Early Allogeneic Hematopoietic Cell Transplantation Research Articles

Intensive Reinduction Chemotherapy Followed by Early Allogeneic Hematopoietic Cell Transplantation for Relapsed/Refractory High-Grade Myeloid Neoplasms

Outcomes for adults with relapsed/refractory (R/R) high-grade myeloid neoplasms remain poor, with allogeneic hematopoietic cell transplant (HCT) the only therapy likely to result in cure. Therefore, we conducted a study to determine the feasibility of early HCT - within 60 days of beginning reinduction chemotherapy - to see if getting patients to HCT in an expeditious manner would facilitate a larger number of patients being offered this curative option. In this proof-of-principle feasibility study, we included adults 18-75 with R/R myeloid malignancies with ≥10% blood/marrow blasts at diagnosis, who were eligible for a reduced-intensity HCT. Subjects received reinducton chemotherapy with cladribine, cytarabine, mitoxantrone, and filgrastim (CLAG-M) and proceeded to HCT with reduced-intensity conditioning (fludarabine/melphalan). We enrolled 30 patients: all received CLAG-M reinduction, although only 9 received HCT within 60 days (< 15, the predetermined threshold for feasibility "success"), with a median time to HCT of 48 days (range 42-60). Eleven additional subjects received HCT beyond the target 60 days (off-study), with a median time to transplant of 83 days (range 53-367). Barriers to early HCT included infection, physician preference, lack of an HLA-matched donor, logistical delays, and disease progression, all of which may limit real-world uptake of such early-to-transplant protocols.

Asparaginase: Understanding and Overcoming Toxicities

Introduction The extension of pediatric-inspired regimens to young adults with newly diagnosed acute lymphoblastic leukemia (ALL) has considerably improved leukemia outcomes in this population,1–3 and nowadays, more young adults are being cured with chemotherapy and successfully spared from complications of early allogeneic hematopoietic cell transplantation consolidation.4 Pediatric-inspired ALL regimens rely heavily on the use of non-myelosuppressive drugs, such as asparaginase, steroid, and vincristine. Asparaginase, in particular, is a key element for pediatric-inspired regimens, and the inclusion of asparaginase and the more extensive use of it in these regimens has led to better ALL outcomes.5,6 In contrast, a summary of approximately 8,000 children enrolled in the Children’s Oncology Group showed a direct correlation between early asparaginase discontinuation as the result of emerging toxicities and inferior outcomes. 7

Clinical Significance of Natural Killer Cell-Mediated Alloreactivity in Unrelated Cord Blood Transplantation for Children with Acute Leukemia: A Japanese National Registry Study

