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Gemtuzumab ozogamicin well tolerated in multiple regimens for acute myeloid leukemia

Photo of Kelda Gardner
Kelda M. Gardner

SAN DIEGO —Gemtuzumab ozogamicin was safe and well tolerated in nearly a dozen different regimens for patients with acute myeloid leukemia or acute promyelocytic leukemia, according to research presented at the ASH Annual Meeting and Exposition.

Kelda M. Gardner, PA-C, an oncology physician assistant at Seattle Cancer Care Alliance and the University of Washington, Seattle, said the findings support the use of gemtuzumab ozogamicin (Mylotarg, Pfizer) in “a number of different regimens in the future.”

“We have a long history with this monoclonal antibody,” she told HemOnc Today. “It’ll be interesting to see where it goes from here.”

Gemtuzumab ozogamicin is a recombinant, humanized anti-CD33 antibody–drug conjugate that was originally approved in May 2000 for elderly patients with relapsed AML. In June 2010, Pfizer voluntarily withdrew the agent from the market after a postmarketing study showed the drug increased the risk for death and did not confer any additional benefit compared with other conventional therapies.

Gemtuzumab ozogamicin was returned to the market in September 2017 after being approved by the FDA for adults with newly diagnosed, CD33-positive AML and pediatric patients aged 2 years and older with CD33-positive AML who experienced a relapse or did not respond to initial treatment.

Before the reapproval, Gardner and colleagues analyzed the safety and tolerability of gemtuzumab ozogamicin in adults (median age, 50) and children (median age, 10) with relapsed or refractory AML (n = 40), mixed acute leukemia phenotypes (n = 3) or APL (n = 1) between 2014 and 2017. The treatment was available through an investigational new drug application that was submitted under the researchers’ Cancer Consortium, which included Fred Hutchinson Cancer Research Center, the University of Washington Medical Center, Seattle Children’s Hospital, and the Seattle Cancer Care Alliance.

During this investigational period, several different regimens containing gemtuzumab ozogamicin were administered to 44 patients. The more intensive regimens included gemtuzumab ozogamicin plus:

  • fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG), assigned to two adults and seven children;
  • FLAG-idarubicin (FLAG-IDA), assigned to seven adults and one child;
  • granulocyte colony-stimulating factor (G-CSF), cladribine, cytarabine and mitoxantrone (G-CLAM), assigned to eight adults; one adult received this regimen without mitoxantrone (GCLA);
  • etoposide, vincristine, doxorubicin, cyclophosphamide and prednisone (EPOCH); assigned to one adult; and
  • mitoxantrone, etoposide and cytarabine (MEC) plus decitabine (DEC), assigned to one adult.

Less intensive regimens included gemtuzumab ozogamicin monotherapy, assigned to two adults, as well as gemtuzumab ozogamicin plus:

  • azacitidine (Vidaza, Celgene) or decitabine (Dacogen, Otsuka), assigned to seven adults and two children;
  • cytarabine (ara-C), assigned to one adult and two children;
  • azacitidine plus ara-C, assigned to one adult; and
  • all-trans-retinoic acid (ATRA)/azacitidine, assigned to the one adult patient with APL.

Patients received a median of two cycles (range, 1-6) of gemtuzumab ozogamicin. The patient with APL received 6 cycles.

Thirteen patients (29%; 95% CI, 18-44) achieved complete remission (CR), including three (7%) with measurable residual disease. Sixteen patients had CR with incomplete hematologic recovery (CRi) and 15 had disease that was resistant to treatment or died before assessment.

Overall, 36 patients died (median survival = 17.2 months; range, 0.5-9.4). At the time data were presented, eight patients remained in CR with a median event-free survival of 31 months (range, 7-47).

CR and CRi rates were higher among patients who received more intensive therapy vs. less intensive therapy (78% vs. 44%), as well as those with fewer prior regimens (100% in patients with one prior regimen vs. 48% with two or more).

CR and CRi occurred in patients with intermediate (58%) or unfavorable (37%) risk cytogenetics. Responses, however, were greater among those with favorable cytogenetics (88%).

“Gemtuzumab ozogamicin initially showed it was effective in patients with intermediate or good cytogenetics, which is one of the prognostic indicators we look at it in patients with leukemia to determine how well they will do with chemotherapy,” Gardner said. “Since then, researchers have found that it can be beneficial in children regardless of cytogenetics risk category, as well as adults with CD33 positivity.”

The most common grade 3 or 4 toxicity events occurring within 60 days of treatment were major infections (44%), such as sepsis and pneumonia, and minor infections (66%), such as a fever of an unknown origin. Six deaths occurred within 60 days of initiating gemtuzumab ozogamicin; none were related to treatment.

The researchers concluded that, based on previous research, the CR rate with gemtuzumab ozogamicin plus intense therapy was comparable to the expected CR rate of patients receiving intense salvage therapy without gemtuzumab ozogamicin. They also reported that gemtuzumab ozogamicin combinations are a reasonable treatment option for patients with relapsed or refractory AML, “but might be of more value in patients with only MRD.”

Gardner noted that gemtuzumab ozogamicin continues to be evaluated in different settings.

“We have two clinical trials that are open and ongoing at our center using Mylotarg,” she said. “Dr. Percival has a trial with gemtuzumab ozogamicin as a solo therapy for MRD, and Dr. Walter has an intensive regimen for newly diagnosed AML patients combining gemtuzumab ozogamicin with G-CLAM, the standard backbone at our center.” – by Stephanie Viguers

Reference:

Gardner KM, et al. Abstract 2710. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.

