Novel drugs expand treatment options for ALL patients

11 Sep 2016

Three novel frontline regimens for acute lymphoblastic leukemia (ALL) produced high rates of complete response in separate small clinical trials.

Arzerra achieved complete remission in ALL patients

Adding the anti-CD20 antibody ofatumumab (Arzerra) to hyperfractionated CVAD (hyper-CVAD) chemotherapy led to complete responses in 49 of 50 evaluable patients with CD20-positive, Philadelphia chromosome (Ph)-negative ALL. The 2-year persistence for complete responses was 74%, and 2-year overall survival was 83%, Ghayas Issa, MD, of the MD Anderson Cancer Center in Houston, and colleagues reported.

The study involved a total of 53 patients, 49 with newly diagnosed Ph-positive ALL and four who had received a single course of therapy. All the patients received eight cycles of hyper-CVAD, alternating with methotrexate and cytarabine. Ofatumumab was administered during the first four cycles. Primary therapy was followed by 30 months of standard maintenance therapy and intensification therapy at 6 and 18 months.

  • The 49 patients who achieved complete remission did so after the first cycle of therapy. Of 52 evaluable patients, 48 achieved minimal residual disease (MRD)-negative status.
  • The median time to MRD negativity was 0.7 month.
  • The median time to neutrophil and platelet recovery was 19 and 21 days, respectively.

Complete response rate of 100% reached with ponatinib treatment

A 55-patient study of untreated Ph-positive ALL showed that the addition of ponatinib (Iclusig) to hyper-CVAD led to a first-cycle complete response rate of 100% in 51 evaluable patients. Additionally, 43 of 47 evaluable patients achieved complete cytogenetic response. Flow cytometry assessment after a median treatment duration of 3 weeks showed that 51 of 52 (98%) evaluable patients had achieved MRD-negative status, Koji Sasaki, MD, also of MD Anderson, and colleagues reported.

After a median follow-up of 38 months, 43 patients remained alive, 40 in first complete remission and three in second complete remission. Eight patients died while in complete remission.

Grade ≥3 toxicity consisted of infection during induction in 47% of patients, transaminitis in 34%, hyperbilirubinemia in 19%, pancreatitis in 19%, elevated amylase/lipase in 15%, skin rash in 15%, and hypertension in 15%. Four patients had thrombotic events and three had myocardial infarctions. No vascular events occurred following a protocol amendment to optimize ponatinib dosing.

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Marquibo for patients with mixed forms of untreated ALL

Sasaki and colleagues also evaluated hyper-CVAD with liposomal vincristine (Marquibo, hyper-CMAD) in 29 patients with mixed forms of untreated ALL. Patients with Ph-positive ALL received a tyrosine kinase inhibitor, and patients with CD20-positive disease also received rituximab (Rituxan). Approved as salvage therapy for relapsed/refractory ALL, liposomal vincristine was designed to reduce neurotoxicity associated with conventional vincristine, which has curative potential for ALL, and increase dose intensity.

The analysis of the results showed that:

  • Hyper-CMAD therapy resulted in complete responses in 28 of 29 (97%), and the remaining patient died early in the course of treatment.
  • Other response data included complete cytogenetic response in 24 of 24 evaluable patients, MRD negativity in 25 of 28 (89%), and complete molecular response in 17 of 18 (94%) evaluable patients.
  • After a median follow-up of 22 months, 20 patients remained alive, including three with disease relapse.
  • The 2-year rate of complete remission and overall survival (OS) were 86% and 60% respectively.

The most common grade 3/4 adverse events were infection (81%), hypokalemia (48%), hyperglycemia (41%), hypophosphatemia (37%), and hypocalcemia (22%). Peripheral neuropathy occurred in 15% of patients.

Combining a novel agent with reduced-intensity chemotherapy for older ALL Patients

The combination of the antibody-drug conjugate inotuzumab ozogamicin and less intensive chemotherapy led to a cycle 1 response rate of 100% in 41 older patients with newly diagnosed Ph-positive ALL. The overall response rate included MRD-negativity in 30 of 40 (75%) evaluable patients, who had a median age of 67. After a median follow-up of 24 months, the cohort had a 2-year relapse-free survival and overall survival of 62% and 67%, respectively, Nicholas J. Short, MD, of MD Anderson, and colleagues reported.

In general, older patients with ALL have a poor prognosis, associated with an induction mortality of 10%, mortality in complete remission of 35%, median overall survival of 15 months, and 3-year overall survival of 20%. Investigators hypothesized that combining a novel agent, such as the CD22-targeted conjugate inotuzumab, with reduced-intensity chemotherapy (mini-hyper-CVD) might improve outcomes.

Grade 3/4 adverse events included prolonged thrombocytopenia (74%), infection during consolidation (74%), infection during induction (53%), hyperglycemia, (50%), hypokalemia (37%), transaminase elevations (24%), and hyperbilirubinemia (21%). The incidence of veno-occlusive disease was 5%.

Source: MedPage Today
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