Multicenter Survey on the Practice Patterns of Post-Transplant Maintenance Treatment in FLT3-ITD Acute Myeloid Leukemia and Philadelphia Positive Acute Lymphoblastic Leukemia: What Is the Common Institutional Policy for Duration of Therapy?

Introduction:

Since leukemia relapse remains a significant cause of mortality after allogeneic stem cell transplant (HCT) for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), interest in post-transplant maintenance (PTM) strategies continues to increase. Specifically, evidence of outcome improvement with the FLT3 inhibitors (FLT3i) sorafenib and gilteritinib in FLT3-ITD AML continues to emerge. Similarly, in Philadelphia positive (Ph+) ALL, tyrosine kinase inhibitor (TKI) maintenance prophylactic or pre-emptive approaches are widely recommended to prevent disease relapse.

However, worldwide clinical practices of PTM strategies are not standardized and significantly influenced by drug availability, funding, and healthcare systems of individual countries. Thus, we conducted a worldwide survey amongst HCT centers (n=21) from 9 countries to understand international PTM strategy usage.

Methods:

We implemented a worldwide survey amongst 21 HCT centers to understand international patterns of clinical practice toward PTM in patients who received allogeneic HCT for FLT3-ITD AML or Ph+ ALL. Thirty-eight centers received the survey, and of these, 21 (55%) replied. Respondent centers were located in Canada (n=7), Saudi Arabia (n=3), China (n=3), South Korea (n=3), Germany (n=1), Lebanon (n=1), Oman (n=1), Kuwait (n=1), and the United Kingdom (n=1).

Results:

For patients with FLT3-ITD AML, 81% (n=17/21) of centers used a FLT3i (either midostaurin, sorafenib, or gilteritinib) as PTM strategy, with 4 centers not having access to medication. The choice of FLT3i varied depending on access and funding of drugs. Of the centers with capacity to provide a FLT3i, 75-100% of candidates would go on to receive a FLT3i, while only 2 centres had a compliance of 5-50%. The duration of FLT3i PTM practices were mostly standard with all but 3 centers aiming to use the medication for 2 years. Two centers used FLT3i PTM for up to 1 year and another center continued it until disease progression. The most common FLT3 inhibitors used were sorafenib and gilteritinib, with midostaurin only used in 2 centers. FLT3-ITD mutation status was determined by NGS or PCR at diagnosis, with heterogeneous access to allele frequency/ratio, with this not being a contributing factor in the decision to use or not maintenance FLT3i.

For patients with Ph+ ALL, 71% (n=15/21) of centers used a TKI as PTM for prophylaxis. Four centers did not have access to medication and 2 centres would only use TKI if measurable residual disease was detected by PCR (pre-emptive strategy). Of the centres that used TKI routinely as a PTM, prescribing compliance was reported to range from 75-100%. Duration of TKI PTM was heterogenous, with 8 centers keeping the approach for 2 years post transplant, 3 centers for 5 years, 1 center for 3 years, 2 centers for 1 year, and one until disease progression. Monitoring practices by quantitative PCR were also variable. The most common approach (12 centers) was PCR monitoring every 3 months for 2 years. Four centers monitored monthly initially, with de-escalation after 1 year or negative PCR to every 3 months. One center monitored every 6 months.

Conclusion:

While there is no standardized recommendation in PTM using FLT3i or TKI for FLT3-ITD AML or Ph ALL, the present study revealed that there is some common practice for PTM approach. Although the duration of maintenance still remains variable and an area of ongoing research, most of HCT centers around the world are currently employing a 2-year duration both in FLT3-ITD AML and Ph ALL. However, worldwide PTM practices still remain heterogeneous, seemingly driven by medication access rather than physician-driven decision. It would highlight urgent need for the development of international standardized treatment guidelines for PTM which can support approval of medication reimbursement or financial support for this approach.

About 80% of the centers that participated in this survey consistently adopted post-transplant maintenance using FLT3i or TKI for FLT3-ITD AML or Ph+ ALL, respectively. For monitoring strategies, especially in Ph+ ALL, qPCR is employed at slightly different schedule with some variation for frequency. In FLT3-ITD, most centres have access to mutational data through PCR or NGS from initial diagnosis, but not employed for follow up or MRD assessment, which is a matter of future research development.

Garcia-Horton:BMS: Honoraria. Lepic:Sanofi: Consultancy, Honoraria; Novartis: Consultancy. Lemieux:Astellas: Honoraria; Jazz Pharma: Honoraria; Amgen: Honoraria; Sanofi: Honoraria. Sanford:Astellas: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding; AbbVie: Consultancy, Research Funding, Speakers Bureau. Jamani:Sanofi: Honoraria. Saad:Sanofi: Consultancy; Kite: Consultancy. Al-Khabori:Novartis: Honoraria. Bazarbachi:Amgen: Honoraria; Pfizer: Research Funding; Roche: Honoraria, Research Funding; Biologix: Research Funding; Takeda: Honoraria; Caribou: Honoraria; Jansen: Honoraria, Research Funding. Zeiser:Neovii: Consultancy; Incyte: Consultancy, Honoraria; Mallinkrodt: Consultancy, Honoraria; Ironwood Pharmaceuticals, Inc.: Consultancy; Sanofi: Honoraria; Medac: Honoraria; Novartis: Consultancy, Honoraria. Mehra:Gilead UK: Honoraria, Research Funding; Cidara: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees. Kim:Jazz Pharmaceuticals, Takeda, Astellas, AbbVie and APLC: Other: Travel; BMS & Celgene, Novartis, APLC, AbbVie, Astellas, Janssen, Handok, Pfizer, Sanofi Genzyme, AML-Hub, Daiichi Sankyo and APBMT: Membership on an entity's Board of Directors or advisory committees; AbbVie, Astellas, BMS, Handok, Novartis, AML-Hub, Jazz Pharmaceuticals and Takeda: Honoraria, Speakers Bureau; AbbVie, AIMS Bioscience, AML-Hub, Astellas, BMS & Celgene, Boryung Pharm Co., Daiichi Sankyo, Janssen, Handok, LG Chem, Novartis, Pfizer, SL VaxiGen, VigenCell, Aston Bioscience, Ingenium, Amgen, Sanofi Genzyme, Takeda, Meiji Pharm Co. and GreenCross Phar: Consultancy; BL&H: Research Funding; AML-Hub, APBMT, ICBMT, APLC, Novartis and BMS: Other: and leadership or fiduciary roles in other board, society, committee or advocacy group . Kim:Ascentage: Consultancy; Pfizer: Honoraria, Research Funding; Paladin: Honoraria, Research Funding; Novartis: Honoraria, Other: Advisory board, Research Funding.