PHARMACEUTICAL NEWS

This issue will be dedicated to new, clinically relevant information from both the 2008 American Society of Hematology (ASH) Annual Meeting and Exposition and the 2008 San Antonio Breast Cancer Symposium (SABCS).


ASH 2008

JAK2 Inhibitor Therapy for Myeloproliferative Disorders
a Hot Topic

Numerous phase I and phase II studies of JAK2 inhibitors for the treatment of myeloproliferative disorders were presented at ASH in San Francisco. The JAK2-V617F mutation is found in 99% of patients with polycythemia vera (PV), 50% of patients with essential thrombocytosis (ET), and half of those with myelofibrosis (MF). Traditionally, these patients suffered from a lack of particularly efficacious therapy; but now, thanks to the strong pipeline of specific and targeted inhibitors of JAK2, they benefit from significant reduction in splenomegaly, dramatic improvement in constitutional symptoms and quality of life, and improvement in hematologic response.

As an example, the histone deacetylase (HDAC) inhibitor ITF2357 inhibits the autonomous proliferation of hematopoietic cells from patients with PV and ET through down modulation of mutated JAK2. ITF2357 was evaluated in a phase IIA safety and efficacy trial in the treatment of patients with JAK2-positive PV, ET, and MF. The oral 50 mg twice daily dosage was well tolerated. In the patients with PV/ET, a complete response (CR) was achieved in 23% and a partial response (PR) in 62%. Rapid improvement of constitutional symptoms, spleen size (75% of patients with splenomegaly), and hematologic response were reported in the great majority of the patients with PV/ET and in some patients with MF.

Rambaldi A, et al. Blood. 2008;112: Abstract 100.

Will One or Both of These Second Generation Tyrosine Kinase Inhibitors Supplant Imatinib as First-Line Therapy for Chronic Myelogenous Leukemia?

A phase II trial of nilotinib (Tasigna^®) 800 mg daily as first-line treatment of patients with Philadelphia chromosome (Ph)–positive chronic myelogenous leukemia (CML) in early chronic phase (ECP) has demonstrated that both cytogenetic response and molecular response to nilotinib are substantially faster than the responses to imatinib (Gleevec^®/Glivec^®). The primary endpoint was the complete cytogenetic response (CCyR) rate at 1 year. Results: CCyR rate 78% at 3 months and 96% at 6 months. In comparison, the IRIS study reported a CCyR rate for the imatinib 400 mg arm of 25% at 3 months and 51% at 6 months. In the current study, a major molecular response (MMR) was achieved by 3% of all nilotinib-treated patients after 1 month on treatment, but this rapidly increased to 22% after 2 months, 59% after 3 months, and 74% after 6 months. Adverse events (AEs): the most frequent biochemical lab abnormalities (grade 3) were total bilirubin increase (15%), GOT/GPT increase (11%), and lipase increase (4%). At 6 months of follow-up, the incidence of any grade 2 and 3 nonhematologic AEs decreased from 50% and 8% (in the first 3 months) to 23% and 6%, respectively.

Rosti G, et al. Blood. 2008;112: Abstract 181.

Dasatinib (SPRYCEL^®) is a multitargeted kinase inhibitor of BCR-ABL and SRC with significant activity in patients with chronic phase CML (CML-CP) resistant to or intolerant of imatinib. A phase II study was designed to investigate the efficacy and safety of dasatinib in patients with previously untreated CML-CP. The primary objective was to estimate the proportion of patients attaining MMR at 12 months. Fifty patients were randomized to either dasatinib 50 mg BID or 100 mg once daily. Median follow-up was 24 months. Results: 98% of evaluable patients achieved a CCyR. Major molecular response was achieved in 34% of patients at 12 months and in 48% at 18 months. Grade 3-4 nonhematologic toxicity: 13% pruritis and 21% pleural effusion. The 24-month event-free survival rate was 81%. While accrual to this trial continues, the investigators have concluded that rapid CCyR occurs in most patients treated with dasatinib front-line therapy.

Cortes J, et al. Blood. 2008;112: Abstract 182.

