By Mikkael A. Sekeres, MD, MSBy Mikkael A. Sekeres, MD, MSBy Mikkael A. Sekeres, MD, MS

2009-12-08

If you were a mad scientist — a real Dr. Destructo type — and wanted to design a disease that is largely incurable, affects people at the twilight of their lives, right around the time they start to enjoy a well-earned retirement, and despite dramatic improvements in biotechnology has caused clinical researchers to beat their heads against a wall (Yiddish, “gai shlog dein kup en vant”) for 35 years, trying to improve on a therapeutic regimen from the early 1970s that is still widely used in 2009, you’d probably consider AML in older adults to be simply too cruel.

And yet, here we are. The median age at diagnosis for AML is approximately 67 years. Less than 10 percent of older adults with AML will be cured of their disease, and that chance of cure comes courtesy of the standard bearer of remission induction therapy, 7+3 (that is, 7 days of low-dose cytarabine administered at 100-200mg/m2 daily by continuous infusion, plus 3 days of an anthracycline such as daunorubicin, given at doses of 45-90mg/m2 daily by intravenous bolus). While altering the amount of chemotherapy administered, using priming agents, or adding other agents to 7+3 have improved remission rates, these interventions have done little to alter the gold standard for AML outcome — overall survival.

Is this viewpoint too nihilistic? Perhaps. In truth, advances have been made in AML, some of which will be highlighted in today’s Oral Session, Acute Myeloid Leukemia  – Therapy, excluding Transplantation: Novel Therapy for Older AML Patients, being held from 7:30 to 9:00 a.m. in rooms 217-219. Two presentations led by Dr. Jason Chandler of The Ohio State University and Dr. Ravi Vij of Washington University in St. Louis  focus on the role of lenalidomide in treating this disease. Dr. Chandler will describe a phase I/II study of 31 patients with relapsed/refractory AML or ALL.  The maximum tolerated dose of lenalidomide was determined to be 50 mg (!) once daily for 21 out of 28 days; complete responses occurred in five patients. The second study enrolled 33 untreated older patients with AML who were treated with lenalidomide at a dose of 50 mg daily for 28 days for two induction cycles, followed by maintenance therapy at a dose of 10 mg/day. The overall response rate was 30 percent. For both studies, responses were not associated with a del (5q) abnormality.

The presentations on lenalidomide will be followed by two presentations by Drs. Sylvain Thépot and Claude Gardin, on behalf of the Groupe Francophone des Myelodysplasies, exploring responses to the DNA methyltranferase inhibitor azacitidine in patients with AML who were considered unsuitable for intensive chemotherapy. The first study retrospectively analyzed 138 patients with AML who received azacitidine in a compassionate use protocol. The patients’ median age was 73 years; 14 percent achieved a complete response, with higher response rates in patients with lower white blood cell counts and normal cytogenetics. In the second study, 46 patients with a median age of 66 years were treated with azacitidine maintenance therapy after having received cytotoxic intensive induction chemotherapy. Using this approach, median disease-free and overall survival were 6.5 and 18 months, respectively. For both studies, it remains to be seen whether these approaches are superior to cytarabine-based management.

The final two presentations will both focus on older patients with acute promyelocytic leukemia (APL). Dr. Lionel Ades and colleagues from the European APL and PETHEMA groups compared 287 patients older than age 60 to 1,288 patients younger than age 60 treated in four studies using chemotherapy combined with all-trans retinoic acid. Despite response rates that are comparable to those of younger patients, overall survival is lower, with a higher incidence of both deaths occurring in CR and early deaths than for younger patients, arguing in favor of approaches that minimize toxicity in the post-remission setting. Dr. Vikram Mathews from Christian Medical College in Vellore, India, will then describe results with single-agent arsenic in APL, a regimen that is much cheaper than ATRA + chemotherapy and that may be useful in parts of the world where ATRA + chemotherapy is unaffordable.

Taken together, these data indicate that less toxic strategies may be an efficacious alternative to 7+3 in older people with AML, providing the potential for disease-modifying therapy that preserves quality of life.

Dr. Sekeres indicated no relevant conflicts of interest.

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