Low Serum Vitamin D Levels are Associated with Inferior Survival in Follicular Lymphoma

SUMMARY: The American Cancer Society estimates that about 71,850 people will be diagnosed with Non-Hodgkin Lymphoma (NHL) in the United States and about 19,800 individuals will die of this disease. Approximately 20% of all NHLs are Follicular Lymphomas. Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Advanced stage Follicular Lymphomas are not curable and as such prolonging Progression Free Survival (PFS) and Overall Survival (OS) while maintaining quality of life (QoL), has been the goals of treatment intervention. Asymptomatic patients with FL 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. Several studies have been underway evaluating the association between serum Vitamin D levels and cancer. Previously published studies have shown a relationship between Vitamin D deficiency and poor outcomes in patients with Diffuse Large B Cell Lymphoma and Chronic Lymphocytic Leukemia. The beneficial effects of Vitamin D in malignancies has been attributed to its antiproliferative and antiangiogenic properties, as well as its effects on cell differentiation, promotion of apoptosis and its ability to decreases oxidative DNA damage. Further, macrophages play an important role in the human body’s response to therapy with monoclonal antibodies, an integral part of Follicular Lymphoma therapies and low serum Vitamin D levels may interfere with macrophage function and this may explain poor outcomes in some Follicular Lymphoma patients with low Vitamin D levels

Indolent Non-Follicular B-Cell Lymphoma Treatment Guidelines

SUMMARY: Indolent Non-Follicular B-Cell Lymphoma (INFBCL) are mature B cell lymphoproliferative disorders and include Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT) lymphoma, Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL).

NMZL, LPL, and SLL

Recommendations for Diagnosis:

1) Excision biopsy of material from the primary disease site (ie, lymph node)

2) Fine Needle Aspiration biopsy is not recommended for the diagnosis or sub-typing. Computed Tomography (CT)-guided core biopsy can be an alternative diagnostic approach when thoracotomy or laparotomy are needed for lymph node biopsy.

3) A definitive diagnosis of LPL can only be made using bone marrow material.

Recommendations for Staging and Pretreatment Evaluation:

1) Complete history and physical examination, assessing Performance Status and B symptoms

2) Lab tests including CBC, CMP, LDH, B2-Microglobulin, hemolysis workup if anemic, SPEP, UPEP with immunofixation, serology for Hepatitis B,C and HIV, Flow Cytometry if peripheral blood shows abnormal lymphocytes or absolute lymphocytosis present and bone marrow aspirate and biopsy

3) CT of the neck, chest, abdomen, and pelvis (FDG-PET is not routinely indicated for this group of lymphomas as the avidity of FDG uptake is lower)

4) In LPL with monoclonal protein in the urine or serum, a fat pad biopsy for Congo red staining and an ultrasound cardiac scan are recommended when Amyloidosis is suspected

5) ECHO or MUGA scan, if treatment with anthracyclines are planned

6) Pregnancy testing in women of child-bearing age and counseling for the preservation of fertility

Recommendations regarding treatment initiation

1) Initiation of Chemotherapy or Immunotherapy should be based on the identification of symptoms as defined by the GELF or BNLI criteria.

2) Monoclonal protein-related symptoms such as hyperviscosity syndrome, renal failure, vasculitis and a lymphocyte doubling time of less than 6 months in those with leukemia, are indications for treatment.

3) Chemoimmunotherapy or Chemotherapy alone as early treatment is not recommended in asymptomatic advanced disease and observation alone is recommended in patients who do not meet the criteria for treatment with Chemotherapy or Immunotherapy

Recommendations for First Line Therapy

1) Patients with stage I or nonbulky stage II disease should be promptly treated with involved field Radiotherapy (RT) with or without chemotherapy. Observation alone may be a reasonable alternative if the potential toxicity of RT outweighs the potential benefits, particularly in elderly patients or if the patient refuses RT.

2) FLUDARA® (Fludarabine) plus RITUXAN® (Rituximab) – FR or TREANDA® (Bendamustine) plus RITUXAN® (BR) is the recommended first line therapy.

3) The combination of FLUDARA®, Cyclophosphamide and RITUXAN® (FCR) should be recommended to patients less than 70 years of age without significant comorbidities, and TREANDA® plus RITUXAN® should be preferred for patients 70 years or older with significant comorbidities.

