Abstract
Background
Patients with acute myeloid leukemia (AML) who achieve complete remission (CR) following induction therapy but continue to have measurable residual disease (MRD) have inferior outcomes following allogeneic hematopoietic cell transplant (alloHCT). Determining the historical rate of MRD clearance in response to standard consolidative therapy is needed as an initial step in developing a new therapeutic strategy to clear MRD prior to alloHCT.
Methods
A multi-institution retrospective analysis was performed on consecutively treated AML patients in morphologic CR with detectable MRD post-induction therapy who received standard chemotherapy consolidation from January 2016 to December 2021. MRD was measured by multiparametric flow cytometry (MPFC, sensitivity 0.01-0.1%), next generation sequencing (NGS, sensitivity 1-5%), real-time quantitative PCR (qPCR, sensitivity 1:100,000-0.5%), and/or fluorescence in situ hybridization (FISH)/karyotype (sensitivity 1-5%). Any detectable disease-related abnormalities were considered to be evidence of MRD for the purpose of this study.
Results
Eighty-three patients met inclusion criteria for this analysis, with a median age at diagnosis of 51 years (IQR 43-63). Adverse-risk disease by ELN 2017 criteria was observed in 36 patients (43%). The majority received induction therapy with "7+3" (cytarabine + idarubicin or daunorubicin, 77 patients, 93%), and most (71 patients, 86%) required only 1 line of therapy to achieve CR.
At the time of CR following induction therapy, 35 patients (42%) had MRD detected by MPFC, 38 patients (46%) had MRD detected by NGS, 10 patients (12%) had MRD detected by qPCR, and 32 patients (39%) were found to have an abnormal FISH or karyotype. Twenty-eight patients had MRD detected by more than 1 method.
Consolidation therapy consisted of intermediate-dose cytarabine (defined as <3 g/m2, 41 patients, 49%) or high-dose cytarabine (defined as 3 g/m2, 39 patients, 47%) in all patients, except for 3 who received daunorubicin and cytarabine (liposomal) consolidation. The number of cycles of cytarabine consolidation were 1 cycle (36 patients, 43%), 2 cycles (23 patients, 28%), 3 cycles (15 patients, 18%), and 4 cycles (9 patients, 11%), respectively. Sixteen patients received cytarabine consolidation in combination with another agent including sorafenib (1 patient), midostaurin (10 patients), gilteritinib (1 patient), enasidenib (1 patient), and gemtuzumab (3 patients).
In response to consolidation therapy, 27 of the 83 patients with measurable disease converted to MRD-negative (33%) after all given cycles of consolidation cytarabine. Of the 35 patients whose AML had MRD detected by MPFC prior to consolidation, 17 converted to MRD-negative (49%). Of the 38 patients whose AML had MRD detected by NGS prior to consolidation, 6 converted to MRD-negative (16%). Of the 10 patients whose AML had MRD detected by qPCR prior to consolidation, 6 converted to MRD-negative (60%). Of the 32 patients whose AML had MRD detected by FISH or karyotype prior to consolidation, 13 converted to MRD-negative (41%). Of note, 22 patients developed progressive disease following consolidation therapy (and therefore also did not achieve MRD-negativity).
Multivariable logistic regression was performed to assess potential associations with MRD conversion during consolidation chemotherapy. Older age decreased the odds of conversion of AML to MRD-negative (OR = 0.96, 95% CI 0.92-1.00, p = 0.04). Higher ELN risk category, higher dose of cytarabine, and more cycles of consolidation did not affect the likelihood of conversion of AML to MRD-negative.
Fifty-five patients received alloHCT following consolidation therapy. Thirty-one of these patients had AML with MRD detected post-consolidation, of whom 14 had MRD measured by MPFC. With a median follow-up time of 437 days post-transplant (IQR 151-914), two-year progression-free survival post-transplant was 57% in AML patients with MRD detected post-consolidation compared to 71% in AML patients with no MRD (p = 0.28).
Conclusions
The rate of MRD eradication with standard consolidation chemotherapy in AML is suboptimal. Combined with the known poor outcomes after alloHCT in patients with AML and detectable MRD pre-transplant, this demonstrates an unmet need to develop a new therapeutic strategy for eradicating MRD after induction therapy.
