Stage set for further trials of rIL-2 in younger AML pts

ATLANTA—Preliminary results suggest that immunotherapy with recombinant interleukin-2 (rIL-2) may prolong survival in younger patients with acute myeloid leukemia in first remission. However, the high rate of refusal or discontinuation of such therapy presents challenges for its acceptance, Jonathan Kolitz, MD, of the Monter Cancer Center, Lake Success, New York, said at ASH 2007 (abstract 157) on behalf of the Cancer and Leukemia Group B.

CALGB conducted a randomized phase III trial (CALGB 19808) of rIL-2 vs observation in 734 younger patients (less than age 60) with AML who were in first remission following consolidation therapy with high-dose cytarabine (HiDAC) or autologous peripheral stem-cell transplantation (ASCT).

The first 302 patients were randomized to receive induction therapy consisting of cytarabine, daunorubicin, and etoposide (ADE) or ADE combined with the P-glycoprotein modulator PSC-833 (Valspodar) (ADEP); all remaining patients received ADE.

Those who achieved a complete response (CR) were treated with post-remission therapy according to cytogenetic risk factors. Patients who had core binding factor AML were administered three courses of HiDAC, while those with non-core binding factor AML underwent ASCT.

Of 716 patients evaluable for re-sponse, 549 (77%) achieved CR. How-ever, less than 40% of these patients (214) proceeded to randomization after HiDAC or ASCT. The remaining 214 patients were equally randomized to rIL-2 for 3 months or observation.

Post-consolidation rIL-2 therapy consisted of alternating low doses (1 106 U/m2) to expand cytotoxic T-cell effector cells with higher-dose bolus treatments (12-15 10⁶ U/m²) to activate this cell population. Median follow-up from post-remission randomization for the surviving patients was 29 months.

Based on an intent-to-treat analysis, the 3-year disease-free survival rate was 56% for patients on the rIL-2 arm and 45% for those on the observation arm (P = .11), with 3-year overall survival rates of 61% and 68%, respectively (P = .09).

Median overall survival was more than 53 months on the observation arm and had not yet been reached in the rIL-2 group (P = .052).

Grade 3-4 hematologic toxicities with rIL-2 included neutropenia (21%) and thrombocytopenia (25%), with 6% febrile neutropenia, while nonhematologic toxicities included hypotension (14%) and fatigue (12%). These and other factors contributed to poor compliance in the trial (see Table) More than half the patients randomized to the rIL-2 arm did not complete therapy as planned.

"Among 107 patients randomized to rIL-2," Dr. Kolitz noted, "23% refused to receive that therapy, which we had not anticipated." Dose reductions of rIL-2 were also common.

Future planning

Dr. Kolitz concluded that although post-consolidation immunotherapy with rIL-2 is feasible, it is poorly tolerated by patients and physicians.

Preliminary efficacy data suggest a possible benefit of rIL-2 in younger AML patients in first remission, which needs to be confirmed through longer follow-up incorporating clinical and laboratory correlates, he added.

This agent may find additional applications in combination regimens to enhance the response to other immunotherapeutics such as antibodies and vaccines, Dr. Kolitz said.

"We are hopeful that the outcomes of this trial will bring immunotherapy of AML in younger patients to the forefront for future planning," he concluded.