FLAG vs FLAG-IDA: outcomes in relapsed/refractory acute leukemias

Farooq, Muhammad; Mushtaq, Fahad; Farooq, Anum; Khan, Danish Hassan; Mir, Muhammad Ayaz

doi:10.1007/s00280-019-03792-8

Cited by 10 publications

(6 citation statements)

References 4 publications

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“…Of note, the allo-HSCT rate in patients receiving salvage chemotherapy in this study was 11%, compared with 15% in patients receiving gilteritinib in the phase 3 ADMIRAL trial [6] and 20% in a phase 2 study of the FLT3 inhibitor lestaurtinib [5] in patients with FLT3-ITD AML. In studies of FLT3-unselected populations, allo-HSCT rates with salvage chemotherapy are variable (% 15%-42%) and are often based on small sample sizes with heterogenous populations of patients with differD 3 4 4 X Xing cytogenetic and molecular features and risk factors [35][36][37][38][39][40][41][42][43].…”

Section: Discussionmentioning

confidence: 99%

Clinical Outcomes in Patients with FLT3-ITD-Mutated Relapsed/Refractory Acute Myelogenous Leukemia Undergoing Hematopoietic Stem Cell Transplantation after Quizartinib or Salvage Chemotherapy in the QuANTUM-R Trial

Ganguly

Cortés

Krämer

et al. 2021

Transplantation and Cellular Therapy

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Despite the substantial clinical activity of fms-related tyrosine kinase 3 (FLT3) inhibitors in relapsed or refractory (R/R) FLT3-ITD-positive acute myelogenous leukemia (AML), durable remissions and prolonged survival in this population require allogeneic hematopoietic stem cell transplantation (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 months versus 4.7 months; hazard ratio [HR], .76; 95% confidence interval [CI], .58 to .98; P = .018; composite complete remission [CRc] rate, 48% versus 27%; median duration of CRc, 2.8 months versus 1.2 months; mortality rate, .8% versus 14% by day 30, 7% versus 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 on-study HSCT in QuANTUM-R at the investigator's discretion and institutional practices. Of 367 randomized patients, 78 (32%) in the quizartinib arm and 14 (11%) in the salvage chemotherapy arm underwent 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 overall survival (OS) in transplant recipients versus those treated without HSCT (12.2 months versus 4.4 months; HR, .315; 95% CI, .233 to .427). Pooled data also showed a longer median OS in patients with a last recorded response of CRc before allo-HSCT versus patients without a CRc (20.1 months versus 8.8 months; HR, .506; 95% CI, .296 to .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 before allo-HSCT. Fortyeight patients in the quizartinib arm continued quizartinib treatment after allo-HSCT. In the 31 patients with a last recorded response of CRc before allo-HSCT who continued quizartinib after allo-HSCT, the 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-transplantation 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 transplantation and achieve durable clinical benefit. In addition,

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Section: Discussionmentioning

confidence: 99%

Clinical Outcomes in Patients with FLT3-ITD-Mutated Relapsed/Refractory Acute Myelogenous Leukemia Undergoing Hematopoietic Stem Cell Transplantation after Quizartinib or Salvage Chemotherapy in the QuANTUM-R Trial

Ganguly

Cortés

Krämer

et al. 2021

Transplantation and Cellular Therapy

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“…For example, in a recent large sample analysis, the combination of fludarabine, high-dose cytarabine, and granulocyte clony-stimulation factor (FLAG) plus idarubine and gemtuzumab-ozogamicin induced CR/CRi of 51% with 9% induction death in salvage of R/R AML patients [15]. Meanwhile, a recently reported outcome of FLAG regimen for R/R AML gave the CR/CRi rate of 41.7% with regimen associated mortality of 37.5%, and the mortality was even higher for those used FLAG plus idarubine [16]. The result of FLAG regimen plus other anthracyclines is still under observation.…”

Section: Discussionmentioning

confidence: 99%

“…The standard of responses was defined as reported [16]. The complete remission (CR) fulfills the conditions of bone marrow blasts of less than 5% in an aspirate with spicules, transfusion independence with absolute neutrophils more than 1000/mcl, platelets no less than 100,000/mcl, and no residual evidence of extramedullary disease.…”

Section: Response Assessmentmentioning

confidence: 99%

FLT3-ITD Negative Refractory/Relapsed or Geratic AML Patients Responded Well to Salvage Treatment with Low Dose Cytarabine and Sorafenib

