GVHD and 3 year incidence of chronic GVHD for hATG vs. rATG groups was 3.9% vs. 0% (p=0.319) and 16.8% vs. 15.5% (p=0.549) respectively. Prevalence of full donor myeloid chimerism was similar between the two groups at Day +30, Day +100 and >6months. Prevalence of full donor whole blood chimerism was significantly lower at day+100 and 1 year (p < 0.05) in the rATG group. Full donor T cell chimerism was similar at Day 30 and Day 100, but significantly less prevalent at >6 months in the rATG group (p = 0.001) (Table 1).Discussion/Conclusion: In our cohort mortality was low overall and the hATG and rATG groups had similar OS, EFS, and similar incidence of acute grade III-IV and chronic GVHD. However the prevalence of full donor T cell chimerism at greater than 6 months after HCT was significantly lower in the rATG group.Table 1. Incidence of full donor chimerism (≥ 95%) by lymphocyte depleting antibody, %Fig 1. Overall and Event Free survival of hATG vs. rATG based conditioning regimens in HCT for SCDFig 2. Incidence of acute grade III-IV and chronic GVHD in hATG vs. rATG based conditioning regimens in HCT for SCD [Display omitted] DisclosuresGuilcher:Jazz pharmaceuticals: Consultancy; Canada Market Research: Consultancy; Patient Access Solutions: Consultancy.

Reduced Intensity Conditioning for Allogeneic Transplantation: Modified Fludarabine Dose Plus Cyclophosphamide/Total Body Irradiation Yields Promising Outcomes

Reduced intensity conditioning (RIC) extends the curative potential of allogeneic hematopoietic cell transplantation (HCT) to patients with hematologic malignancies unsuitable for myeloablative conditioning. We prospectively studied a RIC HCT approach for patients with hematologic malignancies and sibling or unrelated donors (URD) from 2001-2016. Patients received cyclophosphamide (Cy) 50mg/kg/day IV day -6, fludarabine (Flu) 40mg/m2/d IV days -6 to -2 and TBI 200cGy on day -1 +/- anti-thymocyte globulin (ATG) on days -6 to -4 for those without prior autografting or recent multidrug chemotherapy. After identifying potential increased non-relapse mortality from excess fludarabine metabolite (F-ara-A) exposure we reduced the fludarabine dosing to 30 mg/m2/d IV days -6 to -2 in late 2009.The 292 patients (median age 58: range 19-75); median follow-up 8 years (IQR range 4-12) included 127 with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), 40 aggressive non-Hodgkin lymphoma (NHL), 11 indolent NHL, 21 Hodgkin Lymphoma (HL), 26 multiple myeloma, 14 chronic myeloid leukemia (CML), 23 chronic lymphocytic leukemia (CLL), 17 acute lymphocytic leukemia (ALL), 13 myeloproliferative neoplasms (MPN). Five year overall survival (OS) was 73% (95% CL, 37-90%) for patients with indolent NHL, 53% (95% CL, 36-67%) for aggressive NHL, 55% (95% CL, 31-74%) for HL, 39% (95% CL, 30-48%) for AML/MDS, 32% (95% CL, 15-50%) for myeloma, 50% (95% CL, 23-72%) for CML, 45% (95% CL, 24-46%) for CLL, 15% (95% CL, 2-39%) for MPN and 34% (95% CL, 12-59%) for those with ALL. By donor source, 5 year OS was 46% (95% CL, 40-53%), 25% (95% CL, 6-50%), 38% (95% CL, 22-54%), and 11% (95% CL, 1-35%) using matched sibling donors (n=225), mismatched (MM) sibling PBSC (n=12), matched marrow unrelated donor (URD) (n=37), and matched peripheral blood URD (n=18) (p<0.01) (Figure 1). Fludarabine dosing (30 vs. 40 mg/m2/day x 5) had no significant influence on OS (45 vs. 40%, p=0.42) or 2 year NRM (25% vs. 26%, p=0.86). NRM (overall 26%; 95% CI 21-31%) was significantly worse with MM sibling or URD (either BM or PBSC) compared to matched sibling BM/PBSC. Relapse at 5 years was significantly worse in patients with myeloma (76%) and Hodgkins (53%), intermediate in AML/MDS (37%), but lowest in aggressive (25%) and particularly indolent NHL (0%).These results suggest that: 1) this Cy/Flu/TBI RIC conditioning was well tolerated by an older population; 2) indolent and aggressive NHLs responded best to RIC conditioning highlighting the importance of the graft versus lymphoma (GVL) effect; and 3) reduction in fludarabine dosing did not compromise disease control or survival but did not appear to diminish NRM. Diagnosis, donor source, and HCT-CI remain the dominant factors influencing outcomes. Targeted disease treatments or maintenance therapy to limit relapse might be the best approach to improve overall survival. [Display omitted] DisclosuresBrunstein:Novartis: Research Funding; Magenta Therapeutics: Research Funding. MacMillan:Magenta Therapeutics: Research Funding.

