GCLAM therapy shows promise for relapsed/refractory AML

ATLANTA – GCLAM – the combined use of granulocyte colony-stimulating factor (G-CSF), cladribine, high-dose cytarabine, and mitoxantrone – was well tolerated and had potent antileukemia activity in a phase 1/2 trial of adults with relapsed/refractory acute myeloid leukemia or high-grade myeloid neoplasms.

Of 40 patients who were treated with GCLAM (with mitoxantrone at the maximum tolerated dose of 16 mg/m² per day as established in phase 1 of the trial), 11 achieved a complete response (CR), and 13 achieved a complete response with incomplete blood count recovery (CRi), for an overall response rate of 60%, Anna B. Halpern, MD, reported at the annual meeting of the American Society of Hematology.

“Nine of the 11 CR patients and 11 of 13 with CRis were negative for minimal residual disease, for an overall MRD-negative CR rate of 23%,” said Dr. Halpern of the University of Washington and the Fred Hutchinson Cancer Research Center, both in Seattle.

Resistant disease occurred in 11 patients, she noted.

Median overall survival was 11.5 months, and the treatment-related mortality (TRM) rate was 5%.

Overall, 21 of 40 patients went to transplant, with a 49% 1-year survival rate, she said.

The patients had a median age of 63 years. Thirty-four had acute myeloid leukemia (AML), and 6 had high-grade myelodysplastic syndrome; 28 had secondary disease. Nineteen had primary refractory disease, 21 had relapsed disease after a median initial CR duration of 12 months, and 7 had prior allogeneic transplant. The median TRM score for all patients was 2.0, indicating a low risk for treatment-related mortality.

“Cytogenetics distribution, based on Medical Research Council criteria, was as expected,” she added.

At the mitoxantrone maximum tolerated dose of 16 mg/m² per day – which was established during phase 1 in 26 patients in whom higher dose levels (18 mg/m² per day) led to dose-limiting encephalopathy and cardiogenic shock – the most common grade 3 or greater adverse events included neutropenic fever, infectious complications, and hypoxia during therapy. This was largely attributed to volume overload and infection, Dr. Halpern said.

“Although three patients did have decreased ejection fraction in cycle 2, this was largely in the setting of sepsis, making the etiology difficult to ascribe to the anthracycline versus sepsis physiology,” she noted.

The median times to an absolute neutrophil count of 500/mcL or greater and platelet count of 50,000/mcL or greater were 29 days each, she noted.

A multivariable analysis controlling for baseline prognostic features showed that the mitoxantrone dose of 16 mg/m² per day was associated with significantly better overall survival, compared with a dose of 10 mg/m² per day used in a historical cohort according to standard GCLAM dosing (hazard ratio for death, 0.45). Additionally, more of those receiving a dose of 16 mg/m² per day went on to transplant (52% vs. 37%), she said. The overall response rate was also higher with the 16-mg/m² dose, but the difference was not statistically significant (odds ratio, 1.87).

“Further, the outcomes appear to be as good or better with GCLAM with mitoxantrone at 16 mg/m² compared to other salvage regimens used at our institution, including decitabine priming plus mitoxantrone, etoposide, and cytarabine [d/MEC] and G-CSF with clofarabine and high-dose cytarabine [GCLAC],” she said, noting that the examination is currently ongoing in a larger sample.

The initial analysis, however, showed that, after controlling for age, cytogenetic risk, first CR duration, and prior hematopoietic cell transplant, overall response and overall survival rates were better with GCLAM than with d/MEC (OR, 3.23; HR for death, 0.64) and that the overall response rate was similar between GCLAM and GCLAC (OR, 1.75), she said.

The findings are encouraging because outcomes with standard chemotherapies for relapsed/refractory myeloid neoplasms are poor, with complete remission rates rarely exceeding 15%-20%, Dr. Halpern said.

The current study was undertaken based on promising results from a previous phase 2 study in poor-risk relapsed/refractory AML, which also showed encouraging activity with GCLAM and based on data suggesting benefit with escalated doses of anthracyclines in AML, she explained.

Patients 18 years and older were eligible if they had adequate organ function and a TRM score of 6.9 or lower, which corresponds to a predicted 28-day mortality of no more than 6.9% with standard induction chemotherapy. Those with uncontrolled infection or concomitant illness with expected survival of less than 1 year were excluded.

