Expert Discusses Promising Efficacy of Oral Azacitidine in High-Risk Lymphoma

Peter Martin, MD

Peter Martin, MD

While most patients with diffuse large B-cell lymphoma (DLBCL) are cured with standard R-CHOP, 30% to 40% of cases report chemotherapy resistance. In an attempt to counter chemo-resistant DLBCL, Peter Martin, MD, along with several other colleagues at Weil Cornell Medicine, set out to test alternative therapies for such patients with a phase I, open-label, multicenter trial of oral azacitidine (Vidaza) plus R-CHOP in people with high-risk, previously untreated DLBCL, grade 3B follicular lymphoma, or transformed lymphoma.

“We have been up and down, backwards and forwards trying to overcome chemotherapy resistance in these patients…we purposely selected a group of very high-risk lymphoma patients and found promising results,” said Martin, an associate professor at Weil Cornell Medicine.

During an interview withTargeted Oncology, Martin discussed the findings of this study and the implications it could have for the future treatment of patients with chemotherapy resistant DLBCL.

TARGETED ONCOLOGY:Can you give some background on this study?

Martin: Unfortunately, about 30% to 40% of people with DLBCL are not cured with standard R-CHOP chemotherapy because they have chemotherapy resistance. Data from Ari Melnick, MD, Rita Shaknovich, MD, PhD, and Leandro Cerchietti, MD, at Weill Cornell Medicine have suggested that one reason for chemotherapy resistance is aberrant DNA methylation, or changes in the way the genes in the DNA are turned on or off in the tumor. They demonstrated as well that chronic low-dose exposure to demethylating agents, such as azacitidine, can potentially reverse that chemotherapy resistance by turning genes back on.

We previously did a phase I trial with subcutaneous azacitidine in combination with R-CHOP and we found that 11 out of 12 high-risk patients had a complete response (CR). But, the subcutaneous dosing of it was a little inconvenient for patients and there were some side effects. When oral azacitidine began to be developed, we realized that if we want to maximize chronic longer-term low-dose exposure to azacitidine, oral dosing was going to be the way to do it. Thus, we designed a phase I trial to combine lose-dose oral azacitidine in combination with R-CHOP in people with high-risk DLBCL.

TARGETED ONCOLOGY:How was the study designed and what were the findings?

Martin: Overall, we enrolled 33 patients to the dose escalation phase of the trial and there were 59 patients in total. At the 2017 ASH Annual Meeting, we presented data from the first 33 people in the dose escalation phase. They were treated with 100 mg, 150 mg, 200 mg, or 300 mg of oral azacitidine. The majority were treated with 200 mg or 300 mg. Every patient received 7 days of oral azacitidine prior to the first cycle of R-CHOP and 14 days of oral azacitidine prior to cycles 2 through 6. All patients received granulocyte-colony stimulating factor (G-CSF) on day 2 of each cycle of R-CHOP.

We found that we could deliver the treatment as planned and the majority of patients did not require dose modifications. Only 1 person was not able to receive all 6 cycles of oral azacitidine and only 1 patient did not receive all 6 cycles of R-CHOP. Overall, the treatment was pretty well tolerated. We had expected to find some nausea and vomiting and I think, because we had designed the study to try to prevent that by giving oral antiemetics, we were pretty effective there. We did find that there were some myelosuppression. There was a 70% rate of grade 3 and 4 neutropenia and 24% of patients had grade 3 or 4 febrile neutropenia.

Nonetheless, it was a pretty well-tolerated regimen and it was effective. Ninety-seven percent of patients had a response, and 85% of patients had a CR. Four patients had a partial response, although 2 of those we realized later were a CR. In total, about 90% of patients had a CR, and this is not 90% of DLBCL, this is 90% of higher-risk DLBCL patients. Overall, we have a promising efficacy with [azacitidine].

Obviously, when you are doing a study like this it is nice to have additional data that tells you that you’re on the right track. We did that through correlative science. Dr. Cerchietti at Cornell headed the correlative studies from the whole trial. We received plasma samples pre- and post-cycle 1 azacitidine. Additionally, at Cornell we did tumor biopsies prior to the start of azacitidine and after one week of azacitidine, before starting R-CHOP. The Cerchietti lab found exposure to the oral azacitidine resulted in hypomethylation genome-wide and also in very specific genes that we think are responsible for chemotherapy resistance. Not only were those genes hypomethylated following exposure to oral azacitidine, they were also re-expressed. The drug did exactly as we wanted it to do and what we had expected it to do.

Additionally, we found in the plasma samples that there was an increase in secretion of interferon lambda, suggesting that there is an antiviral response that is being induced by it. There is an immune response that is being induced by interferon lambda that may also help to kill some of the resistant tumor cells.

TARGETED ONCOLOGY:What are the next steps with this study?

Martin: Now, we have 10.6 months of follow up with the study. In those 10.6 months of median follow up, only 1 patient has progressed. Obviously, this is pretty promising, but it is still early. Additionally, we treated a total of 59 patients and I think for a little while we need to follow up [with these patients]. Probably by early next year we will have sufficient follow-up from all 59 patients to have a good estimate of a 1-year progression free survival rate. That should give us an idea of how effective this regimen is and we can compare those to historical controls. If it continues to look as promising as we think it will, then I think that you could take this kind of regimen forward into a phase III trial.

TARGETED ONCOLOGY:What do the results of this study say for patients who have poor outcomes?

Martin: People with high-risk DLBCL unfortunately have poor outcomes with R-CHOP chemotherapy. Not only that, they have poor outcomes with R-EPOCH (rituximab plus etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin) and obinutuzumab plus CHOP chemotherapy. We have been up and down, backwards and forwards trying to overcome chemotherapy resistance in these patients. So far, with the exceptions of a few trials that are ongoing where we don’t have the results, all attempts have failed. We purposely selected a group of very high-risk lymphoma patients and found promising results. This represents a real hope that we might finally be on to something that might be a real game changer for these people with DLBCL.