Tag: Chronic Lymphocytic Leukemia

SUMMARY: The FDA on March 4, 2016 approved the expanded use of IMBRUVICA® (Ibrutinib) as first line treatment for patients with Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma. IMBRUVICA® received approval in February 2014 for the treatment of Chronic Lymphocytic Leukemia (CLL) in patients who received at least one prior therapy and in July 2014 for the treatment of CLL with 17p deletion. The American Cancer Society estimates that approximately 18,960 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in 2016 and approximately 4660 patients will die from the disease. CLL is a disease of the elderly and the average age at the time of diagnosis is 72 years. There are two main types of lymphocytes, B and T lymphocytes/cells. B-cell CLL is the most common type of leukemia in adults. Normal B-cell activation and proliferation is dependent on B-cell receptor (BCR) signaling. This signaling is also important for initiation and progression of B-cell lymphoproliferative disorders. Bruton's Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Following binding of antigen to the B-Cell Receptor, kinases such as Syk (Spleen Tyrosine Kinase), Lyn (member of the Src family of protein tyrosine kinases) and BTK (Bruton's Tyrosine Kinase) are activated, with subsequent propagation through PI3K/Akt, MAPK, and NF-κB pathways. This results in B-cell activation and proliferation. IMBRUVICA® (Ibrutinib) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. In elderly CLL patients with comorbid conditions, Chlorambucil is often considered as a standard first-line therapy because of the higher rate of toxicities associated with FLUDARA® (Fludarabine) and TREANDA® (Bendamustine).

RESONATE-2 is a international, open-label, randomized, phase III trial, in which the efficacy of two oral agents , IMBRUVICA® and Chlorambucil, were compared, in previously untreated elderly patients with CLL or Small Lymphocytic Lymphoma. In this study, 269 treatment naïve patients with CLL or Small Lymphocytic Lymphoma, who were 65 years of age or older, were randomly assigned in a 1:1 ratio, to receive IMBRUVICA® 420 mg PO once daily (N=136) or Chlorambucil at a dose of 0.5 mg/kg on days 1 and 15 of each 28 day cycle, increased to a maximum of 0.8 mg/kg, if tolerated (N=133). Patients with chromosome del (17p) were excluded. The median age was 73 years and 70% of patients were over age 70. The primary end point was Progression Free Survival (PFS) and secondary end points included, Overall Response Rate (ORR), Overall Survival (OS), and sustained hematologic improvement.

With a median follow-up of 28.1 months, patients in the IMBRUVICA® group had a significantly longer Progression Free Survival (PFS) compared to the Chlorambucil group (median not reached versus 18.9 months), with a risk of progression or death 84% lower with IMBRUVICA®, compared to Chlorambucil (HR=0.16; P<0.001). IMBRUVICA® significantly prolonged Overall Survival, in spite of 41% of the patients crossing over from the Chlorambucil group to IMBRUVICA®. The 2 year Overall Survival rate was 94.7% in the IMBRUVICA® group and 84.3% in the Chlorambucil group (HR=0.44). Further, IMBRUVICA® significantly improved Overall Response Rate, compared with Chlorambucil (82% vs 35%; P< 0.0001) and also significantly improved hemoglobin and platelets levels from baseline values, compared with Chlorambucil. The most common adverse events associated with IMBRUVICA® were diarrhea, fatigue, cough and nausea and were mostly Grade 1 toxicities.

The authors concluded that IMBRUVICA® significantly improves Progression Free Survival, Overall Survival and Overall Response Rate, compared to Chlorambucil, in previously untreated patients with CLL or Small Lymphocytic Lymphoma, and should therefore be considered for all elderly patients who are not candidates for aggressive systemic therapy. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. Burger JA, Tedeschi A, Barr PM, et al. N Engl J Med 2015; 373:2425-2437