Recommendations for Postinduction Therapy

Maintenance RITUXAN® is not recommended and patients with a partial response (PR) with no symptoms or signs of active disease, should be observed without additional treatment until progression.

Recommendations for Patients with Relapse

BR combination is the preferred treatment and new combinations of RITUXAN® with REVLIMID® (Lenalidomide) or VELCADE® (Bortezomib) should be considered experimental

ENMZL of MALT Lymphoma of Gastric Mucosa (Gastric MALToma)

MALT lymphoma histology is the most frequent among Marginal Zone Lymphomas and the most common extranodal MALT lymphoma involves the gastrointestinal tract.

Recommendations for Diagnosis:

1) Biopsy of material from the primary disease site

2) A molecular genetic analysis of lymphoma tissue for the detection of t(11;18) is recommended to identify disease that is unlikely to respond to antibiotic therapy

3) The presence of active Helicobacter pylori (Hp) infection must be determined using histologic testing. In the case of negative results, serology testing, stool antigen testing, or the urea breath test is recommended

Recommendations for Staging and Pretreatment Evaluation:

1) A detailed description of the extent of gastric lesions, gastric wall infiltration, and involvement of the perigastric lymph nodes, with ultrasound-guided endoscopy.

2) Along with the conventional staging procedures, additional investigations should include CT of the neck, chest, abdomen and pelvis and bone marrow biopsy

3) Staging classification should use the Ann Arbor staging system modified according to the Paris staging system

Recommendations for First Line Therapy

1) The first-line treatment of Hp-positive patients with gastric MALT lymphoma is Hp eradication therapy, independent of the disease stage. Surgery should only be considered for patients with perforation or bleeding, not amenable to endoscopy

2) Patients with Hp-negative localized gastric MALT lymphoma can also be treated with eradication therapy although the chance of a response is low and disease status should be closely monitored during therapy

3) After successful Hp eradication, consolidation chemotherapy is not indicated

Recommendations for non-responding and relapsed Patients

1) Radiation therapy is recommended for patients with stage IE-IIE gastric MALT lymphoma

2) RITUXAN® plus chemotherapy is recommended for those with other disease stages

SMZL (Splenic Lymphoma With Circulating Villous Lymphocytes)

Recommendations for Diagnosis:

1) SMZL can be diagnosed by splenectomy and examination of the splenic tissue

2) SMZL can also be diagnosed by a combination of bone marrow biopsy and an immunocytochemistry profile (intrasinusoidal infiltration by CD20+ cells), peripheral blood and bone marrow aspirate morphology as well as flow cytometry.

Recommendations for Staging and Pretreatment Evaluation:

1) Complete history and physical examination assessing performance status and B symptoms

2) Lab tests should include CBC, CMP, LDH, B2-Microglobulin, hemolysis workup if anemic, SPEP, UPEP with immunofixation, cryoglobulin and cryocrit. Serology for Hepatitis B,C and HIV, flow cytometry if peripheral blood shows abnormal lymphocytes or absolute lymphocytosis present and bone marrow aspirate and biopsy

3) CT of the neck, chest, abdomen, and pelvis (FDG-PET is not routinely indicated for this group of lymphomas as the avidity of FDG uptake is lower)

4) Pregnancy testing in women of child-bearing age and counseling for the preservation of fertility

Recommendations regarding treatment initiation

Patients with SMZL should be initiated on therapy if there is progressive or symptomatic splenomegaly, hemoglobin less than 10 g/dL, neutrophils less than 1000/μL, progressive thrombocytopenia, systemic symptoms, progressive nodal disease and autoimmune hemolytic anemia.

Recommendations for First Line Therapy

1) Patients who are HCV positive with no indications for anti-lymphoma therapy, should be treated for HCV infection.

2) For those requiring therapy for lymphoma, the options include splenectomy, chemotherapy alone, RITUXAN® alone, or chemoimmunotherapy. Chemoimmunotherapy is indicated for good PS patients with disseminated disease. Combinations therapies with proven efficacy include RITUXAN® in combination with Chlorambucil, CVP (Cyclophosphamide, Vincristine, Prednisone), FLUDARA® or 2-CDA (Cladribine).

