The phase III trial comparing the use of gemtuzumab ozogamicin combined with chemotherapy to chemotherapy alone in newly diagnosed acute myeloid leukemia (AML) patients provides evidence that the combination treatment may be promising in this patient population. Using relatively low and frequently repeated doses together with standard chemotherapy may be a viable option for the treatment of older adults, aged 50 to 70 years of age.
In the presented study, gemtuzumab was used upfront in newly diagnosed AML patients. The results show a benefit in this initial treatment and a survival benefit. The current results suggest that this drug was not studied in the correct patient population and at the appropriate dose previously.
Gemtuzumab (Mylotarg) was originally approved by the US Food and Drug Administration through an accelerated process in 2000 for patients older than 60 after a first relapse in AML. Further clinical trials and post-marketing data that did not show any evidence of a clinical benefit in patients with AML compared to conventional chemotherapy—particularly, the SWOG S0106 trial—led to the withdrawal of the treatment, as indicated by the introducer of the trial presenter, Dr. Martin S. Tallman, MD of the department of medicine at Memorial Sloan-Kettering Cancer Center in New York. There were also toxicities particularly in younger patients, increasing mortality in these patients.
Gemtuzumab ozogamicin is a monoclonal antibody to CD33 that is linked to a calicheamicin, a cytotoxic agent. Gemtuzumab ozogamicin binds to CD33, which is expressed on AML cells, but not on normal, mature hematopoietic stem cells.
Because a phase II trial determined that the 9 mg/m2 BID dose could not be safely combined with chemotherapy, the current phase III trial utilized a 3, 3, 3 regiment based on in vitro observations and validation in 2 subsequent phase II trials. A dose of 3 mg/m2 gemtuzumab ozogamicin was given on days 1, 4, and 7 of treatment in conjunction with chemotherapy, arabinofuranosyl cytidine, and daunorubicin(Drug information on daunorubicin).
At a 2-year follow up, event-free survival (EFS) was 15.6% in the chemotherapy arm compared to 41.4% in the combination arm. Median EFS was 11.9 months compared to 19.6 months, in the chemotherapy and combination arms, respectively. The benefit was seen in all age groups and translated into a longer overall survival for the patients treated with the combination, 19 months compared to 34 months, on average in the chemotherapy and combination arms, respectively.
The treatment with the combination increased toxicities. The rate of fatal adverse events potentially attributed to treatment was 2% higher in the gemtuzumab ozogamicin plus chemotherapy arm compared to chemotherapy alone. “Safety was a major issue,” stated Dr. Sylvie Castaigne, MD, professor in the department of hematology at Hôpital de Versailles in Versailles, France, who presented the study. Thrombocytopenia was greater with gemtuzumab ozogamicin as was persistent thrombocytopenia. Three episodes of veno-occlusive disease (VOD) or sinusoidal obstructive syndrome (liver vein blockages) were observed in the arabinofuranosyl cytidine, daunorubicin, plus gemtuzumab ozogamicin arm, two noted as fatal. There was no difference in the nonhematologic safety events including sepsis, bleeding, cardiac events, and liver events.
There are approximately 13,000 new patients diagnosed with follicular lymphoma every year and 9000 patient deaths. The source of the lymphoma may be de novo, therapy-related, or due to a myeloproliferative disease. According to Dr. Tallman, the overall survival for adults younger than age 55 has been improving but there is still no evidence in improvement in older adults despite four decades of investigation.
During the discussion, Dr. Castaigne stated that she believed this is the minimal dose of gemtuzumab ozogamicin and that there were not differences in patients with various CD33 expression in regards to outcomes and response.
“The results are impressive but need further studies before gemtuzumab ozogamicin becomes standard of care,” commented Dr. Tallman, in an email communication with CancerNetwork. “The VOD is worrisome and a strategy needs to be developed to tackle it. Thus makes consideration of using gemtuzumab ozogamicin, as done in the study reported here, problematic in my view. The results suggest we need further studies. Promising, but not standard of care, and I would not use off a study,” he added.