HEMATOLOGIC MALIGNANCY

Combining Targeted Agents in Newly Diagnosed Multiple Myeloma: Will Early Results Lead to a New Standard of Care?
Phase I/II safety and efficacy trial of lenalidomide (Len), bortezomib (Bz), and dexamethasone (Dex) in patients with newly diagnosed multiple myeloma. Primary objectives to define the MTD and assess response rate to Len/Bz/Dex. Patients: 68 enrolled, median age 58 years, 51% men, 67% IgG, 49% ISS stage II/III. Patients have received median of 6 cycles. Toxicities manageable with no unexpected toxicities, no G4 PN, 2 DVTs, no treatment related mortality. ORR 98% with 71% CR/nCR/VGPR. MTD reached: Len 25 mg d 1-14, Bz 1.3 mg/m2 on d 1-4, 5-8 for up to eight 21 day cycles.

Conclusions: Len/Bz/Dex is very active and well tolerated in newly diagnosed patients, and this regimen has no adverse affect on stem cell harvesting. These early results are encouraging and hopefully will be confirmed in phase III trials.
Abstract #8520 P.G. Richardson, et al. J Clin Oncol 26: 2008

Are Responses to Second Generation TKIs Durable in CML?
Extended 2-year follow-up data from the phase II START-C study of dasatinib therapy for patients with chronic phase chronic myelogenous leukemia (CML-CP) with resistance or intolerance to imatinib was reported at the ASCO Annual Meeting in Chicago. The starting dose of dasatinib was 70 mg BID. The primary endpoint was major cytogenetic response rate (M CyR) and 387 patients were evaluated. Results: 24 month response rates with dasatinib MCyR 62%, CCyR (complete cytogenetic response rate) 53%, and MMR (major molecular response) among CCyR 79%. Duration of MCyR at 24 months: 88% of patients without loss of MCyR; duration of CCyR=90% remain in CCyR at 24 months.

Conclusion: These data demonstrate continuing efficacy of dasatinib at 2 years. 70 mg BID dose well tolerated but more non-heme side effects (diarrhea, rash, headache, edema, and pleural effusions) at 24 months compared to 1 year. In a subsequent phase III dose-optimization study, 100 mg once daily was optimal and the most favorable risk-benefit ratio was with this dose that was approved for CML-CP.
Abstract #7009 M.Mauro, et al. J Clin Oncol 26: 2008

What Hematologic Response is Necessary To Get Clinical Benefits in Higher-Risk Myelodysplastic Syndromes?
A large international phase III trial (AZA-001) showed that azacitidine (AZA) is the first myelodysplastic syndromes (MDS) treatment to significantly extend OS vs. conventional care regimens (CCR). While the IWG 2000 emphasizes the importance of CR to extend survival, clinical validation in MDS is lacking. This analysis evaluated effects of AZA vs. CCR on 1-year survival of MDS patients from the AZA-001 trial including those with IPSS Int-2 or high risk. Patients (N=358) randomized to either AZA (75 mg/m2/day SC x 7d q 28d) + best supportive care (BSC) or to CCR (low dose Ara-C, induction 7+3 chemotherapy, or BSC only). One-year survival rates were determined for all treated patients and for AZA subsets according to IWG-defined CR or PR, stable disease (SD), or hematologic improvement as best response, or disease progression (DP). AZA maintained a significant survival benefit vs. CCR with exclusion of CR patients from the analysis (HR for OS=0.65) and 1-year survival rates were significantly higher in AZA-treated patients than in CCR-treated patients: 68.2% vs. 55.6% (p=0.015). When analyzed by IWG best response, all response categories including SD showed an OS benefit with AZA treatment.

Conclusion: Results are the first to show that achievement of CR is not an obligate endpoint to extend OS in higher-risk patients with MDS. IWG responses of HI, PR, or CR are associated with improvement in OS with AZA treatment. AZA is a disease-modifying agent that prolongs OS by effects that appear distinct from its cytotoxic or anti-leukemia action alone. IWG responses of HI, PR, or CR are associated with improvement in OS with AZA treatment.
Abstract #7006 A. List, et al. J Clin Oncol 26: 2008

Expanding the Options for Imatinib-Resistant Chronic Myelogenous Leukemia
Updated phase II results from a trial of nilotinib in patients with imatinib-resistant or –intolerant chronic myelogenous leukemia in chronic phase (CML-CP) confirm that the drug induces significant and durable responses in this patient population, it is well tolerated with minimal occurance of grade 3-4 adverse events (A/E), and minimal cross-intolerance to imatinib. Nilotinib dose was 400 mg p.o. BID (2 hours from meals) with the possibility to dose escalate to 600 mg BID. Primary endpoint was rate of major cytogenetic response rate (MCyR). Total of 321 patients (71% imatinib-resistant and 29% imatinib-intolerant). Results: 72% had received prior imatinib (I) doses >600 mg; of the 206 who did not have a complete hematological remission (CHR) at baseline, 77% achieved CHR during nilotinib therapy. Overall, MCyR observed in 57%; 41% had complete CyR (CCyR). MCyR in 55% of I-resistant and 63% of I-intolerant patients. Median time to CHR 1.0 months, and to MCyR was 2.8 months. 84% maintained MCyR at least 18 months and at 18 months the estimated OS rate was 91%. Nilotinib treatment is ongoing in >50% of patients enrolled. PFS at 12 months 79% and 67% at 18 months. OS at 12 months 95% and at 18 months is 91%. Toxicities: Most frequent grade 3-4 AEs: Thrombocytopenia 28%, neutropenia 30%, and anemia 10%. Non-heme A/Es were evaluated serum lipase 45% with 16% G 3-4. No pericardial or pleural effusions.

Conclusions: With the impressive efficacy, more tolerable safety profile, and minimal cross-intolerance nilotinib is a candidate for both single agent use and for future trials with combination regimens.
Abstract # 7010 H. M. Kantarjian, et al. J Clin Oncol 26: 2008