The phase 1 dose escalation involved cohorts of 6-12 patients who were assigned to receive mitoxantrone dose levels of 12, 14, 16, or 18 mg/m² per day on days 1-3. The doses of the remaining drugs in the combination were fixed at 300 mcg or 480 mcg of G-CSF on days 0-5, 5 mg/m² of cladribine on days 1-5, and 2 mg/m² of cytarabine on days 1-5.

“All patients received GCLAM induction at their assigned mitoxantrone dose level. If CR wasn’t achieved with cycle 1, a second identical course of GCLAM was given,” Dr. Halpern explained, noting that patients with resistant disease after 2 cycles were taken off the study.

If CR or CRi was achieved within 1-2 cycles of induction, up to 4 cycles of consolidation with G-CLA (mitoxantrone omitted) were allowed, and responders could proceed with transplant at any time.

In phase 2, patients received the maximum tolerated dose of mitoxantrone (16mg/m² per day), as defined in phase 1.

“Relapsed and refractory AML and high grade myeloid neoplasms are a challenging disease to treat. With an overall response rate of 60%, this regimen showed efficacy in a heavily pretreated patient population,” Dr. Halpern said. “And many of the responders were able to go on to receive a stem cell transplant, the only known curative option in this situation.”

A follow-up study is currently exploring the relative value of decitabine priming followed by GCLAM in this setting, she said.

Dr. Halpern reported having no relevant financial disclosures.

sworcester@frontlinemedcom.com

SOURCE: Halpern AB et al. ASH 2017, Abstract 149

ATLANTA – GCLAM – the combined use of granulocyte colony-stimulating factor (G-CSF), cladribine, high-dose cytarabine, and mitoxantrone – was well tolerated and had potent antileukemia activity in a phase 1/2 trial of adults with relapsed/refractory acute myeloid leukemia or high-grade myeloid neoplasms.

Of 40 patients who were treated with GCLAM (with mitoxantrone at the maximum tolerated dose of 16 mg/m² per day as established in phase 1 of the trial), 11 achieved a complete response (CR), and 13 achieved a complete response with incomplete blood count recovery (CRi), for an overall response rate of 60%, Anna B. Halpern, MD, reported at the annual meeting of the American Society of Hematology.

“Nine of the 11 CR patients and 11 of 13 with CRis were negative for minimal residual disease, for an overall MRD-negative CR rate of 23%,” said Dr. Halpern of the University of Washington and the Fred Hutchinson Cancer Research Center, both in Seattle.

Resistant disease occurred in 11 patients, she noted.

Median overall survival was 11.5 months, and the treatment-related mortality (TRM) rate was 5%.

Overall, 21 of 40 patients went to transplant, with a 49% 1-year survival rate, she said.

The patients had a median age of 63 years. Thirty-four had acute myeloid leukemia (AML), and 6 had high-grade myelodysplastic syndrome; 28 had secondary disease. Nineteen had primary refractory disease, 21 had relapsed disease after a median initial CR duration of 12 months, and 7 had prior allogeneic transplant. The median TRM score for all patients was 2.0, indicating a low risk for treatment-related mortality.

“Cytogenetics distribution, based on Medical Research Council criteria, was as expected,” she added.

At the mitoxantrone maximum tolerated dose of 16 mg/m² per day – which was established during phase 1 in 26 patients in whom higher dose levels (18 mg/m² per day) led to dose-limiting encephalopathy and cardiogenic shock – the most common grade 3 or greater adverse events included neutropenic fever, infectious complications, and hypoxia during therapy. This was largely attributed to volume overload and infection, Dr. Halpern said.

“Although three patients did have decreased ejection fraction in cycle 2, this was largely in the setting of sepsis, making the etiology difficult to ascribe to the anthracycline versus sepsis physiology,” she noted.

The median times to an absolute neutrophil count of 500/mcL or greater and platelet count of 50,000/mcL or greater were 29 days each, she noted.

A multivariable analysis controlling for baseline prognostic features showed that the mitoxantrone dose of 16 mg/m² per day was associated with significantly better overall survival, compared with a dose of 10 mg/m² per day used in a historical cohort according to standard GCLAM dosing (hazard ratio for death, 0.45). Additionally, more of those receiving a dose of 16 mg/m² per day went on to transplant (52% vs. 37%), she said. The overall response rate was also higher with the 16-mg/m² dose, but the difference was not statistically significant (odds ratio, 1.87).

