Allogeneic Hematopoietic Cell Transplantation For Acute Myeloid Leukemia Research Articles

Specific Cytogenetic Abnormalities at Diagnosis Predict Survival after Hematopoietic Cell Transplant in Poor-Risk Pediatric Acute Myeloid Leukemia: A PDWP/EBMT Study

Introduction: Cytogenetic abnormalities are an important prognostic factor for predicting overall survival (OS) and relapse incidence (RI) in children with acute myeloid leukemia (AML). Although allogeneic hematopoietic cell transplant (HCT) is generally recommended for patients with AML in first complete remission (CR1) and poor-risk (PR) cytogenetics, whether these cytogenetic and molecular features retain their prognostic value after HCT is unknown. Additionally, PR AML is a heterogeneous category that includes several distinct cytogenetic abnormalities, some of which might have a worse prognosis than others. In this study, we evaluated whether the cytogenetic risk classification at diagnosis of AML was predictive of post-HCT outcomes in pediatric patients. Methods: All patients <18 years of age at the time of HCT reported to the European Society for Blood and Marrow Transplantation (EBMT) registry, who had received their first allogeneic HCT for AML in CR1 between 2005 and 2020, and who had their karyotype evaluation at diagnosis available were included in this analysis. Patients were subgrouped as (a) monosomy 7/del7q or monosomy 5/del5q, (b) 11q23 abnormality excluding t(9;11), (c) complex or monosomal karyotype, or (d) other. A complex karyotype was defined as one with three or more structural abnormalities, and a monosomal karyotype was defined as a monosomy with one or more structural abnormalities, excluding WHO-designated recurring translocations or inversions based on 2017 ELN recommendations. Other cytogenetic abnormality subgroup included t(6;9), t(3;5), t(9;22), t(8;16), inv(3) or t(3;3), t(16;21), abn(11p15), and del(12p) or abn(12p13). Cytogenetic subgroup, age at HCT, whether HCT was from a female donor to a male recipient, patient/donor CMV status, time from AML diagnosis to HCT, and year of HCT were included as predictors for OS, RI and non-relapse mortality (NRM) in the multivariate analysis. Results: We included 744 pediatric patients (42.2% female; median age at HCT: 8.6 years [range: 0.3-18 years]) from 139 participating centers in the study. Median follow-up after HCT was 4.4 years. Thirty-seven percent had an 11q23 abnormality, 24% had monosomy 7/del7q or monosomy 5/del5q, 24% had a complex or monosomal karyotype, and 15% met the criteria for other PR cytogenetic abnormalities. Only 7% had secondary AML. Pre-HCT minimal residual disease (MRD) data were available for 346 patients, 86% of whom were MRD negative at the time of HCT. Patients received grafts from a matched related donor (27%), a mismatched related donor (11%), an unrelated donor (46%), or a cord blood donor (16%). Of the total patients, 55% received bone marrow, 29% received peripheral blood-derived stem cells and the rest (16%) received cord blood as the stem cell source. Myeloablative conditioning was used in 97% of the patients. The OS and leukemia free survival for the entire cohort was 76% and 70% respectively at 2 years. In a multivariate model, 11q23 (hazard ratio [HR] = 0.59, P = 0.01) and other poor-risk cytogenetic abnormalities (HR = 0.49, P < 0.01) were associated with significantly better OS when compared with monosomy 7/del7q or monosomy 5/del5q. The "other PR cytogenetic abnormalities" category was also associated with a lower risk of disease relapse after HCT (HR = 0.4, P = 0.01). Receiving an HCT from an unrelated donor, as compared with a matched related donor, was associated with lower RI (HR = 0.58, P = 0.03). Additionally, older age at HCT (12-18 years) was associated with the highest risk of NRM (HR = 1.95, P = 0.02) and with worse OS (HR = 1.71, P < 0.01) than seen in younger patients (aged 4-12 years). Conclusion: PR cytogenetic abnormalities at diagnosis remain predictive of OS after HCT for AML in pediatric patients. Monosomy 7/del7q or monosomy 5/del5q confer a poor prognosis even after HCT, whereas 11q23 abnormality and other PR cytogenetic abnormalities predict a favorable outcome after HCT. Our data also suggest that an HCT from an unrelated donor may offer greater protection against relapse than an HCT from a matched related donor, but this requires further validation. Efforts for improving conditioning regimens and transplant techniques should focus on reducing NRM and reducing RI in this population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Improved trends in survival and engraftment after single cord blood transplantation for adult acute myeloid leukemia

