Tag: Non-Hodgkin Lymphoma

SUMMARY: The FDA on October 18, 2017, granted regular approval to Axicabtagene ciloleucel (YESCARTA®) for the treatment of adult patients with relapsed or refractory Large B-Cell Lymphoma after two or more lines of systemic therapy, including Diffuse Large B-Cell Lymphoma (DLBCL) Not Otherwise Specified, Primary Mediastinal Large B-Cell Lymphoma, High-grade B-Cell Lymphoma, and DLBCL arising from Follicular Lymphoma (Transformed Follicular Lymphoma-TFL).

What is (CAR) T-cell immunotherapy? Chimeric Antigen Receptor (CAR) T-cell therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure, and genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR). These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the patient’s body and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen. It is a therefore a customized treatment created using patient’s own T cells to destroy cancer cells.

YESCARTA® is a Chimeric Antigen Receptor (CAR) T cell immunotherapy and consists of autologous T cells that are genetically modified to produce a CAR protein, allowing the T cells to seek out and destroy cancer cells expressing the antigen CD19, which is found uniquely on B cells. Patients, following treatment with CAR T-cells, develop B-cell aplasia (absence of CD19 positive cells) due to B-cell destruction and may need immunoglobin replacement. Hence, B-cell aplasia can be a useful therapeutic marker, as continued B-cell aplasia has been seen in all patients who had sustained remission, following CAR T-cell therapy. Cytokine Release Syndrome (CRS), an inflammatory process is the most common and serious side effect of CAR T-cell therapy and is associated with marked elevation of Interleukin-6. Cytokine release is important for T-cell activation and can result in high fevers and myalgias. This is usually self limiting although if severe can be associated with hypotension and respiratory insufficiency. Tocilizumab (ACTEMRA®), an Interleukin-6 receptor blocking antibody produces a rapid improvement in symptoms. This is however not recommended unless the symptoms are severe and life threatening, as blunting the cytokine response can in turn negate T-cell proliferation. Elevated serum Ferritin and C-reactive protein levels are surrogate markers for severe Cytokine Release Syndrome. The CAR T-cells have been shown to also access sanctuary sites such as the central nervous system and eradicate cancer cells. CD19 antigen is expressed by majority of the B cell malignancies and therefore most studies using CAR T-cell therapy have focused on the treatment of advanced B-cell malignancies such as Chronic Lymphocytic Leukemia (CLL), Acute Lymphoblastic Leukemia (ALL) and Non Hodgkin lymphoma (NHL), such as Diffuse Large B-Cell Lymphoma (DLBCL).

Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphoma’s in the United States, and the incidence has steadily increased 3 to 4% each year. Outcomes for patients with relapsed/refractory disease is poor, with an Objective response Rate (ORR) of 26%, Complete Response (CR) rate of 8% and a median Overall Survival (OS) of 6.6 months. There is therefore a significant unmet need in this patient group.

The safety and efficacy of YESCARTA® was evaluated in a single arm multicenter clinical trial (ZUMA-1 study) in which 111 patients were enrolled and 101 patients received therapy with YESCARTA®. This study included patients with DLBCL (N=77) and Primary Mediastinal B-Cell Lymphoma (PMBCL)/Transformed Follicular Lymphoma-TFL (N=24), with chemo refractory disease or patients who had relapsed within 12 months post Autologous Stem Cell Transplantation. Following 3 days of conditioning regimen with Cyclophosphamide and Fludarabine, patients received a single infusion of YESCARTA® at a dose of 2 x 106 CAR-positive T cells/kg. The average turnaround time from apheresis to delivery to clinical site for infusion, was 17 days. The Primary end point was Objective Response Rate (ORR) and Secondary endpoints included Duration of Response, Overall Survival and Safety. The preliminary results were reported after the Primary end point was met.

After a median follow up of 8.7 months, the ORR for the entire group was 82% with 54% CR rate (P<0.0001). Among those with DLBCL, the ORR was 82% and the CR rate was 49% and in the PMBCL/TFL group, the ORR was 83% and the CR rate was 71%. At the time of median follow up, 44% of the patients had ongoing responses and the median Duration of Response was 8.2 months and not reached for those in CR. The median Progression Free Survival was 5.9 months and median OS was not reached.

The most common grade 3 or higher adverse reactions included cytopenias, febrile neutropenia, fever, Cytokine Release Syndrome (CRS) and neurologic events. CRS and neurologic events were generally reversible and 43% received Tocilizumb and 27% received steroids and this did not negatively impact outcomes.

