ADC Plus Low-Intensity Chemo Promising in Older Patients With B-Cell ALL

The antibody-drug conjugate (ADC) inotuzumab ozogamicin (Besponsa) combined with low-intensity chemotherapy — with or without blinatumomab (Blincyto) — showed promise in older patients with newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic leukemia (ALL), according to results from a phase II trial.

Among 80 patients at a median follow-up of 92.8 months, the median progression-free survival (PFS) was 40.9 months (95% CI 37.0-60.92), while the 2- and 5-year PFS rates were 58.2% (95% CI 46.7-68.2) and 44.0% (95% CI 31.2-54.3), respectively, reported Elias Jabbour, MD, 0f the University of Texas MD Anderson Cancer Center in Houston, and colleagues.

Given that the 5-year PFS rate represented “a significant improvement” over the historical 2-year PFS rate of 30% previously reported in older patients, the authors concluded the study met its primary outcome measure in Lancet Haematology.

Median overall survival (OS) was 45.0 months (95% CI 38.8-62.1), while the 2-year OS rate was 63.6% (95% CI 51.9-73.3) and the 5-year OS rate was 46.0% (95% CI 33.6-58.0).

“Further refinement of the regimen to reduce or omit conventional chemotherapeutic agents while maximizing the benefit of targeted agents might improve outcomes and tolerability even in patients aged 70 years or older,” Jabbour and team wrote.

In an accompanying commentary, Emily Curran, MD, of the University of Cincinnati Cancer Center in Ohio, agreed that the study “provides impressive results, with survival outcomes that far exceed historic survival data in older adults with acute lymphocytic leukemia.”

Upcoming randomized trials comparing the regimen to hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) — the current standard of care — could establish it as a new standard, she added.

In explaining the rationale for the study, Jabbour and colleagues pointed out that older patients with B-cell ALL are likely to have worse outcomes than their younger peers due to adverse disease biology and their inability to tolerate intensive chemotherapy.

However, treatment options for B-cell ALL have improved with the introduction of targeted agents, such as inotuzumab ozogamicin (an ADC targeting CD22) and blinatumomab (a bispecific T-cell engager therapy directed against CD19).

Early data from this trial showed that inotuzumab ozogamicin in combination with low-intensity chemotherapy was active in older patients. In this follow-up, Jabbour’s group assessed whether the addition of blinatumomab to inotuzumab ozogamicin would further improve outcomes in this older population.

In the first part of the trial, 80 older patients (median age 68 years, 60% men) had been treated with a decreased-intensity hyperCVAD-based backbone (mini-hyper-CVD), which omitted anthracyclines, limited intrathecal chemotherapy, and dose reduced cyclophosphamide, dexamethasone, and methotrexate. Inotuzumab ozogamicin was added to each of the first four cycles.

From patient 50 on, the study protocol was amended, substantially reducing the overall amount of chemotherapy administered during the consolidation and maintenance phases while incorporating sequential blinatumomab therapy.

As for the impact of adding sequential blinatumomab to the inotuzumab ozogamicin/chemotherapy regimen, at a median follow-up of 104.4 months for the patients treated before the protocol amendment and 29.7 months for those treated after, median PFS did not differ significantly (34.7 vs 56.4 months, P=0.77).

“Although we did not yet see an improvement in survival with the addition of blinatumomab, the shorter follow-up of blinatumomab-treated patients compared with patients without blinatumomab exposure might explain this result,” the authors suggested, adding that further follow-up will be needed to see the benefit of added blinatumomab.

Jabbour and colleagues also categorized patients into three groups based on age — 60-64, 65-69, and 70 and older. Median PFS was 70.2 months in those 60-64, 46.6 months in those 65-69, and 34.2 months in those 70 and older, while median OS was 75.2 months, 46.6 months, and 34.7 months, respectively.

After combining patients in the 60-64 and 65-69 age groups, and comparing them with those 70 and older, median PFS was 60.4 months versus 34.2 months (P=0.27), and median OS was 69.0 months versus 34.7 months (P=0.17).

The most common grade 3/4 adverse events were thrombocytopenia (78%) and febrile neutropenia (32%). Six patients developed hepatic sinusoidal obstruction syndrome.

At the time of data cutoff, 47 patients had died, with 67% of deaths in patients ages 60-69 and 85% in those ages 70 and older occurring in remission.

This “suggests that even the less-intensive chemotherapy backbone used in this trial might still be too intensive for older adults with acute lymphocytic leukemia,” Curran observed in her commentary, adding that further reductions in chemotherapy intensity will likely be warranted.

In fact, Jabbour and team noted that their trial is continuing to enroll patients with ongoing protocol modifications, enabling participants 70 and older to be treated with a “near chemotherapy-free approach” of inotuzumab ozogamicin, blinatumomab, vincristine, and dexamethasone.