Introduction: Natural killer (NK) cells are important components of graft-versus-leukemia alloreactivity after allogeneic hematopoietic cell transplantation (HCT) for leukemia, due to the inhibitory killer-cell immunoglobulin-like receptors (KIRs). Only NK cells expressing inhibitory KIRs to self human leukocyte antigen (HLA) can become licensed and more responsive to activating stimuli. However, NK cells with inhibitory KIRs for non-self HLA are proposed to exhibit transient alloreactivity after early allogeneic HCT. The inhibitory KIR2DL group of receptors interacts with HLA-C, which comprises two mutually exclusive groups: HLA-C1 (Asn80) and HLA-C2 (Lys80). KIR2DL1 receptor, which shows the most powerful inhibitory effect and is very frequently expressed in the Japanese population, recognizes the HLA-C2 group. Therefore, we studied combinations of donor and recipient HLA-C groups in children with acute leukemia who underwent unrelated cord blood transplantation (CBT) to clarify the impact of KIR2DL1 mediated-NK alloreactivity on clinical outcomes.Methods: The current study was approved by the institutional review board of Japanese Red Cross Nagoya First Hospital in Nagoya, Japan. A total of 662 children aged 15 years or younger at the time of CBT with acute myeloid leukemia (AML, n = 261) or acute lymphoblastic leukemia (ALL, n = 401) who underwent first unrelated CBT between 1998 and 2015 in Japan were retrospectively analyzed based on the data from the Japanese Data Center for Hematopoietic Cell Transplantation. Patient characteristics are summarized in Table. We compared engraftment rate, cumulative incidence of relapse (CIR), transplantation-related mortality (TRM), leukemia-free survival (LFS), and grade II-IV acute graft-versus-host disease (g2-4 aGVHD) in association with KIR2DL-1 mediated-NK alloreactivity.Results: Patients were divided into three groups according to the donor and recipient HLA-C status; licensedgroup (n = 92) with C1/C2 or C2/C2 donor and C1/C1 recipient, transientlyalloreactivegroup (n = 443) with C1/C1 donor and C1/C1 recipient, and nonreactive group (n = 127) with any donor and C1/C2 or C2/C2 recipients. Median follow-up of survivors was 45 months after CBT. There was no difference in engraftment rates at 50 days after CBT among the three groups, which was 91% for all groups (P= 0.83). The CIR/TRM/LFS at 3 years were 43%/7%/51% for the nonreactive group, 38%/12%/50% for the transiently alloreactive group, and 47%/10%/43% for the licensed group, respectively (P= 0.23, 0.29, and 0.50, respectively). The incidence rates of g2-4 aGVHD were 34%, 41%, and 47% for the nonreactive, transiently alloreactive, and licensed groups, respectively (P= 0.10). The CIR for transiently alloreactive group tended to be lower than those for the others, whereas the TRM for transiently alloreactive group was higher than those for the others; however, there was no difference in LFS among the three groups. Narrowing the cases to the HLA-C mismatch setting, the tendency of lower CIR and higher TRM for transiently alloreactive group became stronger. The CIR/TRM/LFS at 3 years in the HLA-C mismatch setting were 49%/6%/45% for the nonreactive group (n = 83), 36%/16%/48% for the transiently alloreactive group (n = 206), and 48%/11%/41% for the licensed group (n = 87), respectively (P= 0.09, 0.09, and 0.73, respectively, shown in Figure). The trend of lower CIR and higher TRM for the transiently alloreactive group remained unchanged for both AML and ALL patients.Conclusions: There was a significant association between transient KIR2DL1-mediated NK alloreactivity and reduced CIR after HLA mismatch CBT for childhood acute leukemia, which suggests improved LFS with efforts to reduce TRM. Further large studies are warranted. [Display omitted] DisclosuresAtsuta:Otsuka Pharmaceutical Co., Ltd.: Honoraria.

Pretransplantation Red Blood Cell and Platelet Transfusion Burden in De Novo Myelodysplastic Syndrome Undergoing Allogeneic Transplantation

Most patients of myelodysplastic syndrome (MDS) require red blood cell (RBC) or platelet transfusion during their disease courses, which could cause an increased risk of iron overload and alloimmunization. However, it remains less clear whether pretransplantation RBC or platelet transfusion burden affects transplant outcomes in patients with MDS. The objective was to examine the significance of pretransplantation RBC and platelet transfusion burden on transplant outcomes after allogeneic HCT for adults with de novo MDS. We retrospectively evaluated the effect of pretransplantation RBC or platelet transfusion burden on transplant outcomes in a cohort of 1007 adult patients with de novo MDS treated by upfront allogeneic hematopoietic cell transplantation (HCT) between 2006 and 2018. Both higher pretransplantation RBC and platelet transfusion burdens were significantly associated with higher overall mortality and relapse-related mortality, but not non-relapse mortality in the multivariate analysis. Higher pretransplantation RBC transfusion burden was also significantly associated with lower neutrophil, platelet, and reticulocyte recovery in the multivariate analysis. In summary, our study clearly demonstrated that a higher pretransplantation RBC and platelet transfusion burden was independently associated with higher overall mortality, relapse-related mortality, and lower hematopoietic recovery after allogeneic HCT for de novo MDS. Early allogeneic HCT should be considered for patients with de novo MDS who require RBC and platelet transfusion repeatedly.

