Background: Acute myeloid leukemia (AML) with t(6;9)(p22;q34) is a distinct entity in the 2016 World Health Organization classification of myeloid neoplasms and accounts for a small subgroup (1-2%) of AML patients. A substantial proportion of AML patients with t(6;9) have a concomitant FLT3 -ITD. While outcomes are dismal with intensive chemotherapy, limited evidence suggests allogeneic hematopoietic stem cell transplantation (allo-HSCT) may improve survival if applied early during first complete remission (CR). However, neither prospective nor larger retrospective cohort studies are available to support these results which are derived from small series.
Aims: To characterize AML patients with t(6;9)(p22;q34) and compare outcomes with different treatment strategies.
Methods: We retrospectively studied 123 AML patients with t(6;9)(p22;q34) (median age at diagnosis, 46 years; range, 16-76 years) treated between 1989 and 2016 within fourteen study groups/institutions of the US and Europe. Standard statistical methods were applied.
Results: Median white blood cell count at diagnosis was 20/nl (range, 0.5-274/nl) and platelets 52.5/nl (range, 9-332/nl). The type of AML was de novo in 111 (90%), secondary after myelodysplastic syndrome/myeloproliferative neoplasm in 9 (8%), and therapy-related in 3 (2%) of the patients.Fifty-four patients (44%) were female. Cytogenetic analysis revealed additional abnormalities in 25 (20%) patients, most frequently ≥3 (n=15) abnormalities including +8 (n=2), +13 (n=1) or combined +8/+13 (n=4). A total of 76 patients (62%) had FLT3 -ITD mutation testing, and 48 (63%) of those patients harbored FLT3 -ITD mutations.
Data on response to intensive anthracycline-based induction therapy were available in 121 patients. CR was achieved in 79% (n=95) with 16/95 (17%) requiring an intensive salvage treatment cycle with HiDAC. The CR rate in FLT3 -ITD positive patients was 88% (n=42/48) as compared to 68% (n=19/28) in FLT3 -ITD negative patients (p=0.07). An allo-HSCT was performed in 75 (61%) patients, of whom 51 patients were transplanted in first CR after induction therapy. Additionally 6 patients achieved first CR after salvage chemotherapy and went on to allo-HSCT. Overall, the majority of patients underwent allo-HSCT in first (n=57) or second (n=9) CR; another 9 patients received allo-HSCT with active disease. Type of donor was matched-related in 31, matched-unrelated in 31, haplo-identical in 8, cord blood in 4, and unknown in 1 of the 75 patients, respectively. The majority of patients (72%) received myeloablative conditioning, including TBI in half of them. The proportion of patients receiving an allo-HSCT increased over the time.
Median follow-up for the entire cohort was 61 months (95%-CI, 47-83%). Five-year overall survival (OS) was 36% (95%-CI, 28-47%). Five-year relapse-free survival (RFS) and OS were 50% (95%-CI, 36-68%) and 55% (95%-CI, 41-74%) in patients proceeding to allo-HSCT in first CR after induction therapy (n=51), as compared to 8% (95%-CI, 3-24%; p<0.001) and 18% (95-CI, 9-36%; p<0.001), respectively, in those who received consolidation chemotherapy (n=44). Of note, OS rates after allo-HSCT were comparable if performed in CR1 (56%; 95%-CI, 43-73%; n=57), CR2 (58%; 95%-CI, 30-100%; n=9) or active disease (53%; 95%-CI, 28-100%; n=9; p=0.91). In subgroup analysis FLT3 -ITD positivity had no prognostic impact on OS, either in the total analyzed cohort (p=0.11), or in those patients proceeding to allo-HSCT (p=0.37). Similarly, additional chromosomal abnormalities had no prognostic impact on OS in the afore mentioned cohorts (p=0.92; p=0.83; respectively).
Conclusions: Our cohort of AML patients with t(6;9)(p22;q34) showed a high CR rate after intensive induction therapy; however, treatment with chemotherapy alone resulted in dismal survival outcomes. Those patients who proceeded to allo-HSCT achieved very encouraging OS rates, regardless of FLT3- ITD status, additional cytogenetic abnormalities or timing of transplant, suggesting that transplant should be standard of care when possible for these patients.
Kayser: Novartis: Honoraria, Speakers Bureau; TEVA: Honoraria. Perl: Pfizer: Other: Advisory Board; Novartis: Other: Advisory Board; Actinium Pharmaceuticals: Other: Scientific Advisory Board; Arog Pharmaceuticals: Consultancy; Seattle Genetics: Other: Advisory board; Daiichi Sankyo: Consultancy; Asana Biosciences: Other: Scientific advisory board; Astellas: Consultancy. Mayer: Eisai: Research Funding; Novartis: Research Funding. Walter: ADC Therapeutics: Research Funding; Aptevo Therapeutics: Research Funding. Stone: Ono: Consultancy; Celgene: Consultancy; Fuji Film: Consultancy; Arog: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Abbvie: Consultancy; Amgen: Consultancy; Agios: Consultancy; Astellas: Consultancy; Jazz: Consultancy; Sumitomo: Consultancy. Levis: Daiichi Sankyo, Inc.: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; FujiFilm: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astellas Pharma Us: Consultancy, Research Funding.
Asterisk with author names denotes non-ASH members.