Pasien mana yang benar-benar mendapat manfaat dari gipretinib dalam terapi kombinasi untuk leukemia myeloid akut (AML) kambuh/refrakter (R/R) bermutasi FLT3: Analisis satu pusat di Kanada – Nature

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Ethics approval and consent to participate Treatment of relapsed-refractory (R/R) FLT3mut AML is an unmet need. Use of gilteritinib monotherapy in the ADMIRAL trial resulted in a modest prolongation of overall survival (OS) from 5.6 months to 9.3 months. Following the results from in-vitro studies showing synergism between gilteritinib and venetoclax, this combination was studied in a phase Ib/II study, resulting in a median OS of 10.0 months. The combination of gilteritinib with azacytidine-venetoclax in another phase I/II study resulted in a median OS of 5.8 months in the R/R cohort. Thus, even though combination therapy shows improved response rates, cross trial comparisons show the survival with combination therapy to be similar to that of monotherapy at the cost of increased toxicities. Thus, clinical equipoise persists regarding the optimal regimen for R/R FLT3 mutated AML. To address this knowledge gap, we conducted a single center retrospective study to evaluate our experience with use of gilteritinib-based therapy in the R/R FLT3mut AML population. Specifically, we compared the outcomes of patients who received gilteritinib monotherapy with gilteritinib combination therapy. This study included patients from Canada who were: (1) relapsed or refractory (R/R) to first or greater lines of AML treatment (2) have documented FLT3 mutation at the time of relapse, and 3) have used gilteritinib or gilteritinib combinations (gilteritinib + venetoclax, gilteritinib + azacytidine, and gilteritinib + venetoclax + azacytidine) for salvage treatment. FLT3 ITD mutations were identified by fragment analysis performed following multiplex polymerase chain reaction (PCR) using fluorescent primers, while TKD mutations were assessed by restriction enzyme digestion and electrophoresis. A chart review was performed to obtain pertinent clinical information. The study was approved by the University Health Network (UHN) Research Ethics Board (REB CAPCR 19-5870.0). The study was conducted in compliance with the Declaration of Helsinki. Given the retrospective nature of the study, a waiver of consent was obtained. All patients provided written informed consent for the collection of their PB or BM samples as part of the University Health Network Hematologic Malignancy Tissue Bank (REB CAPCR 01-0573). The primary endpoints were event free survival (EFS) and overall survival (OS) of the overall population. Secondary endpoints included comparison of EFS and OS between the gilteritinib monotherapy and gilteritinib combinations, as well as comparing the proportion of patients achieving modified CRc (mCRc) and undergoing allogeneic stem cell transplantation/donor lymphocyte infusion (DLI) between the sub-groups. In addition, we also looked at the genomic profile to identify the most frequent co-occurring mutations. Additionally, we analyzed co-occurring mutations and their associations with response and survival. From the institutional database, we identified 68 patients, amongst them 47 received gilteritinib monotherapy and 21 received gilteritinib combinations (gilteritinib + venetoclax (n = 8), gilteritinib + azacitidine (n = 2) and gilteritinib + venetoclax + azacitidine (n = 11)). Baseline characteristics of the overall population and these subgroups are summarized in Table 1. In the overall cohort, CR was achieved in 5 (7.3%), CRi in 9 (13.2%) and MLFS in 16 (23.5%) patients, resulting in a mCRc (CR + CRi + MLFS) rate of 44% (Supplementary Table 1). Greater proportion of patients receiving combination therapy achieved CR (14.3% vs 4.3%) and MLFS (42.8% vs 14.8%) resulting in higher mCRc rate (71.4% vs 34.0%) (p = 0.009) (Supplementary Fig. 1A). One patient who received gilteritinib monotherapy declined a bone marrow assessment following count recovery. Gilteritinib was continued for a total duration of 14 months, after which the patient had relapsed. For the purpose of analysis, this patient was considered to have a mCRc response. In the overall cohort, 10 (14.7%) patients underwent allogeneic stem cell transplant and 4 (5.8%) patients received DLI. Median time to transplant/DLI from gilteritinib initiation was 3 months. Post-transplant maintenance was administered in 12/14 (85.7%) patients (Gilteritinib—9/12 and Sorafenib—3/12) (Swimmer’s plot, Supplementary Fig. 2). On comparison, 6 (12.8%) and 8 (38.1%) patients received transplant/DLI in monotherapy and combination therapy, respectively (p = 0.039). Median time to transplant/DLI was 4.5 months and 2.5 months, respectively (p = 0.353). After a median follow-up of 34 months (95% CI: 22–43), there were 17 (25.0%) relapses (FLT3-negative: 3, FLT3-positive: 7, not available: 7) and 50 (73.5%) deaths. The median EFS (Supplementary Fig. 3A) and OS (Supplementary Fig. 3B) for the overall cohort was 3.5 months (95% CI: 2.9–4.9) and 7.5 months (95% CI: 4.8 –11.1), respectively. Median EFS and OS in the monotherapy group was 3.5 months (95% CI: 2.9–4.7) and 5.8 months (95% CI: 3.9–8.5) respectively. Median EFS and OS in the combination therapy group was 4.7 months (95% CI: 2.6–NA) and 14.9 months (95% CI: 4.7–NA) (Fig. 1A, B). The most common co-occurring mutations were DNMT3A (44%), NPM1 (41%), RUNX1 (19%), ASXL1 (15%) and IDH2 (15%). There were 21 (30.8%) patients who had co-mutations with NPM1 and DNMT3A (triple-mutated) (Supplementary Fig. 4). Triple-mutated patients had a higher probability of achieving CR/CRi (42.9% vs 10.6%;

