Successful Restoration of Nivolumab Efficacy Post Allogeneic Stem Cell Transplantation in Hodgkin's Lymphoma

Introduction:

Classic Hodgkin's lymphoma (cHL) is a highly curable disease. A minority of patients, however, will have relapse/refractory (RR) disease and these patients are challenging to manage especially those who relapse after autologous hematopoietic cell transplant (auto-HCT). Even though a number of salvage options are available for these patients, none of them is curative except allogeneic hematopoietic cell transplant (allo-HCT) which offers long term disease control for a subgroup of patients at a price of significant therapy related mortality (TRM) and relapses remain frequent. The traditional approach for post allo-HCT relapse is donor lymphocyte infusion (DLI) after controlling the disease with chemotherapy (or brentuximab vedotin (BV) if not used before), alone or with DLI. The results of these approaches are frequently disappointing. Preclinical and clinical studies of peri-allo-HCT immune-manipulation using checkpoint inhibitors (CPI) or ipilimumab in a number of hematologic malignancies including relapses post allo-HCT have shown efficacy at a price of significant toxicities, mainly due to immune phenomena and graft versus host disease (GvHD). But looking at these studies restricted to cHL patients only, the results seem reasonable. Checkpoint inhibitors are approved for RR cHL patients and in the present practice almost all patients will have exposure to this class of drugs before allo-HCT consideration. There are no published reports addressing the re-use of this class of drugs on patients who have been already exposed and failed. We herein report six patients who failed CPI before allo-HCT and responded nicely upon re-exposure post allo-HCT.

Patients and methods:

With data emerging about the safety and efficacy of checkpoint inhibitors after allo-HCT, we generally treated our cHL patients who relapsed post allo-HCT with escalating dose Nivolumab when they failed all other standard of care options including Brentuximab vedotin. The primary objective of this study was to evaluate the safety, efficacy and outcomes of patients who already failed Nivolumab pre-transplant and were challenged again with Nivolumab after relapsing post allo-HCT. After securing institutional review board (IRB) approval, we conducted a retrospective chart review and were able to identify six patients who received Nivolumab prior allo-HCT cell transplant and progressed. All patients had progressive disease post allo-HCT when Nivolumab was started. All patients were started on low dose Nivolumab (40 mg total dose) and monitored for GvHD. Additional doses were based on the response and the presence or absence of GvHD after Nivolumab. Efficacy was assessed clinically and by PET scan (positron emission tomography). Toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). Acute and chronic GvHD were defined and graded according to the standard criteria.

Results:

- Median Age 31 y.o (24-40)

- Median follow up after allo-HCT was 26 months (20.1 -28.5 )

- Median time to progression after allo-HCT and before Nivolumab was 5.8 months (2.7-13.1)

- Median Nivolumab cycles post allo-HCT transplant was 6.5 month (2.75-8.75

- Median time to 1st Nivolumab dose after allo-HCT was 7.6 months (2.9- 23.2)

- All patients started on 40 mg dose and escalated to 240 mg in 3 patients.

- 5 out of 6 patients responded to post allo-HCT Nivolumab. 4 out of 6 patients are alive and GVHD free.

- Best Response to Nivolumab:

2 patients achieved CR

3 patients achieved Partial response,

1 Progressive disease.

- 2 out of 6 patients died. One patient died from disease progression and the second patient from streptococcal sepsis.

- 2 out of 6 patients developed GvHD. The first patient had extensive chronic GvHD of the skin and liver who died later from streptococcal sepsis, he was GvHD and disease free. The second patient developed acute liver GVHD required 2nd line Ruxolutinib and still alive with stable disease despite holding Nivolumab.

- 3 patients received DLI after receiving Nivolumab to augment response. 1 patient developed extensive cGvHD and died from disease progression and 2 patients experienced no GvHD and they are alive and disease free.

Conclusion:

The use of Nivolumab in post allo-HCT relapse of Classic Hodgkin's Lymphoma can elicit a durable response even in those who progressed on Nivolumab pre- allo-HCT. The risk of GvHD does not seem to be increased.

No relevant conflicts of interest to declare.

Nivolumab post allogeneic stem cell transplantation