Inotuzumab ozogamicin combined with a low-intensity chemotherapy called mini-hyper-CVD achieved highly encouraging results in older patients with acute lymphoblastic leukemia (ALL) in a phase II study reported at the 56th Annual Meeting of the American Society of Hematology.¹ After the presentation, oncologists used words like “phenomenal” and “marvelous” to describe the results.

“This combination is safe and highly effective in newly diagnosed ALL in older patients. The overall response rate was 96%, the early mortality rate was very low, and the 1-year overall survival is 81%. Early results compare favorably with our previous experience using hyper-CVAD,” stated lead author Elias ­Jabbour, MD, of The University of Texas MD Anderson Cancer Center, Houston. “This combination may become a new standard for elderly patients with newly diagnosed ALL.”

Regimen Components

Mini-hyper-CVD is a lower intensity regimen than conventional hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine). Cyclophosphamide and dexamethasone were given at a 50% dose reduction; methotrexate was given at a 75% dose reduction; and cytarabine was given at an 83% dose reduction. No anthracycline was included in the regimen.

Inotuzumab ozogamicin was given on day 3 of the first four courses; rituximab (Rituxan) was given on days 2 and 8 for the first four courses for CD20-positive patients; and intrathecal chemotherapy was given on days 2 and 8 to prevent CNS relapse.

Study Findings

Previously reported with hyper-CVAD, 1-year survival was 60%, and in this study, with low-intensity chemotherapy and inotuzumab ozogamicin, it was 81%, he said.

Inotuzumab ozogamicin is a humanized monoclonal antibody that binds to CD22; is rapidly internalized; and delivers calicheamicin, a potent cytotoxic agent that binds to DNA and causes double-strand DNA breaks leading to apoptosis.

This is the first study of inotuzumab ozogamicin in ALL patients over the age of 60. These patients typically have worse outcomes, primarily due to poor tolerance to intensive chemotherapy and inability to tolerate full doses of chemotherapy due to comorbidities.

A previous study by Dr. Jabbour and colleagues found that single-agent inotuzumab ozogamicin achieved an overall response rate of 58% and a median survival of 6.3 months in 89 heavily pretreated patients with relapsed ALL.^2,3 The present study was designed to look at the combination of inotuzumab ozogamicin with chemotherapy.

Results of the phase II study were based on 28 evaluable patients enrolled between April 2012 and September 2014. Patients were at least 60 years of age with untreated Philadelphia chromosome–negative, B-cell acute lymphoblastic leukemia. The median age was 69 years, and the oldest patient was 79 years old.

At the time of the presentation, the overall response rate was 96%; 21 patients were in complete remission, and 5 were in complete remission with incomplete platelet recovery. No deaths were reported in the first 4 weeks of treatment. Currently, Dr. Jabbour told The ASCO Post, 21 remain alive: 1 post allogeneic stem cell transplantation, 17 on maintenance therapy, and 3 receiving consolidation therapy.

Complete cytogenetic response was 100% in 14 patients with an abnormal karyotype; all of these patients achieved minimal residual disease by color flow cytometry. Overall, 77% of patients tested negative for minimal residual disease at complete remission. The median time to platelet recovery was 23 days in cycle 1 and 22 days in subsequent courses of therapy.

Grade 3 and 4 toxicities included infections during induction therapy in about 50% of patients; during consolidation therapy, grade 3 and 4 toxicities occurred in about 75% of patients. One patient in complete remission developed grade 2 venous occlusive disease and was switched to hyper-CVD plus ofatumumab (Arzerra).

At a median of 15 months, one death was reported in a patient with primary refractory disease. Two responding patients experienced a relapse and died, and two other patients in complete remission died. Three patients are receiving consolidation therapy, and 17 are on POMP (mercaptopurine, methotrexate, vincristine, prednisone) maintenance. The median overall survival has not yet been reached. One-year median progression-free survival is 88%, and 1-year overall survival is 81%. ■

Disclosure: Dr. Jabbour has received research grants from Pfizer.

References

1. Jabbour E, O’Brien S, Thomas DA, et al: Inotuzumab ozogamicin in combination with low-intensity chemotherapy (mini-hyper-CVD) as frontline therapy for older patients (≥ 60 years) with acute lymphoblastic leukemia (ALL). ASH Annual Meeting. Abstract 794. Presented December 9, 2014.

2. Kantarjian H, Thomas D, Jorgensen J, et al: Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia. Lancet Oncol 13:403-411, 2012.

3. Kantarjian H, Thomas D, Jorgensen J, et al: Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia. Cancer 119:2728-36, 2013.