Unrelated cord blood transplantation (CBT) is an alternative curative option for adult patients with acute myeloid leukemia (AML) who need allogeneic hematopoietic cell transplantation (HCT) but lack an HLA-matched related or unrelated donor. However, large-scale data are lacking on CBT outcomes for unselected adult AML. To investigate the trends of survival and engraftment after CBT over the past 22 years, we retrospectively evaluated the data of patients with AML in Japan according to the time period of CBT (1998–2007 vs 2008–2013 vs 2014–2019). A total of 5504 patients who received single-unit CBT as first allogeneic HCT for AML were included. Overall survival (OS) at 2 years significantly improved over time. The improved OS among patients in ≥ complete remission (CR)3 and active disease at CBT was mainly due to a reduction of relapse-related mortality, whereas among patients in first or second CR at CBT, this was due mainly to a reduction of non-relapse mortality. The trends of neutrophil engraftment also improved over time. This experience demonstrated that the survival and engraftment rate after CBT for this group has improved over the past 22 years.

Transferred Donor-Derived Virus Specific CD8+ T Cells That Have Been Transduced to Express a WT1-Specific T Cell Receptor Can Persist and Provide Anti-Leukemic Activity in AML Patients Post-Transplant

Relapse is the leading cause of death following allogeneic hematopoietic cell transplant (HCT) for high risk acute myeloid leukemia (AML). Antigen-specific T cells that selectively target leukemia associated antigen (LAA) have the potential to promote graft versus leukemia (GVL) activity without inducing graft versus host disease (GVHD). We previously demonstrated that transferred donor derived WT1-reactive CD8+ cytotoxic T-cells (CTL) clones can persist in post-transplant patients and mediate anti-leukemic activity (Chapuis et al. Sci Transl Med 2013; 5, 174ra27).T cell receptor (TCR) gene transfer offers the potential to reproducibly provide every patient with a high avidity T cell response. In this study, escalating doses of donor-derived virus specific CD8+ T cells transduced to express a high affinity TCR specific for the HLA A*02:01-restricted WT1126-134 (RMFPNAPYL) epitope are being administered to high-risk AML patients after allogeneic HCT, with escalating doses withheld until persistence of the previous dose is at a frequency of ≤3% of peripheral blood CD8+ T cells. Currently, 9 patients have been treated on study and received a total of 22 infusions. Three patients have completed the four T cell infusions, with the last infusion followed by a two week course of Interleukin 2 (Fig.1). CTC Grade ≥ 3Adverse Events have been transient hypotension and a febrile reaction, and transient leukopenia, lymphopenia, and thrombocytopenia. No end-organ toxicities attributed to the infused T cells have been observed. One patient experienced exacerbation of acute GVHD after T cell infusions, and one patient developed chronic GVHD, although there is currently no evidence the GVHD in either patient reflected activity of the infused T cells.Three patients, who were treated with T cells after a second allogeneic HCT for relapsed AML (two of whom had persistent/relapsed disease after second HCT), are alive with no evidence of disease 14, 8 and 7 months after initiation of T cell infusion (16, 26, and 9 months after second transplant) with no additional anti-leukemic therapy after completion of study treatment. One patient with high risk AML was treated prophylactically after allogeneic HCT for AML in second complete remission (CR2), and is alive with no evidence of disease 13 months after initiation of study treatment (15 months after transplant) (Table 1). Transferred CTL were detectable between 4 and >290 days after infusion (Table 1, Fig.2).The study continues to accrue new patients, but the preliminary results suggest that transfer