3) Splenectomy should be recommended when patients present with splenomegaly-related cytopenias in the absence of a high percentage of leukemic cells in the peripheral blood, heavy bone marrow infiltration, and diffuse nodal disease. In patients who are HCV positive, splenectomy should be considered only after the exclusion of a severe chronic liver disease.

4) Single agent RITUXAN® may be considered for patients without disseminated disease and for patients with contraindications to surgery or chemoimmunotherapy.

Italian Society of Hematology, Italian Society of Experimental Hematology, and Italian Group for Bone Marrow Transplantation Guidelines for the Management of Indolent, Nonfollicular B-Cell Lymphoma (Marginal Zone, Lymphoplasmacytic, and Small Lymphocytic Lymphoma). Tarella C, Arcaini L, Baldini L, et al. Clinical Lymphoma, Myeloma & Leukemia. 2015; 15:75–85

Follicular Lymphoma – Evidence Based Treatment Guidelines

SUMMARY: The American Cancer Society estimates that about 71,850 people will be diagnosed with Non-Hodgkin Lymphoma (NHL) in the United States and about 19,800 individuals will die of this disease. Approximately 20% of all NHLs are Follicular Lymphomas (FL). Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Advanced stage Follicular lymphomas are not curable and as such prolonging Progression Free Survival (PFS) and Overall Survival (OS) while maintaining quality of life (QoL), has been the goals of treatment intervention. Asymptomatic patients with FL 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.

The authors in this publication following review of literature from 2000-2014, addressed FOUR important questions

What treatment options should be considered for localized FL?

Recommendation 1: The preferred treatment for localized FL is Radiation Therapy (RT).

Recommendation 2: Given the potential for long term toxicities, lower doses of RT (24 to 30 Gy) in 1.5 to 2Gy fractions and smaller field sizes, is recommended.

Recommendation 3: Combined modality treatments may be considered for patients with localized disease if positive outcomes are proven in randomized studies.

Recommendation 4: Observation alone may be a reasonable alternative if the potential toxicity of RT outweighs the potential benefits or if the patient refuses RT.

How should asymptomatic advanced-stage FL be managed?

Recommendation 1: Initiation of Chemotherapy or Immunotherapy should be based on the identification of symptoms as defined by the GELF or BNLI criteria.

Recommendation 2: Chemoimmunotherapy or Chemotherapy alone as early treatment is not recommended in asymptomatic advanced FL, because of the lack of published randomized studies. Observation alone is therefore recommended in patients who do not meet the criteria for treatment with Chemotherapy or Immunotherapy.

Recommendation 3: If ongoing randomized studies show positive outcomes with reduced risk of relapse, early treatment with RITUXAN® (Rituximab) with or without RITUXAN® maintenance in asymptomatic patients may be considered.

What treatment options should be considered for symptomatic advanced-stage FL?

Recommendation 1: Based on the lower response rate with RITUXAN® monotherapy, Chemoimmunotherapy is preferred over RITUXAN® monotherapy , for the first-line treatment of symptomatic advanced stage FL, except when Chemotherapy is contraindicated.

Recommendation 2: RITUXAN® should be added to chemotherapy in the first line treatment of symptomatic advanced-stage FL given the improved Overall Response Rate (ORR) and Progression Free survival (PFS) demonstrated with the addition of RITUXAN® to a number of Chemotherapy combinations.

Recommendation 3: TREANDA® (Bendamustine) and RITUXAN® (BR) is the preferred Chemoimmunotherapy regimen for the first-line treatment of symptomatic advanced-stage FL given the superior efficacy and favorable tolerability of this regimen compared to R-CHOP, confirmed in 2 randomized trials.

In which patients should additional treatment be considered (ie, maintenance, consolidation, SCT)?

Recommendation 1: Maintenance RITUXAN® is recommended after first-line treatment of FL given the improved response with RITUXAN® maintenance versus observation, demonstrated in 2 randomized trials. The optimal frequency and duration of maintenance RITUXAN® is presently unclear.

Recommendation 2: High Dose Therapy (HDT) followed by Autologous Stem Cell Transplantation (ASCT) is not recommended as part of front-line treatment of FL, given the lack of a survival benefit and the potential toxicity of this approach. There also is no evidence to support the use of Radioimmunotherapy (RIT) after first-line treatment of FL.