p = 0.007), mCRc (71.4% vs 34%; p = 0.008) (Supplementary Fig. 1B), and a lower probability of an EFS event (52.4% vs 91.5%; p = 0.001) or death (42.9% vs 87.2%; p By multivariable analysis using Cox proportional hazards model, receipt of transplant/DLI (HR: 0.15 (0.04–0.56); p = 0.0044) and presence of triple mutation (HR: 0.31 (0.13–0.76);

p = 0.0099) positively influenced the OS whereas the previous use of HMA + venetoclax (HR = 5.09 (1.97–13.14); p = 0.0008) negatively influenced the OS (Supplementary Fig. 6). By logistic regression analysis, use of gilteritinib combination (OR 3.996 (1.235–12.931); p = 0.0208) and presence of triple mutation (OR 3.996 (1.235–12.931);

p = 0.0208) independently predicted for an mCRc response (Supplementary Fig. 7). Propensity score matching was employed to adjust for baseline differences between gilteritinib monotherapy and combination therapy group, using nearest neighbor matching with a caliper width of 0.2 (Supplementary Table 6). After propensity matching, there were 18 patients in the monotherapy arm and 16 in the combination therapy arm. Median OS of the monotherapy and combination therapy were 10.37 months (95% CI: 5.52–NA) and 19.10 months (95% CI: 2.36–NA) (p = 0.8164) (Supplementary Fig. 8). The most common toxicity was febrile neutropenia and infection which occurred in almost half the patients. There was no difference in the incidence of these adverse events based on the type of therapy received. Treatment emergent adverse events are summarized in Supplementary Table 7. In this single center, retrospective analysis of R/R FLT3mut AML patients treated with gilteritinib-based therapy, combination therapy resulted in a better CR rate, mCRc rate and transplant/DLI rate than gilteritinib alone. After a median follow-up of 34 months (95% CI: 22–43), the median OS was 14.9 months (95% CI: 4.7–NA) with combination therapy in comparison to 5.8 months (95% CI: 3.9–8.5) with monotherapy. But this difference was not statistically significant by log-rank test. Univariate and multivariable analyses also showed that the type of therapy (monotherapy or combination therapy) did not impact OS. In addition, after propensity matching for the baseline variables, there was no difference in the OS and EFS between monotherapy and combination therapy. Conversely, receipt of allogeneic stem cell transplantation/DLI and presence of triple mutation significantly influenced OS. Prior exposure to HMA + venetoclax negatively impacted OS. Better survival seen with gilteritinib combination therapy was driven by a high mCRc rate (71.4% vs 34.0%;

p = 0.009) which consequently, resulted in improved transplant eligibility (38.1% vs 12.8%;

p = 0.039). It should be noted that combination therapy resulted in a larger proportion of patients achieving an MLFS response at the time of response assessment (40.9% vs 14.9%). Use of a composite response criterion like mCRc, which incorporates MLFS, is thus of greater relevance in this setting. An important finding in our study was the significantly improved outcome seen in patients with FLT3/NPM1/DNMT3A co-mutations (i. e. triple-mutated). These patients had an increased likelihood of achieving mCRc independent of the type of therapy received. Triple-mutated patients had a prolonged median OS (45 months (95% CI: 4–NA)) compared with non-triple mutated patients (5 months (95% CI: 3–7)). Patients with triple-mutated AML have been identified as a subset associated with a poor prognosis, as described in the seminal paper by Papaemmanuil et al. in 2016. In the combined analysis of NCRI AML17 and AML19 trials by Othman et al. , triple-mutated patients were associated with poorer MRD clearance, higher relapse rate and poorer survival. These datasets included trials and patients before the incorporation of FLT3-inhibitors in induction therapy. On the other hand in the venetoclax + gilteritinib trial, patients with triple mutation had a 100% mCRc rate, confirming that incorporation of a FLT3-inhibitor was particularly important in improving the outcomes of this subset of patients. However, whether an additional agent like venetoclax is required for this subset is not entirely clear. Our data suggest that the mCRc response achieved in these patients are independent of the type of therapy (80.0%(combination) vs 63.6%(monotherapy);

