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Journal for Immunotherapy of Cancer logoLink to Journal for Immunotherapy of Cancer
. 2017 Feb 21;5:11. doi: 10.1186/s40425-017-0211-z

PD-1 blockade induces remissions in relapsed classical Hodgkin lymphoma following allogeneic hematopoietic stem cell transplantation

James Godfrey 1, Michael R Bishop 1, Sahr Syed 2, Elizabeth Hyjek 2, Justin Kline 1,
PMCID: PMC5319147  PMID: 28239465

Abstract

Background

Allogeneic hematopoietic stem cell transplantation and checkpoint blockade therapy are immune-based therapies that have activity in selected refractory hematologic malignancies. Interest has developed in combining these treatments for high-risk hematologic diseases. However, there is concern that checkpoint blockade could augment graft-versus-host disease, and very few studies have evaluated the safety of checkpoint blockade in the post-allogeneic setting. Here, we report the outcomes of three patients with relapsed classical Hodgkin’s lymphoma following allogeneic transplant that were treated with the anti-PD-1 antibody, nivolumab.

Case presentations

Three patients with Hodgkin’s lymphoma relapsed following allogeneic transplant received nivolumab therapy at our institution. All patients were free of graft-versus-host disease and were off of all systemic immunosuppressive medications at the time of nivolumab treatment. Nivolumab was well-tolerated in two of the patients. However, nivolumab had to be discontinued in one patient due to development of immune-related polyarthritis requiring treatment with systemic corticosteroids and methotrexate. Objective responses were observed in all three patients.

Conclusions

Our case series demonstrates that anti-PD-1 therapy with nivolumab can be highly effective following allogeneic transplant for Hodgkin’s lymphoma, but serious immune-related adverse events can occur, requiring very close monitoring and interruption of therapy.

Keywords: Checkpoint blockade, PD-1, Hodgkin lymphoma, Allogeneic transplant

Background

Allogeneic hematopoietic stem cell transplantation (alloHSCT) can be a curative treatment for high-risk and recurrent hematological malignancies [1]. A major therapeutic effect of alloHSCT lies within the graft-versus-tumor (GVT) response, where donor-derived lymphocytes recognize antigens expressed on the surface of malignant cells, and eliminate them from the host [2]. However, it has become clear that disease relapse following alloHSCT can be associated with immune evasion and loss of GVT effects [3]. Concrete examples include upregulation of programmed death-ligand 1 (PD-L1) on leukemia cells, and programmed death-1 (PD-1) on donor-derived T cells at the time of post-alloHSCT relapse, as well as deletion of human leukocyte antigen alleles in some leukemia patients relapsing after haploidentical alloHSCT [4, 5]. New strategies to restore GVT effects in these patients are needed because patients who relapse after alloHSCT have few treatment options and dismal outcomes [6].

Recently, the defined activity of checkpoint blockade therapy (CBT) with anti-PD-1 and anti-cytotoxic lymphocyte antigen-4 (CTLA-4) antibodies in a number of malignancies has generated interest in their use to treat disease relapse following alloHSCT. Preclinical studies of CBT have demonstrated augmentation of GVT effects [79], and two phase I studies of the anti-CTLA-4 antibody, ipilimumab, have been reported in patients with relapse after alloHSCT, where objective responses were observed [10, 11]. In the most recently published study, ipilimumab treatment was associated with a 31% objective response rate, including complete responses in patients with leukemia cutis, myeloid sarcoma, and myelodysplastic syndrome [11].

However, there is concern that enhancing the GVT effect through administration of CBT might also induce or exacerbate graft-versus-host disease (GVHD). Indeed, ipilimumab treatment was discontinued in 4 of 29 patients due to GVHD in the aforementioned study, and 6 patients had other immune-related adverse advents (IrAE) including one treatment-related death [11]. Further, PD-1 blockade has also been associated with induction of severe GVHD in murine models, and a report of fatal GVHD in a patient treated with the anti-PD-1 antibody, pembrolizumab, was recently published [12, 13]. These observations have somewhat tempered enthusiasm for the exploration of PD-1 blockade after alloHSCT to anecdotal reports and a retrospective case series which has been published in abstract form [1416]. However, PD-1 blockade has been associated with a lower incidence of severe IrAE in non-transplant settings compared to CTLA-4 blockade, and is clearly more effective across a number of malignancies, including classical Hodgkin lymphoma (cHL) [17, 18]. We therefore sought to examine the safety and efficacy of PD-1 blockade following alloHSCT, and present data summarizing our experience with nivolumab for the treatment of relapsed cHL after alloHSCT.

