Tag: Chronic Lymphocytic Leukemia

SUMMARY: The American Cancer Society estimates that for 2019, about 20,720 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 3,930 patients will die of the disease. B-cell CLL is the most common type of leukemia in adults, accounting for about 11% of all hematologic malignancies. The FDA in January 2019 approved IMBRUVICA® (Ibrutinib), a Bruton's Tyrosine Kinase Inhibitor, in combination with GAZYVA® (Obinutuzumab) for treatment-naive patients with CLL/Small Lymphocytic Lymphoma (CLL/SLL). This is the first approval of a non-chemotherapy combination regimen for treatment-naive patients with CLL/SLL.

Chronic Lymphocytic leukemia (CLL) is a disease of the elderly, with a median age at diagnosis of 71 years. Given the age at diagnosis, it is not uncommon for these patients to have multiple comorbidities. GAZYVA® is glycoengineered, fully humanized, third generation, type II anti-CD20 antibody (IgG1 monoclonal antibody) that selectivity binds to the extracellular domain of the CD20 antigen on malignant human B cells. By virtue of binding affinity of the glycoengineered Fc portion of GAZYVA® to Fcγ receptor III on innate immune effector cells such as natural killer cells, macrophages and neutrophils, Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) and Antibody-Dependent Cellular phagocytosis is significantly enhanced, whereas it induces very little Complement-Dependent Cytotoxicity. This is in contrast to RITUXAN® (Rituximab), which is a first generation type I, chimeric anti-CD20 targeted monoclonal antibody that kills CLL cells primarily by Complement-Dependent Cytotoxicity and also ADCC. In a previously published study, the combination of GAZYVA® and LEUKERAN® (Chlorambucil) when given to elderly patients with comorbid conditions improved Overall Survival (OS) compared to LEUKERAN® alone, and resulted in higher Response Rates and longer Progression Free Survival (PFS) than RITUXAN® plus LEUKERAN® (NEJM 2014; 370:1101-1110).

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. IMBRUVICA® in phase III trials showed improved PFS and OS when compared to LEUKERAN® alone, in previously untreated, elderly patients with CLL (NEJM 2015; 373:2425-2437).

iLLUMINATE is a multicentre, randomized, open-label, international, Phase III trial which enrolled 229 patients with previously untreated CLL or Small Lymphocytic Lymphoma, either aged 65 years or older and if less than 65 years had at least one of the following criteria: Cumulative Illness Rating Scale (CIRS) more than 6, Estimated Creatinine Clearance of less than 70 mL/min using Cockcroft-Gault equation or del 17p by FISH or TP53 mutation by PCR or Next Generation Sequencing. (CIRS is a tool utilized to assess and quantify burden of comorbidity in individual patients). Patients were randomly assigned 1:1 to receive IMBRUVICA® plus GAZYVA® (N=113) or LEUKERAN® plus GAZYVA® (N=116). IMBRUVICA® plus GAZYVA® regimen consisted of IMBRUVICA® 420 mg PO once daily continuously combined with GAZYVA® 100 mg IV on day 1, 900 mg IV on day 2, 1000 mg IV on day 8, and 15 of cycle 1 and 1000 mg IV on day 1 of subsequent 28-day cycles, for a total of six cycles. LEUKERAN® plus GAZYVA® regimen consisted of LEUKERAN® 0.5 mg/kg PO on days 1 and 15 of each 28-day cycle for six cycles combined with GAZYVA® regimen as described above. Eighty percent (80%) of patients were 65 years or older and the median age was 71 years. Approximately 65% of patients had high-risk genetic abnormalities, 52% of patients had either Rai III or IV disease, with bulky disease at baseline in 27% of IMBRUVICA®-treated patients and 38% of LEUKERAN® treated patients. The Primary Endpoint was Progression Free Survival (PFS) and Secondary endpoints included PFS in High-risk Subpopulation which included those patients with del17p/TP53 mutation or del 11q deletion at baseline and/or unmutated IGHV disease. Patients who progressed on the LEUKERAN®treatment group were allowed by the IRC (Independent Review Committee) to cross over to the IMBRUVICA® treatment group.

