1.
Impact of inotuzumab ozogamicin on outcome in relapsed or refractory acute B-cell lymphoblastic leukemia patients prior to allogeneic hematopoietic stem cell transplantation and risk of sinusoidal obstruction syndrome/venous occlusive disease
Kayser, S., Sartor, C., Giglio, F., Bruno, A., Webster, J., Chiusolo, P., Saraceni, F., Guerzoni, S., Pochintesta, L., Borlenghi, E., et al
Haematologica. 2023
Abstract
We evaluated 58 patients with relapsed or refractory (r/r) acute B-lymphoblastic leukemia (B-ALL; median age, 42.5 years; range, 16-69 years), treated with inotuzumab ozogamicin (INO) between 2016-2022 and who received an allogeneic hematopoietic stem cell transplantation (allo-HCT) consecutively. Forty-seven (81%) of the 58 patients were heavily pretreated receiving intensive chemotherapy +/- TKI, blinatumomab in 24 (41%) and allo-HCT at first-line in 11 (19%) patients. Complete remission (CR) rate prior to allo-HCT was 84%. Median follow-up was 30.5 months and median overall survival (OS) measured from start of INO was 11.2 months. Oneand 2-years OS rates were 50% (95%-CI, 38.4-56.1%) and 36.7% (95%-CI, 25.5-52.9%), respectively. Sinusoidal obstruction syndrome/venous occlusive disease (SOS/VOD) after allo-HCT occurred in 17 (29%) patients. Of those, 9 (53%) patients died due to SOS/VOD and multi-organ failure. Two had received >2 INO cycles (3 cycles, 5 cycles, n=1, each), all others ≤2 INO cycles prior to allo-HCT. Logistic regression analysis revealed conditioning with double alkylators (P=0.038) and allo-HCT during first-line therapy (P=0.050) as significant risk factors for SOS/VOD and in trend allo-HCT ≤ 60 days from last INO application (P=0.07), whereas number of INO cycles before allo-HCT and time between last INO application and allo-HCT were not significant. Relapse/progressive disease occurred in 20 (34%) patients. Of those, five (25%) patients are still alive, whereas 15 succumbed of their disease. Treatment with INO seems to be an effective approach with successful bridge-to-transplant. However, risk of SOS/VOD is high, necessitating continuous monitoring and recognition of SOS/VOD risk factors.
2.
Outcomes in Patients With FLT3-Mutated R/R AML Who Underwent Transplantation in the Phase 3 ADMIRAL Trial of Gilteritinib Versus Salvage Chemotherapy
Perl, A. E., Larson, R. A., Podoltsev, N. A., Strickland, S., Wang, E. S., Atallah, E., Schiller, G. J., Martinelli, G., Neubauer, A., Sierra, J., et al
Transplantation and cellular therapy. 2022
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Abstract
BACKGROUND The fms-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib improved the survival of patients with relapsed or refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) in the phase 3 ADMIRAL trial. OBJECTIVES To assess survival and relapse rates among patients in the ADMIRAL trial who underwent hematopoietic stem cell transplantation (HSCT), as well as safety outcomes in patients who received posttransplant gilteritinib maintenance therapy. STUDY DESIGN ADMIRAL was a global, phase 3, randomized controlled trial, which enrolled adult patients with FLT3-mutated R/R AML. Patients with R/R AML who harbored FLT3 internal tandem duplication mutations in the juxtamembrane domain or D835/I836 point mutations in the tyrosine kinase domain were randomized (2:1) to gilteritinib (120 mg/day) or preselected high- or low-intensity salvage chemotherapy (1-2 cycles) as previously described (Perl AE, et al. N Engl J Med. 2019). Gilteritinib-arm patients who proceeded to HSCT could receive posttransplant gilteritinib maintenance therapy if they were within 30 to 90 days posttransplant and had achieved composite complete remission (CRc) with successful engraftment and no posttransplant complications. Adverse events during HSCT were collected in the gilteritinib arm only. Survival outcomes and the cumulative incidence of relapse were assessed in patients who underwent HSCT during the trial. Treatment-emergent adverse events were evaluated in patients who restarted gilteritinib as posttransplant maintenance therapy. RESULTS Gilteritinib-arm patients underwent HSCT more frequently (n=64; 26%) than chemotherapy-arm patients (n=19; 15%). For all transplanted patients, 12- and 24-month overall survival (OS) rates were 68% and 47%, respectively. Despite a trend toward longer OS after pretransplant CRc, posttransplant survival was comparable across arms. Patients who resumed gilteritinib after HSCT had low relapse rates after pretransplant CRc (20%) or CR (0%). The most common adverse events observed with posttransplant gilteritinib therapy were increased alanine aminotransferase (40%), pyrexia (43%), and diarrhea (40%); grade ≥3 adverse events were primarily related to myelosuppression. Incidences of grade ≥3 graft-versus-host disease and related mortality were low. CONCLUSION Posttransplant survival was similar across the two study arms in ADMIRAL, but higher remission rates with gilteritinib facilitated receipt of HSCT. Gilteritinib as posttransplant maintenance therapy had a stable safety and tolerability profile and was associated with low relapse rates. Taken together, these data support a preference for bridging therapy with gilteritinib over chemotherapy in transplant-eligible patients.
