Initial treatment of newly diagnosed acute lymphoblastic leukemia (ALL) in adults has included multi-agent chemotherapy for several decades and induces remissions in most patients.1 Unfortunately, these remissions tend not to be long-lasting, with many patients eventually relapsing and requiring additional treatment.2-4
Several new highly active therapies for relapsed ALL have been approved since 2010 but have yet to be incorporated into initial regimens. Blinatumomab (Blincyto; Amgen), a bispecific CD3/CD19 T-cell activator, is one such molecule that has received FDA approval.5.6 As an indication of its activity, blinatumomab induces remissions in patients with openly relapsing disease as a single agent with a composite response rate of 42% compared to a combined response rate of 20% for standard chemotherapy. In the BLAST study (NCT01207388), subjects with low-level disease treated with blinatumomab achieved high rates of minimal residual disease (MRD) negativity (85%), which corresponded to a long median recurrence-free survival of 35 months.
Given the activity of blinatumomab as a single agent in relapsing disease and as an “MRD eraser”, a clinical study (NCT02003222) evaluated combination chemotherapy with or without blinatumomab in patients with new BCR-ABL1 negative line B ALL diagnosis, incorporating this new agent into the frontline setup.
During this study, patients aged 30 to 70 years with Philadelphia chromosome negative ALL received a standard regimen of induction and consolidation. Responders were then randomly assigned to continue with 4 cycles of consolidation and maintenance chemotherapy or 4 cycles of blinatumomab interspersed between 4 cycles of the same consolidation and maintenance chemotherapy.
The primary endpoint of the study was overall survival (OS) from the time of randomization, with secondary endpoints of event-free survival and MRD negativity rates. Because of the FDA approval of blinatumomab during the study, patients who were MRD positive after consolidation only progressed to the blinatumomab arm after March 2018 (ie, they were not randomly assigned).
At the 64th Annual Meeting and Exposition of the American Society of Hematology, Litzow et al. presented the first reported results from this study, which was activated in December 2013 and closed for enrollment in October 2019. Of the 772 patients screened for the study, 488 were enrolled in induction therapy. Ultimately, 224 patients who were MRD negative were randomly assigned, with 122 to each arm.
In terms of allogeneic stem cell transplantation, the arms were well balanced, with 22 patients each proceeding to induction therapy. A significant improvement in OS in favor of the blinatumomab arm (median OS, not reached versus 71.4 months; HR, 0.42; 95% CI, 0.24-0.75; 2-sided P = 0.003) was was observed at a median follow-up of 43 months. Notably, at 3.5 years of follow-up, 83% of patients treated with blinatumomab were still alive compared with only 65% of those treated with chemotherapy alone.
This practice-changing study is one of the first to document improved outcomes for ALL patients who were treated with a new immunotherapy in an initial setting. The median OS of these patients appears longer than in historical comparisons, setting a new standard of care for patients aged 30 to 70 years with Philadelphia chromosome negative ALL. As study data matures, overall and recurrence-free survival outcomes of randomly assigned patients who achieved MRD negativity with blinatumomab are eagerly awaited.
Furthermore, the role of allogeneic stem cell transplantation in MRD-negative patients remains undetermined. Given the negative prognostic value of a Philadelphia chromosome-like genetic signature, the results of this subgroup of patients treated with the E1910 regimen are of considerable interest.
Ultimately, this study demonstrates a major breakthrough for newly diagnosed patients with Philadelphia chromosome negative ALL. Future directions should focus on the prior incorporation of other new agents, such as chimeric antigen receptor T-cell therapy and venetoclax (Venclexta; AbbVie and Genentech). As OS improves for the group as a whole, tapering therapy for those with early and profound MRD negativity should also be pursued in large cooperative group studies.
ABOUT THE AUTHOR
Neil Palmisiano, MD, MS is Deputy Director of Phase 1 Hematologic Malignancies Therapy and Leukemia System Leader at RWJBarnabas Health, and Co-Medical Director of the Office of Human Research Services at Rutgers Cancer Institute of New Jersey.
1. Rowe JM, Buck G, Burnett AK, et al. Induction therapy for adults with acute lymphoblastic leukaemia: results of over 1500 patients from the international ALL study: MRC UKALL XII/ECOG E2993. Blood. 2005;106(12):3760-3767. doi:10.1182/blood-2005-04-1623
2. Fielding AK, Richards SM, Chopra R, et al. Outcome of 609 adults after acute lymphoblastic leukemia (ALL) relapse; a UKALL12/ECOG 2993 MRC study. Blood. 2007;109(3):944-950. doi:10.1182/blood-2006-05-018192
3. Gökbuget N, Stanze D, Beck J, et al. The outcome of relapsed adult lymphoblastic leukemia depends on the response to salvage chemotherapy, prognostic factors, and stem cell transplant performance. Blood. 2012;120(10):2032-2041. doi:10.1182/blood-2011-12-399287
4. Aguayo A, Cortes J, Thomas D, Pierce S, Keating M, Kantarjian H. Combination therapy with methotrexate, vincristine, polyethylene glycol conjugate asparaginase, and prednisone in the treatment of patients with refractory or recurrent acute lymphoblastic leukemia. Cancer. 1999;86(7):1203-1209. doi:10.1002/(sici)1097-0142(19991001)86:7<1203::aid-cncr15>3.0.co;2-3
5. Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N English J Med. 2017;376(9):836-847. doi:10.1056/NEJMoa1609783
6. Gökbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual disease in adults with B-precursor acute lymphoblastic leukemia. Blood. 2018;131(14):1522-1531. doi:10.1182/blood-2017-08-798322