Novel Drugs for Chronic Lymphocytic Leukemia in 2014


Ann Hematol Oncol. 2014;1(1): 1001.

Novel Drugs for Chronic Lymphocytic Leukemia in 2014

Tadeusz Robak

Department of Hematology, Medical University of Lodz, Poland

*Corresponding author: Tadeusz Robak, Department of Hematology, Medical University of Lodz, Lodz, Copernicus Memorial Hospital, 93-510 Lodz, Ul. Ciolkowskiego 2, Poland

Received: August 05, 2014; Accepted: August 15, 2014; Published: August 15, 2014

Chronic lymphocytic leukemia (CLL) is a mature B-cell lymphoid neoplasm characterized by the proliferation and accumulation of small CD5/CD19/CD23-positive lymphocytes in the blood, lymph nodes, spleen, liver and bone marrow [1]. It is the most prevalent leukemia in the western world with an estimated 15, 720 new cases in 2014 and almost 4600 attributable deaths per year in the United States [2]. The management of CLL is determined by the stage and activity of the disease, as well as age and comorbidities [3]. CLL is typically sensitive to a variety of cytotoxic drugs, but the disease is considered incurable. Over the past few years, more effective therapies have emerged in the treatment of CLL, especially combinations of anti-CD20 monoclonal antibodies (mAbs) with purine analogs and bendamustine. These more intensive treatments induce higher response rates and longer response duration and longer survival in younger, fit patients. Currently FCR immune chemotherapy (Fludarabine + Cyclophosphamide + Rituximab) is the first-line choice for younger, physically-fit patients with CLL [4]. Chemo immunotherapy with bendamustine and rituximab (BR) is also effective and safe in patients with previously treated and untreated CLL [5]. Therefore, BR can be considered as a therapeutic option for previously untreated CLL patients, particularly those who are less suitable for FCR. However, older patients with several comorbidities experience increased toxicity with these newer therapies. In addition, there is still a subset of patients who are refractory to standard treatments based on purine analogs, and who demonstrate very poor survival. Recently, significant progress in the knowledge of the biology of CLL has promoted the development of new drugs directed to new biological targets that have shown promise in treating this disease [6]. Several new mAbs directed against lymphoid cells have been developed and investigated in preclinical studies and clinical trials [7], some of which are highly active in chronic lymphoid malignancies and are potentially useful in the treatment of CLL.

Anti-CD20 Monoclonal Antibodies

New mAbs directed against CD20, ofatumumab and obinutuzumab (GA-101) have been recently approved for the treatment of CLL.

Ofatumumab (HuMax-CD20; Arzerra ™, GlaxoSmithKline plc/Genmab A/S) is a fully human, IgG1 mAb which recognizes a different CD20 epitome than rituximab and demonstrates a higher cytotoxic potential [8]. Ofatumumab is more effective than rituximab at CDC induction and killing target cells. The results of a phase III study demonstrate that ofatumumab monotherapy shows promising efficacy in heavily pretreated patients with fludarabineand alemtuzumab-refractory CLL [9]: the overall response (OR) rates were 58% and 47% in the fludarabine- and alemtuzumab-refractory groups and fludarabine-refractory CLL with bulky lymphadenopathy groups, respectively. Median progression free survival (PFS) and overall survival (OS) times were 5.7 and 13.7 months in the fludarabine- and alemtuzumab-refractory groups, and 5.9 and 15.4 months, respectively, in the group of fludarabine-refractory patients with bulky lymphadenopathy. In 2009, the FDA granted accelerated approval to ofatumumab for the treatment of patients with fludarabine- and alemtuzumab-refractory CLL.

In a recent randomized trial (Complement1), ofatumumab + chlorambucil therapy was compared with chlorambucil alone in patients with CLL who required therapy and were considered inappropriate for fludarabine-based therapy due to advanced age and/or co-morbidities [10]. The results of this study indicate that ofatumumab + chlorambucil is superior to chlorambucil alone in this patient population. The ofatumumab + chlorambucil arm demonstrated a higher OR rate than the chlorambucil arm (82% vs. 69%) (p=0.001), as well as a superior CR rate (12% vs 1%). PFS was also significantly prolonged in the ofatumumab + chlorambucil arm (22.4 months) compared to chlorambucil alone (13.1 months, p<0.001). With a median follow-up of 29 months, median OS was not reached for both groups.

Obinutuzumab (Gazyva™, GA-101, RO5072759, Roche) is a novel third generation monoclonal antibody which is distinct from Rituximab [11]. The antibody is based on proprietary GlycoMAb(®) technology, which incorporates glycol engineered antibodies that specifically increase antibody-dependent cellular cytotoxicity (ADCC) and thereby increase immune-mediated target cell death. The results of a large randomized phase III trial testing two first-line chemo-immunotherapy regimes, i.e. obinutuzumab and rituximab combined with chlorambucil, and chlorambucil monotherapy as a comparator, in CLL patients with comorbidities have been recently reported (CLL11) [12]. The trial included 781 patients with previously untreated CLL and a score higher than 6 on the Cumulative Illness Rating Scale (CIRS) or an estimated creatinine clearance of 30 to 69 ml per minute. Treatment with obinutuzumab + chlorambucil resulted in higher rates of complete response than rituximab-chlorambucil (20.7% vs. 7.0%). Treatment with combined obinutuzumab + chlorambucil or Rituximab +chlorambucil therapy increased OR rates and prolonged PFS as compared with chlorambucil monotherapy. Median PFS was 26.7 months with obinutuzumab + chlorambucil, 15.2 months for rituximab + chlorambucil, and 11.1 months for chlorambucil alone (P<0.001). In addition, patients treated with obinutuzumab + chlorambucil demonstrated longer OS then chlorambucil alone (P=0.002). However, infusion-related reactions and neutropaenia were more common in patients treated with obinutuzumab + chlorambucil than with rituximab + chlorambucil. The U.S. Food and Drug Administration (FDA) and European Medicinal Agency (EMA) have approved obinutuzumab for use with chlorambucil in patients with previously untreated CL [13].

Citation: Robak T. Novel Drugs for Chronic Lymphocytic Leukemia in 2014. Ann Hematol Oncol. 2014;1(1): 1001. ISSN:2375-7965