Case presentation

We treated three cHL patients who had relapsed after alloHSCT with off-label nivolumab at a dose of 3 mg/kg every 2 weeks. Patient and disease characteristics are summarized in Table 1. Briefly, all patients had multiply relapsed cHL despite treatment with conventional chemotherapy regimens and autologous hematopoietic stem cell transplantation. Patients received T cell-depleted grafts after reduced-intensity conditioning regimens. None developed acute GVHD, although two patients developed limited-stage chronic GVHD requiring short courses of steroids. Disease relapse occurred at an average of 1,008 days from alloHSCT (181, 389, and 2456 days), and was histologically confirmed in all cases. One patient received a donor lymphocyte infusion (DLI) at the time of relapse, but failed to achieve an objective response. After exhausting all conventional treatment options, patients were consented to treatment with nivolumab after discussing potential risks including life-threatening GVHD.

Table 1.

Patient characteristics, adverse events, and response to nivolumab treatment

Patient 1 Patient 2 Patient 3
Age 47 25 55
Sex Male Male Male
Prior therapies (no.) 6 6 5
Stem cell source Matched-related Matched-related Haploidentical and umbilical cord blood
Conditioning regimen Reduced intensity Reduced intensity Reduced intensity
T cell depleted graft Yes Yes Yes
Prior GVHD No Chronic GVHD of gut Chronic oral GVHD
Days to relapse following AlloHSCT (no.) 181 2456 389
Localization and size of relapse Diffuse bone and splenic involvement Multifocal adenopathy in mediastinum, retroperitoneum and pelvis. Largest lymph node 2.3 × 1.5 cm in mediastinum Multifocal adenopathy in neck, chest, abdomen and pelvis. Largest lymph node 4.2 × 1.8 cm in right axilla
Prior DLI No Yes No
Immune-related adverse events Grade 2 Keratoconjunctivitis Grade 3 Inflammatory polyarthritis and grade 2 keratoconjunctivitis Grade 1 Rash
Response to nivolumab Partial response Partial response Partial response
Duration of response 6 Months+ 10 Months+ 14 Months+
Donor CD3+ chimerism before and after treatment 18 to 49% Not available Not available

All three patients had no clinical evidence of acute or chronic GVHD at the time of initiating nivolumab, and immunosuppressive medications had been discontinued at least a year prior to starting therapy. Observed nivolumab IrAE are listed in Table 1, and included grade 2 keratoconjunctivits in 2 patients, responsive to corticosteroid eye drops in both, grade 1 rash (possibly representing limited-stage chronic GVHD) in 1 patient, successfully treated with topical steroids, and one grade 3 episode of inflammatory polyarthritis, that required treatment discontinuation and administration of systemic corticosteroids and methotrexate to control. Mean duration of therapy is 8.3 months and is continuing in two patients. All patients had objective partial responses to treatment based on the results of interim PET scans (Fig. 1a). Responses are ongoing in all patients at the time of publication. In addition to radiographic responses, one patient with severe pancytopenia due to marrow involvement by cHL achieved a marked improvement in peripheral blood counts, as well as an objective improvement in bone marrow involvement by cHL (Fig. 1b). Immunohistochemistry studies on bone marrow biopsy samples before and after 5 cycles of nivolumab therapy in this patient demonstrated abundant PD-L1 expression in Hodgkin cells, with an increase in tumor-infiltrating CD8+ T cells and decreased CD4+ T cells with therapy (Fig. 2). Furthermore, bone marrow chimerism studies demonstrated an increase in the donor CD3+ compartment from 18 to 49% with treatment.

Fig. 1.

Fig. 1

Radiographic and hematologic responses with therapy. a Response as assessed by sequential PET scan images. Images are shown for Patients 2 and 3. The response for Patient 1 was more difficult to illustrate on PET scan as his disease was primarily confined to the bone marrow. b Serial complete blood counts during treatment with nivolumab demonstrating significant tri-lineage improvement for Patient 1. *Platelet units (×10^3/uL) are provided on the left y-axis, while hemoglobin (g/dL) and white blood cell count units (×10^3/uL) are on the right y-axis

Fig. 2.