The authors concluded that ZUMA-1 is the first pivotal trial of CD19-specific CAR T-cell therapy in patients with refractory aggressive Non Hodgkin Lymphoma, demonstrating significant clinical activity, with a Complete Response rate 7 times higher than the historic control rate. Primary results from ZUMA-1: a pivotal trial of axicabtagene ciloleucel (Axi-cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL). Locke FL, Neelapu SS, Bartlett NL, et al. Presented at: 2017 AACR Annual Meeting; April 1-5, 2017; Washington, DC. Abstract CT019.

SUMMARY: The FDA on September 14, 2017, granted accelerated approval to ALIQOPA® (Copanlisib) for the treatment of adult patients with relapsed Follicular Lymphoma, who have received at least two prior systemic therapies. The American Cancer Society estimates that in 2017, about 72,240 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,140 individuals will die of this disease. Indolent NHLs are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT), Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL). Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 20% of all NHLs are Follicular Lymphomas. Advanced stage indolent NHL is not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining Quality of Life, have been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach whereas those with B symptoms (fever, night sweats, and weight loss), painful lymphadenopathy/splenomegaly, organ compromise and cytopenias are generally considered candidates for therapy.. Follicular Lymphoma International Prognostic Index (FLIPI) is of prognostic value and is used to help with treatment choices. The Ann Arbor classification divides FL into four stages. Patients with stages I and II have localized disease and those with stages III and IV have advanced disease. The World Health Organization (WHO) further classified FL based on histology into low grade (grades 1 and 2) and high grade (grade 3a) FLs. Grade 3b FL which demonstrates diffuse areas of involvement is designated as Diffuse Large B-cell Lymphoma (DLBCL) and is treated as such. Patients with advanced stage symptomatic Follicular Lymphoma are often treated with induction chemoimmunotherapy followed by maintenance RITUXAN® (Rituximab). This can result in a median PFS of 6-8 yrs and a median Overall Survival of 12-15 yrs. However, approximately 30% of the patients will relapse in 3 years and treatment options are limited for patients with relapses, after multiple treatments.

ALIQOPA® is a pan-class 1, PI3K inhibitor with inhibitory activity predominantly against PI3K-α and PI3K-δ Isoforms expressed in malignant B cells. The alpha isoform is broadly expressed and involved in insulin signaling and angiogenesis, as well as resistance mechanisms to lymphoma whereas the delta isoform is expressed by leukocytes and is involved in B-cell signaling, development, and survival. ALIQOPA® has been shown to induce tumor cell death by apoptosis and inhibition of proliferation of primary malignant B cell lines. ALIQOPA® also inhibits several key cell-signaling pathways, including B-cell receptor (BCR) signaling, CXCR12 (C-X-C chemokine receptor 12) mediated chemotaxis of malignant B cells, and NFÏ°B (Nuclear Factor Kappa B) signaling in lymphoma cell lines.

The approval of ALIQOPA® was based on data from the CHRONOS-1 trial, which is an open-label, single arm, multicenter, phase II study of patients with relapsed, Indolent or aggressive Non Hodgkin Lymphomas. This trial included patients with Follicular lymphoma (Grades 1-3a), Marginal Zone Lymphoma, Small Lymphocytic Lymphoma, and LymphoPlasmacytic Lymphoma /Waldenstrom Macroglobulinemia . Eligible patients had relapsed or refractory disease and had received at least two prior systemic therapies. The efficacy data leading to the FDA approval included 104 patients with Follicular B-cell Non Hodgkin Lymphoma. In this trial, patients received 0.8 mg/kg or 60 mg of ALIQOPA® by IV infusion on days 1, 8, and 15 of a 28-day treatment cycle, until disease progression or development of unacceptable toxicity. The median patient age was 63 yrs and all study patients had prior exposure to RITUXAN® and one or more alkylating agents, and 60% of the patients had disease that was refractory to the last regimen received. The Primary endpoint was Objective Response Rate after a minimum of 16 weeks of treatment. Secondary endpoints included Progression Free Survival, Duration of Response, Overall Survival, safety, and Quality of Life.

The Objective Response Rate was 58.7%, with an estimated median response duration of 12.2 months. The Complete Response rate was 14.4% and partial response rate was 44.3% and 33.7% has stable disease. The most common adverse reactions included nausea, hyperglycemia, diarrhea, fatigue, hypertension, cytopenias and lower respiratory tract infections. According to the authors, safety was manageable compared with the other PI3K inhibitor approved by the FDA, ZYDELIG® (Idelalisib), which targets only the δ-isoform and has warnings against fatal or severe colitis, intestinal perforation, hepatotoxicity, and pneumonitis The safety advantage with ALIQOPA® may be due to the dose scheduling or the IV mode of delivery.

