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Combination Therapy Achieves High Response in Ph+ ALL

— Ponatinib-blinatumomab offers promising regimen in frontline and relapse/refractory disease

Ƶ MedicalToday

A combination of ponatinib (Iclusig) and blinatumomab (Blincyto) achieved high rates of complete molecular remission and durable responses in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), according to results of a .

Newly diagnosed Ph+ ALL patients treated with the combination had complete response and complete molecular response rates of 100% and 85%, respectively, while patients with relapsed/refractory disease had rates of 89% and 88%, reported Nicholas Short, MD, of the MD Anderson Cancer Center in Houston.

"The combination of ponatinib and blinatumomab appears to be a promising regimen in both frontline and relapse/refractory Ph+ ALL, as well as in chronic myeloid leukemia in lymphoid blast phase," said Short during a presentation at the American Society of Clinical Oncology virtual meeting. "Given the particularly favorable outcomes in patients with newly diagnosed Ph+ ALL who are not transplanted in first remission, these data suggest this regimen may serve as an effective transplant-sparing regimen in this population."

The current standard of care for most patients with newly diagnosed Ph+ ALL is a combination of chemotherapy plus a BCR-ABL tyrosine-kinase inhibitor (TKI), Short pointed out.

While a combination of chemotherapy and first- and second-generation TKI has achieved 5-year overall survival (OS) rates of 35%-50%, relapses are common and frequently driven by the development of T315I mutations in the BCR-ABL gene, which could be prevalent in as many as 75% of cases, he noted.

Ponatinib is a third-generation TKI designed to potently inhibit BCR-ABL, and has activity against these T315I mutations. Blinatumomab has also been shown to be an effective monotherapy in treating relapsed/refractory Ph+ ALL, and in combination with the TKI dasatinib (Sprycel) in treating newly diagnosed patients. Thus, Short and colleagues wanted to evaluate the combination of ponatinib and blinatumomab in newly diagnosed and relapsed/refractory Ph+ ALL patients.

The trial included 35 patients treated with ponatinib and blinatumomab, including 20 with newly diagnosed Ph+ALL in the first line, 10 with relapsed/refractory Ph+ALL, and five with CML-Lymphoid blast phase crisis (CML-LBP).

The trial endpoint was complete molecular response for newly diagnosed patients and overall response for patients with relapsed/refractory disease. Secondary endpoints included event-free and OS, as well as safety.

Overall, the study cohort had a complete response or pathologic complete response rate of 96%, a major molecular response of 91%, and complete molecular response rate of 79%.

In addition to the high response rates in frontline and relapsed/refractory Ph+ ALL, Short and colleagues reported patients with CML-LBP had a complete or pathologic complete response rate of 100%, a major molecular response rate of 60%, and complete molecular response rate of 40%.

After a median follow-up of 12 months, the estimated 2-year event-free survival (EFS) for the entire cohort was 70%, while the estimated 2-year OS 80%. Among newly diagnosed patients, EFS and 2-year OS was 93%. The estimated 2-year EFS and OS rates were 41% and 53%, respectively for the relapsed/refractory cohort, and 60% and 100% for the CML-LBP group.

No patient in the frontline cohort relapsed or underwent hematopoietic stem cell transplantation in first remission, according to the researchers.

The toxicity profile of both drugs was comparable with that seen in previous studies, and Short noted that no grade ≥4 adverse events were observed in this study.

During a panel discussion following the presentation, the question of the role of allogeneic transplant in first remission was addressed.

"I think we're moving away from transplant, for sure," said Matthew J. Wieduwilt, MD, PhD, of the University of California San Diego. "Particularly in patients who achieve a molecular response. But it's still not supported by good randomized data and comparative data."

"We're still in kind of a data-free zone," he added. "We're going more based on outcomes rather than randomized studies, which is common in that acute lymphoblastic leukemia is a rare disease."

"What is real is that the need [for transplant] is becoming less," said Jorge Cortes, MD, of the Georgia Cancer Center at Augusta University. "At the very least we can say that the patient who doesn't have access to transplant can feel a lot better today than before when we didn't have these treatment options."

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    Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.

Disclosures

The study was funded by Takeda and Amgen.

Short disclosed relevant relationships with Amgen, AstraZeneca, Astellas Pharma, and Takeda. Co-authors disclosed multiple relevant relationships with industry.

Primary Source

American Society of Clinical Oncology

Short N, et al "Combination of ponatinib and blinatumomab in Philadelphia chromosome-positive acute lymphoblastic leukemia: Early results from a phase II study" ASCO 2021; Abstract 7001.