Frontline Sequential Allogeneic Stem Cell Transplantation for Newly Diagnosed Acute Myeloid Leukemia with 3q26.2/Mecom Rearrangement
Authors: Žučenka Andrius , Kevličius Lukas , Davainis Linas , Trociukas Igoris , Čekauskienė Rita , Jaraminė Vaida , Strumskytė Justė , Batiuškaitė Raminta , Norvilas Rimvydas , Valčeckienė Vilma , Dirsė Vaidas , Gineikienė-Valentinė Eglė , Jakubauskas Artūras , Griškevičius Laimonas 
Published: December 2024

BACKGROUND

Acute myeloid leukemia with 3q26.2/MECOM rearrangement (MECOMr AML) is a rare entity with very poor prognosis due to the low efficacy of standard treatments. Allogeneic stem cell transplantation (alloSCT) remains the only curative or remission-prolonging therapy, thus optimal bridging strategies are highly needed. Recent reports suggest that hypomethylating agent-based induction may be preferred mainly due to lower toxicity and aberrant hypermethylation of MECOMr leukemic cells. Herein, we report a sequential, triple therapy consisting of HMA + Ven, directly followed by FLAG-Ida + Ven and myeloablative alloSCT.

METHODS

We report the outcomes of 2 patients with newly diagnosed MECOMr AML for whom sequential alloSCT was used as frontline therapy. Both patients gave informed consent for data sharing and the Institutional Ethics Committee approved the treatment. We collected baseline characteristics, AML genomics, alloSCT-related parameters, response evaluation, measurable residual disease (MRD) data, overall survival, remission duration, time to neutrophil (ANC) and platelet (PLT) engraftment, grade 3-5 non-hematological toxicity.

The first part of the frontline sequential triple treatment consisted of cytoreductive hypomethylation/priming with 5-day HMA + Ven (Decitabine 20 mg/m2 + Venetoclax 400 mg/d, on days 1-5).

On day 6 FLAG-Ida + Ven was initiated (Fludarabine 30 mg/m2, Cytarabine 2000 mg/m2, G-CSF 5 mcg/kg, and Venetoclax 400 mg/d, on days 6-10, Idarubicin 8 mg/m2, on days 8-10).

On day 12 or 14 (wash-out period of 1 or 3 days after FLAG-Ida + Ven) patients proceeded to 7-day Busulfan-based myeloablative conditioning (MAC) and conventional alloSCT.

RESULTS

Patient No. 1 (23-year-old female, ECOG 0, otherwise healthy) was diagnosed with MECOMr AML (FISH: inv(3)(q21q26.2), SNP karyotyping: -7, NGS: GATA2, NRAS, SF3B1 mutations). Notably, the patient presented with elevated PLT count and AML-related diabetes insipidus - both clinical features indicative of MECOMr AML. The patient proceeded to the preconditioning with HMA + Ven (days 1-5) followed by FLAG-Ida + Ven (days 6-10) resulting in morphological leukemia-free state (MLFS) on day 13. MAC (Busulfan + Fludarabine + Cyclophosphamide) was initiated on day 14 with the haploidentical donor (patient's brother) stem cell infusion on day 21 (day 0 of alloSCT). Standard immunosuppression (IS) with post-transplant Cyclophosphamide, Mycophenolate Mofetil, and Cyclosporine A (CsA) was used. ANC and PLT recoveries were reported on day +16 and day +32 post alloSCT, respectively. Pneumonia, sepsis, mucositis, and the hand-foot syndrome were reported as Grade 3 adverse events. Complete remission (CR) with negative MRD (multiparameter flow cytometry &lt;0.1%, NRAS RT-PCR &lt;0.1%) and full donor chimerism (99.57%) was confirmed on day +31. IS was tapered and stopped early on day +115 in the absence of graft-versus-host disease (GVHD). At last follow-up the patient remains in good health and in sustained, MRD-negative CR with full donor chimerism for 13.3 months post alloSCT.

Patient No. 2 (33-year-old female, ECOG 0, otherwise healthy) was diagnosed with MECOMr AML (FISH: inv(3)(q21q26.2), SNP karyotyping: -7, NGS: NRAS mutation). The patient proceeded to the preconditioning with HMA + Ven (days 1-5) followed by FLAG-Ida + Ven (days 6-10) resulting in MLFS on day 11. MAC (Busulfan + Cyclophosphamide) was initiated on day 12 with the matched-related donor (patient's brother) stem cell infusion on day 19 (day 0 of alloSCT). IS with ATG, CsA, and Methotrexate was given. ANC and PLT recoveries were reported on day +22 and day +15 post alloSCT, respectively. Grade 3 adverse events were febrile neutropenia and mucositis. CR with negative MRD (multiparameter flow cytometry &lt;0.1%) and full donor chimerism (99.5%) was confirmed on day +30. NRAS MRD negativity (RT-PCR &lt;0.1%) was confirmed on day +90. IS was tapered and stopped early on day +62 in the absence of GVHD. At last follow-up the patient remains in good health and is in sustained, MRD-negative CR with full donor chimerism for 7.7 months post alloSCT.

CONCLUSIONS

Sequential triple therapy consisting of HMA + Ven, directly followed by FLAG-Ida + Ven and myeloablative alloSCT was safe and effective for young patients with newly diagnosed MECOMr AML. Further evaluation of frontline sequential alloSCT for very poor-risk AML should be addressed in clinical trials.