of donor-derived virus specific CD8+ T cells transduced to express a WT1-specific TCR can be accomplished without significant toxicity and that such therapy can potentially provide anti-leukemic activity. Additionally, no immunogenicity of transferred cells has been observed, suggesting the possibility of retreatment at later time points in case of subsequent relapse.Abstract 3939. Table1Clinical OutcomesPatientDiagnosisDisease status prior to study treatmentDisease burden during T cell infusionNumber of infusionsCTL persistence (days after last infusion)Outcome*Survival*1AMLRelapse 5 years after allogeneic HCT (medullary and extramedullary disease)Present314+Progressive diseaseAlive2AMLRelapse 10 years after first allogeneic HCT. MRD early after second HCTPresent4(+IL2)290+Remission 16 months after transplantAlive3AMLHCT at CR2. No evidence of disease after HCTAbsent4(+IL2)20Remission 15 months after transplantAlive4AMLRelapse with extramedulary disease one year after second allogeneic HCTAbsent1210+Remission 26 months after transplant (8 months after treatment)Alive5MDS → AMLPersistent disease after HCTPresent15+Progressive diseaseDead6AMLSecond HCT for relapse 4 years after first HCTAbsent4(+IL2)4Remission 9 months after transplantAlive7AMLPersistence disease after HCTPresent130+Progressive diseaseDead8AMLHCT in CR2. MRD early after transplantPresent150+Ongoing treatmentAlive9AMLHCT in CR2. Relapse early after transplantAbsent314+Ongoing treatmentAlive* as of 7/10/14+ persistence T cells detected at most recent analysisFigure 1. Treatment plan [Display omitted] [Display omitted] Figure 2. In vivo persistence of WT1-specific donor derived transduced CTL [Display omitted] DisclosuresGreenberg:Juno Therapeutics: Consultancy, Equity Ownership, Patents & Royalties, Research Funding.

Treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) relapsing after allogeneic hematopoietic cell transplantation (HCT).

6539 Background: Disease relapse is a major cause of treatment failure after allogeneic HCT for AML and MDS. Therapeutic options after relapse are limited and the prognosis remains dismal. Methods: We analyzed 245 patients who received allogeneic HCT for MDS/AML using the conditioning regimen of fludarabine 40 mg/m2 and busulfan 130 mg/m2 for four days, between April 2001 and June 2008: 88 patients recurred. Results: Median age was 45 (range:18-66) years. Diagnosis was AML (n=72; 82%) or MDS (n=16; 18%). Donors were related (n=56) or unrelated (n=32). Relapse treatment: 21% (N=18) received supportive care only while 76% (N=67) received salvage (3 patients were lost to follow-up). Median complete remission (CR) duration after first HCT for the recurred group was 4 months; 67% of the patients relapsing <4 months received salvage treatment versus 90% of those that relapsed in >4 months (p=0.02). Salvage included: chemotherapy only (N=31), donor lymphocyte infusion (DLI) with or without chemotherapy (N=11), other (N=3), and second HCT with or without preceding salvage chemotherapy (n=22; 25%). Disease status at second HCT: CR2 (n=5) or active disease (n=17). Median survival after relapse was 3 months; 9 patients are alive (10%; 7 of 9 received second HCT. 2-year over all survival (OS) for second HCT and chemotherapy groups was 45% and 10%, respectively. Whereas 2-year OS was 0% for both DLI and supportive care only group. One-year OS was 45% (N=43) versus 10% (N=45) for patients whose post-transplant remission lasted >4 and <4 months, respectively (P=0.009). Conclusions: Survival after relapse is dictated primarily by post-transplant remission duration. A second HCT holds promise for long-term disease control in a subset of patients. 2-year OS 2-year OS Second allogeneic HCT 45% Chemotherapy 10% Donor lymphocyte infusion (DLI) 0% Supportive care only 0% CR duration after 1st HCT 1-year OS > 4 mo 45% < 4 mo 10% ü(p=0.009) No significant financial relationships to disclose.

