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Mitoxantrone, Etoposide, and Cytarabine With or Without Valspodar in Patients With Relapsed or Refractory Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome: A Phase III Trial (E2995)

From the Stanford University Medical Center, Stanford; VA Palo Alto Health Care System, Palo Alto, CA; Dana- Farber Cancer Institute, Boston, MA; Northwestern University Feinberg School of Medicine, Chicago, IL; Mayo Clinic, Rochester, MN; Our Lady of Mercy Medical Center, Bronx; Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY; and Rambam Medical Center, Haifa, Israel

Address reprint requests to Peter Greenberg, MD, Hematology Division, Stanford University Medical Center, 703 Welch Rd, Suite G-1, Stanford, CA 94305; e-mail: peterg{at}stanford.edu

PURPOSE: To determine whether adding the multidrug resistance gene-1 (MDR-1) modulator valspodar (PSC 833; Novartis Pharmaceuticals, Hanover, NJ) to chemotherapy provided clinical benefit to patients with poor-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS).

PATIENTS AND METHODS: A phase III randomized study was performed using valspodar plus mitoxantrone, etoposide, and cytarabine (PSC-MEC; n = 66) versus MEC (n = 63) to treat patients with relapsed or refractory AML and high-risk MDS.

RESULTS: For the PSC-MEC versus MEC arms, complete response (CR) was achieved in 17% versus 25% of patients, respectively (P = not significant). For patients who had not received prior intensive chemotherapy (ie, with secondary AML or high-risk MDS), the CR rate was increased—35% versus 15% for the remaining patients (P = .018); CR rates did not differ between treatment arms. The median disease-free survival in those achieving CR was similar in the two arms (10 versus 9.3 months) as was the patients’ overall survival (4.6 versus 5.4 months). The CR rates in MDR+ (69% of patients) versus MDR- patients were similar for those receiving either chemotherapy regimen (16% versus 24%). The CR rate for unfavorable cytogenetic patients (45% of patients) was 13% compared to the remainder, 28% (P = .09). Population pharmacokinetic analysis demonstrated that the clearances of mitoxantrone and etoposide were decreased by 59% and 50%, respectively, supporting the empiric dose reductions in the PSC-MEC arm designed in anticipation of drug interactions between valspodar and the chemotherapeutic agents.

CONCLUSION: CR rates and overall survival were not improved by using PSC-MEC compared to MEC chemotherapy alone in patients with poor-risk AML or high-risk MDS.

This study was conducted by the Eastern Cooperative Oncology Group (Robert L. Comis, MD, Chair) and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA13650, CA17145, CA11083, and from the National Cancer Institute (NCI), National Institutes of Health (NIH), and the Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCI. The pharmacokinetic studies were also supported by NIH grants R01 CA 52168 (B.I.S.) and M01 RR 00070 (General Clinical Research Center, Stanford University School of Medicine).

Reported in part at the American Society of Hematology meeting, New Orleans, LA, December 6, 1999.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

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