3 - A Multi-Center Biologic Assignment Trial Comparing Reduced Intensity Allogeneic Hematopoietic Cell Transplantation to Hypomethylating Therapy or Best Supportive Care in Patients Aged 50-75 with Advanced Myelodysplastic Syndrome: Blood and Marrow Transplant Clinical Trials Network Study 1102

3 - A Multi-Center Biologic Assignment Trial Comparing Reduced Intensity Allogeneic Hematopoietic Cell Transplantation to Hypomethylating Therapy or Best Supportive Care in Patients Aged 50-75 with Advanced Myelodysplastic Syndrome: Blood and Marrow Transplant Clinical Trials Network Study 1102

A Multi-Center Biologic Assignment Trial Comparing Reduced Intensity Allogeneic Hematopoietic Cell Transplantation to Hypomethylating Therapy or Best Supportive Care in Patients Aged 50-75 with Advanced Myelodysplastic Syndrome: Blood and Marrow Transplant Clinical Trials Network Study 1102

A Multi-Center Biologic Assignment Trial Comparing Reduced Intensity Allogeneic Hematopoietic Cell Transplantation to Hypomethylating Therapy or Best Supportive Care in Patients Aged 50-75 with Advanced Myelodysplastic Syndrome: Blood and Marrow Transplant Clinical Trials Network Study 1102

Comparison of Outcomes and Quality-of-Life Measures Following Haploidentical Vs. Matched Related/Unrelated Donor Allogeneic Hematopoietic Cell Transplantation