A Canadian Evidence-Based Guideline for the First-Line Treatment of Follicular Lymphoma: Joint Consensus of the Lymphoma Canada Scientific Advisory Board.  Kuruvilla J, Assouline S, Hodgson D, et al. Clinical Lymphoma Myeloma and Leukemia 2015; 15:59-74

A Prospective Multicenter Study Of The Bruton’s Tyrosine Kinase Inhibitor Ibrutinib In Patients With Relapsed Or Refractory Waldenstrom’s Macroglobulinemia

SUMMARY: The US Food and Drug Administration on January 29, 2015, approved Ibrutinib (IMBRUVICA®) for the treatment of patients with Waldenstrom Macroglobulinemia (WM). Waldenstrom Macroglobulinemia is classified as a LymphoPlasmacytic Lymphoma (LPL) according to the Revised European American Lymphoma (REAL) and WHO (World Health Organization) classifications. It is estimated that about 1500 new cases of WM will be diagnosed each year in the US. Chromosome 6q deletion detected by FISH technique on bone marrow evaluation, is seen in 40-50% of the patients with WM. Whole genome sequencing of lymphoplasmacytic cells has revealed activating somatic mutations in MYD88 (L265P) and CXCR4 genes, in Waldenstrom Macroglobulinemia (WM). About 90% of patients with Waldenstrom Macroglobulinemia demonstrate a mutation in chromosome 3p (MYD88 L265P), which is specific to WM and may be an early oncogenic event in WM pathogenesis.. It appears that MYD88 L265P promotes malignant cell proliferation via the Bruton’s Tyrosine Kinase (BTK) signaling pathway. Mutations in CXCR4 gene are present in 30% of patients with WM, and their expression induces BTK activity and may confer resistance to BTK inhibitors. IMBRUVICA® (Ibrutinib) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis). Preliminary studies in WM patients have revealed that IMBRUVICA® prevents the binding of MYD88 L265P (mutated gene) to BTK thereby selectively killing tumor cells. On the other hand it was noted that a major response to IMBRUVICA® was less likely when mutations in CXCR4 gene were present in the tumor cells. With this molecular understanding of WM, the authors enrolled 63 patients with relapsed/refractory symptomatic WM and were treated with IMBRUVICA®, 420 mg PO daily for 2 years or until disease progression or unacceptable toxicity. Anemia was main indication for treatment initiation (87.3% of patients) and the mean baseline hemoglobin level was 10.5 g/dL, mean serum IgM level was 3610 mg/dL, 70% had bone marrow involvement and 60% of patients had lymphadenopathy. Sanger sequencing was used to determine MYD88 and CXCR4 mutations in the bone marrow lymphoplasmacytic cells. At best response, the median serum IgM levels declined to 1340 mg/dL (P<0.00001), median hemoglobin rose to 12.6 g/dL, (P<0.00001). At 6 months, bone marrow assessment post treatment, demonstrated a reduction in WM disease involvement from 70% to 45% (P=0.0006). With a median follow up at 6 cycles, the best overall response rate was 81% and a median time to response was 4 weeks. In patients who underwent tumor sequencing, mutations in CXCR4 gene impacted response rates. The major response rate for patients with wild-type CXCR4 gene was 77% compares to 30% in those with CXCR4 mutations (p=0.018). Further, patients with wild-type CXCR4 also had increased peripheral lymphocytosis following treatment with IMBRUVICA® compared to those with CXCR4 mutations (P=0.001). The most common more than grade 2 treatment related toxicities included thrombocytopenia (14.3%) and neutropenia (19.1%). The authors concluded that IMBRUVICA® is highly active in patients with relapsed or refractory Waldenstrom Macroglobulinemia, with rapid reductions in serum IgM level and improved hemoglobin levels. The presence of CXCR4 mutations negatively impact response rates in this patient group. Treon SP, Tripsas CK, Yang G, et al. Presented at: 55th ASH Annual Meeting; December 7-10, 2013; New Orleans, LA. Abstract 251.

