The Idea

To this day, patients with acute myeloid leukemia (AML) and primary induction failure (PIF) are often not considered for allogeneic stem cell transplantation (HCT), despite being the standard consolidation treatment for adverse-risk AML and the only curative option in this situation (1-6). Recent data by Stelljes et al. showed similar survival rates after a median follow-up of 37 months for relapsed/refractory AML patients who either proceeded directly to allogeneic HCT or underwent intensive remission induction prior to HCT within the ASAP trial (6). To explore long-term prognosis in this clinical setting, we analyzed outcomes of AML patients with PIF undergoing allogeneic HCT with active disease at our institution over a period of 30 years, and investigated associations with molecular and clinical features.

The Setup

We retrospectively explored long-term data from 220 AML patients undergoing allogeneic HCT at the University Medical Center Freiburg (Germany) between 1989 and 2019 without ever achieving complete remission prior to allogeneic HCT. Data was analyzed for the entire cohort as well as distinct periods: i) 1989-2000, ii) 2001-2010, iii) 2011-2019. Primary endpoints were disease-free survival (DFS) and overall survival (OS). Other endpoints were time to relapse and time to non-relapse mortality (NRM).

The Outcome

Median follow-up of our cohort was 8.5 years (range: 0.06-25.4) and the median age of patients was 55 years (range: 20-75). Patients received in median two lines of treatment before allogeneic HCT, with a range of 1 to 6 prior treatment regimens. Blast count in bone marrow before conditioning therapy was in median 36% (range: 0-95%). Molecular risk was assessed in 63.2% of patients, while genetic information was missing in 36.8% of AML cases.

39.8% of AML patients were disease-free after 1 year, 25.2% after 5, and 18.7% after 10 years from allogeneic HCT. 206 patients (93.6%) were alive at day 30 after HCT, and 59 patients (26.8%) were alive at the time of the analysis. Median OS was 1.05 years, with 1-year, 5-year, and 10-year OS rates being 50.4%, 29.8%, and 21.6%, respectively. Survival rates were largely stable over time: 5-year OS in patients treated between 1989-2000 was 28.7%, in those receiving HCT between 2001 and 2010 28.7%, and 30.3% in patients transplanted between 2011 and 2019. NRM was 29.3% after 5 years and 32.5% after 10 year. Over time, relapse rates decreased, with 5-year relapse rates of 45.7% between 1989 and 2000 and 33.3% between 2011 and 2019, reflecting variations in the cohorts. The main cause of death after HCT was AML progression/relapse (57.8%), while infections (19.3%), GvHD (11.2%), and treatment-related toxicity (8.4%) were leading causes of NRM.

In Cox regression analyses incorporating known molecular and clinical risk factors, poor performance status (ECOG > 1 vs. 0-1; DFS: p=0.001, HR 2.3, 95% CI 1.4-3.7; OS: p=8*10^-5, HR 2.8, 95% CI 1.7-4.6,), adverse molecular risk at AML diagnosis (vs. intermediate/favorable risk; DFS: p=0.03, HR 1.6, 95% CI 1.1-2.4; OS: p=0.01, HR 1.7, 95% CI 1.1-2.6), and long diagnosis-to-HCT interval (DFS: p=0.01, HR 1.1, 95% CI 1.0-1.2; OS: p=0.005, HR 1.1, 95% CI 1.0-1.2) were strongly and independently associated with unfavorable DFS and OS. Importantly, the association between these clinical features and outcomes was maintained when restricting the analysis to patients proceeding to allogeneic HCT after PIF during first line therapy.

The Conclusion

Our data demonstrates that immediate allogeneic HCT in AML patients with active disease represents a valid alternative to intensive remission induction and provides long-term survival and cure in a significant proportion of patients, highlighting the importance of allogeneic HCT as the most effective treatment option in this high-risk group. Our data further suggests starting donor search at AML diagnosis and to immediately proceed with conditioning and allogeneic HCT in refractory patients whenever a donor is available.

1. for the European Society for Blood and Marrow Transplantation (EBMT), Passweg JR, Baldomero H, Bader P, Bonini C, Cesaro S, et al. Hematopoietic stem cell transplantation in Europe 2014: more than 40 000 transplants annually. Bone Marrow Transplant. 2016 Jun;51(6):786–92.
2. Döhner H, Wei AH, Appelbaum FR, Craddock C, DiNardo CD, Dombret H, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022 Sep 22;140(12):1345–77.
3. Burnett AK, Wheatley K, Goldstone AH, Stevens RF, Hann IM, Rees JHK, et al. The value of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing risk of relapse: results of the UK MRC AML 10 trial. British Journal of Haematology. 2002;118(2):385–400.
4. Ustun C, Le-Rademacher J, Wang HL, Othus M, Sun Z, Major B, et al. Allogeneic Hematopoietic Cell Transplantation Compared to Chemotherapy Consolidation in older Acute Myeloid Leukemia (AML) Patients 60–75 Years in First Complete Remission (CR1): An Alliance (A151509), SWOG, ECOG-ACRIN and CIBMTR Study. Leukemia. 2019 Nov;33(11):2599–609.
5. Jabbour E, Daver N, Champlin R, Mathisen M, Oran B, Ciurea S, et al. Allogeneic Stem Cell transplantation as Initial Salvage for Patients with Acute Myeloid Leukemia Refractory to High-Dose Cytarabine-Based Induction Chemotherapy. Am J Hematol. 2014 Apr;89(4):395–8.
6. Stelljes M, Middeke JM, Bug G, Wagner EM, Mueller LP, Christoph S, et al. In Patients with Relapsed/Refractory AML Sequential Conditioning and Immediate Allogeneic Stem Cell Transplantation (allo-HCT) Results in Similar Overall and Leukemia-Free Survival Compared to Intensive Remission Induction Chemotherapy Followed By Allo-HCT: Results from the Randomized Phase III ASAP Trial. Blood. 2022 Nov 15;140(Supplement 1):9–11.