‘Encouraging’ phase 2 results in rel/ref AML

MD Anderson Cancer Center

The combination of azacitidine and nivolumab produced “encouraging” results in a phase 2 trial of patients with relapsed or refractory acute myeloid leukemia (AML), according to researchers.

The overall response rate was 33%, and the median overall survival (OS) was 6.3 months.

However, the researchers identified factors associated with improved response and survival that they believe could be used to select patients for this treatment.

A quarter of patients on this trial had immune-related adverse events (AEs) that were considered related to treatment, and two patients died of AEs that may have been treatment-related.

Naval Daver, MD, of The University of Texas MD Anderson Cancer Center in Houston, and his colleagues reported these results in Cancer Discovery.

The trial included 70 patients with a median age of 70 (range, 22-90). Fifty-six percent had de novo AML, and 44% had secondary AML.

The median number of prior therapies was 2 (range, 1 to 7). Sixty-four percent of patients had received hypomethylating agents, 47% had received targeted therapies, and 19% had received allogeneic stem cell transplant (SCT).

For this trial, patients received azacitidine at 75 mg/m² on days 1 to 7 and nivolumab at 3 mg/kg on days 1 and 14 of each cycle. The median number of cycles was 3 (range, 1 to 25).

Patients had a median time on study of 3.5 months (range, 0.3 to 26.3 months). Reasons for discontinuation included primary refractory disease (n=27), relapse after initial response (n=19), death (n=16), proceeding to SCT (n=3), and patient preference (n=3).

Safety

The most common treatment-related, non-hematologic AEs were constipation (26%), diarrhea (20%), pneumonitis (13%), nausea (11%), and lung infection (11%).

The rate of immune-related AEs was 25% (n=18), with grade 2-4 immune-related AEs occurring in 16 patients (8 with grade 3-4). Fourteen of these patients responded to steroids and were safely re-challenged with nivolumab, according to the researchers.

Nine patients (13%) discontinued nivolumab (but continued with azacitidine) due to AEs—pneumonitis (n=7), cytokine release syndrome (n=1), and immune nephritis (n=1).

Two patients died of AEs that were considered possibly related to treatment. One death was due to progressive pneumonia/pneumonitis, and one was due to hemophagocytosis lymphohistiocytosis.

Response

The overall response rate was 33% (n=23). Four patients had a complete response (CR), and 11 had a CR with incomplete count recovery (CRi).

One patient had a partial response, and seven had hematologic improvement in one or more parameter maintained for more than 6 months. Six patients had stable disease lasting more than 6 months.

The researchers noted that the response rate was higher among patients who had not received prior treatment with hypomethylating agents. In addition, a higher frequency of pre-therapy CD3 and CD8 cells in the bone marrow or peripheral blood appeared to predict response.

“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,” Dr. Daver said.

Survival

At a median follow-up of 21.4 months, 81% of patients (n=57) had died. Sixteen patients died on study treatment, and 41 died after discontinuation.

The median OS was 6.3 months, and the median event-free survival was 4.5 months.

The median OS was 16.1 months in patients with CR/CRi,  partial response, hematologic improvement, or stable disease and 4.1 months in non-responders (P<0.0001). This difference was still significant after the researchers censored the three patients who had gone on to SCT in CR/CRi (P<0.001).

The researchers also found that being in first salvage was associated with improved OS in a univariate analysis and in a comparison with historical controls.

Dr. Daver and his colleagues concluded that azacitidine and nivolumab “produced an encouraging response rate and overall survival” in patients with relapsed/refractory 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,” Dr. Daver noted.

This research was supported by Bristol-Myers Squibb, MD Anderson, and the Dick Clark Immunotherapy Research Fund. In addition, individual researchers reported financial relationships with Bristol-Myers Squibb.

MD Anderson Cancer Center

The combination of azacitidine and nivolumab produced “encouraging” results in a phase 2 trial of patients with relapsed or refractory acute myeloid leukemia (AML), according to researchers.

The overall response rate was 33%, and the median overall survival (OS) was 6.3 months.

However, the researchers identified factors associated with improved response and survival that they believe could be used to select patients for this treatment.

A quarter of patients on this trial had immune-related adverse events (AEs) that were considered related to treatment, and two patients died of AEs that may have been treatment-related.

Naval Daver, MD, of The University of Texas MD Anderson Cancer Center in Houston, and his colleagues reported these results in Cancer Discovery.

The trial included 70 patients with a median age of 70 (range, 22-90). Fifty-six percent had de novo AML, and 44% had secondary AML.

The median number of prior therapies was 2 (range, 1 to 7). Sixty-four percent of patients had received hypomethylating agents, 47% had received targeted therapies, and 19% had received allogeneic stem cell transplant (SCT).

For this trial, patients received azacitidine at 75 mg/m² on days 1 to 7 and nivolumab at 3 mg/kg on days 1 and 14 of each cycle. The median number of cycles was 3 (range, 1 to 25).

Patients had a median time on study of 3.5 months (range, 0.3 to 26.3 months). Reasons for discontinuation included primary refractory disease (n=27), relapse after initial response (n=19), death (n=16), proceeding to SCT (n=3), and patient preference (n=3).

Safety

The most common treatment-related, non-hematologic AEs were constipation (26%), diarrhea (20%), pneumonitis (13%), nausea (11%), and lung infection (11%).

The rate of immune-related AEs was 25% (n=18), with grade 2-4 immune-related AEs occurring in 16 patients (8 with grade 3-4). Fourteen of these patients responded to steroids and were safely re-challenged with nivolumab, according to the researchers.

