A new treatment option may be on the horizon for patients with the 17p deletion subtype of relapsed or refractory chronic lymphocytic leukemia (CLL), an ultra-high risk subtype with a poor prognosis (<12 months with frontline chemoimmunotherapy) and limited treatment options. Results presented by Stephan Stilgenbauer, MD, PhD, University of Ulm, Ulm, Germany, showed a high overall response rate (ORR) of nearly 80% and sustained remission with venetoclax monotherapy in the pivotal, international, single arm, phase 2 study.
Previously, the first-in-human study with venetoclax demonstrated a 79% ORR in relapsed or refractory CLL with the oral, selective BCL2 inhibitor [Roberts AW et al. N Engl J Med 2015
For the present study, 17p deletion was confirmed by a central laboratory, and patients were required to have an Eastern Cooperative Oncology Group score ≤2 and a creatinine clearance ≥50 mL/min. Patients who had a previous allogenic stem cell transplantation (SCT) were excluded.
The 107 study patients received oral venetoclax once daily, with escalating doses from week 1 to week 5 to reach the target dose, starting at 20 mg on Day 1 and 50 mg on Day 2, and thereafter increasing to 50 mg, 100 mg, 200 mg, and 400 mg. Prophylaxis against tumor lysis syndrome (TLS) was also given.
The efficacy analyses were prespecified for Week 36 or when there was disease progression or treatment was permanently discontinued. Physical examinations and blood counts occurred monthly, and a computed tomography (CT) scan was prespecified for Week 36. A clinical response was confirmed by CT and bone marrow biopsy.
The baseline characteristics of the patients are outlined in Table 1. Fifty-one percent had an absolute lymphocyte count (ALC) ≥25 x 109/L, leading to 42% being categorized as high-risk for TLS.
The median time on study was 12.1 months and 70 patients remained on active treatment. Of the 37 patients who discontinued treatment, 22 had disease progression (CLL in 11 patients) and 3 underwent SCT. Eighteen patients died, 14 of whom dies from disease progression. Nine patients stopped treatment because of adverse events. Of the 107 patients evaluated, 79.4% responded to venetoclax monotherapy, including 8 patients (7.5%) who experienced a complete response (CR) or a CR with incomplete marrow recovery (CRi). Most patients experienced a deep response, according to Prof. Stilgenbauer, as shown by the high levels of response to treatment (Table 2). The median time to first response was 0.8 months (range, 0.1-8.1 months) and the median time to CR/CRi was 8.2 months (3.0-16.3 months).
No CLL was found in the bone marrow of 25 of 48 patients, and 18 of 45 patients were negative for minimal residual disease (MRD) in peripheral blood. Amongst the 87 patients who had lymphocytosis at baseline, only 4 did not have normalization of ALC levels to <4 x 109/L. The median time to normalization was 22 days (range, 2-122). The response to venetoclax was durable, with 84.7% of all responders continuing to respond to treatment at 12 months, and 100% of patients with a CR, CRi, or nodal partial response continuing to respond, and 94.4% of patients with MRD-negativity. The 12-month estimates for progression free survival was 72% and 86.7% for OS. The most common treatment-emergent adverse events were neutropenia (43%), diarrhea (29%), and nausea (29%), while thrombocytopenia occurred in 19% of patients. Grade 3/4 neutropenia occurred in 40% of patients, and 22.4% of patients had neutropenia at baseline. Infections occurred in 72% of patients, 20% of whom had grade ≥3 infection, most commonly upper respiratory (15%, nasopharyngitis (14%), and urinary tract (9%). Laboratory TLS was found in 5 patients during the dose escalation period, but only 2 patients had a dose interruption which lasted only 1 day, while there as no clinical TLS. Serious adverse events occurred in 55% of patients, most commonly pyrexia in 7%.
Deep clinical responses with an acceptable level of toxicity was achieved with venetoclax monotherapy, with a >10% CR, CRi, and nPR conformed by the independent committee and MRD negativity in more than 20% of responders. There was no clinical TLS and neutropenia and infection were similar to that with frontline chemoimmunotherapy, suggesting a favorable risk-benefit profile. Venetoclax may be a beneficial treatment option for patients with 17p-CLL, alone or combined with other novel treatments. Data from this and the previous study have been submitted to the regulatory authorities in the United Stated and Europe seeking approval of this drug for this indication.
Source: ASH 2015,