Hepatitis B Reactivation in Patients with Previous Hepatitis B Virus Exposure Undergoing Rituximab-Containing Chemotherapy for Lymphoma A Prospective Study

SUMMARY:The Centers for Disease Control and Prevention (CDC) estimates that there are 800,000 -1.4 million individuals with Chronic Hepatitis B infection in the United States. Reactivation of HBV is a major concern in cancer patients who may be on chemotherapy or other immunosuppressive therapies, with the incidence of HBV reactivation ranging from 40%-60% in those who are positive for Hepatitis B surface antigen (HBsAg). HBV reactivation is preventable with prophylactic antiviral therapy, failing which it can result in delays in cancer treatment as well as potentially fatal outcomes. The CDC updated their recommendations in 2008 and recommended HBV screening for patients receiving cytotoxic chemotherapy or immunotherapy. The American Society of Clinical Oncology in 2010 rendered a Provisional Clinical Opinion (PCO) suggesting that there was insufficient evidence to recommend routine screening for HBV in cancer patients, but screening may be considered for patient populations at high risk or for those who are to receive highly immunosuppressive therapies including anti-CD20 monoclonal antibody therapy such as RITUXAN® (Rituximab). According to the International recommendations, HBV reactivation is defined as the detection of serum HBV DNA of 10 IU/mL or more, by a real-time polymerase chain reaction–based assay. Because of the ambiguity regarding HBV reactivation in lymphoma patients receiving immunosuppressive therapy, the authors conducted a prospective trial to determine the frequency and factors predictive of HBV reactivation in HBsAg-negative, anti-HBc–positive patients treated with RITUXAN® based chemotherapy regimens. In this observational study, 260 patients with hematologic malignancies who were HBsAg-negative, anti-HBc–positive, with undetectable serum HBV DNA (< 10 IU/mL) and treated with RITUXAN® containing chemotherapy, were prospectively monitored every 4 weeks for up to 2 years. Patients were started on BARACLUDE® (Entecavir), when HBV reactivation (serum HBV DNA of 10 IU/mL or more), was documented. The cumulative rate of HBV reactivation over the 2 year observation period was high at 41.5%. The HBV reactivation occurred at a median of 23 weeks after RITUXAN® treatment and the median HBV DNA level at reactivation was 43 IU/mL. Undetectable antibody level to HBsAg (anti-HBs; < 10 mIU/mL) at baseline, prior to treatment with RITUXAN®, was the only significant risk factor that was strongly associated with HBV reactivation (P=0.009). Patients with negative baseline antibody level to HBsAg (anti-HBs) had a significantly higher 2-year cumulative rate of HBV reactivation, compared with those who had positive baseline antibody level to HBsAg (68.3% vs 34.4%; P=0.012). All patients had normal ALT when HBV reactivation occurred and except for one patient, were HBsAg negative. More importantly, all patients with HBV reactivation were successfully treated with BARACLUDE®. The authors concluded that HBsAg-negative, anti-HBc–positive lymphoma patients, receiving RITUXAN® based chemotherapy regimens experience a high rate of HBV reactivation, with this rate even significantly higher in patients with negative baseline antibody level to HBsAg. Periodic monitoring for HBV reactivation can enable early detection and intervention,thereby avoiding HBV related morbidities and mortality. Seto W, Chan T, Hwang Y, et al. JCO 2014;32:3736-3743

Randomized phase 3 study of rituximab, cyclophosphamide, doxorubicin, and prednisone plus vincristine (R-CHOP) or bortezomib (VR-CAP) in newly diagnosed mantle cell lymphoma (MCL) patients (pts) ineligible for bone marrow transplantation (BMT)