Nine patients (13%) discontinued nivolumab (but continued with azacitidine) due to AEs—pneumonitis (n=7), cytokine release syndrome (n=1), and immune nephritis (n=1).

Two patients died of AEs that were considered possibly related to treatment. One death was due to progressive pneumonia/pneumonitis, and one was due to hemophagocytosis lymphohistiocytosis.

Response

The overall response rate was 33% (n=23). Four patients had a complete response (CR), and 11 had a CR with incomplete count recovery (CRi).

One patient had a partial response, and seven had hematologic improvement in one or more parameter maintained for more than 6 months. Six patients had stable disease lasting more than 6 months.

The researchers noted that the response rate was higher among patients who had not received prior treatment with hypomethylating agents. In addition, a higher frequency of pre-therapy CD3 and CD8 cells in the bone marrow or peripheral blood appeared to predict response.

“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,” Dr. Daver said.

Survival

At a median follow-up of 21.4 months, 81% of patients (n=57) had died. Sixteen patients died on study treatment, and 41 died after discontinuation.

The median OS was 6.3 months, and the median event-free survival was 4.5 months.

The median OS was 16.1 months in patients with CR/CRi,  partial response, hematologic improvement, or stable disease and 4.1 months in non-responders (P<0.0001). This difference was still significant after the researchers censored the three patients who had gone on to SCT in CR/CRi (P<0.001).

The researchers also found that being in first salvage was associated with improved OS in a univariate analysis and in a comparison with historical controls.

Dr. Daver and his colleagues concluded that azacitidine and nivolumab “produced an encouraging response rate and overall survival” in patients with relapsed/refractory 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,” Dr. Daver noted.

This research was supported by Bristol-Myers Squibb, MD Anderson, and the Dick Clark Immunotherapy Research Fund. In addition, individual researchers reported financial relationships with Bristol-Myers Squibb.

MD Anderson Cancer Center

The combination of azacitidine and nivolumab produced “encouraging” results in a phase 2 trial of patients with relapsed or refractory acute myeloid leukemia (AML), according to researchers.

The overall response rate was 33%, and the median overall survival (OS) was 6.3 months.

However, the researchers identified factors associated with improved response and survival that they believe could be used to select patients for this treatment.

A quarter of patients on this trial had immune-related adverse events (AEs) that were considered related to treatment, and two patients died of AEs that may have been treatment-related.

Naval Daver, MD, of The University of Texas MD Anderson Cancer Center in Houston, and his colleagues reported these results in Cancer Discovery.

The trial included 70 patients with a median age of 70 (range, 22-90). Fifty-six percent had de novo AML, and 44% had secondary AML.

The median number of prior therapies was 2 (range, 1 to 7). Sixty-four percent of patients had received hypomethylating agents, 47% had received targeted therapies, and 19% had received allogeneic stem cell transplant (SCT).

For this trial, patients received azacitidine at 75 mg/m² on days 1 to 7 and nivolumab at 3 mg/kg on days 1 and 14 of each cycle. The median number of cycles was 3 (range, 1 to 25).

Patients had a median time on study of 3.5 months (range, 0.3 to 26.3 months). Reasons for discontinuation included primary refractory disease (n=27), relapse after initial response (n=19), death (n=16), proceeding to SCT (n=3), and patient preference (n=3).

Safety

The most common treatment-related, non-hematologic AEs were constipation (26%), diarrhea (20%), pneumonitis (13%), nausea (11%), and lung infection (11%).

The rate of immune-related AEs was 25% (n=18), with grade 2-4 immune-related AEs occurring in 16 patients (8 with grade 3-4). Fourteen of these patients responded to steroids and were safely re-challenged with nivolumab, according to the researchers.

Nine patients (13%) discontinued nivolumab (but continued with azacitidine) due to AEs—pneumonitis (n=7), cytokine release syndrome (n=1), and immune nephritis (n=1).

Two patients died of AEs that were considered possibly related to treatment. One death was due to progressive pneumonia/pneumonitis, and one was due to hemophagocytosis lymphohistiocytosis.

Response

The overall response rate was 33% (n=23). Four patients had a complete response (CR), and 11 had a CR with incomplete count recovery (CRi).

One patient had a partial response, and seven had hematologic improvement in one or more parameter maintained for more than 6 months. Six patients had stable disease lasting more than 6 months.

The researchers noted that the response rate was higher among patients who had not received prior treatment with hypomethylating agents. In addition, a higher frequency of pre-therapy CD3 and CD8 cells in the bone marrow or peripheral blood appeared to predict response.

“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,” Dr. Daver said.

Survival

At a median follow-up of 21.4 months, 81% of patients (n=57) had died. Sixteen patients died on study treatment, and 41 died after discontinuation.

The median OS was 6.3 months, and the median event-free survival was 4.5 months.

The median OS was 16.1 months in patients with CR/CRi,  partial response, hematologic improvement, or stable disease and 4.1 months in non-responders (P<0.0001). This difference was still significant after the researchers censored the three patients who had gone on to SCT in CR/CRi (P<0.001).

The researchers also found that being in first salvage was associated with improved OS in a univariate analysis and in a comparison with historical controls.

Dr. Daver and his colleagues concluded that azacitidine and nivolumab “produced an encouraging response rate and overall survival” in patients with relapsed/refractory 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,” Dr. Daver noted.

This research was supported by Bristol-Myers Squibb, MD Anderson, and the Dick Clark Immunotherapy Research Fund. In addition, individual researchers reported financial relationships with Bristol-Myers Squibb.