Chemotherapy-free induction, consolidation therapy induces molecular response in Ph+ ALL
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A chemotherapy-free first-line treatment strategy led to high rates of molecular response and survival among a subset of adults with acute lymphoblastic leukemia, according to study results published in The New England Journal of Medicine.
Researchers evaluated the treatment, which consisted of induction with dasatinib (Sprycel, Bristol Myers Squibb), a second-generation inhibitor of the ABL tyrosine kinase, and consolidation with blinatumomab (Blincyto, Amgen), a bispecific anti-CD19 and anti-CD3 monoclonal antibody, among adults with Philadelphia chromosome-positive ALL. Results of the phase 2 study also showed few grade 3 or higher toxic effects of this therapy, which was based on a targeted and immunotherapeutic strategy.
The prognosis of adults with Philadelphia chromosome-positive (Ph+) ALL has improved greatly since the approval of ABL-specific tyrosine kinase inhibitors (TKIs), with many patients achieving complete hematologic response with or without systemic chemotherapy.
“Our TKI-based approach without systemic chemotherapy for front-line induction for these patients goes back about 15 years,” Robin Foá, MD, professor of hematology and head of the division of hematology at Sapienza University of Rome in Italy, told Healio. “It started with imatinib (Gleevec, Novartis), then it went to masitinib (AB Science) and then ponatinib (Iclusig, Takeda/Millennium Pharmaceuticals). The bottom line was that, through this approach, you could achieve hematologic complete responses in 94% to 100% of patients, irrespective of age.
“Importantly, the toxicity was very limited, and the deaths were close to zero,” Foá added. “Here, we extended this approach by adding a consolidation with the bispecific antibody blinatumomab.”
The GIMEMA cooperative trial group has adopted a chemotherapy-free induction strategy that involves prephase treatment with glucocorticoids for a 7-day period. Patients with Ph+ ALL then undergo an induction phase of TKIs with glucocorticoids and central nervous system prophylaxis, but with no systemic chemotherapy. This regimen results in complete hematologic responses among 94% to 100% of patients regardless of age, with very few deaths during the induction phase, according to study background.
For the GIMEMA LAL2116 D-ALBA trial, Foà and colleagues assigned 63 patients (median age, 54 years; range, 24-82; 54% women) with newly diagnosed Ph+ ALL to first-line therapy with dasatinib in combination with glucocorticoids, followed by two cycles of blinatumomab.
Sustained molecular response in the bone marrow after treatment served as the study’s primary endpoint.
Nearly all patients (98%) patients achieved complete remission.
At the end of dasatinib induction therapy at day 85, 29% of patients demonstrated a molecular response. This increased to 60% after two cycles of blinatumomab, 70% after three cycles and 81% after four cycles, with a rate of 72% after the fifth cycle.
After median follow-up of 18 months (range, 1-25), results showed an OS rate of 95% (95% CI, 90-100) and a DFS rate of 88% (95% CI, 80-97). The probability of DFS was 100% among patients who achieved molecular response at the end of induction therapy, compared with 85% among patients without a molecular response.
DFS among patients with no IZKF1 deletions was 100% (95% CI, 100-110), with lower rates observed among patients with IKZF1 deletion alone (92%; 95% CI, 79-100) or with other genetic aberrations, which included CDKN2A or CDKN2B, PAX5 or both (64%; 95% CI, 41-100).
Researchers observed ABL1 mutations in six patients who had increased minimal residual disease during induction therapy. Blinatumomab cleared all these mutations.
Six relapses occurred, for a cumulative incidence of relapse of 8% (95% CI, 8-8).
Sixty adverse events occurring, including 21 of grade 3 or higher. These included cytomegalovirus reactivation or infection (n = 6), neutropenia (n = 4) and persistent fever (n = 2).
Twenty-four patients received stem-cell allografts, including one who died of transplantation-related causes.
“In our protocol, blinatumomab was given to all patients, including those who were minimal residual disease negative,” Foá told Healio. “This combination could be widely used if the drugs were to be available because it is not toxic, it reduced hospitalization, induces high molecular response and is doable at all ages. In addition, the transplant data, though not an endpoint, are extremely promising with a very low transplant-related mortality.”
The results of this change in treatment approach raise many questions, Dieter Hoelzer, MD, PhD, professor of internal medicine at University of Frankfurt in Germany, wrote in an accompanying editorial.
“Will the excellent outcomes be preserved with longer follow-up? The answer is probably yes, given that the majority of relapses in ALL occur within the first 1.5 to 2 years after the initiation of treatment,” Hoelzer wrote. “Will there be a difference in long-term outcomes between patients who do not undergo transplantation and those who do? Will ABL1 mutations, including T315I, emerge, and will minimal residual disease recur with longer follow-up? Can this overall approach in Ph+ ALL be used in patients with other subtypes of ALL, such as Ph-negative, B-lineage ALL or even T-cell ALL?
“If these promising trial results hold, chemotherapy-free induction without the immediate and long-term toxic effects of intensive chemotherapy regimens could also be used in adolescents and, finally, in children,” he added. “These questions will need to be addressed with longer follow-up and large, prospective trials.”
For more information:
Robin Foà, MD, can be reached at rfoa@bce.uniroma1.it.
References:
- Foà R, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2016272.
- Hoelzer D. N Engl J Med. 2020;doi:10.1056/NEJMe2027937.
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