SUMMARY: The U.S. Food and Drug Administration (FDA) on October 9, 2014, approved VELCADE® (Bortezomib), a proteasome inhibitor, as combination regimen, for use in previously untreated patients with Mantle Cell Lymphoma (MCL). Non-Hodgkin Lymphoma (NHL) is one of the most common cancers in the United States and the American Cancer Society estimates that in 2014, about 70,800 people will be diagnosed with NHL in the US and close to 19,000 people will die of the disease. Mantle Cell Lymphomas constitute approximately 5% of all Non Hodgkin lymphomas and have a high relapse rate following dose-intensive therapies. VELCADE® was initially approved by the FDA in 2006 for the treatment of relapsed or refractory Mantle Cell Lymphoma and has a response rate of 30%. This latest approval was based on the results of an international, randomized, open-label phase III trial in which 487 patients with stage II to IV MCL, who were ineligible or not considered for Bone Marrow Transplantation, received VR-CAP (N = 243) or R-CHOP (N = 244). VR- CAP is essentially R-CHOP with the Vincristine replaced by VELCADE®. So, VR-CAP regimen consisted of VELCADE® administered IV at 1.3 mg/m2 on days 1, 4, 8, and 11, RITUXAN® (Rituximab) 375 mg/m2 IV given on day 1, Cyclophosphamide 750 mg/m2 IV on day 1, Doxorubicin 50 mg/m2 IV on day 1 and Prednisone at 100 mg/m2 PO on days 1 to 5 of a 21 day cycle for 6-8 cycles. R-CHOP regimen was exactly similar except that Vincristine 1.4 mg/m2 (max 2 mg) IV was administered on day 1 of each cycle instead of VELCADE®. The primary endpoint was Progression Free Survival (PFS) and secondary endpoints included Time To Progression (TTP), Time To Next Treatment (TTNT), Overall Survival (OS) and safety. Patients received a median of 6 cycles and after a median follow up of 40 months, patients in the VR-CAP group demonstrated a significantly longer median PFS (25 months vs. 14 months; HR=0.63;P<0.001) with a 37% relative improvement in the PFS compared to those who were treated with standard R-CHOP. Patients in the VR-CAP group also had a higher overall response rate (88 vs 85%) and a higher rate of complete response (44% vs. 34%). The most common adverse reactions occurring in 20% or more of patients receiving the VR-CAP regimen were neutropenia, leukopenia, anemia, thrombocytopenia, lymphopenia, peripheral neuropathy, pyrexia, nausea and diarrhea. Infections were reported for 31% of patients in the VR-CAP group compared to 23% of the patients in the R-CHOP group. The authors concluded that VR-CAP significantly prolonged PFS and consistently improved secondary efficacy endpoints, compared to R-CHOP, in newly diagnosed, Bone Marrow Transplant ineligible Mantle Cell Lymphoma patients with manageable toxicity. Proteosome inhibition with a VELCADE® based chemotherapy regimen has opened the doors for more effective therapies for Mantle Cell Lymphoma patients. Cavalli F, Rooney B, Pei L, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8500)</s

Rituximab Extended Schedule or Re-Treatment Trial for Low–Tumor Burden Follicular Lymphoma Eastern Cooperative Oncology Group Protocol E4402

SUMMARY: Non-Hodgkin Lymphoma (NHL) is one of the most common cancers in the United States and the American Cancer Society estimates that in 2014, about 70,800 people will be diagnosed with NHL in the US and close to 19,000 people will die of the disease. RITUXAN® (Rituximab) is a first generation type I, chimeric anti-CD20 targeted monoclonal antibody that destroys malignant human B cells primarily by complement-dependent cytotoxicity (CDC) and Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC). Since its approval in 1997, immunochemotherapy regimens incorporating RITUXAN® has had a major impact in treatment outcomes for patients with Follicular Lymphomas both in first line as well as relapsed settings. Two years of RITUXAN® maintenance therapy after induction immunochemotherapy as first-line treatment for high tumor burden Follicular Lymphoma, significantly improved Progression Free Survival, as was shown in the PRIMA study. Similarly, maintenance RITUXAN® has been shown to improve Progression Free Survival when compared with observation, in patients with low tumor burden Follicular Lymphoma. Whether maintenance RITUXAN® provides superior long term disease control compared with retreatment with RITUXAN® when disease progression is noted, has remained unclear. RESORT [Rituximab Extended Schedule or Re-Treatment Trial] is a randomized trial designed to determine whether maintenance treatment with RITUXAN® provided superior disease control compared with retreatment with RITUXAN® at disease progression, in patients with previously untreated low tumor burden Follicular Lymphoma. Low tumor burden was defined as no mass more than 7 cm, fewer than three masses more than 3 cm, no B symptoms, spleen size less than 16 cm by CT scan, no evidence of organ compromise, circulating lymphocytes less 5,000/μL, and no evidence of cytopenias defined as platelets less than 100,000/μL, hemoglobin less than 10 g/dL, or absolute neutrophil count less than 1,500/μL. Of the 408 patients with Follicular Lymphoma included in this study, 289 patients responded to induction treatment with 4 weekly doses of RITUXAN® given at 375mg/m2. These patients were then randomly assigned to maintenance RITUXAN® (N= 146) or retreatment with RITUXAN® (N=143) at each disease progression, until treatment failure. Maintenance RITUXAN® treatment consisted of a single dose of RITUXAN® given every 3 months until treatment failure. The primary end point of this study was time to treatment failure. Secondary end points included time to first cytotoxic therapy, toxicity, and health-related quality of life (HRQOL). With a median follow-up of 4.5 years, there was no difference in the median time to treatment failure amongst the maintenance RITUXAN® and retreatment RITUXAN® groups (4.3 years vs 3.9 years, P=0.54). The median number of RITUXAN® doses was 18 for those receiving maintenance RITUXAN® compared to 4 for those receiving retreatment RITUXAN®. Grade 3 or 4 toxicities were uncommon in both treatment groups and there was no difference in health-related quality of life. The authors concluded that in low tumor burden Follicular Lymphoma, a retreatment strategy at disease progression utilizes fewer doses of RITUXAN® with outcomes equivalent to that achieved with maintenance RITUXAN®. Kahl BS, Hong F, Williams ME, et al. J Clin Oncol 2014;32:3096-3102