Xu¹,

Yao²,

Zhong³

et al. 2019

IJCEMS

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There are great needs to explore more efficient and low-cytotoxic treatment for refractory/relapsed (R/R) or old acute myeloid leukemia (AML) patients without FLT3-ITD mutation. We observed the procedures and outcomes of 13 such patients subsequently treated by sorafenib in our departments. Five of them used low-dose cytorabine concomitantly and 8 patients took sorafenib alone as induction therapy. Five patients achieved complete remission (CR) and the needed time ranged from 31 to 100 days. Four patients achieved CR by concomitantly using low-dose cytorabine and sorafenib, but only one patient achieved CR by taking sorafenib alone. The difference of CR induction rates between the two groups was significant. Sorafenib was then prescribed as the maintenance treatment to these AML patients achieving CR until adverse event happening or stem cell transplantation received. Only one patient developed adverse event of grade 3 during the maintenance with sorafenib and it was relieved by withdrawal of the drug. The event free survival with sorafenib ranged from 2 to 20 months. The median survival time of these CR patients was 520 days since the beginning of taking sorafenib. The median survival time of those not achieved CR with sorafenib was 344 days. But we found no significant differences of survival time between those achieving and not achieving CR. Our results of the observation suggested a group of R/R or geratic AML patients unfit for intensive chemotherapy induction and without FLT3-ITD mutation may well respond to single sorafenib treatment. The combination of low-dose cytarabine with sorafenib improved the response rate comparing with using sorafenib alone. This treatment is safe and the survival time is acceptable for such formidable patients.

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“…Recent comparison between FLAG and FLAG-IDA, in 76 adults and pediatric patients with relapsed and refractory acute leukemia, showed a significant higher CR rate, OS and subsequent transplant rate for FLAG regimen (p= 0.033). 58 Bertaina and cols. 59 evaluated bortezomib in combination with dexamethasone, doxorubicin, vincris-tine and pegylated asparaginase (VXLD) in 30 and 7 children with B-cell precursor (BCP) and T-cell ALL, respectively.…”

Section: Treatments Options For Hematologic and Extramedullary Relapsementioning

confidence: 97%

Prevention and Management of Relapse of Acute Leukemia and Myelodysplastic Syndrome After Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients

Tavares

Pelegrina²

2021

jbmtct

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The best way to manage acute leukemia relapse after HCT is to prevent it, buying time for GVL with immunomodulation and, if no GVHD between days +60 and + 90, prophylactic DLI can be indicate for very high or high risk patients. Short-term low dose of cyclosporine or methotrexate can add safety to pro-DLI, particularly after mismatched or unrelated transplantation. Maintenance with imatinib or dastinib, recommended for Ph-positive ALL, with sorafenib, for FLT3-ITD AML, or azacitidine, for myelodysplastic syndrome patients, can be effective in reducing relapse rates. However, target agent maintenance can add toxicity, depends on patient adherence and demands physician experience to know when is safe to start, how adjust the dose according individual tolerance after transplant and to detect undesirable drug interactions. The second step to avoid hematological relapse is preemptive approach guided by measurable residual disease or mixed chimerism. In patients off immunosuppression, chemotherapy followed by DLI is a useful strategy, and if no response, interferon alpha can be associated to enhance GVL. Target-specific agents can be start at this point either. After relapse, antigen-directed therapy with blinatumumab for CD19 ALL, inotuzumab for CD22 ALL are excellent options to induce MRD negativity and facilitate HCT. Disadvantages of new immunotherapies are: high incidence of VOD with inotuzumab and gemtuzumab; lower response in patients with high leukemia burden or concurrent extramedullary relapse; necessity of consolidation with HCT after a bridging therapy with BiTE and probably with CAR-T cell therapy also. It is important to realize that if remission after chemotherapy is associated with the development of GVHD, then there may be limited benefit (and possibly harm) in consolidating with any kind of cellular therapy. However, for patients who achieved remission without GVHD, either DLI or second transplant can be recommend. Further studies are necessary to determine at which point each strategy might yield the best results.

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FLAG vs FLAG-IDA: outcomes in relapsed/refractory acute leukemias

Cited by 10 publications

References 4 publications

Clinical Outcomes in Patients with FLT3-ITD-Mutated Relapsed/Refractory Acute Myelogenous Leukemia Undergoing Hematopoietic Stem Cell Transplantation after Quizartinib or Salvage Chemotherapy in the QuANTUM-R Trial

Clinical Outcomes in Patients with FLT3-ITD-Mutated Relapsed/Refractory Acute Myelogenous Leukemia Undergoing Hematopoietic Stem Cell Transplantation after Quizartinib or Salvage Chemotherapy in the QuANTUM-R Trial

FLT3-ITD Negative Refractory/Relapsed or Geratic AML Patients Responded Well to Salvage Treatment with Low Dose Cytarabine and Sorafenib

Prevention and Management of Relapse of Acute Leukemia and Myelodysplastic Syndrome After Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients

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