p = 0.635). Similarly, the 24-month OS in the triple-mutated patients was similar in combination therapy (60.0% (95% CI: 16.4–86.5)) compared to monotherapy (54.5% (95% CI: 22.9–78%);

p = 0.562). We propose that the type of therapy in the R/R FLT3mut AML patients should depend on the fitness and the eventual intent of the treatment. In an unfit patient with palliative intent of treatment, monotherapy would suffice, especially if the patient has triple mutation. In a fit patient with eventual goal for transplant, achievement of an mCRc response would be the goal, hence using a combination therapy to achieve this would be ideal. The ideal combination therapy (Venetoclax + Gilteritinib or Azacytidine + Venetoclax + Gilteritinib) needs to be determined in future trials. Future trials must also address whether the assignment of monotherapy or combination therapy can be decided based on the presence or absence of triple mutation. One of the major limitations of this analysis is its retrospective nature, which brings an inherent bias in the assignment of therapy. We acknowledge that fitter patients would have been assigned combination therapy and patients who were unfit or had advanced disease would have been assigned gilteritinib monotherapy. The combination therapy cohort had only 21 patients and there were 3 different combinations of therapy. In conclusion, in R/R FLT3mutAML, presence of triple mutation, achievement of mCRc and undergoing transplant/DLI independently predicted for better OS. The likelihood of achieving an mCRc response was greatest with gilteritinib combination therapy and in patients with triple mutation, with both factors being independent of each other. Patients with triple mutation (FLT3/NPM1/DNMT3A co-mutation) is a distinct subset which responds particularly well to FLT3-inhibitor. We thank all the patients who underwent treatment with us at the Princess Margaret Cancer Centre, University Health Network. AR and HS designed and implemented the study;

AR, ES and HS contributed to acquisition of the data and documentation process; AR, HS and EGA planned and conducted data analysis; AR, HS and EGA drafted the paper; VG, KT, MDM and MAP contributed to the critical revision of the paper;

and AB, SC, MD, DM, GRC, ADS, ACS and KY reviewed the paper and approved the final version for publication. Correspondence to Hassan Sibai. This study has not been funded by any pharmaceutical companies. There were no direct COI specifically related to this research project. ADS has received research funding from Takeda Pharmaceuticals, BMS and Medivir AB, and consulting fees/honorarium from Takeda, Novartis, Jazz, and Otsuka Pharmaceuticals. ADS is named on a patent application for the use of DNT cells to treat AML. ADS is a member of the Medical and Scientific Advisory Board of the Leukemia and Lymphoma Society of Canada. The remaining authors declare no competing interests. The study was approved by research ethics board (REB) and waiver of consent was granted. Waiver of consent was granted by the REB. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http: //creativecommons. org/licenses/by-nc-nd/4.0/. Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, CanadaAkhil Rajendra, Maria Agustina Perusini, Aniket Bankar, Steven Chan, Marta B. Davidson, Vikas Gupta, Dawn Maze, Mark D. Minden, Guillaume Richard-Carpentier, Aaron D. Schimmer, Andre C. Schuh, Karen Yee & Hassan Sibai Princess Margaret Cancer Center, University of Toronto, Toronto, ON, CanadaElliot Smith Staff Specialist Haematologist, Blacktown and Mt Druitt Hospital, Conjoint Lecturer Western Sydney University, Penrith, AustraliaKenny Tang Biostatistics department, University Health Network, Toronto, ON, CanadaEshetu G. Atenafu Malignant Hematology Tissue Bank, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, CanadaMark D. Minden Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada Akhil Rajendra, Maria Agustina Perusini, Aniket Bankar, Steven Chan, Marta B. Davidson, Vikas Gupta, Dawn Maze, Mark D. Minden, Guillaume Richard-Carpentier, Aaron D. Schimmer, Andre C. Schuh, Karen Yee & Hassan Sibai