It was concluded that ALIQOPA® has significant activity in patients with relapsed/refractory indolent B-cell lymphoma, and the safety was manageable, compared with other PI3K inhibitors. Two phase III trials are underway, using ALIQOPA® in combination with RITUXAN®. Dreyling M, Santoro A, Mollica L, et al. Copanlisib in patients with relapsed or refractory indolent B-cell lymphoma: Primary results of the pivotal CHRONOS-1 study. Presented at: 2017 AACR Annual Meeting; April 1-5, 2017; Washington, DC. Abstract CT149.

SUMMARY: The American Cancer Society estimates that in 2017, about 72,240 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,140 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphoma’s in the United States, and the incidence has steadily increased 3 to 4% each year. The etiology of Diffuse Large B-Cell Lymphoma is unknown. Contributing risk factors include immunosuppression (AIDS, transplantation setting, autoimmune diseases), ultraviolet radiation, pesticides, hair dyes, and diet. DLBCL is a neoplasm of large B cells and the most common chromosome abnormality involves alterations of the BCL-6 gene at the 3q27 locus, which is critical for germinal center formation. Two major molecular subtypes of DLBCL arising from different genetic mechanisms have been identified, using gene expression profiling: Germinal Center B-cell-like (GCB) and Activated B-Cell-like (ABC). Patients in the GCB subgroup have a higher five year survival rate, independent of clinical IPI risk score whereas patients in the ABC subgroup have a significantly worse outcome. Regardless, R-CHOP regimen (RITUXAN®-Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), given every 21 days, for 6 cycles, delivered with curative intent, is the current standard of care for patients of all ages, with newly diagnosed DLBCL, regardless of molecular subtype. Approximately 30-40% of patients experience disease progression or relapse, during the first 2 years and attempts to improve on R-CHOP regimen have not been successful. Maintenance treatment strategy following R-CHOP, to better control the disease, delay disease progression and improve long term survival, have included Autologous Stem Cell Transplantation, maintenance treatment with agents such as oral protein kinase inhibitor Enzastaurin and Everolimus. None of these interventions have been successful.

REVLIMID® (Lenalidomide) is an oral immunomodulatory agent (IMiD) with activity in lymphoid malignancies, primarily through immune modulation (repair T-cell immune synapse dysfunction and Natural Killer cell/T-cell effector augmentation). It additionally has antiproliferative effects. REVLIMID® was shown to have significant activity in relapsed DLBCL when given alone or along with RITUXAN®.

The REMARC study is an international, multicenter, double-blind, randomized, placebo-controlled phase III trial which compared REVLIMID® as maintenance therapy with placebo, in elderly patients with DLBCL, who achieved a Complete Response (CR) or Partial Response (PR) to R-CHOP induction treatment. A total of 650 patients who had CR or PR after 6-8 cycles of R-CHOP were randomly assigned in a 1:1 ratio to receive oral REVLIMID® maintenance 25 mg daily or placebo, for 21 days of every 28-day cycle, for 24 months. The median age was 68 years and approximately 90% of the patients had stage III-IV disease. The Primary end point was Progression Free Survival (PFS) and Secondary end points included safety, the percentage of patients who converted from PR to CR, Event Free Survival and Overall Survival (OS).

With a median follow up of 39 months, median PFS was not reached in the REVLIMID® group compared to 58.9 months in the placebo group (HR=0.70; P=0.013) favoring REVLIMID®. This PFS benefit with REVLIMID® maintenance was seen in all predefined subgroups (all age groups, all IPI scores, molecular subtypes, CR versus PR after R-CHOP, Positive versus Negative PET status at the time of randomization). The Overall Survival however was similar between the treatment groups after a longer median follow up of 52 months (P=0.26). The most common grade 3 or 4 toxcities associated with REVLIMID® maintenance were neutropenia and cutaneous reactions.

It was concluded that maintenance treatment with REVLIMID® for 24 months, after obtaining a CR or PR to R-CHOP, significantly prolonged Progression Free Survival in elderly patients with Diffuse Large B-Cell Lymphoma. This is the first randomized study showing a PFS benefit with an immunomodulatory agent as maintenance therapy, in this patient population. Lenalidomide Maintenance Compared With Placebo in Responding Elderly Patients With Diffuse Large B-Cell Lymphoma Treated With First-Line Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone. Thieblemont C, Tilly H, Gomes da Silva M, et al. DOI: 10.1200/JCO.2017.72.6984 Journal of Clinical Oncology – published online before print April 20, 2017