CancerNetwork® Inaugural Face-Off - Episode 3

HyperCVAD in Frontline ALL

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Nikesh Shah, MD, explains a key trial evaluating the efficacy and toxicity of hyper-CVAD in acute lymphocytic leukemia (ALL).

Nikesh Shah, MD: On the note of induction therapy, let’s talk a little about the original hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone] in ALL [acute lymphocytic leukemia] trial by Dr [Hagop] Kantarjian and colleagues from [The University of Texas] MD Anderson [Cancer Center] published in JCO [Journal of Clinical Oncology] in 2000. Prior to hyper-CVAD, long-term disease-free survival for patients with ALL was less than 40%. Hyper-CVAD is a pediatric-inspired protocol. This was a phase 2 single-arm trial evaluating the efficacy and toxicity of hyper-CVAD in patients with ALL. They enrolled newly diagnosed patients with ALL aged 15 years and older. You couldn’t have any second malignancy, as expected. You couldn’t have HIV. It’s important that they didn’t exclude patients for performance status, organ function, or active infection, which helps to simulate real-world scenarios.

Patients were planned to receive a total of 8 cycles of hyper-CVAD. Hyper-CVAD was given on odd cycles. High-dose methotrexate and cytarabine were given on even cycles. Patients also received intrathecal CNS [central nervous system] prophylaxis. After induction therapy, patients with Ph [Philadelphia chromosome]–positive disease went on to allogeneic transplant in CR [complete response]. Patients with mature B-ALL [Burkitt-type acute lymphoblastic leukemia] didn’t receive any maintenance therapy. All other patients were planned to receive 2 years of POMP [6-mercaptopurine, vincristine, methotrexate, prednisone] maintenance. They enrolled 204 patients, and 91% of patients achieved CR. Median duration of CR was 33 months. Median overall survival for the whole cohort was 35 months. Five-year survival was 39%.

In multivariate analysis, age, initial platelet count, and Ph-positive status were associated with CR duration and overall survival. We’re well-aware of toxicities associated with hyper-CVAD, including myelosuppression, infection in over a quarter of patients, and fever in about 50% of patients. In the total follow-up period, 53% of the patients died. Twelve of these patients died during induction therapy. All deaths were attributed to infection. Most of the patients who passed away were older patients. In general, for patients aged 60 or older, the induction mortality rate was 16%. Of the patients who achieved CR, 11 died in CR from treatment-related infection.

Overall, this was a well-designed study. They had wide inclusion criteria with few exclusions, helping simulate real-world patients. The few weaknesses I can mention include that it was a single-arm study. They used a historical cohort comparison with VAD [vincristine, doxorubicin, dexamethasone], but we know that historical cohorts have inherent bias to them. As much as we try to account for other variables, we can’t, so it would be nice to see a randomized trial of hyper-CVAD compared with something else. This is an impactful trial and regimen. This is arguably still the standard of care therapy for patients with ALL over 20 years out from the initial trial publication. It was interesting to go back and see how this trial was conducted and what the data show.

Transcript edited for clarity.