New immunotherapy in the initial setting shows improved outcomes in ALL

Prior treatment for newly diagnosed acute lymphoblastic leukemia (ALL) in adults has included multiple chemotherapy regimens for several decades, and has induced remission in most patients.1 Unfortunately, these remissions are usually not long-lasting, and many patients eventually relapse and require additional treatment.2-4

Since 2010, several new highly active therapies have been approved for relapsed ALL, but have yet to be included in initial regimens. Blinatumomab (Blincyto; Amgen), a CD3/CD19 bispecific 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 apparent disease recurrence as a single agent with a combined response rate of 42% versus a combined response rate of 20% for standard chemotherapy. In the BLAST study (NCT01207388), those with low-grade disease treated with blinatumomab achieved high rates of minimal residual disease (MRD) negativity (85%), which corresponded to a long median relapse-free survival of 35 months.

Given the activity of blinatumomab as a single agent in relapsed disease and as an “MRD eraser”, a clinical trial (NCT02003222) evaluated combination chemotherapy with or without blinatumomab in patients with newly diagnosed BCR-ABL1-negative B-lineage ALL, including of this new agent to the frontline setting.

During this trial, patients aged 30 to 70 years with Philadelphia chromosome-negative ALL received a standard induction and consolidation regimen. Responders were then randomized to continue with 4 cycles of consolidation chemotherapy and maintenance or 4 cycles of blinatumomab between 4 cycles of the same consolidation chemotherapy and maintenance.

The primary endpoint of the trial was overall survival (OS) from the time of randomization, with secondary endpoints being event-free survival and MRD negativity rate. Due to FDA approval of blinatumomab during the trial, patients who were MRD-positive after consolidation crossed over to the blinatumomab arm only after March 2018 (ie, were not randomized).

At the American Society of Hematology’s 64th Annual Meeting and Exposition, Litzow and colleagues presented the first reported results of this trial, which was initiated in December 2013 and closed for enrollment in October 2019. Of the 772 patients screened for the trial, 488 were included in the induction therapy. Ultimately, 224 MRD-negative patients were randomized, with 122 to each arm.

For allogeneic stem cell transplantation, the arms were well balanced, with 22 patients in each crossing over to induction therapy. A significant improvement in OS in favor of the blinatumomab group (median OS, not reached vs. 71.4 months; HR, 0.42; 95% CI, 0.24-0.75; two-sided P = .003) was observed is in the mean follow-up of 43 months. Notably, after 3.5 years of follow-up, 83% of patients treated with blinatumomab were still alive versus only 65% ​​of those treated with chemotherapy alone.

This practice-changing study is one of the first to document improved outcomes for patients with ALL treated with a new immunotherapy in the early stages. The median OS of these patients appears to be longer than historical comparisons, setting a new standard of care for patients aged 30 to 70 years with Philadelphia chromosome-negative ALL. As trial data mature, overall survival and relapse-free survival outcomes of non-randomized patients who achieved MRD negativity with blinatumomab are eagerly awaited.

Furthermore, the role of allogeneic stem cell transplantation in MRD-negative patients remains undefined. Given the negative prognostic value of the Philadelphia chromosome-like genetic signature, the outcomes of this subgroup of patients treated with the E1910 regimen are of considerable interest.

Ultimately, this study represents a major step forward for newly diagnosed Philadelphia chromosome-negative ALL patients. Future guidelines should focus on earlier incorporation of other novel agents, such as chimeric antigen receptor T-cell therapy and venetoclax (Venclexta; AbbVie and Genentech). As OS improves for the cohort as a whole, de-escalation of therapy for those with early and deep MRD negativity should also be pursued in large cooperative cohort trials.

ABOUT THE AUTHOR

Neil Palmisiano, MD, MS, is Deputy Director of Phase 1 Therapeutics for Hematologic Malignancies and System Leader for Leukemia at RWJBarnabas Health, and Co-Medical Director of the Office of Human Research at Rutgers Cancer Institute of New Jersey.

REFERENCES

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2. Fielding AK, Richards SM, Chopra R, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); study MRC UKALL12/ECOG 2993. Blood. 2007;109(3):944-950. doi:10.1182/krv-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 the success of stem cell transplantation. Blood. 2012;120(10):2032-2041. doi:10.1182/krv-2011-12-399287

4. Aguayo A, Cortes J, Thomas D, Pierce S, Keating M, Kantarjian H. Combination therapy with methotrexate, vincristine, polyethylene glycol-conjugated dasparaginase, 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 Engl 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-cell precursor acute lymphoblastic leukemia. Blood. 2018;131(14):1522-1531. doi:10.1182/krv-2017-08-798322

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