SUMMARY: The FDA on April 11, 2016, granted an accelerated approval to Venetoclax (VENCLEXTA®) for the treatment of patients with Chronic Lymphocytic Leukemia (CLL) with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy. The FDA also approved Vysis CLL FISH probe kit, as a companion diagnostic to VENCLEXTA®, for detection of the del(17p). There are two main types of lymphocytes, B and T lymphocytes. B-cell CLL is the most common type of leukemia in adults. Normal B-cell activation and proliferation is dependent on B-cell receptor (BCR) signaling. This signaling is also important for initiation and progression of B-cell lymphoproliferative disorders. Bruton's Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Following binding of antigen to the B-Cell Receptor, kinases such as Syk (Spleen Tyrosine Kinase), Lyn (member of the Src family of protein tyrosine kinases) and BTK (Bruton's Tyrosine Kinase) are activated, with subsequent propagation through PI3K/Akt, MAPK, and NF-κB pathways. This results in B-cell activation and proliferation. PI3K (PhosphoInositide 3-Kinase) delta signaling, is hyperactive in B-cell malignancies and is important for the activation, proliferation, homing of malignant B cells in the lymphoid tissues and their survival. The delta isoform of PI3K enzyme is predominantly expressed in leukocytes. Targeting proteins in key pathways of B-cell biology has fundamentally changed the management and outcomes of CLL, over the past 5 years. IMBRUVICA® (Ibrutinib) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. ZYDELIG® (Idelalisib) is a highly selective oral inhibitor of the enzyme PI3K and specifically blocks the delta isoform of PI3K enzyme and its signaling pathway. The pro-survival (anti-apoptotic) protein BCL2, is over expressed by CLL cells and regulates clonal selection and cell survival. A new class of anticancer agents known as BH3-mimetic drugs are in development that mimic the activity of the physiologic antagonists of BCL2 and related proteins and promote apoptosis (programmed cell death).

VENCLEXTA® is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. VENCLEXTA® causes markedly less thrombocytopenia but more neutropenia compared to its first generation predecessor, Navitoclax. In the phase I study by Roberts, et al. (N Engl J Med 2016;374:311-322), high response rates of 71 to 79% were observed in CLL patients with poor prognostic features, when treated with VENCLEXTA®, with a 15-month Progression Free Survival (PFS) of 69%.

Based on this phase I data, a pivotal phase II, single-arm, multicenter study was conducted, to evaluate the efficacy of VENCLEXTA® monotherapy in patients with Relapsed/Refractory del(17p) CLL. This study included 106 patients with a median age of 67 years and patients had received a median of 2 prior chemotherapy regimens. More than a third of the patients were refractory to prior therapy with Fludarabine and Bendamustine. Treatment consisted of VENCLEXTA® tablets given once daily with a weekly dose ramp-up schedule (20 mg for 1 week, followed by 1 week at each dose level of 50 mg, 100 mg, and 200 mg and then the recommended daily dose of 400 mg), over a period of 5 weeks, given along with Tumor Lysis Syndrome (TLS) prophylaxis. Patients were treated with the daily 400 mg dosing until disease progression or unacceptable toxicity. The primary endpoint was Overall Response Rate (ORR). Secondary endpoints included Complete Response (CR), Partial Response (PR) rates, Time to first response, Duration of Response (DoR), Progression Free Survival (PFS), Overall Survival (OS), the proportion of patients proceeding to allogeneic Stem Cell Transplant (allo-SCT) and Safety.

The ORR was 79.4% with 8% Complete Response (including 2% Complete Response with incomplete marrow recovery-CRi). Minimal Residual Disease (MRD) was evaluated in peripheral blood and bone marrow for patients who achieved CR or CRi, following treatment with VENCLEXTA®. Forty five (N=45) patients were evaluated for MRD and 18 attained MRD-negative status in their peripheral blood. The median time to first response was 0.8 months (range: 0.1 to 8.1 months) and median time to CR/CRi was 8.2 months. With a median follow up of 12 months, the median Duration of Response (DoR) has not been reached (2.9-19.0 months).

The most common adverse reactions of any grade were neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, and fatigue. Patients should be closely monitored and should receive prophylaxis for Tumor Lysis Syndrome, which can occur as a result of rapid reduction in tumor volume.

The authors concluded that monotherapy with VENCLEXTA® resulted in a high ORR and sustained remissions, in high risk patients with CLL. Undetectable Minimal Residual Disease was noted in more than 20% of responders, with more than 10% of all patients achieving a deep response. Venetoclax (ABT-199/GDC-0199) monotherapy induces deep remissions, including complete remission and undetectable MRD, in ultra-high risk relapsed/refractory chronic lymphocytic leukemia with 17p deletion: results of the pivotal international phase II study. Stilgenbauer S, Eichhorst BF, Schetelig JS, et al. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract LBA6.

