Relapsed/Refractory Leukemia Responds to Experimental Inotuzumab

CHICAGO – The investigational antibody-drug conjugate inotuzumab ozogamicin delivered weekly produced a high objective response rate in heavily pretreated patients with relapsed or refractory acute lymphocytic leukemia, investigators reported.*

"Inotuzumab ozogamicin is very active in relapsed/refractory ALL. We’re reporting an objective response rate of 52%, most likely the highest activity for a single agent in this setting," said Dr. Elias Jabbour of the department of leukemia at the University of Texas M.D. Anderson Cancer Center, Houston.

Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody conjugated to calecheamicin, a cytotoxic antibiotic. The investigators recently reported that the compound, delivered at a dose of 1.8 mg/m² IV over 1 hour once monthly, was associated with a 57% overall response rate in 49 patients, but with a dose-limiting toxicity of thrombocytopenia (Lancet Oncol. 2012;13:403-11).

The current study was designed to see whether lower but more frequent doses might offer better anti-ALL activity and have a better safety profile, as suggested by preclinical studies. Dr. Jabbour presented the results at the annual meeting of the American Society of Clinical Oncology.

The investigators enrolled adults and children with relapsed/refractory CD22-positive ALL and treated them with inotuzumab 0.8 mg/m² on day 1 and 0.5 mg/m² on days 8 and 15; they repeated the cycle every 3-4 weeks for up to eight cycles.

Of the 27 patients available for analysis, 10 had a failed first remission lasting less than 12 months and one had a remission of more than 12 months’ duration. Six patients had undergone two salvage regimens and 10 had received at least three. Two patients had previously undergone an allogeneic stem cell transplant.

Three of the patients had a complete remission (CR), defined as the disappearance of all clinical and/or radiologic evidence of disease, a neutrophil count greater than 1.0 × 10⁹/L, a platelet count greater than 100 × 10⁹/L, and normal marrow differential with less than 5% blasts. Eight patients had complete remission except for platelet recovery (CRp) and three had a complete remission in marrow but without recovery of neutrophil or platelet counts (CRi), Dr. Jabbour said.

Eleven patients had disease resistant to the therapy and two died within 4 weeks of treatment.

Among patients evaluable for cytogenetic response, there were responses in two of two patients with a complete remission, in five of six patients with a CRp, and in two of two with a CRi. Of 14 patients evaluable for minimal residual disease (MRD), three of three with a CR were MRD negative, as were seven of eight with a CRp and one of three with a CRi. In all, 11 of the 27 patients in the analysis were MRD negative, he reported.

Median progression-free survival and median duration of response were 5 months each. Median overall survival was 7 months and did not differ significantly when patients were censored at the time of transplant. Median overall survival in this study compared favorably with that of the once-monthly dosing schedule (5 months).

Adverse events included infusion-related fever (grade 1/2 in three patients and grade 3/4 in four) and hypotension (grade 1/2 in one patient). There was one case of grade 1/2 bilirubin elevation, six grade 1/2 liver enzyme elevations, and two grade 3/4 enzyme elevations. All of the liver changes were reversible.

Prognostic factors for worse outcome were three or more salvage regimens and Philadelphia chromosome positivity.

Dr. Bruno Medeiros of Stanford (Calif.) University, the invited discussant, commented that intozumab has "impressive" single-agent activity in relapsed/refractory ALL, and that it appears to be safe before allogenic transplant. It remains to be seen whether the agent may have efficacy when combined with chemotherapy or other monoclonal antibodies in the relapsed and front-line settings, or activity when used as a single agent up front, he said.

Dr. Jabbour disclosed ties with Pfizer, which funded the study. Dr. Medeiros disclosed ties with Milennium, Celgene, and Novartis.

*This paragraph was revised June 19, 2012.

CHICAGO – The investigational antibody-drug conjugate inotuzumab ozogamicin delivered weekly produced a high objective response rate in heavily pretreated patients with relapsed or refractory acute lymphocytic leukemia, investigators reported.*

"Inotuzumab ozogamicin is very active in relapsed/refractory ALL. We’re reporting an objective response rate of 52%, most likely the highest activity for a single agent in this setting," said Dr. Elias Jabbour of the department of leukemia at the University of Texas M.D. Anderson Cancer Center, Houston.

Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody conjugated to calecheamicin, a cytotoxic antibiotic. The investigators recently reported that the compound, delivered at a dose of 1.8 mg/m² IV over 1 hour once monthly, was associated with a 57% overall response rate in 49 patients, but with a dose-limiting toxicity of thrombocytopenia (Lancet Oncol. 2012;13:403-11).

The current study was designed to see whether lower but more frequent doses might offer better anti-ALL activity and have a better safety profile, as suggested by preclinical studies. Dr. Jabbour presented the results at the annual meeting of the American Society of Clinical Oncology.

The investigators enrolled adults and children with relapsed/refractory CD22-positive ALL and treated them with inotuzumab 0.8 mg/m² on day 1 and 0.5 mg/m² on days 8 and 15; they repeated the cycle every 3-4 weeks for up to eight cycles.

Of the 27 patients available for analysis, 10 had a failed first remission lasting less than 12 months and one had a remission of more than 12 months’ duration. Six patients had undergone two salvage regimens and 10 had received at least three. Two patients had previously undergone an allogeneic stem cell transplant.

Three of the patients had a complete remission (CR), defined as the disappearance of all clinical and/or radiologic evidence of disease, a neutrophil count greater than 1.0 × 10⁹/L, a platelet count greater than 100 × 10⁹/L, and normal marrow differential with less than 5% blasts. Eight patients had complete remission except for platelet recovery (CRp) and three had a complete remission in marrow but without recovery of neutrophil or platelet counts (CRi), Dr. Jabbour said.