Disclosure: Gardner reports no relevant financial disclosures.

Photo of Kelda Gardner
Kelda M. Gardner

SAN DIEGO —Gemtuzumab ozogamicin was safe and well tolerated in nearly a dozen different regimens for patients with acute myeloid leukemia or acute promyelocytic leukemia, according to research presented at the ASH Annual Meeting and Exposition.

Kelda M. Gardner, PA-C, an oncology physician assistant at Seattle Cancer Care Alliance and the University of Washington, Seattle, said the findings support the use of gemtuzumab ozogamicin (Mylotarg, Pfizer) in “a number of different regimens in the future.”

“We have a long history with this monoclonal antibody,” she told HemOnc Today. “It’ll be interesting to see where it goes from here.”

Gemtuzumab ozogamicin is a recombinant, humanized anti-CD33 antibody–drug conjugate that was originally approved in May 2000 for elderly patients with relapsed AML. In June 2010, Pfizer voluntarily withdrew the agent from the market after a postmarketing study showed the drug increased the risk for death and did not confer any additional benefit compared with other conventional therapies.

Gemtuzumab ozogamicin was returned to the market in September 2017 after being approved by the FDA for adults with newly diagnosed, CD33-positive AML and pediatric patients aged 2 years and older with CD33-positive AML who experienced a relapse or did not respond to initial treatment.

Before the reapproval, Gardner and colleagues analyzed the safety and tolerability of gemtuzumab ozogamicin in adults (median age, 50) and children (median age, 10) with relapsed or refractory AML (n = 40), mixed acute leukemia phenotypes (n = 3) or APL (n = 1) between 2014 and 2017. The treatment was available through an investigational new drug application that was submitted under the researchers’ Cancer Consortium, which included Fred Hutchinson Cancer Research Center, the University of Washington Medical Center, Seattle Children’s Hospital, and the Seattle Cancer Care Alliance.

During this investigational period, several different regimens containing gemtuzumab ozogamicin were administered to 44 patients. The more intensive regimens included gemtuzumab ozogamicin plus:

  • fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG), assigned to two adults and seven children;
  • FLAG-idarubicin (FLAG-IDA), assigned to seven adults and one child;
  • granulocyte colony-stimulating factor (G-CSF), cladribine, cytarabine and mitoxantrone (G-CLAM), assigned to eight adults; one adult received this regimen without mitoxantrone (GCLA);
  • etoposide, vincristine, doxorubicin, cyclophosphamide and prednisone (EPOCH); assigned to one adult; and
  • mitoxantrone, etoposide and cytarabine (MEC) plus decitabine (DEC), assigned to one adult.

Less intensive regimens included gemtuzumab ozogamicin monotherapy, assigned to two adults, as well as gemtuzumab ozogamicin plus:

  • azacitidine (Vidaza, Celgene) or decitabine (Dacogen, Otsuka), assigned to seven adults and two children;
  • cytarabine (ara-C), assigned to one adult and two children;
  • azacitidine plus ara-C, assigned to one adult; and
  • all-trans-retinoic acid (ATRA)/azacitidine, assigned to the one adult patient with APL.
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Patients received a median of two cycles (range, 1-6) of gemtuzumab ozogamicin. The patient with APL received 6 cycles.

Thirteen patients (29%; 95% CI, 18-44) achieved complete remission (CR), including three (7%) with measurable residual disease. Sixteen patients had CR with incomplete hematologic recovery (CRi) and 15 had disease that was resistant to treatment or died before assessment.

Overall, 36 patients died (median survival = 17.2 months; range, 0.5-9.4). At the time data were presented, eight patients remained in CR with a median event-free survival of 31 months (range, 7-47).

CR and CRi rates were higher among patients who received more intensive therapy vs. less intensive therapy (78% vs. 44%), as well as those with fewer prior regimens (100% in patients with one prior regimen vs. 48% with two or more).

CR and CRi occurred in patients with intermediate (58%) or unfavorable (37%) risk cytogenetics. Responses, however, were greater among those with favorable cytogenetics (88%).

“Gemtuzumab ozogamicin initially showed it was effective in patients with intermediate or good cytogenetics, which is one of the prognostic indicators we look at it in patients with leukemia to determine how well they will do with chemotherapy,” Gardner said. “Since then, researchers have found that it can be beneficial in children regardless of cytogenetics risk category, as well as adults with CD33 positivity.”

The most common grade 3 or 4 toxicity events occurring within 60 days of treatment were major infections (44%), such as sepsis and pneumonia, and minor infections (66%), such as a fever of an unknown origin. Six deaths occurred within 60 days of initiating gemtuzumab ozogamicin; none were related to treatment.

The researchers concluded that, based on previous research, the CR rate with gemtuzumab ozogamicin plus intense therapy was comparable to the expected CR rate of patients receiving intense salvage therapy without gemtuzumab ozogamicin. They also reported that gemtuzumab ozogamicin combinations are a reasonable treatment option for patients with relapsed or refractory AML, “but might be of more value in patients with only MRD.”

Gardner noted that gemtuzumab ozogamicin continues to be evaluated in different settings.

“We have two clinical trials that are open and ongoing at our center using Mylotarg,” she said. “Dr. Percival has a trial with gemtuzumab ozogamicin as a solo therapy for MRD, and Dr. Walter has an intensive regimen for newly diagnosed AML patients combining gemtuzumab ozogamicin with G-CLAM, the standard backbone at our center.” – by Stephanie Viguers

Reference:

Gardner KM, et al. Abstract 2710. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.

Disclosure: Gardner reports no relevant financial disclosures.

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