SUMMARY: The American Cancer Society estimates that approximately 18,960 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in 2016 and approximately 4660 patients will die from the disease. CLL is a disease of the elderly and the average age at the time of diagnosis is 72 years. There are two main types of lymphocytes, B and T lymphocytes/cells. B-cell CLL is the most common type of leukemia in adults. Normal B-cell activation and proliferation is dependent on B-cell receptor (BCR) signaling. This signaling is also important for initiation and progression of B-cell lymphoproliferative disorders. Bruton's Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Following binding of antigen to the B-Cell Receptor, kinases such as Syk (Spleen Tyrosine Kinase), Lyn (member of the Src family of protein tyrosine kinases) and BTK (Bruton's Tyrosine Kinase) are activated, with subsequent propagation through PI3K/Akt, MAPK, and NF-κB pathways. This results in B-cell activation and proliferation. IMBRUVICA® (Ibrutinib) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. The FDA initially granted accelerated approval to IMBRUVICA® in February 2014 for previously treated patients with CLL and this was followed by full FDA approval and a new treatment indication for high-risk CLL patients with 17p deletions, in July 2014. Previously published studies had shown significant Response Rates and and Event-Free Survival with BR (Bendamustine-TREANDA® and Rituximab-RITUXAN®) in FLUDARA® (Fludarabine) refractory patients, with Chronic Lymphocytic Leukemia.

The HELIOS study is a double-blind, randomized, phase III trial which evaluated the benefit of combining IMBRUVICA® with BR compared to placebo plus BR, in patients with previously treated, relapsed/refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. In this study, of the 578 randomized patients, 289 patients received a maximum of six cycles of BR with IMBRUVICA® 420 mg PO daily and 289 patients received BR with placebo. The median patient age was 64 years, patients had received a median of two prior therapies and 38% of the patients had Rai Stage III/IV disease. Patients with 17p deletions in more than >20% of cells, were excluded. The planned six cycles of BR were completed by 83% in the IMBRUVICA® group and 78% in the placebo group. The primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS) and Overall Response Rate (ORR).

Following an interim analysis, this study was unblinded as there was a significant PFS benefit with IMBRUVICA® and patients receiving placebo, were allowed to cross over to the IMBRUVICA® group, per study protocol,. Thirty one percent (31%) of the patients in the BR plus placebo group with confirmed progressive disease crossed over to receive BR plus IMBRUVICA®. At a median follow up of 17.2 months, the PFS in the IMBRUVICA® plus BR group was not yet reached whereas the PFS was 13.3 months for patients receiving placebo plus BR (HR=0.203; P<0.0001). This PFS benefit was seen across subgroups of high-risk patients as well. The ORR was 82.7% in the IMBRUVICA® plus BR group compared to 67.8% in the placebo plus BR group (P <0.0001). Complete Response (CR) rates which included CR with incomplete blood count recovery were 10.4% versus 2.8% with IMBRUVICA® and placebo, respectively. The median OS was not reached. The incidence of most adverse events were comparable between the two treatment groups and the most frequent side effects were neutropenia affecting about 55% of the patients and nausea experienced by about 35% of the patients.

The authors concluded that IMBRUVICA® plus BR resulted in an 80% reduction in the risk of disease progression, as well as improved Overall Response Rates, compared to placebo plus BR. This triplet combination of IMBRUVICA®, TREANDA® and RITUXAN® should therefore be considered an important treatment option for patients with previously treated Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Chanan-Khan A, Cramer P, Demirkan F, et al. The Lancet Oncology 2016;17:200-211

SUMMARY: The FDA on January 19, 2016 approved ARZERRA® (Ofatumumab) for extended treatment of patients who are in complete or partial response after at least two lines of therapy for recurrent or progressive Chronic Lymphocytic Leukemia (CLL). The American Cancer Society estimates that approximately 14,620 new cases of Chronic Lymphocytic Leukemia (CLL) were diagnosed in 2015 and approximately 4650 patients died from the disease. CLL is a disease of the elderly and the average age at the time of diagnosis is 72 years. ARZERRA® was previously approved for the treatment of treatment naive patients with CLL for whom FLUDARA® (Fludarabine) based therapy was considered inappropriate and also for patients with CLL refractory to FLUDARA® and CAMPATH® (Alemtuzumab). ARZERRA® is a second generation fully human IgG 1 monoclonal antibody. Unlike RITUXAN® (Rituximab), which is a chimeric monoclonal antibody, ARZERRA® targets a different region (different epitope) of the CD20 molecule. Monoclonal antibodies targeting CD20 destroy CD20 positive B cells by 3 different mechanisms. They include Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Dependent Cytotoxicity (CDC) and programmed cell death (Apoptosis). Unlike RITUXAN®, ARZERRA® targets the small loop epitope of CD20 molecule which is proximal to the B cell membrane and this has been shown to be associated with highly efficient cell lysis through Complement Dependent Cytotoxicity. So, compared to RITUXAN®, ARZERRA® has stronger CDC, similar ADCC and does not appear to induce Apoptosis.