ZYDELIG® – A New Treatment Option for Non-Hodgkin Lymphoma

The FDA granted ZYDELIG®, accelerated approval in relapsed Follicular B-cell Non-Hodgkin Lymphoma and Small Lymphocytic Lymphoma. The approval was based on ZYDELIG®’s significant single agent activity with an acceptable safety profile, in heavily pretreated patients with indolent Non Hodgkin Lymphomas. ZYDELIG® is a highly selective, small molecule, oral inhibitor of the enzyme Phosphoinositide 3-Kinase delta (PI3K delta) and blocks the delta isoform of PI3K enzyme and its signaling pathway, thus promoting apoptosis. More information is available at www.oncoprescribe.com

PI3Kδ Inhibition by Idelalisib in Patients with Relapsed Indolent Lymphoma

SUMMARY: Non-Hodgkin Lymphoma (NHL) is one of the most common cancers in the United States and the American Cancer Society estimates that in 2014, about 70,800 people will be diagnosed with NHL in the US and close to 19,000 people will die of the disease. PI3K 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. PI3K (PhosphatidylInositol 3-Kinase) is a lipid kinase and has four distinct isoforms – alpha, beta, gamma and delta. The alpha and beta isoforms are expressed in a wide variety of tissues whereas the gamma and delta isoforms are only expressed in hematopoietic cells. PI3K delta (the delta isoform of PI3K enzyme) is predominantly expressed in leukocytes and plays an important role in the normal B lymphocyte development as well as signal transduction from B cell receptor as well as receptors for various cytokines and chemokines. PI3K delta is activated by BCR signaling resulting in the production of a second messenger, Phosphatidylinositol 3,4,5-triphosphate (PIP3) which in turn activates Bruton’s Tyrosine Kinase (BTK) and AKT, a prosurvival kinase. Idelalisib (ZYDELIG®) is a highly selective, small molecule, oral inhibitor of the enzyme Phosphoinositide 3-Kinase delta (PI3K delta) and blocks the delta isoform of PI3K enzyme and its signaling pathway, thus promoting apoptosis. The FDA granted ZYDELIG® accelerated approval in relapsed Follicular B-cell Non-Hodgkin Lymphoma and Small Lymphocytic Lymphoma based on the results of a single-arm, open-label, phase II trial. Patients with indolent Non-Hodgkin Lymphomas (N=125), who were refractory to Rituximab (RITUXAN®) and an alkylating agent or had relapsed within 6 months after receipt of these therapies, received ZYDELIG®, 150 mg PO BID. Treatment was continued until disease progression or unacceptable toxicities developed. The median age was 64 years and enrolled patients had received a median of four prior therapies. The indolent Non-Hodgkin Lymphoma subtypes included Follicular lymphoma (N=72), Small Lymphocytic Lymphoma (N=28), Marginal Zone Lymphoma (N=15), and Lymphoplasmacytic Lymphoma with or without Waldenström's Macroglobulinemia (N=10). The primary end point of this study was Overall Response Rate and secondary end points included the Duration of Response, Progression Free Survival, and Safety. The median follow up was 9.7 months. The Overall Response Rate was 57% with 50% partial responses and 6% complete responses. There was no difference in the Reponse Rates across the various subtypes of Indolent Non-Hodgkin Lymphomas. The median time to response was 1.9 months and the median duration of response was 12.5 months. The median Progression Free Survival was 11 months and the Overall Survival at one year was estimated to be 80%. The most common grade 3 or higher adverse events were diarrhea (13%), neutropenia (27%) and elevations in SGOT and SGPT levels (13%). These toxicities were manageable with dose modifications and dose interruptions. The authors concluded that ZYDELIG® has significant single agent activity, with an acceptable safety profile, in heavily pretreated patients with indolent Non Hodgkin Lymphomas. Gopal AK, Kahl BS, de Vos S, et al. N Engl J Med 2014; 370:1008-1018