At a median follow-up time was 31.3 months, the median PFS was significantly longer in the IMBRUVICA® plus GAZYVA® group compared to the LEUKERAN® plus GAZYVA® group ((median not reached versus 19.0 months (HR=0.23; P<0.0001), with a 77% reduction in the risk of progression or death. Patients with high-risk disease such as those with 17p deletion/TP53 mutation, 11q deletion, or unmutated immunoglobulin heavy chain variable region gene treated with IMBRUVICA® plus GAZYVA® experienced an 85% reduction in risk of progression or death (HR= 0.15). The IRC-evaluated Overall Response Rate was 89% in the IMBRUVICA® plus GAZYVA® group versus 73% in the LEUKERAN® plus GAZYVA® arm. The estimated 30-month PFS was 79% in the IMBRUVICA® plus GAZYVA® group and 31% in the LEUKERAN® plus GAZYVA® group. The most common Grade 3 or 4 adverse events in both treatment groups were neutropenia and thrombocytopenia.

It was concluded that a combination of IMBRUVICA® and GAZYVA® is a safe and effective chemotherapy-free regimen for previously untreated patients with CLL or Small Lymphocytic Lymphoma, independent of high-risk features, and provides an alternative first line treatment option for this patient group. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Moreno C, Greil R, Demirkan F, et al. Lancet Oncol. 2019;20:43-56.

SUMMARY: The FDA on Sept. 24, 2018 granted regular approval to COPIKTRA® (Duvelisib), for adult patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL), after at least two prior therapies. In addition, COPIKTRA® received accelerated approval for adult patients with Relapsed or Refractory Follicular Lymphoma (FL) after at least two prior systemic therapies.

COPIKTRA® is a first-in-class novel, oral, dual inhibitor of PhosphoInositide 3-Kinase (PI3K)-delta and PI3K-gamma, two enzymes/isoforms known to help support the growth and survival of malignant B-cells and T-cells. PI3K-delta is constitutively expressed in hematologic malignancies and its inhibition has been shown to reduce the proliferation and survival of malignant leukemia and lymphoma cells, while allowing normal immune cell survival. Inhibiting PI3K-gamma impairs the function of cancer-supportive macrophages and T cells, which sustain leukemia and lymphoma cells in a protective tumor microenvironment. This broader dual inhibition may provide greater benefit than inhibiting just one isoform alone, by significantly inhibiting chemokines from both cancer cells and the tumor microenvironment.

DUO Trial is a randomized, multicenter, open-label, Phase III study in which COPIKTRA® was compared to ARZERRA® (Ofatumumab), in patients with Relapsed or Refractory CLL or SLL. This study randomized 319 patients in a 1:1 ratio to receive either COPIKTRA® 25 mg orally twice daily or ARZERRA®. ARZERRA® was administered at an initial dose of 300 mg IV, followed one week later by 2000 mg once weekly for 7 doses, and then 2000 mg once every 4 weeks for 4 additional doses. The median age was 69 years and 23% of patients had tumors with 17p deletion. All patients received Pneumocystis prophylaxis while on treatment. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Overall Response Rate (ORR), Duration of Response (DOR) and Overall Survival (OS). The FDA approval of COPIKTRA® for CLL and SLL was based on a subset of these 319 patients (N=196), with CLL or SLL, who had received at least 2 prior therapies. In this subset, 95 patients were randomized to the COPIKTRA® group and 101 patients to ARZERRA® group. The estimated median PFS as assessed by an Independent Review Committee (IRC), was 16.4 months in the COPIKTRA® group and 9.1 months in the ARZERRA® group (HR=0.40). The Overall Response Rate (ORR) per IRC was 78% and 39% for the COPIKTRA® and ARZERRA® arms, respectively.

The accelerated approval for Follicular Lymphoma was based on a single-arm, multicenter, Phase II monotherapy study (DYNAMO Trial), in patients with refractory, indolent Non-Hodgkin Lymphoma. In this study, 83 patients with Follicular Lymphoma who were refractory to RITUXAN® (Rituximab) and to either chemotherapy or radioimmunotherapy, were enrolled. The median age was 64 years, 37% had bulky disease with lesions 5 cm or more and 81% were refractory to 2 or more prior lines of therapy. The ORR determined by an IRC, was 42%, with 41% of patients experiencing Partial Responses and one patient having a Complete Response. Of the 35 responding patients, 43% maintained responses for at least 6 months and 17% maintained responses for at least 12 months. The most common adverse reactions were nausea, diarrhea or colitis, anemia, neutropenia, rash, fatigue, fever, cough, upper respiratory infection, pneumonia and musculoskeletal pain.