The PROLONG trial is an open-label, multicentre, randomised phase III study in which 474 patients with CLL whose disease had a complete or partial response after at least two lines of prior therapy, were randomly assigned in a 1:1 ratio to ARZERRA® (N=238) or observation (N=236). Patients in the ARZERRA® group received an initial dose of 300 mg given as an IV infusion followed by 1000 mg IV on Day 8. They subsequently received ARZERRA® 1000 mg IV every 8 weeks for up to 2 years. The median age was 65 years. The baseline characteristics in both treatment groups were well balanced. The primary endpoint was Progression Free Survival (PFS). Secondary endpoints included duration of response, Overall Survival, and safety. The median follow-up was 19•1 months. The median PFS with maintenance ARZERRA® was 29.4 months compared with 15.2 months in the observation group. This meant a 50% reduction in the risk of progression with maintenance ARZERRA® compared to observation (HR=0.50; P< 0.0001).

The most common adverse reactions in the ARZERRA® group were infusion reactions, neutropenia and upper respiratory tract infections. It was concluded that ARZERRA® is an important and new maintenance strategy in patients with relapsed CLL, to help delay disease progression. Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study. van Oers MHJ, Kuliczkowski K, Smolej L, et al. The Lancet Oncology 2015: 16;1282-1284

SUMMARY: The American Cancer Society estimates that approximately 14,620 new cases of Chronic Lymphocytic Leukemia (CLL) were diagnosed in 2015 and approximately 4650 patients died from the disease. CLL is a disease of the elderly and the average age at the time of diagnosis is 72 years. There are two main types of lymphocytes, B and T lymphocytes/cells. B-cell CLL is the most common type of leukemia in adults. Normal B-cell activation and proliferation is dependent on B-cell receptor (BCR) signaling. This signaling is also important for initiation and progression of B-cell lymphoproliferative disorders. Bruton's Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Following binding of antigen to the B-Cell Receptor, kinases such as Syk (Spleen Tyrosine Kinase), Lyn (member of the Src family of protein tyrosine kinases) and BTK (Bruton's Tyrosine Kinase) are activated, with subsequent propagation through PI3K/Akt, MAPK, and NF-κB pathways. This results in B-cell activation and proliferation. IMBRUVICA® (Ibrutinib) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. The FDA initially granted accelerated approval to IMBRUVICA® in February 2014 for previously treated patients with CLL and this was followed by full FDA approval and a new treatment indication for high-risk CLL patients with 17p deletions, in July 2014.

In elderly CLL patients with comorbid conditions, Chlorambucil is often considered as a standard first-line therapy because of the higher rate of toxicities associated with FLUDARA® (Fludarabine) and TREANDA® (Bendamustine). RESONATE-2 is a international, open-label, randomized, phase III trial, in which the efficacy of two oral agents , IMBRUVICA® and Chlorambucil, were compared, in previously untreated elderly patients with CLL or Small Lymphocytic Lymphoma.

In this study, 269 treatment naïve patients with CLL or Small Lymphocytic Lymphoma, who were 65 years of age or older, were randomly assigned in a 1:1 ratio, to receive IMBRUVICA® 420 mg PO once daily (N=136) or Chlorambucil at a dose of 0.5 mg/kg on days 1 and 15 of each 28 day cycle, increased to a maximum of 0.8 mg/kg, if tolerated (N=133). Patients with chromosome del (17p) were excluded. The median age was 73 years and 70% of patients were over age 70. The primary end point was Progression Free Survival (PFS) and secondary end points included, Overall Response Rate (ORR), Overall Survival (OS), and sustained hematologic improvement.

With a median follow-up of 18.4 months, patients in the IMBRUVICA® group had a significantly longer Progression Free Survival (PFS) compared to the Chlorambucil group (median not reached versus 18.9 months), with a risk of progression or death 84% lower with IMBRUVICA®, compared to Chlorambucil (HR=0.16; P<0.001). IMBRUVICA® significantly prolonged Overall Survival, with an estimated Overall Survival rate of 98% at 24 months, compared to 85% with Chlorambucil, with a 84% reduction in the risk of death (HR=0.16; P=0.001). Further, IMBRUVICA® significantly improved Overall Response Rate, compared with Chlorambucil (86% vs 35%; P< 0.001) and also significantly improved hemoglobin and platelets levels from baseline values, compared with Chlorambucil. The most common adverse events associated with IMBRUVICA® were diarrhea, fatigue, cough and nausea and were mostly Grade 1 toxicities. The authors concluded that IMBRUVICA® significantly improves PFS, OS and ORR, compared to Chlorambucil, in previously untreated patients with CLL or Small Lymphocytic Lymphoma, and should be considered for all elderly patients who are not candidates for aggressive systemic therapy. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. Burger JA, Tedeschi A, Barr PM, et al. N Engl J Med 2015; 373:2425-2437