An Effective, Safe Oral Monotherapy for Relapsed or Refractory Mantle Cell Lymphoma

A recent phase II trial (NHL-002) of single-agent lenalidomide (REVLIMID^®) in patients with relapsed or refractory mantle cell lymphoma (MCL) demonstrated a promising overall response rate (ORR) of 53% with a median duration of response of 11.9 months. A confirmatory international phase II trial (NHL-003) of lenalidomide was initiated for patients with relapsed/refractory non-Hodgkin lymphoma (NHL) that had received at least one prior treatment and had measurable disease ≥2 cm. Analysis of the 39 patients with MCL in this trial is reported here. Lenalidomide 25 mg was given orally once daily on days 1-21 of every 28-day cycle until disease progression or toxicity. Median time from diagnosis to lenalidomide treatment was 3.4 years. The ORR was 41%, including 13% CR/unconfirmed CR and 28% PR; stable disease was reported in 26%. The most common grade 3 or 4 AE was neutropenia, reported in 10% of patients. Conclusion: These results confirm that lenalidomide oral monotherapy is an effective treatment, with manageable side effects, for patients with relapsed/refractory MCL.

Zinzani PL, et al. Blood. 2008;112: Abstract 262.

Chemoimmunotherapy in Chronic Lymphocytic Leukemia: Is It the New Standard First-Line Therapy and What Will Be the Role of the New Anti-CD20 Antibody?

Three previous phase II studies have suggested that the addition of rituximab (Rituxan^®/MabThera^®, R) to fludarabine plus cyclophosphamide (FC) chemotherapy may increase the outcome of both untreated and relapsed patients with chronic lymphocytic leukemia (CLL). The first randomized phase III trial (CLL 8) compared chemotherapy with FCR versus FC for the first-line treatment of patients with advanced CLL. Six cycles of treatment were planned. Of 817 patients enrolled, 761 were evaluable; median age was 61 years; 64% were Binet B, 32% Binet C, and 5% Binet A. Results: median follow-up was 25.5 months; ORR was 95% for patients treated with FCR vs 88% for patients in the FC arm (P = .001). Progression-free survival at 2 years was 76.6% vs 62.3%, respectively (hazard ratio [HR] 0.59; P<.0001). A 52% CR was reported for the FCR arm vs 27% for the FC arm (P<.0001). There was a trend for increased overall survival (OS) in patients treated with FCR, 91% vs 88% at 2 years (HR = 0.76; P = .18). The longest benefit for FCR was seen in patients with Binet stage A and B with regard to CR, ORR, and PFS. Conclusion: FCR improves response rates (superior ORR and CR) and PFS compared to FC; causes more neutropenia/leukopenia without increasing incidence of severe infections; and is safe and well tolerated in patients 65-70 years old. These findings suggest that FCR could possibly become the new standard first-line treatment for fit elderly patients with advanced CLL.

Hallek M, et al. Blood. 2008112: Abstract 325.

Ofatumumab (HuMax-CD20^®/Arzerra™) is a fully human anti-CD20 monoclonal antibody that is active in NHL and CLL. It was found to have single-agent activity in patients with refractory CLL (double-refractory to both fludarabine and alemtuzumab) achieving an ORR of 58% in double refractory patients and 47% ORR in patients with bulky fludarabine-refractory CLL. Since this monoclonal antibody is fully human and has potential, could it become an alternate to rituximab in the future?

Osterborg A, et al. Blood. 2008;112: Abstract 328.

Dual Pathway Blockade Regimen Achieves High Quality Responses in High-Risk Myeloma

Bortezomib (VELCADE^®, Bz) and lenalidomide (Len) affect different pathways; therefore, when used together, multiple pathways may be blocked. A phase I/II study was designed to determine the maximum planned dose of Len/Bz/dDex (RVD) and to assess safety and efficacy in previously untreated patients with myeloma in high-risk groups. Patients with at least a PR could proceed to autologous stem cell transplantation (ASCT) after 4 cycles. Data are available for 66 patients (median age 58 years, 67% IgG disease, 50% International Staging System [ISS] stage II/III). Patients have received a median of 10 cycles and toxicities have been manageable. The ORR (≥PR) is 98%, including 71% ≥ very good partial response and 36% CR/near CR; at the maximum planned dose, ORR is 100%. Efficacy was independent of baseline cytogenetics or ISS stage. Fifteen patients have proceeded to ASCT. After a median follow-up of 8 months, the median time to progression, PFS, and OS have not been reached. Conclusion: RVD produces high quality responses and is well tolerated in this patient population, regardless of cytogenetics and ISS stage. Maximum planned dose was reached at Len 25 mg, Bz 1.3 mg/m², and Dex 20 mg. Stem cell mobilization was successful in almost all patients.

Richardson P, et al. Blood. 2008;112: Abstract 92.

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