It was concluded that monotherapy with COPIKTRA® is an effective oral treatment option for patients with Relapsed or Refractory CLL/SLL and Follicular Lymphoma and addresses an unmet need for patients who have limited options, once they have progressed after two prior therapies. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm621503.htm

SUMMARY: The American Cancer Society estimates that for 2018, about 20,940 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4,510 patients will die of the disease. CLL accounts for about 25% of the new cases of leukemia and the average age at the time of diagnosis is around 71 years. B-cell CLL is the most common type of leukemia in adults.

The National Cancer Institute sponsored International Workshop on CLL, issued an update to its consensus guidelines originally published in 2008, prompted by the recent advances in the biology and treatment of patients with CLL. The goal of the updated guidelines is to integrate these new findings into clinical practice and CLL clinical trials.

The following are the major changes or additions reflected in the guidelines

Molecular Genetics

Patients with 17p deletion and TP53 mutations have inferior outcomes and have disease, resistant to standard chemotherapy regimens. These genetic abnormalities can also be acquired over the course of the disease. Patients with CLL should therefore be evaluated for these genetic abnormalities at the time of initial diagnosis and prior to any subsequent line of treatment. These patients have better outcomes when treated with non-chemotherapeutic agents, such as Bruton’s Tyrosine Kinase (BTK) inhibitors, Phosphatidylinositol 3-Kinase (PI3K) inhibitors and BCL2 inhibitors. Even though mutations in NOTCH1 or SF3B1 identified by Next-Generation sequencing have pathogenic as well as prognostic significance, the importance of these mutations has not been validated in prospective trials and their use is therefore not recommended in routine practice.

IGHV Mutational status

Retrospective studies have suggested that patients with CLL whose leukemic cells have clonotypically rearranged immunoglobulin genes in germline configuration (Unmutated IGHV gene) demonstrated more aggressive disease and shorter survival time compared to those patients with somatic hypermutations in their IGHV genes (Mutated IGHV gene). The presence of mutated IGHV genes, when combined with additional prognostic factors such as favorable cytogenetics or attainment of a Minimal Residual Disease (MRD) negative state after therapy, characterizes a subgroup of CLL patients with excellent outcome following chemoimmunotherapy with Fludarabine, Cyclophosphamide, and Rituximab. Assessment of IGHV stereotypes however is presently not a part of the routine prognostic work up in CLL.

Serum Biomarkers

Serum markers such as levels of soluble CD23, Thymidine Kinase, and Beta 2-microglobulin are poor prognostic factors and have been shown in several studies to be associated with inferior Overall Survival or Progression Free Survival. Of these, Beta 2-microglobulin has retained independent prognostic value in several multiparameter scores. Assays for these markers should be standardized, and used in prospective clinical trials to validate their relative value in the management of patients with CLL.

Clinical Staging

The two widely accepted staging systems for use in both patient care and clinical trials, the Rai and Binet staging systems rely solely on a physical examination and standard laboratory tests and do not require imaging studies. They are simple and inexpensive and can be readily and consistently applied by physicians worldwide.

Response Definition after Treatment of CLL patients

Assessment of response should include a careful physical examination and evaluation of the blood and bone marrow. For continued therapies or treatment strategies that contain a maintenance phase, the assessment of response should be performed at least 2 months after patients achieve their maximum response or at a time point that is predefined in the protocol and it is not necessary to interrupt therapy for response assessment. The updated guidelines also recommended monitoring for lymphadenopathy, splenomegaly, and hepatomegaly to define relapsed disease and treatment failure, and suggested that the use of imaging in CLL does not typically add much information to the detection of progression or relapse.

MRD Assessment

The desired outcome is complete eradication of the leukemic cells.It was recommended that MRD assessment via multicolor Flow Cytometry, Polymerase Chain Reaction, or Next-Generation sequencing after therapy, be evaluated in the blood and bone marrow, and in clinical trials should be reported with the intent-to-treat population as the denominator and not as a proportion of the responders.