Fig. 2

Immunohistochemistry changes with therapy. Immunohistochemistry results on bone marrow biopsies from patient 1 before and after 5 cycles of nivolumab. There is an increase in tumor-infiltrating CD8+ T cells and a decrease in CD4+ T cells with treatment. PD-L1 staining was positive both before and after treatment. Images were captured using a Jenoptik ProgRes® Speed XT core 5 series camera on an Olympus BX53 microscope at 50× magnification using Adobe Photoshop Software

Discussion and Conclusions

Our data conclusively demonstrate that anti-PD-1 therapy with nivolumab is effective for relapsed cHL following alloHSCT. All three patients have achieved objective and ongoing responses to treatment. These findings are consistent with previous observations demonstrating immune escape as a mechanism of relapse following alloHSCT, and that immune activating therapies such as DLI and CBT have the potential to restore GVT effects [35, 711, 19]. The finding of an objective response in a patient refractory to DLI, also demonstrates that PD-1 blockade reinvigorates GVT responses through distinct pathways that potentially more effectively activate GVT effects.

The toxicity of PD-1 blockade following alloHSCT will be an important measure to continue to assess in prospective studies. We did not observe any GVHD; however, several IrAEs occurred among the three patients reported here, none of which was life-threatening. It is expected, as has recently been reported [13], that the use of anti-PD-1 antibodies may result in severe immune-related toxicities in the post-allo-HSCT setting.

While our results are encouraging, it is not known whether other hematologic cancers will also be responsive to PD-1 blockade in the post-alloHSCT setting. That being said, complete responses to ipilimumab were observed after alloHSCT in patients with relapsed leukemia cutis and myelodysplastic syndrome [11]. This is an important observation since single-agent ipilimumab has only modest activity in hematologic malignancies outside of the alloHSCT setting [20], and may indicate that CBT and alloHSCT have therapeutically synergistic effects. In support of this, our finding of increased donor CD3+ chimerism at the site of disease involvement in one of our patients, suggests that anti-tumor effects are preferentially driven by donor-derived T cells following PD-1 blockade. Biologically, the enhanced activity of combining CBT with alloHSCT could be related to the observation that immune responses generated by PD-1 blockade are likely restricted to tumor neo-antigens in the non-transplanted host [21], whereas immune responses from donor-derived T cells are targeted against minor histocompatibility antigens that are more uniformly expressed [22]. Furthermore, anti-PD-1 antibodies may enhance the efficacy of alloHSCT by reinvigorating the GVT effect in hematological cancers that acquire PD-L1 expression as an adaptive response to immune pressure. Therefore the complementary immune effects of alloHSCT and PD-1 blockade hold promise in both the prevention and treatment of relapse following alloHSCT.

Acknowledgements

Not applicable.

Funding

There were no funding sources used for the study.

Availability of data and materials

Not applicable.

Author contributions

JG, MRB and JK were responsible for the primary writing of the manuscript with the assistance of the other coauthors. JG, MRB and JK were the primary physicians caring for the 3 patients in the case series and assisted in collection of patient data. EH and SS performed the histological analysis of the bone marrow biopsy and provided the images demonstrating the immunohistochemical changes occurring with therapy. All authors read and approved the final manuscript.

Consent for publication

Written informed consent was obtained from all patients for publication of this case report and any accompanying images.

Competing interests

JK has research support from Merck. The remaining authors declare no other competing financial interests.

Ethics approval and consent to participate

The study was approved by the University of Chicago institutional review board, and all patients consented to participate in our study.

Abbreviations

AlloHSCT

Allogeneic hematopoietic stem cell transplant

CBT

Checkpoint blockade therapy

cHL

Classical Hodgkin’s Lymphoma

CTLA-4

Cytotoxic T-lymphocyte associated protein-4

DLI

Donor lymphocyte infusion

GVHD

Graft-versus-host disease

GVT

Graft-versus-tumor

IrAE

Immune-related adverse event

PD-1

Programmed death receptor-1

PD-L1

Programmed death ligand-1

PET

Positron emission tomography

Contributor Information

James Godfrey, Email: jgodfrey@medicine.bsd.uchicago.edu.

Michael R. Bishop, Email: mbishop@medicine.bsd.uchicago.edu

Sahr Syed, Email: sahr.syed@uchospitals.edu.

Elizabeth Hyjek, Email: ehyjek@bsd.uchicago.edu.

Justin Kline, Phone: (773) 702-5550, Email: jkline@medicine.bsd.uchicago.edu.