Background: Haploidentical (haplo) transplantation using post-transplant cyclophosphamide (Cy) based GVHD prophylaxis is a well-established alternative donor approach for allogeneic hematopoietic cell transplantation (HCT). Although outcomes from haplo HCT have been compared to matched related (MRD) and unrelated donor (MUD) allo HCT, quality-of-life (QOL) recovery between these transplant modalities has not been described. We hypothesized that post-transplant QOL is similar between Haplo and MRD/MUD grafts. A single-institution, retrospective cohort study was therefore conducted to compare outcomes including QOL between these groups. Methods: From May 2014 through December 2019, 90 haplo, 102 MRD and 229 MUD adult 1st allo HCTs were performed. Myeloablative conditioning (MAC) for haplo grafts (n=35) included fludarabine (Flu)/ total body irradiation (TBI) and reduced-intensity conditioning (RIC) haplo transplants (n=55) included Flu/Cy/TBI. QOL was assessed prior to transplant and at days +100 and +180 by the FACT-BMT which consisted of the following subdomains: "Physical well-being," "Social well-being," "Emotional well-being," "Functional well-being," "Additional concerns," and sum of all these subdomains as "Total score." Outcomes were estimated and compared with the Kaplan-Meier and log-rank test or cumulative incidence and Gray test. FACT-BMT scores were compared with repeated measures analysis of variance. Results: Patient and transplant characteristics were comparable among the donor sources except for higher median age at HCT in MUD transplants, and haplo grafts were more commonly used non-Caucasians, used RIC regimens and bone marrow grafts (Table 1). Median transplant hospital length of stay was longer for haplo vs. MRD vs. MUD grafts (31 vs.25 vs. 25 days, p&amp;lt;0.001) with longer median time until neutrophil and platelet recovery for haplo compared to MRD and MUD grafts (20 vs. 14 vs. 15 days, p&amp;lt;0.001, and 31 vs. 21 vs. 22 days, p&amp;lt;0.001, respectively). MAC haplo HCT had a higher incidence of CMV (p=0.05) and other infections (p=0.003), but no difference in other outcomes compared to MRD/MUD grafts, including all of the QOL domains. The mean Total scores from baseline to day +180 for haplo HCT were 157-157, MRD 153-166, and MUD HCT 152-163. RIC haplo HCT was associated with higher incidences of infections (p&amp;lt;0.001) and relapse mortality (p=0.04), but lower NRM (p=0.008) and no differences in other outcomes. When comparing RIC haplo to MUD transplants there was significantly better Emotional well-being (p=0.008) and Functional well-being (p=0.011) at day+180; respective mean emotional well-being score for haplo 19-23 and MUD 16-19; mean functional well-being score for haplo 19-24 and MRD 19-19 (Figures 1a and 1b). No difference for the other QOL measures were found; the mean Total scores from baseline to day +180 for haplo HCT were 155-180, and MUD HCT were 150-158 (p=0.25). Discussion: Among MAC recipients, we observed no differences in total FACT QOL scores and individual domains among haplo, MRD and MUD HCT recipients through 6 months post-HCT. After RIC HCT, haplo recipients reported better Emotional and Functional well-being compared to those receiving a MUD graft, although Total FACT score and other QOL domains were comparable through 6 months. Future strategies to lessen infectious complications and relapse may further improve QOL outcomes. Interrogation of QOL among disease specific groups may also elucidate whether additional benefits exist between these different transplant modalities. Disclosures Gerds: Sierra Oncology: Research Funding; Gilead Sciences: Research Funding; Celgene: Consultancy, Research Funding; Imago Biosciences: Research Funding; Roche/Genentech: Research Funding; Incyte Corporation: Consultancy, Research Funding; CTI Biopharma: Consultancy, Research Funding; Apexx Oncology: Consultancy; AstraZeneca/MedImmune: Consultancy; Pfizer: Research Funding. Hamilton:Syndax Pharmaceuticals: Consultancy, Honoraria. Majhail:Nkarta Therapeutics: Honoraria; Incyte: Honoraria; Mallinckrodt: Honoraria; Anthem, Inc.: Consultancy.

Long-Term Outcomes of Allogeneic Hematopoietic Cell Transplant with Fludarabine and Melphalan Conditioning and Tacrolimus/Sirolimus as Graft-versus-Host Disease Prophylaxis in Patients with Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is associated with poor survival in older adults, and allogeneic hematopoietic cell transplant (HCT) with reduced-intensity conditioning (RIC) has been an increasingly used strategy in this population. At City of Hope we conducted a retrospective analysis of 72 patients who underwent allogeneic HCT with fludarabine and melphalan (FluMel) as the conditioning regimen between 2005 and 2018, from either a matched sibling or fully matched unrelated donor while in complete remission. Tacrolimus and sirolimus (T/S) were used as graft-versus-host disease (GVHD) prophylaxis. Overall survival and progression-free survival at 4 years post-HCT were 58% and 44%, respectively. The cumulative incidences of relapse/progression and nonrelapse mortality at 4 years were 34% and 22%, respectively. Patients with Philadelphia chromosome-positive (Ph+) ALL had a significantly lower cumulative incidence of relapse/progression (20% versus 48% for patients with Ph-negative status, P=.007). In conclusion, RIC HCT with FluMel conditioning and T/S GVHD prophylaxis was associated with favorable outcomes in patients with Ph+ ALL and should be considered as a viable consolidative therapy for adult patients with ALL.