Early Allogeneic Hematopoietic Cell Transplantation in Patients with High Risk AML - Final Results From the Randomized AML 2003 Trial

AbstractAbstract 229▪▪This icon denotes a clinically relevant abstract Background:The optimal timing of hematopoietic cell transplantation (HCT) in AML and its use in risk groups defined by genetic markers or early blast clearance is still under debate. We addressed this question in the AML 2003 study, a large multicenter, randomized, open-label study within the German SAL group. All patients received one cycle of induction therapy (IT) with a 3+7 regimen combining daunorubicin and continuous infusion cytarabine. Upfront cytogenetic and molecular characterization, HLA typing, related donor search and a preliminary search for an unrelated donor were performed for all patients. The subsequent transplant strategy was tailored to the biological risk and donor availability. Patients and Methods:Patients aged 18–60 years were randomly assigned upfront 1:1 to either of two transplant strategies: In the control arm allogeneic HCT was scheduled in first complete remission for patients with intermediate risk cytogenetics and an HLA-identical sibling and for patients with a complex karyotype (CK) and a related or unrelated HLA-compatible unrelated donor. In the experimental arm the indication for allogeneic HCT was extended to patients with an FLT3-ITD allelic ratio >0.8 (mutant/wild type), >10% marrow blasts on day 15 after IT1 and patients with adverse karyotypes, including: −7, −5, del(5q), inv(3q), t(3;3), t(6;9), t(6;11), t(11;19)(q23;p13.1). Furthermore, allogeneic HCT was scheduled at an early time-point, i.e. in aplasia after the first or the second cycle of IT in the experimental arm. Patients without an HLA-compatible donor assigned to the transplant strategy were scheduled for high-dose busulfan and cyclophosphamide followed by autologous SCT. Here, we present the final analysis of this study according to the intent-to-treat principle. Results:Between December, 1, 2003 and November, 26, 2009 1179 patients were randomized between the experimental (N=598) and the control intervention (N=581). The median age was 48 years (range, 18 to 60 years). The distribution of age, ECOG performance status, type of AML, cytogenetic risk groups, NPM1- and FLT3-ITD-mutations, LDH, white blood cell and platelet count was not statistically different between the two treatment arms. However, more males and patients with higher marrow blast counts at diagnosis were randomized to the experimental treatment arm. The median observation time for all patients was 52 months.The hazard ratio of the treatment effect (experimental versus control) was 0.92 (95% CI, 0.75 to 1.14; p=0.45) for primary endpoint overall survival and 0.85 (95% CI, 0.71 to 1.02; p=0.08) for the secondary endpoint event-free survival. Patients in both arms had an excellent long-term overall survival of 50% (95% CI, 46% to 54%) at 5 years after enrollment in the experimental arm and 47% (95% CI, 42% to 51%) in the control arm (see Figure). Across all risk groups the rate of early allogeneic HCT performed per protocol was 22% in the experimental arm and 8% in the control arm. Among patients with high risk cytogenetics this rate was 48% and 17%, respectively. These numbers point at the difficulty to deliver allogeneic HCT within two months after diagnosis of AML in the context of a multicenter trial. However, since HLA-typing and preliminary donor search was done for all patients and allogeneic HCT was standard for relapsed or refractory AML in both arms, the rates of allogeneic HCT as first post remission therapy or after induction failure/relapse were substantially higher than in previous studies and almost equal in the experimental and control arm (63% versus 56%). Conclusions:Although a survival benefit by early allogeneic HCT could not be demonstrated in this large randomized study in newly diagnosed AML, the study treatment resulted in excellent overall survival rates in both arms. Relatively small differences between the per-protocol transplantation rates and crossover effects may partially explain why a benefit of early allogeneic HCT could not be demonstrated. Early awareness of donor availability and the option of allogeneic HCT in patients with primary induction failure or AML relapse resulted in a high overall rate of allogeneic transplantation. This may have contributed to the excellent overall survival in both arms. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Hematopoietic Cell Transplantation for Children with Acute Lymphoblastic Leukemia in Second Complete Remission: Similar Outcomes in Recipients of Unrelated Marrow and Umbilical Cord Blood versus Marrow from HLA Matched Sibling Donors