“Further, the outcomes appear to be as good or better with GCLAM with mitoxantrone at 16 mg/m² compared to other salvage regimens used at our institution, including decitabine priming plus mitoxantrone, etoposide, and cytarabine [d/MEC] and G-CSF with clofarabine and high-dose cytarabine [GCLAC],” she said, noting that the examination is currently ongoing in a larger sample.

The initial analysis, however, showed that, after controlling for age, cytogenetic risk, first CR duration, and prior hematopoietic cell transplant, overall response and overall survival rates were better with GCLAM than with d/MEC (OR, 3.23; HR for death, 0.64) and that the overall response rate was similar between GCLAM and GCLAC (OR, 1.75), she said.

The findings are encouraging because outcomes with standard chemotherapies for relapsed/refractory myeloid neoplasms are poor, with complete remission rates rarely exceeding 15%-20%, Dr. Halpern said.

The current study was undertaken based on promising results from a previous phase 2 study in poor-risk relapsed/refractory AML, which also showed encouraging activity with GCLAM and based on data suggesting benefit with escalated doses of anthracyclines in AML, she explained.

Patients 18 years and older were eligible if they had adequate organ function and a TRM score of 6.9 or lower, which corresponds to a predicted 28-day mortality of no more than 6.9% with standard induction chemotherapy. Those with uncontrolled infection or concomitant illness with expected survival of less than 1 year were excluded.

The phase 1 dose escalation involved cohorts of 6-12 patients who were assigned to receive mitoxantrone dose levels of 12, 14, 16, or 18 mg/m² per day on days 1-3. The doses of the remaining drugs in the combination were fixed at 300 mcg or 480 mcg of G-CSF on days 0-5, 5 mg/m² of cladribine on days 1-5, and 2 mg/m² of cytarabine on days 1-5.

“All patients received GCLAM induction at their assigned mitoxantrone dose level. If CR wasn’t achieved with cycle 1, a second identical course of GCLAM was given,” Dr. Halpern explained, noting that patients with resistant disease after 2 cycles were taken off the study.

If CR or CRi was achieved within 1-2 cycles of induction, up to 4 cycles of consolidation with G-CLA (mitoxantrone omitted) were allowed, and responders could proceed with transplant at any time.

In phase 2, patients received the maximum tolerated dose of mitoxantrone (16mg/m² per day), as defined in phase 1.

“Relapsed and refractory AML and high grade myeloid neoplasms are a challenging disease to treat. With an overall response rate of 60%, this regimen showed efficacy in a heavily pretreated patient population,” Dr. Halpern said. “And many of the responders were able to go on to receive a stem cell transplant, the only known curative option in this situation.”

A follow-up study is currently exploring the relative value of decitabine priming followed by GCLAM in this setting, she said.

Dr. Halpern reported having no relevant financial disclosures.

sworcester@frontlinemedcom.com

SOURCE: Halpern AB et al. ASH 2017, Abstract 149

ATLANTA – GCLAM – the combined use of granulocyte colony-stimulating factor (G-CSF), cladribine, high-dose cytarabine, and mitoxantrone – was well tolerated and had potent antileukemia activity in a phase 1/2 trial of adults with relapsed/refractory acute myeloid leukemia or high-grade myeloid neoplasms.

Of 40 patients who were treated with GCLAM (with mitoxantrone at the maximum tolerated dose of 16 mg/m² per day as established in phase 1 of the trial), 11 achieved a complete response (CR), and 13 achieved a complete response with incomplete blood count recovery (CRi), for an overall response rate of 60%, Anna B. Halpern, MD, reported at the annual meeting of the American Society of Hematology.

“Nine of the 11 CR patients and 11 of 13 with CRis were negative for minimal residual disease, for an overall MRD-negative CR rate of 23%,” said Dr. Halpern of the University of Washington and the Fred Hutchinson Cancer Research Center, both in Seattle.

Resistant disease occurred in 11 patients, she noted.

Median overall survival was 11.5 months, and the treatment-related mortality (TRM) rate was 5%.

Overall, 21 of 40 patients went to transplant, with a 49% 1-year survival rate, she said.

The patients had a median age of 63 years. Thirty-four had acute myeloid leukemia (AML), and 6 had high-grade myelodysplastic syndrome; 28 had secondary disease. Nineteen had primary refractory disease, 21 had relapsed disease after a median initial CR duration of 12 months, and 7 had prior allogeneic transplant. The median TRM score for all patients was 2.0, indicating a low risk for treatment-related mortality.

