Tag: Chronic Lymphocytic Leukemia

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

SUMMARY: The American Cancer Society estimates that approximately 18,960 new cases of Chronic Lymphocytic Leukemia (CLL) were diagnosed in 2016 and approximately 4660 patients died from the disease. CLL is a disease of the elderly and the average age at the time of diagnosis is 72 years. A new treatment algorithm for the upfront treatment of CLL divides treatment naïve CLL patients into three groups and therapy should be chosen accordingly:

GROUP 1 consists of elderly patients with comorbidities who are unfit for aggressive interventions. The goal of therapy for this patient group should be to minimize toxicity rather than achieve long term remissions. In elderly CLL patients with comorbid conditions, Chlorambucil was often considered as a standard first-line therapy because of the higher rate of toxicities associated with FLUDARA® (Fludarabine) and TREANDA® (Bendamustine). The preferred choice for this group now is IMBRUVICA® (Ibrutinib). IMBRUVICA® 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 CLL patients 65 years or older with relapsed or refractory disease (94%), or who were treatment-naive (85%), long term treatment and follow up with single-agent IMBRUVICA® resulted in high response rates across all subgroups of patients. It was noted that there has been increasing Complete Response Rate with each follow up in the treatment naïve group with a Complete Response Rate of 26%. (2015 AACR Annual Meeting. Abstract CT132). Of the 94 patients treated with IMBRUVICA®, at 45 months of follow up, the Progression Free Survival (PFS) at 30 months was 96% and Overall Survival (OS) rate was 96% in treatment-naive group, whereas the 30 month PFS was 76% and OS rate was 87% in relapsed/refractory patient group. The median PFS in patients with del(17p) was 32.4 month compared to 12 months with previously published best front line therapies.

In the RESONATE trial, which compared IMBRUVICA® to ARZERRA® (Ofatumumab) in patients with relapsed/refractory CLL (N Engl J Med 371:213-223, 2014), median PFS was not reached with IMBRUVICA® compared to a median PFS of 8.1 months with ARZERRA®, representing a 78% reduction in the risk of progression (HR=0.22; P<0.001). IMBRUVICA® also significantly improved Overall Survival (HR=0.43; P=0.005). The Overall Response Rate was also significantly higher in the IMBRUVICA® group than in the ARZERRA® group (42.6% versus 4.1%; P<0.001). Toxicities with IMBUVICA® are mild and include diarrhea and ecchymoses. Atrial fibrillation is seen in approximately 8% of elderly patients and needs attention.

GROUP 2 includes young fit patients with IGVH mutations for whom more aggressive combination therapy should be recommended for long term benefit. This group of patients should be offered three drug regimen consisting of FCR – FLUDARA®/Cyclophosphamide/RITUXAN® (Rituximab). The long term follow up of the pivotal FCR300 study revealed that 40% of patients were progression free at 14 years with a plateau noted in the PFS curve (Blood 127:303-309, 2016). About 60% of the patients with the IGVH mutation who were negative for Minimal Residual Disease (MRD) at the end of treatment, were progression free at 14 years. It was also demonstrated in a subsequent cohort that testing negative for Minimal Residual Disease after a response to FCR regimen was the most important determinant of Progression Free and Overall Survival. Among responders to FCR who were MRD negative, there was only one progression and no deaths after 4 years. Patients with IGVH-mutated disease had a 2.7-fold higher chance of being MRD negative after treatment with FCR. Bendamustine/RITUXAN® regimen is also often recommended for young and fit patients with Chronic Lymphocytic Leukemia, as the risk of neutropenia and infections are lower. However, FCR is associated with longer remissions by at least one year compared to Bendamustine/RITUXAN®.

GROUP 3 comprises of fit patients who are IGVH mutation-negative and will not achieve long remissions with combination chemotherapy. FCR regimen will not achieve 10-15 year remissions in this patient group and these patients should either be treated with IMBRUVICA® or enrolled in clinical trials.

ZYDELIG® (Idelalisib) is a highly selective oral inhibitor of the enzyme phosphoinositide 3-kinase (PI3K) and specifically blocks the delta isoform of PI3K enzyme and its signaling pathway. In the pivotal trial of previously treated patients with recurrent CLL (N Engl J Med 370:997-1007, 2014), the median PFS for the RITUXAN®/ ZYDELIG® combination group has not yet been reached, whereas the median PFS for the RITUXAN®/placebo arm was 5.5 months (HR=0.15; P<0.0001). This suggested an 85% reduction in the risk of progression. Further, the PFS was favorable in the poor prognosis patients with either a 17p deletion or p53 mutation, when ZYDELIG® was combined with RITUXAN® (HR=0.12). An improvement in the Overall Survival (OS) was also noted in the ZYDELIG® group compared with patients in the RITUXAN® alone group (HR=0.28; P=0.018). The combination of ZYDELIG® and RITUXAN® had an Overall Response Rate of 81% compared with 13% in the RITUXAN® alone group (P<0 .0001). Patients treated with a combination of ZYDELIG® and RITUXAN® also had a higher decrease in lymphadenopathy (93%) compared with 4% in the RITUXAN® alone group (P<0.0001). Lymphocytosis resolves more slowly with ZYDELIG® than with IMBRUVICA® and therefore, ZYDELIG® is combined with RITUXAN®. ZYDELIG® should not be used as first line therapy due to associated toxicities such as colitis, elevated transaminases and pneumonitis seen more so in treatment naïve patients, as these patients have less T-cell depletion.

Chronic Lymphocytic Leukemia with del(17p)

IMBRUVICA® is the preferred first line therapy. VENCLEXTA® (Venetoclax) is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. In a pivotal study, VENCLEXTA® monotherapy in patients with Relapsed/Refractory del(17p) CLL resulted in a ORR of 79.4% with 8% Complete Responses and some patients attained MRD-negative status in their peripheral blood which is remarkable (N Engl J Med 374:311-322, 2016). The median Duration of Response (DoR) has not been reached. This drug should be considered as second line therapy.

Dr O’Brien concluded that this new evidence based treatment algorithm stratifies patients differently from the traditional algorithm. O’Brien SM: How do we sequence the best treatment options for patients with CLL based on age and prognostic features? 2016 Pan Pacific Lymphoma Conference. Presented July 22, 2016. Koloa, HI, United States