Transplant decisions for children with acute lymphoblastic leukemia (ALL) in second complete remission (CR2) are often based on the type of available donor. In many cases, allogeneic hematopoietic cell transplantation (HCT) is considered only if a human leukocyte antigen (HLA) matched sibling donor (MSD) is available. The role of unrelated donor (URD) HCT in this patient population is not well established. As advances in supportive care and donor selection have improved, the use of URD HCT in such patients should be reevaluated. We analyzed the outcomes of 87 consecutive children with ALL in CR2 who underwent allogeneic HCT at the University of Minnesota between 1990 and 2007. Donor sources included MSD bone marrow (n = 32), well and partially matched (M, n = 18) and mismatched (MM, n = 16) URD bone marrow and URD umbilical cord blood (UCB, n = 21). Although the incidence of neutrophil recovery was similar in all groups, the overall incidence of grades II-IV acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD) was 37% and 9%, respectively, with a higher incidence of aGVHD in recipients of URD grafts. Leukemia-free survival (LFS) at 5 years was lower in recipients of MM-URD grafts, but was comparable in all other groups. Although relapse at 5 years was highest in recipients of MSD (50%), results were not significantly different compared to recipients of M-URD (17%), MM-URD (6%), and UCB (33%) (P = .17). The development of grades II-IV aGVHD and a first remission >3 years were associated with a lower risk of relapse (relative risk [RR] 0.2, P = .03; RR 0.2. P = .01 respectively). Together, these results support the continued investigation of URD HCT for ALL in CR2, and suggest the timing of HCT in these children should be based primarily on the risk of relapse with conventional chemotherapy and not on the type of donor available.

Early Allogeneic Hematopoietic Cell Transplantation during Induction Chemotherapy in High-Risk Acute Myeloid Leukemia.

Objectives: In patients with acute myeloid leukemia and high-risk cytogenetic aberrations or minor response to the first cycle of induction chemotherapy (IC) the probability of achieving a sustained complete remission is low. Thus early treatment intensification may be warranted in order to achieve long-term disease control. We performed a prospective trial to evaluate whether reduced-intensity conditioning followed by allogeneic hematopoietic stem cell transplantation (HSCT) from related or unrelated donors can be performed during the aplastic phase of IC in patients with poor-risk AML. Methods: Seventeen patients (n=17) aged between 17 and 63 years (median 45) with acute myeloid leukemia and high-risk cytogenetic aberrations (n=14, complex, inv3 or t(3;3), t(3;5), −7 or del 7q, +8) or more than 10 % marrow blasts on day 15 after the first cycle of IC (n=3) were included so far. During aplasia a median of thirteen days (range 7–35) after the first (n=8) or second (n=9) cycle of IC patients received 5 x 30 mg/m2 fludarabine i.v. combined with either 8 mg/kg busulfan p.o. (n=4) or 150 mg/m2 melphalan iv. (n=13) followed by allogeneic G-CSF mobilized peripheral blood stem cells (PBSC, n=16) or bone marrow (n=1) from related (n=7) or unrelated (n=10) donors. Nine out of seventeen patients were not in complete remission before conditioning therapy was started. Patients with unrelated grafts received antithymocyte globulin (4 x 10 mg/kg ATG Fresenius). GvHD prophylaxis was performed with cyclosporine A (CSP). Results: All patients engrafted (ANC &gt; 0.5 Gpt/l on day 11, range 8–19, platelets &gt; 50 Gpt/l day 15, range 11–32) and went into remission. Acute GvHD grade II-IV occurred in 8 patients and extensive chronic GvHD was documented in 5 patients with a follow-up of &gt; 100 days. Two patients died while being in remission from infectious complications associated with acute (n=1) or chronic (n=1) GvHD and two patients died during relapse eight and twelve months after PBSC. With a median follow-up of 15 months (range 1–65) thirteen out of seventeen patients (76 %) are alive and in remission. Conclusion: Early allogeneic HSCT as part of primary induction therapy seems to be an effective strategy in AML patients with either poor risk karyotype or minor response to the first induction cycle.