Obesity Does Not Preclude Safe and Effective Myeloablative Hematopoietic Cell Transplantation (HCT) for Acute Myeloid Leukemia (AML) in Adults

INTRODUCTION: Obesity is increasingly common in the US and is frequently associated with co-morbid medical conditions that may increase the risk of HCT, often the optimal treatment for AML. HCT risk and outcomes for AML on the basis of body mass index (BMI) have not been well-characterized. Using data from the Center for International Blood and Marrow Transplant Research (CIBMTR), we have previously shown no significant difference in outcomes for autologous HCT for lymphoma among normal weight, overweight, and obese patients (pts) but worse outcomes for underweight pts (Navarro et al, BBMT 2006, 12(5): 541–51). Here, we compare outcomes by weight groups for AML patients who underwent autologous, related, or unrelated HCT.METHODS: Our final population included patients age ≥ 18 who underwent myeloablative unpurged autologous or allogeneic HCT for AML in 1st or 2nd complete remission, primary induction failure, or 1st relapse reported to the CIBMTR from 1995 to 2004. Cord blood HCTs were excluded. Four weight groups were defined based on BMI (BMI=weight (kg)/ height (m2)): underweight <18; normal=18–25; overweight >25–30; and obese >30. Treatment-related mortality (TRM), relapse, leukemia-free survival (LFS), and overall survival (OS) were compared using multivariable proportional hazards regression analysis accounting for patient, disease and HCT-related variables.RESULTS: We included 373 autologous, 2041 related, and 1801 unrelated transplant recipients. Patient-, disease-, and transplant characteristics were well-matched across weight groups and transplant types. Multivariable analysis examining risks (95% confidence intervals) relative to the normal weight group are:HCT TypeNormalUnderweightOverweightObeseAutologousn=164n=5n=112n=81Death–NSNSTreatment failure–NSNSRelapse–NSNSTRM–NSNSRelated Allogeneicn=1161n=31n=543n=268Death1.86 (1.24–2.78)NS1.23 (1.04–1.47)Treatment failure2.08 (1.37–3.15)NS1.19 (1.00–1.42)Relapse2.02 (1.18–3.47)NSNSTRM2.22 (1.17–4.22)NS1.32 (1.02–1.70)Unrelated Allogeneicn=846n=31n=523n=368DeathNSNSNSTreatment failureNSNSNSRelapseNS0.82 (0.68–0.99)0.76 (0.60–0.96)TRMNSNSNS– =not done due to insufficient number of pts; NS=not significant; treatment failure = death or recurrence of disease.CONCLUSIONS: There were no significant differences in risk of TRM, LFS, relapse or OS for normal weight, overweight or obese patient groups who received autologous HCT. Obese recipients of related HCT for AML had increased risk of death, treatment failure, and TRM, though the magnitude was small, an effect was not seen in the unrelated HCT group. Underweight patients who received a related, but not unrelated HCT, fared substantially worse than normal weight patients for all outcomes. It may be that the higher risk of the unrelated HCT procedure masks important but less obvious risks associated with being underweight whereas in the related donor HCT setting, such risks become manifest. Small numbers of patients limit the ability to better characterize this finding in underweight patients. Disproportionately, fewer transplants have been reported in underweight patients which suggest they experience disease and patient-related factors that preclude transplantation. No differences were observed for incidence of acute or chronic GVHD for any weight group. Overweight and obesity should not be a barrier to HCT; however, caution should be exercised in selecting underweight patients for HCT.