ASH News Daily - Monday, December 12, 2011 - (Page A-2)

Page A–2 ® AML Gemtuzumab Ozogamicin: Miraculous Recovery Or Late Rally Before (Ultimate) Death? By Michael r. BiShop, Md mended that anti-CD33 immunotoxin gemtuzumab ozogamicin, which had received accelerated approval for the treatment of acute myeloid leukemia (AML), should no longer be commercially available to new patients. The recommendation was based on the results of the Southwest Oncology Group trial, SWOG S0106, which had raised concerns about the safety, specifically hepatotoxicity, and clinical efficacy of gemtuzumab ozogamicin. On the same day, Pfizer Inc., the parent company that produced gemtuzumab ozogamicin, announced that it would be discontinuing commercial availability of gemtuzumab ozogamicin in the United States, as well as voluntarily withdrawing a new drug application for the agent. However, the subsequent reported results of a number of studies, most notably the MRC AML15 trial, suggested a potential survival advantage with the addition of gemtuzumab ozogamicin. Despite these promising results in selected AML populations, there appeared to be very little hope that there would be continued sponsorship of trials involving gemtuzumab ozogamicin. In Sunday’s Plenary Scientific session, we were presented with O n June 21, 2010, the United States Food and Drug Administration (FDA) recom- However, they hypothesized that the toxicity could be reduced and the efficacy enhanced by using re- peated and small doses of gemtuzumab ozogamicin. additional data supporting the efficacy of gemtuzumab ozogamicin in the treatment of AML, as Dr. Sylvie Castaigne, representing the Acute Leukemia French Association (ALFA), presented the results of a prospective randomized (0701) phase 3 trial (ALFA 0701) of fractionated doses of gemtuzumab ozogamicin in combination with standard chemotherapy for newly diagnosed de novo AML patients between the ages of 50 and 70 years. Dr. Castaigne shared with ASH News Daily that she and her colleagues were quite aware that “there exists a thin gap between efficacy and toxicity” with the use gemtuzumab ozogamicin. However, they hypothesized that the toxicity could be reduced and the efficacy enhanced by using repeated and small doses of gemtuzumab ozogamicin. After preliminary testing of this hypothesis in phase II studies for relapsed AML, they moved forward to design and conduct ALFA 0701. Patients were randomized to receive a standard induction regimen of daunorubicin and cytosine arabinoside given in a standard “3+7” manner (“DA” arm) or to receive the same regimen plus gemtuzumab ozogamicin given at a dose of 3 mg/m2 on days 1, 4, and 7 of treat- ment (“DAGO” arm). A total of 280 patients were enrolled in the study. Complete remissions were achieved in 75 percent in the DA arm, while 80 percent of patients achieved a CR on ASH NEWS DAILY Monday, December 12, 2011 Dr. Sylvie Castaigne presents the final abstract in the Plenary Scientific session. the DAGO arm. There was no significant difference in deaths (4 vs. 6%) between the two arms. There was a highly significant advantage in event-free and disease-free survival at two years for patients who were treated on the DAGO arm. More importantly, this translated into a 10-month overall survival advantage for DAGO. The investigators concluded that the data from ALFA 0701 demonstrated a clear benefit in event-free survival, overall survival, and remission duration for patients treated in the DAGO arm. Plenary Introducer Dr. Martin Tallman, Memorial SloanKettering Cancer Center, commented BMT «« From Page A-1 He went on to explain that causes of treatment failure were also different in the two groups. More graft failure (8% vs. none in PBSC) and infection occurred in the marrow group, whereas more chronic and severe GVHD occurred in the BM group. Dr. Armand Keating, soon-to- be-minted president of ASH and former president of the American Society of Blood and Marrow Transplantation, commented on the significance of this study: “This is an impressive achievement by BMT-CTN, an important milestone in transplantation … the results suggest the need to reassess which patients will benefit from PBSC versus BM unrelated transplantation, including an evaluation of quality-of-life issues.” Indeed, this study sheds fur- ASH President Dr. J. Evan Sadler presents Dr. David G. Nathan with the Wallace H. Coulter Award for Lifetime Achievement in Hematology. ther light on the importance of individualizing the choice of graft that “This does not change the standard of care for this patient population; however, it does suggest that gemtuzumab warrants further investigation.” These data further perpetuate the ongoing debate on the use of gemtuzumab ozogamicin for the treatment of AML. Given the paucity of new agents that have proven efficacy in AML, it is truly hoped that these data will provide a new life for gemtuzumab ozogamicin, which has been clinging to life support these past years after being given up for dead in the United States. Dr. Bishop indicated no relevant conflicts of interest. source in patients undergoing transplant. PBSC may be preferred in patients with little previous cytotoxic chemotherapy, who are at greater risk of marrow failure. It may also be beneficial in patients who require more rapid engraftment, such as those at high risk of infection. By contrast, BM may be preferred in patients with better marrow function at time of transplant. Further studies and longer-term analysis will dictate the precise role of both modalities in patients undergoing transplant. In the interim, Dr. Anasetti stated plainly, “This study shows no survival differences between the arms, and therefore both sources are acceptable.” As a result, it is likely that both sources of grafts will continue to play a role in unrelated transplants, and you just may see more of your colleagues in the OR at harvest time. Dr. Mikhael indicated no relevant conflicts of interest.

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ASH News Daily - Monday, December 12, 2011

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