14 November 2018

Combining a chemotherapy drug with immunotherapy yielded “promising” results for people with relapsed or refractory acute myeloid leukaemia (AML), a US-based phase II study has reported.

The study, published in the journal Cancer Discovery last week, tested a combination of azacitidine, the standard-of-care chemotherapy drug, and nivolumab, an immune checkpoint inhibitor. Amongst the 70 patients, there was an overall response rate of 33%, with 22% in complete remission.

The combination was found to be particularly effective in patients who had not previously received hypomethylating agents (HMAs) such as azacitidine or decitabine, with an overall response rate of 52% amongst these patients.

Dr Naval Daver, associate professor of leukaemia at The University of Texas MD Anderson Cancer Center, said: “In addition, bone marrow samples taken prior to treatment indicated a higher frequency of pre-therapy bone marrow CD3 and CD8 cells predicted for response to therapy.

 “In particular, CD3 appeared to have a high sensitivity and specificity rate for predicting response, indicating it might serve as a reliable biomarker for selecting patients for this combination therapy.”

The 70 patients taking part in the trial were given azacitidine intravenously or subcutaneously, while nivolumab was given as an infusion. The majority were successfully treated, although 11% of patients experienced severe or potentially life-threatening side effects.

Overall survival in all patients was 6.3 months, and survival in first relapsed patients was 10.6 months – double the observed survival with azacitidine alone in similar patients at MD Anderson, the researchers report.

Azacitidine is approved in both the USA and Europe to treat myelodysplastic syndrome and is approved in Europe for treating older patients with newly diagnosed AML.

HMAs, such as azacitidine, promote anti-tumour signalling and dampen anti-tumour immunity by increasing expression of immune checkpoint antibodies PD-1 and PD-L1 in AML and other cancers.

Dr Daver said that over the past ten years, six immune checkpoint inhibitor antibodies have been approved in the USA and Europe, for more than 25 indications in 10 tumour types.

 “However, single agent PD-1 antibodies have shown little effect in patients with relapsed AML or high-risk MDS. This study was designed to assess whether the addition of nivolumab to azacitidine was safe and effective,” he added.

A randomised phase III study has now begun to test the combination in the frontline setting for people with AML.

"We believe that implementation of clinical and immune biomarkers to select patients are likely to yield further improved outcomes with these types of therapies in AML," added Dr Daver.

Source: Daver, N., Garcia-Manero, G., Basu, S., Boddu, P.C., Alfayez, M., Cortes, J.E., Konopleva, M., Ravandi-Kashani, F., Jabbour, E., Kadia, T.M., Nogueras-Gonzalez, G.M., Ning, J., Pemmaraju, N., DiNardo, C.D., Andreeff, M., Pierce, S.A., Gordon, T., Kornblau, S.M., Flores, W., Alhamal, Z., Bueso-Ramos, C., Jorgensen, J.L., Patel, K.P., Blando, J., Allison, J.P., Sharma, P., Kantarjian, H. (2018) “Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Non-randomized, Open-label, Phase 2 Study”, Cancer Discovery, available at doi: 10.1158/2159-8290.CD-18-0774


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