Circulating Memory T-cell Isolated from Hodgkin Lymphoma Patients Display Evidence of Exhaustion and Chronic Activation

Picture2By Jia Ruan, MD, PhD

Although Hodgkin Reed-Sternberg (HRS) cells comprise only a small number of tumor cells, their number is outweighed by their relative importance as the orchestrators of an inflammatory microenvironment that allows for the growth of Hodgkin Lymphoma (HL). The peritumoral CD4 and CD8 cells in patients with HL, display high expression of the receptor programmed death-1 (PD-1). PD-1 is involved in the functional impairment and “exhaustion” of T-cells. Recent data confirms that the effects of HL-mediated immune suppression may stretch beyond the tumor microenvironment, with reports of high levels of inflammatory cytokines and chemokines in patients with both newly diagnosed and relapsed HL.

In results presented from an abstract presented during the 2014 American Society of Hematology conference (ASH), we found that HL patients have evidence of chronic activation/exhaustion in their central memory and effector T-cells. Informed consent was requested for correlative blood testing was obtained from patients with both newly diagnosed and relapsed HL. For patients with progressive disease persistence of this phenotype is worthy of further investigation as to whether immune dysfunction results from or is caused by resistance to therapy. An answer to this question may provide the rationale for an immune targeted therapy in patients with relapsed or resistance HL.

Brentuximab Vedotin is Efficacious as First Line Salvage Therapy in Patients with Relapsed/Refractory Hodgkin Lymphoma Prior to Autologous Hematopoietic Cell Transplantation

Picture1By Peter Martin, MD

Brentuximab vedotin (BV), is an antibody drug conjugate that selectively binds to a protein called CD30 on the surface of cells (e.g., Hodgkin lymphoma cells) and delivers a payload of toxin (monomethyl auristatin E) directly to that cell; i.e., a Trojan horse approach to cancer therapy. In 2011, the United States Food and Drug Administration (FDA) approved BV based on a phase II trial in which BV demonstrated an overall response rate (ORR) of 75% and complete response rate (CR) of 34% in patients with Hodgkin lymphoma that had relapsed following autologous hematopoietic cell transplantation (AHCT). Given the promising data, investigators at City of Hope and Weill Cornell Medical College-New York collaborated to evaluate the use of BV prior to AHCT. The standard approach for patients that relapse after first-line therapy includes cytotoxic chemotherapy followed by AHCT. However, this approach can be challenging for some patients and may be associated with some short-term and long-term toxicity. Use of BV prior to AHCT may cause patients some side effects and improve their quality of life prior to AHCT. Preliminary data from this trial were presented yesterday at the 56th Annual Meeting of the American Society of Hematology (ASH).

All patients had biopsy proven Hodgkin lymphoma that had relapsed following therapy with ABVD, BEACOPP, or a combination +/- radiation. Patients were treated with a standard dose of BV intravenously every 3 weeks for a maximum of 4 cycles. Over two-thirds of patients responded, including one third of patients that obtained a CR) and roughly half of the patients were able to proceed to AHCT without receiving additional chemotherapy. Treatments were well tolerated by all patients and no transfusions were required or neutropenic fevers developed.

The results from this trial suggest that BV may be an efficacious option as a first line salvage therapy. It is well tolerated and does not hinder stem cell collection or engraftment. Additional studies will be required to confirm these results. Moreover, this study may lay the groundwork for future studies with promising combinations.

Chemotherapy Free Novel Combination of Lenalidomide and Rituximab Displays Promising Results as Initial Therapy for Patients with Mantle Cell Lymphoma

Ruan FaceBy Jia Ruan, MD, PhD

Yesterdays results presented at ASH 2014 provides the first demonstrated feasibility and efficacy of a chemotherapy-free, biologic approach using lenalidomide and rituximab as an initial therapy for mantle cell lymphoma (MCL).  These findings present an important chemotherapy-free alternative initial treatment for MCL, as current conventional upfront chemoimmunotherapies are generally not curative.

During this multi-center phase II study patients were administered lenalidomide at 20 mg in days 1-21 of a 28-day cycle for a total of 12 cycles, with doses escalated to 25 mg when tolerated. Rituximab was administered weekly x 4 during first cycle and then once every other cycle for a total of 9 doses.  The induction phase was followed by a maintenance phase, which at the 13th cycle, lenalidomide was administered at 15 mg on days 1-21 of a 28 day cycle, while rituximab maintenance was employed once every other cycle until disease progression.

Of the 38 patients with previously untreated MCL the median age was 65 years (range 42-86), with a male to female ratio of 2.5:1. Treatment was generally well tolerated with mild to moderate side effects. The overall response rate in patients was 84.2%, complete response rate was over 50%, with median time to objective response being 2.8 months. The median progression-free survival has not been reached, and the 2 year progression free survival rate is estimated to be 83.9%.

This study demonstrated that a high proportion of MCL patients can achieve durable remissions while maintaining a high quality of life. The data gathered from this trial justifies further evaluations of the lenalidomide and rituximab regimen both alone and in combination with other treatment approaches to MCL.

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