Composite GRFS and CRFS Outcomes After Adult Alternative Donor HCT.

There is no consensus on the best choice of an alternative donor (umbilical cord blood [UCB], haploidentical, one-antigen mismatched [7/8]-bone marrow [BM], or 7/8-peripheral blood [PB]) for hematopoietic cell transplantation (HCT) for patients lacking an HLA-matched related or unrelated donor. We report composite end points of graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) and chronic GVHD (cGVHD)-free relapse-free survival (CRFS) in 2,198 patients who underwent UCB (n = 838), haploidentical (n = 159), 7/8-BM (n = 241), or 7/8-PB (n = 960) HCT. All groups were divided by myeloablative conditioning (MAC) intensity or reduced intensity conditioning (RIC), except haploidentical group in which most received RIC. To account for multiple testing, P < .0071 in multivariable analysis and P < .00025 in direct pairwise comparisons were considered statistically significant. In multivariable analysis, haploidentical group had the best GRFS, CRFS, and overall survival (OS). In the direct pairwise comparison of other groups, among those who received MAC, there was no difference in GRFS or CRFS among UCB, 7/8-BM, and 7/8-PB with serotherapy (alemtuzumab or antithymocyte globulin) groups. In contrast, the 7/8-PB without serotherapy group had significantly inferior GRFS, higher cGVHD, and a trend toward worse CRFS (hazard ratio [HR], 1.38; 95% CI, 1.13 to 1.69; P = .002) than the 7/8-BM group and higher cGVHD and trend toward inferior CRFS (HR, 1.36; 95% CI, 1.14 to 1.63; P = .0006) than the UCB group. Among patients with RIC, all groups had significantly inferior GRFS and CRFS compared with the haploidentical group. Recognizing the limitations of a registry retrospective analysis and the possibility of center selection bias in choosing donors, our data support the use of UCB, 7/8-BM, or 7/8-PB (with serotherapy) grafts for patients undergoing MAC HCT and haploidentical grafts for patients undergoing RIC HCT. The haploidentical group had the best GRFS, CRFS, and OS of all groups.

Prognostic Score and Cytogenetic Risk Classification for Chronic Lymphocytic Leukemia Patients: Center for International Blood and Marrow Transplant Research Report.

To develop a prognostic model and cytogenetic risk classification for previously treated patients with chronic lymphocytic leukemia (CLL) undergoing reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT). We performed a retrospective analysis of outcomes of 606 patients with CLL who underwent RIC allogeneic HCT between 2008 and 2014 reported to the Center for International Blood and Marrow Transplant Research. On the basis of multivariable models, disease status, comorbidity index, lymphocyte count, and white blood cell count at HCT were selected for the development of prognostic model. Using the prognostic score, we stratified patients into low-, intermediate-, high-, and very-high-risk [4-year progression-free survival (PFS) 58%, 42%, 33%, and 25%, respectively, P < 0.0001; 4-year overall survival (OS) 70%, 57%, 54%, and 38%, respectively, P < 0.0001]. We also evaluated karyotypic abnormalities together with del(17p) and found that del(17p) or ≥5 abnormalities showed inferior PFS. Using a multivariable model, we classified cytogenetic risk into low, intermediate, and high (P < 0.0001). When the prognostic score and cytogenetic risk were combined, patients with low prognostic score and low cytogenetic risk had prolonged PFS (61% at 4 years) and OS (75% at 4 years). In this large cohort of patients with previously treated CLL who underwent RIC HCT, we developed a robust prognostic scoring system of HCT outcomes and a novel cytogenetic-based risk stratification system. These prognostic models can be used for counseling patients, comparing data across studies, and providing a benchmark for future interventions. For future study, we will further validate these models for patients receiving targeted therapies prior to HCT.