Antiviral Prophylaxis

Patients treated with agents such as Alemtuzumab and Idelalisib (alone or in combination) should be monitored for symptoms or laboratory evidence of opportunistic infections such as Pneumocystis jiroveci or Herpes viridae (Herpes Simplex virus, Varicella-Zoster virus, Cytomegalo virus, Epstein-Barr virus). HBV serological status should be evaluated before treatment with anti-CD20 antibodies as patients may experience reactivation of HBV infections. Appropriate antiviral prophylaxis should be initiated in patients with a history of HBV infection. Infections with JC virus should be ruled out in situations of unclear neurological symptoms, as Progressive Multifocal Leukoencephalopathy has been reported in a few CLL patients treated with anti-CD20 antibodies.

iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Hallek M, Cheson BD, Catovsky D, et al.Blood 2018 131:2745-2760

SUMMARY: The FDA on June 8, 2018, granted regular approval to VENCLEXTA® (Venetoclax) for patients with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy. The American Cancer Society estimates that for 2018, about 20,940 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4,510 patients will die of the disease. CLL accounts for about 25% of the new cases of leukemia and the average age at the time of diagnosis is around 71 years. B-cell CLL is the most common type of leukemia in adults.

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 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. The FDA granted an accelerated approval to VENCLEXTA® in 2016, for the treatment of patients with CLL with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy.

The present FDA approval was based on MURANO, which is an open-label, randomized, international, multicenter, phase III study which included 389 patients with Relapsed/Refractory CLL, who had received 1-3 prior lines of therapy, including at least one chemotherapy regimen. Patients were randomized 1:1 to receive a combination of either VR – VENCLEXTA® plus RITUXAN® (N=194) or BR – Bendamustine plus RITUXAN® (N=195). In the VR group, VENCLEXTA® tablets were 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 prophylaxis. Patients were treated with the 400 mg daily dosing for a maximum of 2 yrs or until disease progression. RITUXAN® (Rituximab) was given beginning week 6, and was administered at 375 mg/m2 on day 1, cycle 1, followed by 500 mg/m2 on day 1 of cycles 2 thru 6, of a 28 day cycle. In the BR group, Bendamustine was given at 70 mg/m2 on days 1 and 2 of each 28 day cycle for a total of 6 cycles along with RITUXAN®, using the same RITUXAN® dosing schedule as in the VR group. Patients were stratified based on del(17p) status and responsiveness to prior therapy. The median age was 65 years, 26% of the patients had del(17p) and 15% of the patients were refractory to Fludarabine. The Primary end point was Progression Free Survival (PFS) and Secondary end points included Overall Survival (OS), Overall Response Rate (ORR) and Complete Response (CR). The median follow up was 23.8 months.

It was noted that the median PFS was significantly superior in the VR group compared to BR and was not reached in the VR group and was 18.1 months in the BR group (HR=0.19; P<0.0001). The 2-year PFS rates were 84.9% versus 36.3%, respectively, favoring VENCLEXTA® (HR=0.17, P<0.0001). This meant an 83% reduction in the risk of disease progression or death in the VR group compared with the BR group. This PFS benefit was consistently seen in all subgroups assessed, including those with del(17p), p53 mutation and IgVH unmutated status. The 2-year PFS rate among patients with chromosome 17p deletion was 81.5% in the VR group versus 27.8% in the BR group (HR=0.13), and the 2-year PFS rate among those without chromosome 17p deletion was 85.9% versus 41.0% (HR=0.19). The Overall Response Rate, as assessed by the Independent Review Committee was 92.3% in the VR group, and 72.3% in the BR group (a difference of 20 percentage points). The rate of MRD (Minimal Residual Disease)-negativity based on peripheral blood samples, defined as less than 1 CLL cell in 10,000 leukocytes and attained at any time, was also higher with VR at 83.5% versus 23.1% with BR. Further, the MRD negativity was more durable in the VENCLEXTA® group. It has been noted that patients who are negative for MRD on the basis of peripheral blood sampling have better survival outcomes than patients who have a complete response and are positive for minimal residual disease. The high MRD clearance rate observed in the VR group exceed those previously attained with other regimens, in trials of Relapsed or Refractory CLL or SLL. The time to the next treatment for CLL was also longer in the VR group compared to BR group and at 2 years, 90% and 52.1%, respectively, had not received a next line of treatment for CLL (Hazard Ratio for receipt of next treatment or death= 0.19). Overall Survival evaluation is ongoing. Grade 3/4 neutropenia was higher in VR group but there was no increase in febrile neutropenia or Grade 3/4 infection.

It was concluded that VENCLEXTA® in combination with RITUXAN® resulted in a significant improvement in Progression Free Survival, Overall Response Rate, along with durable improvement in peripheral blood MRD negativity, when compared with Bendamustine and RITUXAN®, in patients with Relapsed/Refractory CLL. Venetoclax–Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. Seymour JF, Kipps TJ, Eichhorst B, et al. N Engl J Med 2018; 378:1107-1120