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The future of treatment for chronic lymphocytic leukemia: targeted therapies improve efficacy and limit toxicity


Several new, targeted therapies show promise to expand treatment options for chronic lymphocytic leukemia ( CLL ) and are more effective and better tolerated than standard chemotherapy, according to studies presented during the 55th American Society of Hematology Annual Meeting and Exposition in New Orleans.

Chronic lymphocytic leukemia is a blood cancer that occurs when abnormal white blood cells called lymphocytes accumulate in the blood, bone marrow, and lymph nodes or other organs, causing these organs to enlarge. Approximately 15,000 Americans are diagnosed with chronic lymphocytic leukemia every year, and nearly 70% of those affected are 65 or older. For some patients with a slower progressing disease, many physicians employ watch and wait strategies to minimize unnecessary toxic treatments. However, patients with high-risk features or a more rapidly progressing disease require prompt treatment.

While the current standard chemotherapy-based treatment regimen for patients with chronic lymphocytic leukemia has been effective in improving outcomes for these patients, it remains highly toxic, prompting additional research to identify strategies to further reduce the treatment burden. Newer drugs that more precisely target pathways and proteins known to trigger chronic lymphocytic leukemia development, and leave normal cells unharmed, are proving to be more effective in promoting cancer cell death while safer for the patient.
Three studies presented reveal data on the performance of several new chronic lymphocytic leukemia therapies that demonstrate potent effects on key regulators of cancer cell behavior.

Head-to-head comparison of Obinutuzumab plus Chlorambucil versus Rituximab plus Chlorambucil in patients with chronic lymphocytic leukemia and co-existing medical conditions: final stage II results of the CLL11 trial

A commonly used combination treatment for chronic lymphocytic leukemia consists of chemotherapy and Rituximab, a synthetic molecule engineered to target a protein on the surface of CLL cells ( CD20 ). While effective, Rituximab has less potency in chronic lymphocytic leukemia than in other cancers, and chemotherapy used in combination with Rituximab may not be well tolerated among elderly patients. In an effort to improve treatment options for chronic lymphocytic leukemia patients, investigators conducted a head-to-head comparison of Rituximab and Obinutuzumab ( GA101; Gazyva ), a novel monoclonal antibody engineered to attack CD20, but hypothesized to have more potent anti-leukemic effects.

To test their hypothesis, investigators enrolled 781 patients ( average age 73 ) and split them into three treatment arms: one arm received Obinutuzumab in combination with the standard chemotherapy Chlorambucil ( Clb; GClb, n=333 ), a second arm received Rituximab and Chlorambucil ( RClb, n=330 ), and a third arm received Chlorambucil alone (n=118). In combination with Chlorambucil, Obinutuzumab has demonstrated more anti-leukemic activity than Rituximab, leading to a statistically significant and clinically meaningful prolongation of the median progression-free survival ( 26.7 months in the GClb arm and 15.2 months in the RClb arm ) as well as a higher overall response rate (7 8% GClb vs 65% RClb ) with acceptable toxicity and no added risk of infection.

The results suggest that Obinutuzumab may be a stronger CD20 antibody than Rituximab. This could lead to a potential decrease in the total amount of chemotherapy required for an effective combination regimen, translating to less toxicity for the patient. Obinutuzumab has the potential to eventually replace Rituximab for the care of CLL patients.

A phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of Idelalisib and Rituximab for previously treated patients with chronic lymphocytic leukemia

This study presents results of a phase III clinical trial of a new, first-in-class oral kinase inhibitor, called Idelalisib, for patients with chronic lymphocytic leukemia ( CLL ) who have already received other standard treatments for their disease and were not considered candidates for additional chemotherapy. This highly selective compound targets the delta isoform of the PI3 kinase enzyme, which is critical for the activation and survival of CLL cells and other low-grade B cell lymphomas. To better gauge the drug’s safety and efficacy, investigators randomized 220 adult CLL patients to receive a combination of either Idelalisib twice daily and Rituximab or placebo twice daily and Rituximab ( the control arm ) continuously through disease progression or death.

