NHL updates (2016)

Noha El Baghdady, M.Sc.

Non-Hodgkin lymphomas (NHLs)

Tumors originating from lymphoid tissues, mainly

of lymph nodes.

Epidemiology

Incidence• NHL occurs with increasing

frequency, with about 60.000 new cases annually in the United States.

• According to The NCCN guidelines In 2015, an estimated 71,850 people will be diagnosed with NHL and will be approximately 19,790 deaths due to the disease.

Etiology

1- Pathogens (Infections).2- Immunodeficiency or immune dysregulation.3- Treatment related.4- Environmental factors (Toxins).5- genetics (Chromosomal translocations).

WHO / Revised European American Lymphoma ( REAL) Classification

B-cell lymphomas( 80% - 85%) T-cell lymphomas (15% - 20%)

• Diffuse large B-cell lymphoma• Follicular lymphoma• Chronic lymphocytic leukemia /small

lymphocytic lymphoma• Mantle cell lymphoma• Marginal zone B-cell lymphomas• Burkitt lymphoma• Lymphoplasmacytic lymphoma

(Waldenstrom macroglobulinemia)• Hairy cell leukemia• Primary central nervous system (CNS)

lymphoma

• Precursor T-lymphoblastic lymphoma/leukemia

• Peripheral T-cell lymphomas• Cutaneous T-cell lymphomas (mycosis

fungoides, Sezary syndrome, and others)• Adult T-cell leukemia/lymphoma• Angioimmunoblastic T-cell lymphoma• Extranodal natural killer/T-cell

lymphoma, nasal type• Enteropathy-associated intestinal T-cell

lymphoma (EATL)• Anaplastic large cell lymphoma (ALCL)• Peripheral T-cell lymphoma, unspecified

Follicular Lymphoma (FL)• FL represents 22% of total NHL.

About 85% of cases are stage III or IV at presentation.

• FL cells are positive for CD 10 & CD 20 and bear the t(14;18) translocation That results in upregulation of BCL – 2 expression.

• FL are highly responsive to therapy but survival is modest and few are cured.

• Average survival vary with possible increases in median Survival times in the (MAB era).

Chronic Lymphocytic Leukemia (CLL)

• Estimated new cases and deaths from CLL in the United States in 2016:

- New cases: 18,960.- Deaths: 4,660.• CLL lymphocytes co-

express the B-cell antigens CD19 and CD20.

The treatment of non-Hodgkin lymphoma (NHL) varies greatly, depending on the following factors

• Tumor stage• Phenotype (B-cell, T-cell or natural killer (NK) cell/null-

cell)• Histology (i.e: low, intermediate, or high-grade)• Symptoms• Performance status (PS)• Patient age• Comorbidities

Anti- CD20 mAb

Anti- CD20 mAb• Preclinical studies have indicated a

positive correlation between increasing numbers of genetic alterations and the progression from follicular lymphoma in situ to grade 3A follicular lymphoma.

• The B-cell receptor was fond that it is a critical cellular factor in the development of the disease.

Anti- CD20 mAb

• Activation of these pathways ultimately results in the: maturation, proliferation, and survival of malignant lymphocytes.

Anti- CD20 mAb

first FDA-approved monoclonal antibody (mAb)

Rituximab (chimeric anti-CD20 mAb) for the treatment of B-NHL cells

Subsequently, over 20 approved mAbs have been in use clinically for the treatment of various cancers and several non-cancer related diseases.

1997

Anti- CD20 mAb• Two anti-CD20 antibodies, Ofatumumab and

Obinutuzumab, have been approved by the US Food and Drug Administration (FDA) for indications in NHL.

Ofatumumab (Arzerra®)

Ofatumumab (Arzerra®)

• On October 27, 2009, The Food and Drug Administration (FDA) approved ofatumumab (Arzerra®) for patients with chronic lymphocytic leukemia (CLL) whose cancer is no longer being controlled by other forms of chemotherapy.

• On April 17, 2014, the FDA approved ofatumumab (Arzerra® Injection, for intravenous infusion) in combination with chlorambucil, to treat patients with treatment-naive CLL for whom fludarabine-based therapy would not be appropriate.

