We Need Gemtuzumab Available Again to Treat AML

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Farhad Ravandi, MD

In an era of personalized and targeted therapy, it seems illogical to withdraw gemtuzumab, the only agent newly approved for the treatment of AML in the past 15 years.

—Farhad Ravandi, MD, Jorge Cortes, MD, and Hagop Kantarjian, MD

The word “revival” signifies a renewed use or acceptance after a period of inactivity; similarly, the word “resurrection” refers to the concept of an entity coming back to life after death. In the past year, these terms have been used frequently by us (and others) in articles calling for the return of gemtuzumab ozogamicin (Mylotarg).1-3 Some may wonder about the intense interest in bringing this drug back to clinical oncology. Do the available data support the assertion that gemtuzumab is an important drug in the treatment of patients with acute myeloid leukemia (AML)? Do they justify a reversal of the decision by the producers of the drug to withdraw it from the market?

Efficacy and Economics

In previous commentaries, we have discussed the data supporting the role of gemtuzumab in the treatment of patients with acute promyelocytic leukemia (APL).1 A significant number of clinical trials have clearly established the activity of gemtuzumab in patients with APL, both in the front-line and relapse settings.

The argument against its use is that APL is now highly curable using all-trans retinoic acid, arsenic trioxide (Trisenox), and anthracyclines, and we can do without gemtuzumab.4 However, the advantages of a “chemotherapy-free” regimen are becoming more apparent, with recent trials demonstrating the superiority of such regimens in low-risk APL and the effectiveness of gemtuzumab in replacing anthracyclines in high-risk patients, thereby avoiding the well described risk of late cardiomyopathy.5,6

Several recent large prospective randomized clinical trials have shown that the addition of a small dose of gemtuzumab to cytarabine and anthracycline-based induction and consolidation provides a survival advantage to patients with core-binding factor leukemias. In randomized trials by the Southwest Oncology Group (SWOG) and the UK’s Medical Research Council (MRC) analyzing the subset of core-binding factor AML, the addition of gemtuzumab was associated with significantly improved survival.7,8

Furthermore, accumulating data have shown the benefit of gemtuzumab in intermediate-risk AML, both in younger patients (MRC study7) and older patients (French study9), when added to chemotherapy. Thus, in an era of personalized and targeted therapy, it seems illogical to withdraw gemtuzumab, the only agent newly approved for the treatment of AML in the past 15 years.

This is particularly of concern when many new agents in various solid tumors have been approved with only limited benefits in progression-free survival with or without survival benefits. In renal cell cancer alone, the FDA approved seven agents between 2005 and 2012 based on improvements in progression-free survival, with survival improvement for only one of those drugs, temsirolimus (Torisel).

Also, in contrast to solid tumors, where the market share of new targeted agents can represent billions of dollars, the total market share of gemtuzumab at the time of its withdrawal was only $20 million annually. This raises the question of whether economic considerations dominated the decision, discouraging Pfizer from stronger efforts to keep gemtuzumab available in the U.S. market.

Important Step Forward

The question that arises then is, even if we accept the benefit of gemtuzumab in AML subsets, does it justify the reversal of the decision in a relatively uncommon disease with a relatively favorable prognosis? The answer is a resounding yes.

In the past century, we have witnessed significant progress in medicine leading to a gradual but steady rise in life expectancy and quality of life in the industrialized world. With the exception of a few notable giant leaps, such progress has been accomplished mainly through incremental steps.

What may be considered minimal progress in clinical trials, such as improvements in survival of a few months, can lead, over the long haul, to meaningful improvements in life expectancy. The reintroduction of gemtuzumab would likely benefit only a subset of patients with AML, but it remains an important step toward curing leukemia.