PICO Summary
Population
Adults with FLT3-mutated R/R AML who underwent transplantation and were enrolled in the ADMIRAL Trial (n=371; HSCT n=83)
Intervention
Gilteritinib 120 mg/day (n=246; HSCT n=64)
Comparison
Salvage chemotherapy (n=109; HSCT n=19)
Outcome
For all transplanted patients, 12- and 24-month overall survival (OS) rates were 68% and 47%, respectively. Despite a trend toward longer OS after pretransplant composite complete remission (CRc), posttransplant survival was comparable across arms. Patients who resumed gilteritinib after HSCT had low relapse rates after pretransplant CRc (20%) or complete remission (0%). The most common adverse events observed with posttransplant gilteritinib therapy were increased alanine aminotransferase (40%), pyrexia (43%), and diarrhea (40%); grade ≥3 adverse events were primarily related to myelosuppression. Incidences of grade ≥3 graft-versus-host disease and related mortality were low.
3.
Clinical Outcomes in Patients With FLT3-ITD-Mutated Relapsed/Refractory Acute Myeloid Leukemia Undergoing Hematopoietic Stem Cell Transplant After Quizartinib or Salvage Chemotherapy in the QuANTUM-R Trial
Ganguly, S., Cortes, J. E., Krämer, A., Levis, M. J., Martinelli, G., Perl, A. E., Russell, N. H., Arunachalam, M., Santos, C. D., Gammon, G., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
Despite the substantial clinical activity of fms-related tyrosine kinase 3 (FLT3) inhibitors in relapsed or refractory (R/R) FLT3-ITD?positive acute myeloid leukemia (AML), durable remissions and prolonged survival in this population require allogeneic hematopoietic stem cell transplant (allo-HSCT). Quizartinib, a once-daily, oral, highly potent and selective FLT3 inhibitor, significantly prolonged overall survival (OS) and improved clinical benefit compared with salvage chemotherapy (median OS, 6.2 vs 4.7 months; hazard ratio [HR], 0.76 [95% CI, 0.58-0.98]; P?=?0.018; composite complete remission [CRc] rate, 48% vs 27%; median duration of CRc, 2.8 vs 1.2 months; mortality rates, 0.8% vs 14% [by day 30], 7% vs 24% [by day 60]) in patients with R/R FLT3-ITD AML in the phase 3 QuANTUM-R trial. In this post hoc analysis, we described the characteristics of and clinical outcomes in patients who underwent an on-study HSCT in QuANTUM-R per investigator discretion and institutional practices. Of 367 randomized patients, 78 (32%) in the quizartinib arm and 14 (11%) in the salvage chemotherapy arm underwent an on-study allo-HSCT without any intervening therapy for AML after quizartinib or study-specified salvage chemotherapy. Pooled data of patients from both treatment arms showed a longer median OS in transplanted patients vs those treated without a transplant (12.2 vs 4.4 months; HR, 0.315 [95% CI, 0.233-0.427]). Pooled data also showed a longer median OS in patients with a last recorded response of CRc before allo-HSCT vs patients without a CRc (20.1 vs 8.8 months; HR, 0.506 [95% CI, 0.296-0.864]). By treatment arm, the median OS was 25.1 months with quizartinib and 20.1 months with salvage chemotherapy in patients with a last recorded response of CRc prior to allo-HSCT. Forty-eight patients in the quizartinib arm continued quizartinib treatment after allo-HSCT. In the 31 patients with a last recorded response of CRc prior to allo-HSCT who continued quizartinib after allo-HSCT, median OS was 27.1 months. Continuation of quizartinib after allo-HSCT was tolerable and no new safety signals were identified. These results suggest that post-transplant survival following salvage chemotherapy and quizartinib treatment are similar. However, quizartinib response occurs more frequently than with salvage chemotherapy, potentially allowing more patients to undergo transplant and achieve durable clinical benefit. Additionally, post-HSCT quizartinib was found to be tolerable and may be associated with prolonged survival in some patients, highlighting its potential value in the management of patients with FLT3-ITD R/R AML.