Reduced Intensity Conditioning for Allogeneic Hematopoietic Cell Transplantation Utilizing Cladribine and Melphalan

Introduction Reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) has been shown to be successful; however, the ideal RIC regimen is not known. In this study, we report the pooled results of three separate prospective studies utilizing cladribine (2CdA) and melphalan (Mel) based conditioning in patients undergoing allogeneic HCT. Objectives To determine the feasibility, toxicity, and efficacy of a 2Cda/Mel based regimen in patients requiring RIC HCT. Methods 63 adult patients were treated with 2Cda/Mel and included for analysis (84% greater than 50 years of age). 40 men and 23 women received HCT between 1999 and 2014 at Scripps Clinic. 17 patients had previously undergone autologous HCT. All patients received 2CdA 0.14 mg/kg/day for either 4 or 5 days and Mel at either 100 mg/m2 or 180mg/m2 total dose. All patients received rabbit-derived anti-thymocyte globulin (ATG). 22 unrelated recipients received Methotrexate. 41 related recipients received oral cyclosporine as GVHD prophylaxis. 22 patients received tacrolimus as GVHD prophylaxis. Donor lymphocyte infusions (DLI) were allowed but not scheduled. Results Two patients expired prior to neutrophil engraftment; for the remaining 61 the median time to recovery of absolute neutrophil count > 0.5 × 109/L was 12 days (range 9-21). 7 patients expired prior to platelet engraftment; for the remaining 56 the median time to platelets >20 × 109/L without transfusion support was 19 days (12-55). Median overall survival for all 63 patients was 17 months (11 days to 16 years). 10 patients expired prior to day 100, 19 between day 101 and 365, and 14 greater than one year. Diseases included AML (18), Lymphoma (15), MDS (8), Multiple Myeloma (5) and others (17). Non-relapse mortality (NRM) at 100 days, NRM at 365 days, and 1 year OS were 18%, 53%, and 26% for AML, 0%, 37%, and 63% for MDS, and 13%, 27%, and 73% for Lymphoma. In evaluable patients, Grade 2-4 acute GVHD was seen in 47%. Grade 3-4 acute GVHD was seen in 34%. Chronic GVHD was seen in 45% of patients. For 2 patients, acute GVHD was the primary cause of death. 18 patients received DLI; reasons for DLI were relapse (11), mixed chimerism (5), post-transplant lymphoproliferative disorder (PTLD) (1), and idiopathic hemolytic anemia (1). Several patients developed second malignancies after HCT including non-melanoma skin cancers (8), melanoma (1), PTLD (4), myeloproliferative disorder (1), breast cancer (1), cervical cancer (1), and tonsillar squamous cell carcinoma (1). Conclusion 2CdA and Mel are effective agents for RIC HCT. This is the largest study of this regimen published to date. Though it is difficult to fully compare the results from different non-randomized trials, rates of NRM, OS, and GVHD appear similar to other published RIC regimens.

Outcome of hematopoietic cell transplantation for DNA double-strand break repair disorders