Resurrected Agents

In the history of medicine, few drugs have been worthy of the label ”Lazarus-like,” having been resurrected from obscurity to full FDA approval, usually for indications unrelated to the ones they were previously used for. Thalidomide (Thalomid), a drug originally developed and used as a sedative, was withdrawn by the FDA, only to be re-introduced for a variety of indications such as mouth ulcers, leprosy, and, most recently, multiple myeloma.10

Arsenic trioxide was used at the turn of the 20th century for a variety of ailments as a component of Fowler’s solution. Its reappearance in Western medicine was largely due to the demonstration of its significant activity in relapsed APL by Chinese investigators.11

The recent approval of omacetaxine mepesuccinate (aka homoharringtonine [Synribo]) in advanced chronic myelogenous leukemia is another example of a drug abandoned after prior significant enthusiasm, only to be resurrected for special indications.12

Closing Thoughts

Clearly, we are making progress in treating various cancers through better understanding of the mechanisms of carcinogenesis and identification of targets for drug development. A great deal of enthusiasm has been generated in favor of targeted and personalized therapies for increasingly smaller subsets of patients with different cancers. Such examples are numerous and include the use of RAF inhibitors in BRAF-mutated melanoma, monoclonal antibodies in various lymphoid malignancies, ALK inhibitors in ALK-positive lymphomas and lung cancer, and so forth.

In this exciting era, it seems anachronic that gemtuzumab would be withdrawn from the United States as a treatment for AML. We therefore renew our call for restoration of gemtuzumab ozogamicin as a treatment option for patients with AML. ■

Disclosure: Drs. Ravandi, Cortes, and Kantarjian reported no potential conflicts of interest.

Dr. Ravandi and Dr. Cortes are Professors in the Department of Leukemia, and Dr. Kantarjian is Chair of the Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston.


1. Ravandi F, Estey EH, Appelbaum FR, et al: Gemtuzumab ozogamicin: Time to resurrect? J Clin Oncol 30:3921-3923, 2012.

2. Ravandi F, Kantarjian H: Haematological cancer: Gemtuzumab ozogamicin in acute myeloid leukaemia. Nat Rev Clin Oncol 9:310-311, 2012.

3. Estey E: Treatment of AML: Resurrection for gemtuzumab ozogamicin? Lancet 379:1468-1469, 2012.

4. Iland HJ, Bradstock K, Supple SG, et al: All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood 120:1570-1580, 2012.

5. Lo-Coco F, Avvisati G, Orlando SM, et al: ATRA and arsenic trioxide (ATO) versus ATRA and idarubicin (AIDA) for newly diagnosed, non high-risk acute promyelocytic leukemia (APL): Results of the phase III, prospective, randomized, intergroup APL0406 study by the Italian-German Cooperative Groups Gimema-SAL-AMLSG. 2012 ASH Annual Meeting. Abstract 6. Presented December 9, 2012.

6. Ravandi F, Estey E, Jones D, et al: Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 27:504-510, 2009.

7. Burnett AK, Hills RK, Milligan D, et al: Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: Results of the MRC AML15 trial. J Clin Oncol 29:369-377, 2010.

8. Petersdorf S, Kopecky K, Stuart RK, et al: Preliminary results of Southwest Oncology Group Study S0106: An international intergroup phase 3 randomized trial comparing the addition of gemtuzumab ozogamicin to standard induction therapy versus standard induction therapy followed by a second randomization to post-consolidation gemtuzumab ozogamicin versus no additional therapy for previously untreated acute myeloid leukemia. Blood (ASH Annual Meeting Abstracts) 114:Abstract 790, 2009.

9. Castaigne S, Pautas C, Terre C, et al: Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): A randomised, open-label, phase 3 study. Lancet 379:1508-1516, 2012.

10. Singhal S, Mehta J, Desikan R, et al: Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341:1565-1571, 1999.

11. Shen ZX, Chen GQ, Ni JH, et al: Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 89:3354-3360, 1997.

12. Cortes J, Lipton JH, Rea D, et al: Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood 120:2573-2580, 2012.