TKI/BiTE Combo Extends Survival of Older Patients With Ph+ALL

Neil Osterweil

December 14, 2021

ATLANTA — Older patients with acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL) are often not fit enough to withstand intensive chemotherapy and stem cell transplants, but remissions with alternative therapies are usually short lived.

Now, results from an ongoing study suggest that the combination of the tyrosine kinase inhibitor (TKI) dastatinib (Sprycel) with the bispecific T-cell engager (BiTE) blinatumomab (Blincyto), together with prednisone, may significantly improve remission rates and prolong both progression-free and overall survival among older and/or less fit patients with Ph+ALL.

The new results were reported by investigators in the SWOG Cancer Research Network and come from a cohort of 25 patients with a median age of 73 years with newly diagnosed Ph+ALL or ALL with dasatinib-sensitive fusions of mutations (Ph-like ALL).

Nearly all (23 of 25 patients, 92%) had complete remissions, and 5 of 16 patients for whom minimal residual disease (MRD) data were available were MRD-negative at day 28, said Anjali Advani, MD, from the Cleveland Clinic in Cleveland, Ohio.

At a median follow-up of 1.7 years, the estimated 3-year disease-free survival rate was 80%, and the estimated overall survival rate was 85%, the investigators reported in a poster presentation here at the American Society of Hematology 2021 Annual Meeting.

"I think the biggest question will be longer-term follow-up. We clearly see high remission rates in this population, but the issue is whether in these elderly patients who are not candidates for chemo we can prolong remission by the addition of other treatments, such as blinatumomab," she said in an interview with Medscape Medical News.

"The follow-up is reasonable at this point, and as we get longer follow-up, if the current 3-year survival estimates hold up, that would be very encouraging," she said.

Early Promise

A leukemia specialist who was not involved in the study told Medscape Medical News that the results are promising, but added that it's too early to make definitive judgments about the efficacy of the combination.

"People have used just a tyrosine kinase inhibitor and prednisone in these patients and gotten remissions, but they just don't last," said Peter Emanuel, MD, from CHI St. Vincent Infirmary in Little Rock, Arkansas.

"The promise with this approach is that you're getting a longer-lasting remission ― maybe not a cure, but a longer-lasting remission ― without having to use intensive chemotherapy," he said.

"It's still a pretty small study, so I think this is going to require a bigger trial, looking at more patients, but it's certainly very encouraging and very promising," he added.

Hanno Hock, MD, PhD, a leukemia researcher at the Mass General Cancer Center in Boston, Massachusetts, told Medscape in an interview that "the whole idea here is to add this newer agent, blinatumomab, to make those good initial responses more durable, and it looks like it is able to do that with very impressive initial data," he said.

"The caveat is that this is still early, and one needs to wait and see how it all pans out, but it's very well tolerated, and definitely the next logical step in trying to offer something to people who cannot tolerate more aggressive therapy such as transplant," Hock added.

Study Results

The new results come a feasibility cohort of patients enrolled in the SWOG S1318 trial, which studied blinatumomab plus chemotherapy and prednisone in older patients with Ph-ALL, as well as blinatumomab, dasatinib, and prednisone in older adults with Ph+ ALL.

Patients 65 and older with newly diagnosed or relapsed/refractory Ph+ALL or Ph-like ALL and no central nervous system disease were eligible for the arm of the trial described here. All patients with data reported in this analysis had newly diagnosed ALL.

Patients first received a single induction cycle of dasatinib and prednisone and were then evaluated for response. Patients with a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) would them undergo prednisone tapering while continuing dasatinib until day 84. Patients without a CR or CRi at day 28 who had remissions by day 56 then also continued dasatinib until day 84.

Those patients still in remission at day 84 went on to three cycles of blinatumomab and dasatinib, followed by dasatinib and prednisone maintenance until unacceptable toxicity or disease progression. Patients may remain on maintenance for up to 10 years after registration.

Patients who do not have a CR or CRi by day 84 can receive reinduction with up to two total cycles of blinatumomab, with those who get a remission moving on to the blinatumomab/ dasatinib combination and those who do not going off protocol.

Of the 25 patients, 23 had a CR following dasatinib/prednisone induction. As noted, 5 of 16 patients evaluable for MRD were MRD-negative.

Four patients did not receive postremission therapy, two because of adverse events, one who went on to transplant, and one because of insurance issues.

In a safety review early in the study, 4 of 12 evaluable patients were found to have dose-limiting toxicities, including one case each of grade 3 dyspnea and gastrointestinal pain (in a single patient), hypertension, dyspnea, and hyperglycemia.

These adverse events were deemed acceptable by both US Food and Drug Administration and National Cancer Institute reviewers, and this arm of the study was allowed to continue, Advani noted.

The study was funded by grants from the National Institutes of Health. Advani disclosed financial relationships with several companies. Emanuel and Hock have disclosed no relevant financial relationships.

American Society of Hematology 2021 Annual Meeting: Abstract 3397. Presented December 13, 2021.

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.

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