Eleven patients had disease resistant to the therapy and two died within 4 weeks of treatment.

Among patients evaluable for cytogenetic response, there were responses in two of two patients with a complete remission, in five of six patients with a CRp, and in two of two with a CRi. Of 14 patients evaluable for minimal residual disease (MRD), three of three with a CR were MRD negative, as were seven of eight with a CRp and one of three with a CRi. In all, 11 of the 27 patients in the analysis were MRD negative, he reported.

Median progression-free survival and median duration of response were 5 months each. Median overall survival was 7 months and did not differ significantly when patients were censored at the time of transplant. Median overall survival in this study compared favorably with that of the once-monthly dosing schedule (5 months).

Adverse events included infusion-related fever (grade 1/2 in three patients and grade 3/4 in four) and hypotension (grade 1/2 in one patient). There was one case of grade 1/2 bilirubin elevation, six grade 1/2 liver enzyme elevations, and two grade 3/4 enzyme elevations. All of the liver changes were reversible.

Prognostic factors for worse outcome were three or more salvage regimens and Philadelphia chromosome positivity.

Dr. Bruno Medeiros of Stanford (Calif.) University, the invited discussant, commented that intozumab has "impressive" single-agent activity in relapsed/refractory ALL, and that it appears to be safe before allogenic transplant. It remains to be seen whether the agent may have efficacy when combined with chemotherapy or other monoclonal antibodies in the relapsed and front-line settings, or activity when used as a single agent up front, he said.

Dr. Jabbour disclosed ties with Pfizer, which funded the study. Dr. Medeiros disclosed ties with Milennium, Celgene, and Novartis.

*This paragraph was revised June 19, 2012.

CHICAGO – The investigational antibody-drug conjugate inotuzumab ozogamicin delivered weekly produced a high objective response rate in heavily pretreated patients with relapsed or refractory acute lymphocytic leukemia, investigators reported.*

"Inotuzumab ozogamicin is very active in relapsed/refractory ALL. We’re reporting an objective response rate of 52%, most likely the highest activity for a single agent in this setting," said Dr. Elias Jabbour of the department of leukemia at the University of Texas M.D. Anderson Cancer Center, Houston.

Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody conjugated to calecheamicin, a cytotoxic antibiotic. The investigators recently reported that the compound, delivered at a dose of 1.8 mg/m² IV over 1 hour once monthly, was associated with a 57% overall response rate in 49 patients, but with a dose-limiting toxicity of thrombocytopenia (Lancet Oncol. 2012;13:403-11).

The current study was designed to see whether lower but more frequent doses might offer better anti-ALL activity and have a better safety profile, as suggested by preclinical studies. Dr. Jabbour presented the results at the annual meeting of the American Society of Clinical Oncology.

The investigators enrolled adults and children with relapsed/refractory CD22-positive ALL and treated them with inotuzumab 0.8 mg/m² on day 1 and 0.5 mg/m² on days 8 and 15; they repeated the cycle every 3-4 weeks for up to eight cycles.

Of the 27 patients available for analysis, 10 had a failed first remission lasting less than 12 months and one had a remission of more than 12 months’ duration. Six patients had undergone two salvage regimens and 10 had received at least three. Two patients had previously undergone an allogeneic stem cell transplant.

Three of the patients had a complete remission (CR), defined as the disappearance of all clinical and/or radiologic evidence of disease, a neutrophil count greater than 1.0 × 10⁹/L, a platelet count greater than 100 × 10⁹/L, and normal marrow differential with less than 5% blasts. Eight patients had complete remission except for platelet recovery (CRp) and three had a complete remission in marrow but without recovery of neutrophil or platelet counts (CRi), Dr. Jabbour said.

Eleven patients had disease resistant to the therapy and two died within 4 weeks of treatment.

Among patients evaluable for cytogenetic response, there were responses in two of two patients with a complete remission, in five of six patients with a CRp, and in two of two with a CRi. Of 14 patients evaluable for minimal residual disease (MRD), three of three with a CR were MRD negative, as were seven of eight with a CRp and one of three with a CRi. In all, 11 of the 27 patients in the analysis were MRD negative, he reported.

Median progression-free survival and median duration of response were 5 months each. Median overall survival was 7 months and did not differ significantly when patients were censored at the time of transplant. Median overall survival in this study compared favorably with that of the once-monthly dosing schedule (5 months).

Adverse events included infusion-related fever (grade 1/2 in three patients and grade 3/4 in four) and hypotension (grade 1/2 in one patient). There was one case of grade 1/2 bilirubin elevation, six grade 1/2 liver enzyme elevations, and two grade 3/4 enzyme elevations. All of the liver changes were reversible.

Prognostic factors for worse outcome were three or more salvage regimens and Philadelphia chromosome positivity.

Dr. Bruno Medeiros of Stanford (Calif.) University, the invited discussant, commented that intozumab has "impressive" single-agent activity in relapsed/refractory ALL, and that it appears to be safe before allogenic transplant. It remains to be seen whether the agent may have efficacy when combined with chemotherapy or other monoclonal antibodies in the relapsed and front-line settings, or activity when used as a single agent up front, he said.

Dr. Jabbour disclosed ties with Pfizer, which funded the study. Dr. Medeiros disclosed ties with Milennium, Celgene, and Novartis.

*This paragraph was revised June 19, 2012.