Rare DNA breakage repair disorders predispose to infection and lymphoreticular malignancies. Hematopoietic cell transplantation (HCT) is curative, but coadministered chemotherapy or radiotherapy is damaging because of systemic radiosensitivity. We collected HCT outcome data for Nijmegen breakage syndrome, DNA ligase IV deficiency, Cernunnos-XRCC4-like factor (Cernunnos-XLF) deficiency, and ataxia-telangiectasia (AT). Data from 38 centers worldwide, including indication, donor, conditioning regimen, graft-versus-host disease, and outcome, were analyzed. Conditioning was classified as myeloablative conditioning (MAC) if it contained radiotherapy or alkylators and reduced-intensity conditioning (RIC) if no alkylators and/or 150mg/m2 fludarabine or less and 40mg/kg cyclophosphamide or less were used. Fifty-five new, 14 updated, and 18 previously published patients were analyzed. Median age at HCT was 48months (range, 1.5-552months). Twenty-nine patients underwent transplantation for infection, 21 had malignancy, 13 had bone marrow failure, 13 received pre-emptive transplantation, 5 had multiple indications, and 6 had no information. Twenty-two received MAC, 59 received RIC, and 4 were infused; information was unavailable for 2 patients. Seventy-three of 77 patients with DNA ligase IV deficiency, Cernunnos-XLF deficiency, or Nijmegen breakage syndrome received conditioning. Survival was 53 (69%) of 77 and was worse for those receiving MAC than for those receiving RIC (P=.006). Most deaths occurred early after transplantation, suggesting poor tolerance of conditioning. Survival in patients with AT was 25%. Forty-one (49%) of 83 patients experienced acute GvHD, which was less frequent in those receiving RIC compared with those receiving MAC (26/56 [46%] vs 12/21 [57%], P=.45). Median follow-up was 35months (range, 2-168months). No secondary malignancies were reported during 15years of follow-up. Growth and developmental delay remained after HCT; immune-mediated complications resolved. RIC HCT resolves DNA repair disorder-associated immunodeficiency. Long-term follow-up is required for secondary malignancy surveillance. Routine HCT for AT is not recommended.

Fludarabine/Busulfan Plus Low Dose TBI As Reduced Intensity Conditioning in Older Patients Undergoing Allogeneic Hematopoietic Cell Transplant for Myeloid Malignancies

Allogeneic hematopoietic cell transplant (HCT) is potentially curative for myeloid malignancy when indicated. In patients age 60 years or older HCT has become feasible with the use of reduced intensity conditioning (RIC) and studies have shown improved outcome in this older population. There is no clear consensus concerning the superiority of any single reduced intensity conditioning regimen for elderly patients with myeloid malignancies. At the Princess Margaret Cancer Centre we have been using a combination of fludarabine/busulfan plus low dose total body irradiation (TBI) as the sole RIC regimen since the year 2006. We present a retrospective analysis on the outcomes of 116 patients aged 60 to 71 years who underwent allogeneic HCT during the time period 2006-2015 for myeloid malignancies.A total of 40 patients (34%) underwent RIC HCT during the years 2006-2010 and 76 patients (66%) during the years 2011-2015. Median age at HCT was 64 years (range 60-71). AML was diagnosed in 73 patients (63%) while 43 had other myeloid malignancies (MDS=34, CMML=8, blastic plasmacytoid dendritic cell neoplasm=1). Seventy four patients (64%) had de novo and 42 (36%) had secondary disease. Cytogenetics were available for 108 patients (93%), 17 favorable (16%), 59 intermediate (54%) and 32 unfavorable risk (30%) (MRC criteria for AML and IPSS for MDS/CMML). All leukemia patients were in first remission (<5% blasts) and MDS/CMML patients had less than 10% marrow blasts at HCT. As for pre-transplant comorbidity risk, 59 patients (51%) had HCT-CI score of 0-2 and 57 (49%) had a score of 3 or more. Donors were HLA matched related in 63 patients (54%), all other donors were unrelated including 19 mismatched (16%). Both recipient and donor were cytomegalovirus sero-negative in 28 (24%) cases. Female donor to male recipient occurred in 27 (23%) cases. Grafts were peripheral blood stem cells (PBSC) in almost all the patients (n=114, 98%). All patients (n=116) received RIC conditioning with fludarabine 30mg/m2/day for 4 days (day -5 to day -2), busulfan 3.2mg/kg (adjusted BW)/day for 2 days (day -3 to day -2 and TBI 200 cGy x one dose (on day -1).Median follow-up of survivors was 39 months (range 6.5 -121). Median neutrophil engraftment (≥0.5 x10e9/L) was 18 days (range 12-35 days), median platelet engraftment (≥20 x10e9/L) was 11 days (range 7-49 days). Two patients never engrafted and 23 patients did not have a decrease in platelets <20 x10e9/L at any time. Acute graft versus host disease (GVHD) grade II-IV occurred in 59 patients (51%) while grade III-IV was seen in 34 patients (29%). Chronic GVHD at any time was seen in 52 patients (45%). Relapse occurred in 27 patients (23%). Of the 81 patients that died, the primary cause of death was GVHD in 25 patients (31%), disease relapse in 25 patients (31%), infection in 18 patients (22%), and graft failure in 6 patients (7%). Data was not available in 3 patients (4%) and 4 patients (5%) died from other causes.Overall survival (OS) for the entire cohort at 3 years was 33% (95% CI 24-42) on univariate analysis. Type of myeloid malignancy (AML versus others, p=0.007), donor type (p= 0.001), HLA mismatch (p= 0.06) and transplant time period (p= 0.05) were the only variables which showed p<0.1 on univariate analysis for OS. Cumulative incidence of relapse (CIR) at 3 years was 24% (95% CI 16-32). Non-relapse mortality (NRM) at 3 years was 43% (95% CI 34-52). Multivariable analysis for OS using the variables with p<0.1 demonstrated AML patients to have a superior outcome compared to other myeloid malignancies (HR 0.62, 95% CI 0.39-0.99, p=0.045), as well as patients with related donors (HR 0.52, 95% CI 0.33-0.82, p=0.005). For CIR none of the variables were found to be significant. For NRM, AML patients had superior outcome (HR 0.57, 95% CI 0.33-0.97, p=0.038), as well as patients with related donors (HR 0.55, 95% CI 0.33-0.94, p=0.028).Based on the above findings, OS was determined for the AML patients that underwent related donor transplant with this regimen (n=45). Three year OS was 51% (95% CI 36-65) for the AML patients who underwent related donor transplant versus 21% (95% CI 12-32) for the group which included AML with unrelated donors and those with other myeloid malignancies (p= 0.0003) (see figure). We conclude that fludarabine/busulfan plus low dose TBI is an effective conditioning regimen for older patients with myeloid malignancies, in particular for AML patients in first remission with matched related donors. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Reduced intensity conditioned allograft yields favorable survival for older adults with B-cell acute lymphoblastic leukemia.