“Cytogenetics distribution, based on Medical Research Council criteria, was as expected,” she added.

At the mitoxantrone maximum tolerated dose of 16 mg/m² per day – which was established during phase 1 in 26 patients in whom higher dose levels (18 mg/m² per day) led to dose-limiting encephalopathy and cardiogenic shock – the most common grade 3 or greater adverse events included neutropenic fever, infectious complications, and hypoxia during therapy. This was largely attributed to volume overload and infection, Dr. Halpern said.

“Although three patients did have decreased ejection fraction in cycle 2, this was largely in the setting of sepsis, making the etiology difficult to ascribe to the anthracycline versus sepsis physiology,” she noted.

The median times to an absolute neutrophil count of 500/mcL or greater and platelet count of 50,000/mcL or greater were 29 days each, she noted.

A multivariable analysis controlling for baseline prognostic features showed that the mitoxantrone dose of 16 mg/m² per day was associated with significantly better overall survival, compared with a dose of 10 mg/m² per day used in a historical cohort according to standard GCLAM dosing (hazard ratio for death, 0.45). Additionally, more of those receiving a dose of 16 mg/m² per day went on to transplant (52% vs. 37%), she said. The overall response rate was also higher with the 16-mg/m² dose, but the difference was not statistically significant (odds ratio, 1.87).

“Further, the outcomes appear to be as good or better with GCLAM with mitoxantrone at 16 mg/m² compared to other salvage regimens used at our institution, including decitabine priming plus mitoxantrone, etoposide, and cytarabine [d/MEC] and G-CSF with clofarabine and high-dose cytarabine [GCLAC],” she said, noting that the examination is currently ongoing in a larger sample.

The initial analysis, however, showed that, after controlling for age, cytogenetic risk, first CR duration, and prior hematopoietic cell transplant, overall response and overall survival rates were better with GCLAM than with d/MEC (OR, 3.23; HR for death, 0.64) and that the overall response rate was similar between GCLAM and GCLAC (OR, 1.75), she said.

The findings are encouraging because outcomes with standard chemotherapies for relapsed/refractory myeloid neoplasms are poor, with complete remission rates rarely exceeding 15%-20%, Dr. Halpern said.

The current study was undertaken based on promising results from a previous phase 2 study in poor-risk relapsed/refractory AML, which also showed encouraging activity with GCLAM and based on data suggesting benefit with escalated doses of anthracyclines in AML, she explained.

Patients 18 years and older were eligible if they had adequate organ function and a TRM score of 6.9 or lower, which corresponds to a predicted 28-day mortality of no more than 6.9% with standard induction chemotherapy. Those with uncontrolled infection or concomitant illness with expected survival of less than 1 year were excluded.

The phase 1 dose escalation involved cohorts of 6-12 patients who were assigned to receive mitoxantrone dose levels of 12, 14, 16, or 18 mg/m² per day on days 1-3. The doses of the remaining drugs in the combination were fixed at 300 mcg or 480 mcg of G-CSF on days 0-5, 5 mg/m² of cladribine on days 1-5, and 2 mg/m² of cytarabine on days 1-5.

“All patients received GCLAM induction at their assigned mitoxantrone dose level. If CR wasn’t achieved with cycle 1, a second identical course of GCLAM was given,” Dr. Halpern explained, noting that patients with resistant disease after 2 cycles were taken off the study.

If CR or CRi was achieved within 1-2 cycles of induction, up to 4 cycles of consolidation with G-CLA (mitoxantrone omitted) were allowed, and responders could proceed with transplant at any time.

In phase 2, patients received the maximum tolerated dose of mitoxantrone (16mg/m² per day), as defined in phase 1.

“Relapsed and refractory AML and high grade myeloid neoplasms are a challenging disease to treat. With an overall response rate of 60%, this regimen showed efficacy in a heavily pretreated patient population,” Dr. Halpern said. “And many of the responders were able to go on to receive a stem cell transplant, the only known curative option in this situation.”

A follow-up study is currently exploring the relative value of decitabine priming followed by GCLAM in this setting, she said.

Dr. Halpern reported having no relevant financial disclosures.

sworcester@frontlinemedcom.com

SOURCE: Halpern AB et al. ASH 2017, Abstract 149