A study from The University of Texas MD Anderson Cancer Center that evaluated long-term outcomes in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) found that the combination treatment of a hyper-CVAD regimen (cyclophosphamide, vincristine, doxorubicin, dexamethasone) and imatinib has more benefits than hyper-CVAD alone, according to results presented at the 2010 ASCO Annual Meeting by Deborah Thomas, MD, Associate Professor in the Department of Leukemia at M. D. Anderson. In the study of 54 de novo or minimally treated patients with Ph+ ALL, the 3-year rate of complete response duration for those receiving hyper-CVAD plus imatinib was 68%, compared with 24% for a historical cohort treated with hyper-CVAD alone (P < .001). The combination regimen also resulted in significantly improved overall survival of 54% at 3 years, compared with 15% for hyper-CVAD.

"Ph+ ALL has historically been very difficult to treat, although 90% of patients achieve an initial complete response even with traditional chemotherapy regimens-but long-term survival is only in the region of 10% to 20%," said Farhad Ravandi, MD, Associate Professor in the Department of Leukemia at MD Anderson. Dr. Ravandi presented the data at the Best of ASCO meeting in San Francisco.¹

"The regimen of hyper-CVAD plus imatinib is very effective and does improve outcomes, especially for patients who do not go on to a stem cell transplant," he added.

Of 35 patients in the study who received imatinib and did not proceed to an allogeneic stem cell transplant (aSCT) after complete response, 10 are still in complete remission, he said. Yet Dr. Ravandi noted that the study's long-term data suggest that aSCT remains important for those who receive hyper-CVAD plus imatinib, particularly for patients under age 40.

Study Design

The study included de novo and primary refractory imatinib-naive Ph+ ALL patients as well as those who achieved a complete response after one cycle of an alternative induction therapy without imatinib. The regimen consisted of eight cycles of alternating hyper-CVAD with methotrexate/cytarabine as well as 600 mg of imatinib on days 1 to 14 of induction and continuously during courses 2 through 8. Patients received 800 mg of imatinib (or best tolerated dose) during 24 months of maintenance therapy with monthly vincristine/prednisone interrupted by two intensifications of hyper-CVAD plus imatinib, and then imatinib indefinitely. Results were compared to a historical cohort of 50 patients treated with hyper-CVAD without imatinib, also at MD Anderson.

Initial results after induction indicated that 36 (92%) of 39 de novo patients achieved a complete response as well as 100% of 6 patients with primary refractory disease. Also, more patients achieved a complete response after just one cycle of the imatinib regimen (85%) compared to those who received hyper-CVAD (70%).

Subgroup Results

Although initial study data did not indicate a benefit for aSCT in those who received imatinib, continued follow-up revealed that patients who went on to stem cell transplants experienced superior outcomes. When the investigators looked at use of aSCT in de novo patients younger than age 60 who received hyper-CVAD plus imatinib vs those in the same treatment group who did not go on to aSCT, the trend favored stem cell transplant-although the difference had not yet reached significance. The 3-year overall survival rates for these patients were 77% with aSCT vs 57% without aSCT (P = .1) When the researchers compared patients on chemotherapy alone who went on to aSCT vs those who did not, however, they found that patients in the hyper-CVAD historical cohort derived more survival benefits from stem cell transplant (P = .02).

Dr. Ravandi pointed out that the use of aSCT was particularly beneficial for de novo patients under age 40 in first complete remission after chemotherapy and imatinib. In this group, patients treated with imatinib had a 3-year overall survival rate of 90% with aSCT vs 33% without aSCT (P = .05). "It's very significant that only 1 out of the 10 who got a transplant has died, as opposed to 4 out of 6 patients who did not receive a transplant," he said.

Patients over age 60 who received imatinib fared worse than younger subjects because of the intensity of the regimen, Dr. Ravandi said. Among 16 de novo patients under age 40, treatment failed in 5, for instance, whereas among 13 patients over age 60, treatment failed in 10. The investigators did not find that persistence of BCR-ABL transcripts by quantitative polymerase chain reaction (PCR) testing was predictive of relapse.

Other TKIs

Dr. Thomas noted that second- or later-generation tyrosine kinase inhibitors used with hyper-CVAD might further improve treatment outcomes for patients with Ph+ ALL.

In fact, researchers at MD Anderson are now studying the use of dasatinib (Sprycel) combined with hyper-CVAD in patients with Ph+ ALL. In a recent phase II study of 35 previously untreated patients with Ph+ ALL, published in Blood,² Dr. Ravandi and fellow researchers found that the dasatinib/chemotherapy regimen achieved a 94% initial complete response rate. The median disease-free survival and overall survival had not been reached after 14 months, but the estimated 2-year survival rate was 64%. Although the dasatinib regimen does not appear to produce improved survival over one containing imatinib, Dr. Ravandi noted that 10% of patients in the dasatinib study went on to aSCT in first remission, compared with 20% of patients in the imatinib study reported at the Annual Meeting.

"One could argue hypothetically that dasatinib may negate the need for transplant in a subset of this population," Dr. Ravandi said. ■

References

1. Thomas DA, O'Brien SM, Faderl S, et al: Long-term outcome after hyper-CVAD and imatinib for de novo or minimally treated Philadelphia chromosome-positive acute lymphoblastic leukemia. Best of ASCO Annual Meeting San Francisco. Abstract 6506. Presented July 17, 2010, by Farhad Ravandi, MD.

2. Ravandi F, O'Brien S, Thomas D, et al: First report of phase II study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia. B lood. May 13, 2010 (epub ahead of print).