Belinostat, a novel pan-histone deacetylase inhibitor (HDACi), in relapsed or refractory peripheral T-cell lymphoma (R/R PTCL) Results from the BELIEF trial

SUMMARY: Non-Hodgkin lymphoma (NHL) is one of the most common cancers in the United States and the American Cancer Society estimates that in 2014, about 70,800 people will be diagnosed with NHL in the US and close to 19,000 people will die of the disease. T cell Lymphomas are a heterogenous group of lymphoid malignancies representing less than 15% of all Non-Hodgkin Lymphomas. Peripheral T-cell lymphoma – NOS (PTCL-Not Otherwise Specified) is the most common of the aggressive T-cell lymphoma subtypes and accounts for 26% of all non-cutaneous PTCL’s. These malignancies are derived from mature post thymic T-cells and NK cells. These tumors are uncommon, tend to be aggressive and majority of the patients with T-cell lymphoma present with advanced stage disease and respond poorly to treatment. Relapse rates tend to be high and few patients achieve durable remission with treatment. For these reasons, prognosis remains poor. Agents from two pharmacological classes are presently available for the treatment of PTCL. The FDA granted accelerated approval to FOLOTYN® (Pralatrexate), an antifolate, in 2009, for use in patients with relapsed or refractory PTCL and to ISTODAX® (Romidepsin), a histone deacetylase (HDAC) inhibitor in 2011, for the treatment of PTCL patients, who had received at least one prior therapy. HDACs are a family of enzymes that play an important role in the regulation of gene expression. To briefly summarize the structure of a chromosome, individual loops of coiled double-helix DNA wrap around a histone protein to form a nucleosome. Nucleosomes are then coiled together to form chromatin fibers, which looks like beads on a string. The chromatin fibers are coiled even more tightly to form chromosomes. HDAC enzymes catalyze the removal of acetyl groups and regulate the level of acetylation of the histones and non-histone proteins and transcription of several genes. Hypoacetylation of histones has been associated with a condensed chromatin structure that results in the repression of gene transcription, whereas acetylated histones are associated with a more open chromatin structure and activation of gene transcription. HDACs are grouped into four major classes and regulate cell-cycle progression, cell survival, angiogenesis and immunity. BELEODAQ® (Belinostat) is a novel pan-histone deacetylase inhibitor and inhibits all 3 classes of the zinc-dependent HDAC enzymes. The approval of BELEODAQ® was based on the results of a multi-center, single-arm, phase II trial, in which 129 patients with relapsed or refractory PTCL, who had received a median of 2 prior therapies, were enrolled and evaluated. BELEODAQ® was administered as a 30 minute IV infusion at 1000 mg/m2 on days 1–5 of a 3 week cycle until progression or unacceptable toxicity. The median age was 63 years. The primary endpoint was Overall Response Rate (ORR). The ORR was 26% with 10% Complete Responses and 10% Partial responses and the median time to response was 5.6 weeks and the median duration of response was 8.3 months. The most common adverse events were nausea, vomiting, fatigue, fever and anemia. The most common grade 3/4 adverse events were thrombocytopenia (13%), neutropenia (13%), anemia (10%), dyspnea (6%), pneumonia (6%), and fatigue (5%). The authors concluded that BELEODAQ® demonstrated a significant overall response rate in relapsed /refractory PTCL patients, thus expanding the treatment options for these difficult to treat individuals. This was accomplished with a low incidence of myelosuppression and favorable safety profile. O'Connor OA, Masszi T, Savage KJ, et al. J Clin Oncol 31, 2013 (suppl; abstr 8507)