After 24 weeks of follow-up, investigators observed that those patients treated with the combination Idelalisib / Rituximab therapy had significantly improved progression-free survival and overall response rates ( ORR ) compared with those patients who received Rituximab and placebo. The progression-free survival at 24 weeks for the combination Idelalisib / Rituximab group was 93%, compared with 46% for those treated with Rituximab alone. Patients treated with Idelalisib / Rituximab had significantly better ORR relative to the patients treated with Rituximab alone ( 81 vs 13%, respectively ) and also had a higher lymph node response rate ( 93 vs 4% respectively ).Notably, the patients treated with Idelalisib / Rituximab also experienced improvements in overall survival compared with the control group.
The majority of study discontinuations were due to disease progression, though nine patients in the combination arm and 11 in the control arm discontinued due to adverse events.

The combination of Idelalisib / Rituximab appears to offer quite a significant improvement in progression-free and overall survival over Rituximab and placebo. Given the efficacy and low risk for long-term toxicities demonstrated, the researchers believe this treatment could be applicable to all CLL patients because it eliminates the need for chemotherapy.

Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-delta,gamma, in patients with chronic lymphocytic leukemia

Several new treatments for lymphoid malignancies such as chronic lymphocytic leukemia belong to an emerging class known as small molecule inhibitors. Unlike chemotherapy or traditional drugs that attack proteins on the surface of cancer cells, these therapies are engineered to work inside the cancer cell and can be given in a patient-friendly, pill form. This study reports on the efficacy and safety of the investigational small molecule inhibitor IPI-145, which is designed to block the activity of a certain enzyme responsible for CLL cell signaling ( phosphoinositide-3-kinase or PI3K ).

To investigate the safety and efficacy of IPI-145, investigators enrolled 193 patients ( average age 67 ), including 52 CLL patients with treatment-resistant or relapsed disease and 15 untreated CLL patients, in a phase I trial to determine the maximum tolerated dose of the drug. Researchers administered the compound twice daily in 28-day cycles and observed clinical activity in relapsed or treatment-resistant patients at all doses studied ( from 8mg to 75mg ). Importantly, IPI-145 demonstrated activity in approximately half of the patients enrolled in the trial with a mutated form of a tumor suppressor gene ( p53 ) that makes their cancer particularly hard to treat.
The drug was generally well tolerated in the study, without the blood cell reduction observed with traditional chemotherapy.
Results of the study indicated that the 25 mg twice-daily dose may be the optimal dose for this patient population; this dosage will be further evaluated in a randomized phase III trial.

The study results suggest that IPI-145 may lend itself well to long-term therapy of patients with CLL. While it has a well-tolerated profile similar to other drugs in its class, it may actually be more potent, which could contribute to its value for patients with relapsed or refractory disease in particular.

Bcl-2 inhibitor ABT-199 monotherapy shows anti-tumor activity including complete remissions in high-risk relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma

The development of chronic lymphocytic leukemia ( CLL ) and other hematologic malignancies is often associated with the dysfunction of certain proteins that regulate cell death ( apoptosis ), known as B-cell lymphoma-2 ( BCL-2 ) proteins, which allow cancerous cells to live longer and replicate in the body. Using these proteins as a treatment target, researchers have developed a novel compound, ABT-199, that may be able to help trigger cell death in these tumors.

To determine the maximum tolerated dose of ABT-199, researchers have enrolled 56 patients with relapsed or treatment-resistant chronic lymphocytic leukemia or small lymphocytic lymphoma ( SLL ) in an ongoing phase I study. Patients are divided into several cohorts to receive different doses of the drug ( ranging from 150 to 1200 mg ).
The preliminary study results have shown encouraging drug activity, as evidenced by an 84% overall response rate and a 21% complete response rate in the study population. Early in the treatment period, some patients experienced tumor lysis syndrome ( TLS ), a treatment toxicity that occurs when contents of tumor cells that have been rapidly destroyed by effective therapy are released into the blood, potentially causing organ damage. Investigators therefore reduced the initial dose and instituted a progressive, slow increase in dose over the first several weeks of ABT-199 treatment, which helped to prevent and control TLS during the remainder of the treatment period. ( Xagena )

Source: American Society of Hematology ( ASH ) 55th Annual Meeting, 2013

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