Older adults with B-cell acute lymphoblastic leukemia (B-ALL) have poor survival. We examined the effectiveness of reduced intensity conditioning (RIC) hematopoietic cell transplant (HCT) in adults with B-ALL age 55 years and older and explored prognostic factors associated with long-term outcomes. Using CIBMTR registry data, we evaluated 273 patients (median age 61, range 55-72) with B-ALL with disease status in CR1 (71%), >CR2 (17%) and Primary Induction Failure (PIF)/Relapse (11%), who underwent RIC HCT between 2001 and 2012 using mostly unrelated donor (59%) or HLA-matched sibling (32%). Among patients with available cytogenetic data, the Philadelphia chromosome (Ph+) was present in 50%. The 3-year cumulative incidences of nonrelapse mortality (NRM) and relapse were 25% (95% confidence intervals (CI): 20-31%) and 47% (95% CI: 41-53%), respectively. Three-year overall survival (OS) was 38% (95% CI: 33-44%). Relapse remained the leading cause of death accounting for 49% of all deaths. In univariate analysis, 3 year risk of NRM was significantly higher with reduced Karnofsky performance status (KPS <90: 34% (95% CI: 25-43%) versus KPS ≥90 (18%; 95% CI: 12-24%, P = 0.006). Mortality was increased in older adults (66+ vs. 55-60: Relative Risk [RR] 1.51 95% CI: 1.00-2.29, P = 0.05) and those with advanced disease (RR 2.13; 95% CI: 1.36-3.34, P = 0.001). Survival of patients in CR1 yields 45% (95% CI: 38-52%) at 3 years and no relapse occurred after 2 years. We report promising OS and acceptable NRM using RIC HCT in older patients with B-ALL. Disease status in CR1 and good performance status are associated with improved outcomes. Am. J. Hematol. 92:42-49, 2017. © 2016 Wiley Periodicals, Inc.