Novel Combinations Could Improve Cure Rates for Adult ALL

Hagop M. Kantarjian, MD

Novel combinations of biologic therapies, third-generation TKIs, and chemotherapy could lead to significantly higher cure rates for adult patients with acute lymphoblastic leukemia (ALL), with a number of early stage studies already showing promising results, according to Hagop M. Kantarjian, MD, at the 37th Annual CFS^®.¹

“If we can find new antibodies that are effective not only as single agents, [but can be added] to chemotherapy, my hope, or prediction, is that in adult ALL we will improve the cure rates to be the same as [those seen in] childhood ALL, with much less chemotherapy,” said Kantarjian, professor and chair of the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. “I think the future might be the third-generation agent ponatinib, to which we add antibodies, rather than chemotherapy.”

Outcome are less favorable in adult patients with ALL compared with pediatric patients, mainly caused by difference cytogenetics. Approximately 50% of adult patients with ALL have Philadelphia chromosome-positive (Ph+) or Ph-like ALL, which denotes a poor prognosis, compared with 15% in pediatric patients.

Over the past few years, a number of promising therapies have gained single-agent approvals for the treatment of adult patients with refectory ALL, including chimeric antigen receptor (CAR) T cells, blinatumomab (Blincyto), inotuzumab ozogamicin (Besponsa), and ponatinib (Iclusig). Now, as more is learned, many of these agents are being combined in earlier settings, with not only promising response rates but also overall survival (OS) findings.

Combination Promising for Ph+ ALL

Findings from a phase II study exploring hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin [Adriamycin], and dexamethasone with methotrexate and cytarabine) plus ponatinib were presented at the 2019 European Hematology Association (EHA) meeting.² In this study, the combination led to a complete remission (CR) rate of 100% and a complete molecular remission (CMR) rate of 77% for patients with newly diagnosed Ph+ ALL. At 3 years, 79% of patients continued to have a CR and the 3-year OS rate was 77%, which is above the historical OS rate of approximately 50%, Kantarjian noted.

Findings from the study led researchers to question whether similar results could be achieved in the absence of chemotherapy. To this end, the phase II D-ALBA study was conducted, looking at the combination of dasatinib (Sprycel) plus blinatumomab as a frontline treatment for adult patients with Ph+ ALL. Preliminary findings from the study were presented at the 2019 EHA meeting.³

In the preliminary findings, the molecular response rate was 54% with blinatumomab and dasatinib, which included a CMR rate of 29%. The 12-month OS rate was 96% and 92% of patients were free of disease and alive at 12 months. The ability of blinatumomab to improve molecular responses in this study further places importance on minimal residual disease (MRD) as an end point, Kantarjian said.

In March 2018, the FDA granted an accelerated approval to blinatumomab for adult and pediatric patients with B-cell precursor ALL following first or second complete remission (CR1 and CR2, respectively) with MRD greater than or equal to 0.1%. The approval was based on findings from the single-arm BLAST trial, in which blinatumomab induced MRD-negativity in 85% of patients in CR1 and for 72% of those in CR2.⁴

“Blinatumomab now is an established treatment for patients who are MRD-positive in complete remission,” said Kantarjian. “One could use it before the allogeneic transplantation and then consider whether transplant is needed.”

Novel Combinations for Ph- ALL

In the absence of effective TKIs for Ph-negative (Ph-) ALL, other novel combinations are under exploration. Investigators at the MD Anderson launched a phase II study looking at mini-HCVD (dose-reduced and hyperfractionated cyclophosphamide, vincristine, and dexamethasone with methotrexate and cytarabine) plus inotuzumab ozogamicin with or without blinatumomab in patients with relapsed/refractory Ph- ALL.⁵ These therapies could have synergistic activity, as blinatumomab targets CD19 and inotuzumab targets CD22, Kantarjian noted.

Across all patients (n = 89), whether they received blinatumomab or not, the objective response rate (ORR) was 79%. The ORR in the first salvage setting was 91%. In the second and third salvage settings, the ORRs were 56% and 60%, respectively. Eighty-two percent of patients were MRD-negative. At a median follow-up of 31 months, the 2-year OS rate was 39% and the median OS was 14 months. The median duration of CR was 30 months. In those receiving inotuzumab ozogamicin alone in prior studies, the 2-year OS rate was 18% and the median OS was 6 months, Kantarjian said.

In the study, the dose of inotuzumab ozogamicin was separated into a weekly fractionated dose to avoid veno-occlusive disease (VOD). Across the full study, grade 3/4 VOD occurred in 6% of patients, which was less than in prior studies. “The veno-occlusive disease rate is down to about 6%, which is the baseline when you conduct allogeneic transplantation,” Kantarjian said.

In a separate phase II study,⁶ the combination of mini-HCVD plus inotuzumab ozogamicin with or without blinatumomab was also tried in older patients with ALL. In this study, the ORR was 98%, all of which were CRs or CRs with incomplete platelet or hematologic recovery. There were no early deaths in the study and the MRD response rate was 95%. The median OS was not yet reached, and the 3-year OS rate was 56%. Kantarjian estimated median OS at this time to be around 45 months.

Additional studies are being designed to further test the combinations, Kantarjian noted. A study is being designed for ponatinib plus blinatumomab in Ph+ ALL and another study is being designed for inotuzumab ozogamicin with blinatumomab with chemotherapy for Ph- ALL.

References

1. Kantarjian H. Immuno-Rx in the management of adult-elderly ALL in 2019. Presented at: 37th Annual CFS^®, hosted by Physicians’ Education Resource^®, LLC; New York, New York, November 6-8, 2019.
2. Short N, Kantajian H, Ravandi F, et al. Updated results of a phase II study of hyper-CVAD plus ponatinib as frontline therapy for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Presented at: 2019 EHA Congress; June 13-16, 2019; Amsterdam, The Netherlands. Abstract P518. bit.ly/2Nm1xQQ.
3. Chiaretti S, Bassan R, Vitale A, et al. A dasatinib-blinatumomab combination for the front-line treatment of adult Ph+ all patients. preliminary results of the GIMEMA LAL2116 D-ALBA trial; on behalf of GIMEMA acute leukemia working party. Presented at: 2019 EHA Congress; June 13-16, 2019; Amsterdam, The Netherlands. Abstract S1617. bit.ly/2JVMT0E.
4. FDA granted accelerated approval to blinatumomab (Blincyto, Amgen Inc.) for the treatment of adult and pediatric patients with B-cell precursor acute lymphoblastic leukemia [press release]. FDA. Published March 29, 2018. bit.ly/2NMRVha. Accessed November 6, 2019.
5. Sasaki K, Kantarjian HM, Ravandi F, et al. Sequential combination of low-intensity chemotherapy (mini-hyper-CVD) plus inotuzumab ozogamicin with or without blinatumomab in patients with relapsed/refractory Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL): a phase 2 trial. Blood. 2018;132(suppl 1;abstract 533).
6. Kantarjian H, Ravandi F, Short NJ, et al. Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2018;19(2):240-248. doi: 10.1016/S1470-2045(18)30011-1.

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