Disclosures
Oliai:Pfizer: Research Funding; Orca Bio: Research Funding; Jazz Pharmaceuticals: Research Funding; Arog: Research Funding; Seagen: Research Funding. Patel:Servier/Agios: Research Funding; Kronos Bio: Research Funding; Pfizer: Research Funding; Celgene/BMS: Research Funding; AbbVie: Consultancy. Jeyakumar:Pfizer: Research Funding; Jazz Pharmaceuticals: Research Funding. Mannis:ImmuneOnc: Research Funding; Gilead: Research Funding; Forty Seven: Research Funding; Jazz: Research Funding; Astex: Research Funding; Glycomimetics: Research Funding; Stemline: Consultancy; Pfizer: Consultancy; Macrogenics: Consultancy; Genentech: Consultancy; BMS/Celgene: Consultancy; Astellas: Consultancy; Agios: Consultancy; Abbvie: Consultancy; Syndax: Research Funding; Servier: Consultancy. Logan:Amgen: Research Funding; Amphivena: Research Funding; Astellas: Research Funding; Autolus: Research Funding; Jazz: Research Funding; Kadmon: Research Funding; Kite/Gilead: Research Funding; BMS: Consultancy; Pfizer: Consultancy; Pharmacyclics: Research Funding; Abbvie: Consultancy. Jonas:Jazz: Consultancy, Research Funding; Gilead: Consultancy, Other: data monitoring committee , Research Funding; BMS: Consultancy, Research Funding; 47: Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Other: Travel Reimbursement, Research Funding; Pfizer: Consultancy, Research Funding; GlycoMimetics: Consultancy, Other: protocol steering committee , Research Funding; Servier: Consultancy; Takeda: Consultancy; Tolero: Consultancy; Treadwell: Consultancy; Accelerated Medical Diagnostics: Research Funding; Amgen: Research Funding; AROG: Research Funding; BMS: Consultancy, Research Funding; Celgene: Research Funding; Daiichi Sankyo: Research Funding; F. Hoffmann-La Roche: Research Funding; Forma: Research Funding; Roche: Research Funding; Hanmi: Research Funding; Immune-Onc: Research Funding; Incyte: Research Funding; Loxo Oncology: Research Funding; LP Therapeutics: Research Funding; Pharmacyclics: Research Funding; Sigma Tau: Research Funding. Schiller:Johnson & Johnson: Current equity holder in publicly-traded company; Astellas: Research Funding, Speakers Bureau; Bristol Myers Squibb: Current equity holder in publicly-traded company, Speakers Bureau; Genentech-Roche: Research Funding; Agios: Consultancy, Honoraria; Incyte: Other: speaker fees, Research Funding, Speakers Bureau; FujiFilm: Research Funding; Amgen: Current equity holder in publicly-traded company, Honoraria; AltruBio: Research Funding; CTI: Research Funding; Janssen: Research Funding; Cellectis: Research Funding; Kite, a Gilead Company: Research Funding, Speakers Bureau; Medimmune: Research Funding; Daiichi-Sankyo: Research Funding; Cyclacel: Research Funding; Glycomimetics: Research Funding; Cellerant: Research Funding; Deltafly: Research Funding; Samus: Research Funding; AVM Biopharma: Research Funding; AstraZeneca: Honoraria; Forma: Research Funding; Gilead: Research Funding; PreCOG LLC: Research Funding; Actuate: Research Funding; Regimmune: Research Funding; Mateon: Research Funding; Karyopharm: Research Funding, Speakers Bureau; Actinium: Research Funding; Stemline: Speakers Bureau; Ono Pharma: Honoraria; Stemline: Research Funding; Millennium: Research Funding; Onconova: Research Funding; Constellation: Research Funding; AbbVie: Research Funding, Speakers Bureau; Sellas: Research Funding; Pfizer: Research Funding; Arog: Research Funding; Geron: Research Funding; Trovagen: Research Funding; Gamida: Research Funding; Novartis: Honoraria, Other: Speaker fees, Research Funding; Deciphera: Research Funding; Jazz: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Sangamo: Research Funding; Takeda: Research Funding; Tolero: Research Funding.