Ofatumumab (Arzerra®)

• On January 19, 2016, the U.S. Food and Drug Administration approved ofatumumab (Arzerra® Injection) for extended treatment of patients who are in complete or partial response after at least two lines of therapy for recurrent or progressive chronic lymphocytic leukemia (CLL).

(( Ofatumumab Approved as Maintenance Therapy for CLL))

Ofatumumab (Arzerra®)

• This approval was based on clinical trials results that showed that patients with CLL assigned maintenance therapy with ofatumumab had close to double the progression-free survival (PFS) compared with patients who did not undergo maintenance therapy.

Results of the phase III PROLONG study were published in the October 2015 issue of Lancet Oncology.

Compared to Rituximab

Ofatumumab (Arzerra®)Extended treatment in CLL recommended dosage and schedule is:

• 300 mg on Day 1 1,000 mg on Day 8

• 1,000 mg after 7 weeks and every 8 weeks thereafter for up to a maximum of 2 years.

Preparation & Storage• Preparation:300-mg dose: Withdraw and discard 15 mL from a 1,000-mL bag of 0.9% Sodium Chloride Injection, USP. Withdraw 5 mL from each of 3 single-use 100-mg vials of ARZERRA and add to the bag. • Storage:- Start infusion within 12 hours of preparation. -Discard prepared solution after 24 hours. -Store diluted solution between 2° to 8°C .

Ofatumumab (Arzerra®)• The serious adverse reactions(Reported 30% of

patients ):

1- Pneumonia2- Pyrexia3- Neutropenia (including febrile neutropenia).

• The most common adverse reactions (greater than or equal to 10%):

1- Infusion reactions2- Neutropenia 3- Upper respiratory tract infection.

Obinutuzumab (Gazyva®)

Obinutuzumab (Gazyva®)• The first FDA approval was in 2013 for use in combination with

chlorambucil for previously untreated chronic lymphocytic leukemia.

• On February 26, 2016, the U. S. Food and Drug Administration approved obinutuzumab (Gazyva®) for use in combination with bendamustine followed by obinutuzumab monotherapy for the treatment of patients with follicular lymphoma (FL), the most common type of indolent non-Hodgkin's lymphoma (NHL), who relapsed after, or are refractory to, a rituximab-containing regimen.

Obinutuzumab (Gazyva®)

• This new approval was based on demonstration of an improvement in progression-free survival (PFS) in patients with FL who had no response to or have progressed during or within 6 months of a rituximab-containing regimen.

Sehn LH, Chua N, Mayer J, et al. GADOLIN: Primary results from a phase III study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2015

Compared To Rituximab

Mechanism Compared to rituximabAntibody – dependent Cellular Cytotoxicity (ADCC)

GAZYVA delivered up to a 35- fold increase in ADCC

Direct Cell DeathGAZYVA activated intracellular death signaling pathway in preclinical studies.

1.GAZYVA full Prescribing Information. South San Francisco, CA: Genentech USA, Inc.; September 2015.2.Mössner E, Brunker P, Moser S, et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell–mediated B-cell cytotoxicity.Blood. 2010;115(22):4393-4402.3.Herter S, Herting F, Mundigl O, et al. Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models. Mol Cancer Ther. 2013;12(10):2031-2042.

Obinutuzumab (Gazyva®)Day of treatment cycle Dose of GAZYVA

Rate of infusion (in the absence of infusion reactions/hypersensitivity during previous infusions)

Cycle 1 Day 1 1000 mg Administer at 50 mg/hr. The rate of the infusion can be escalated in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr.

Day 8 1000 mg

If no infusion reaction occurred during the previous infusion and the final infusion rate was 100 mg/hr or faster, infusions can be started at a rate of 100 mg/hr and increased by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr.

Day 15 1000 mg Cycles (2–6) every month

Day 1 1000 mg

Monotherapy Every two months for two years

1000 mg

Preparation & StoragePreparation of solution for infusion:

• Withdraw 40 mL of GAZYVA solution from the vial.

• Dilute 40 mL (1000 mg) into a 250 mL 0.9% sodium chloride infusion bag.

• Mix diluted solution by gentle inversion. Do not shake or freeze.

Storage:• At 2°C to 8°C for up to 24 hours prior to

use. • After allowing the diluted bag to come

to room temperature, use immediately.

The most common side effects

Further Readings:

http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/

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