References

  • 1.Stem Cell Trialists’ Collaborative Group Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of nine randomized trials. J Clin Oncol. 2005;23(22):5074–87. doi: 10.1200/JCO.2005.09.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Zilberberg J, Feinman R, Korngold R. Strategies for the identification of T cell-recognized tumor antigens in hematological malignancies for improved graft-versus-tumor responses after allogeneic blood and marrow transplantation. Biol Blood Marrow Transplant. 2015;21(6):1000–7. doi: 10.1016/j.bbmt.2014.11.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Toffalori C, Riba M, Zito L, et al. Acute myeloid leukemia relapses after allogenenic HSCT display a distinctive immune-related signature, with frequent and functionally relevant alterations in HLA class II antigen presentation and T cell costimulation [abstract] Blood. 2014;124(21):427. [Google Scholar]
  • 4.Kong Y, Zhang J, Claxton DF, et al. PD-1(hi)TIM-3(+) T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation. Blood Cancer J. 2015;5:e330. doi: 10.1038/bcj.2015.58. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Vago L, Perna SK, Zanussi M, et al. Loss of mismatched HLA in leukemia after stem-cell transplantation. N Engl J Med. 2009;361(5):478–88. doi: 10.1056/NEJMoa0811036. [DOI] [PubMed] [Google Scholar]
  • 6.van den Brink MR, Porter DL, et al. Relapse after allogeneic hematopoietic cell therapy. Biol Blood Marrow Transplant. 2010;16(1 Suppl):S138–45. doi: 10.1016/j.bbmt.2009.10.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Blazar BR, Taylor PA, Panoskaltsis-Mortari A, Sharpe AH, Vallera DA. Opposing roles of CD28:B7 and CTLA-4:B7 pathways in regulating in vivo alloresponses in murine recipients of MHC disparate T cells. J Immunol. 1999;162(11):6368–77. [PubMed] [Google Scholar]
  • 8.Norde WJ, Maas F, Hobo W, et al. PD-1/PD-L1 interactions contribute to functional T-cell impairment in patients who relapse with cancer after allogeneic stem cell transplantation. Cancer Res. 2011;71(15):5111–22. doi: 10.1158/0008-5472.CAN-11-0108. [DOI] [PubMed] [Google Scholar]
  • 9.Koestner W, Hapke M, Herbst J, et al. PD-L1 blockade effectively restores strong graft-versus-leukemia effects without graft-versus-host disease after delayed adoptive transfer of T-cell receptor gene-engineered allogeneic CD8+ T cells. Blood. 2011;117(3):1030–41. doi: 10.1182/blood-2010-04-283119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Bashey A, Medina B, Corringham S, et al. CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation. Blood. 2009;113(7):1581–8. doi: 10.1182/blood-2008-07-168468. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Davids MS, Kim HT, Bachireddy P, et al. Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med. 2016;375(2):143–53. doi: 10.1056/NEJMoa1601202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Saha A, Aoyama K, Taylor PA, et al. Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality. Blood. 2013;122(17):3062–73. doi: 10.1182/blood-2013-05-500801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Singh AK, Porrata LF, Aljitawi O, et al. Fatal GVHD induced by PD-1 inhibitor pembrolizumab in a patient with Hodgkin’s lymphoma. Bone Marrow Transplant. 2016;51(9):1268–70. doi: 10.1038/bmt.2016.111. [DOI] [PubMed] [Google Scholar]
  • 14.Angenendt L, Schliemann C, Lutz M, et al. Nivolumab in a patient with refractory Hodgkin’s lymphoma after allogeneic stem cell transplantation. Bone Marrow Transplant. 2016;51(3):443–5. doi: 10.1038/bmt.2015.266. [DOI] [PubMed] [Google Scholar]
  • 15.Villasboas JC, Ansell SM, Witzig TE. Targeting the PD-1 pathway in patients with relapsed classic Hodgkin lymphoma following allogeneic stem cell transplant is safe and effective. Oncotarget. 2016;7(11):13260–4. doi: 10.18632/oncotarget.7177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Herbaux C, Gauthier J, Brice P, et al. Nivolumab is effective and reasonably safe in relapsed or refractory Hodgkin’s lymphoma after allogeneic hematopoietic cell transplantation: a study from the LYSA and SFGM-TC [abstract] Blood. 2015;126(23):3979. [Google Scholar]
  • 17.Armand P. Immune checkpoint blockade in hematologic malignancies. Blood. 2015;125(22):3393–400. doi: 10.1182/blood-2015-02-567453. [DOI] [PubMed] [Google Scholar]
  • 18.Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311–9. doi: 10.1056/NEJMoa1411087. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Bachireddy P, Hainz U, Rooney M, et al. Reversal of in situ T-cell exhaustion during effective human antileukemia responses to donor lymphocyte infusion. Blood. 2014;123(9):1412–21. doi: 10.1182/blood-2013-08-523001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Ansell SM, Hurvitz SA, Koenig PA, et al. Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma. Clin Cancer Res. 2009;15(20):6446–53. doi: 10.1158/1078-0432.CCR-09-1339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.McGranahan N, Furness AJ, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351(6280):1463–9. doi: 10.1126/science.aaf1490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Feng X, Hui KM, Younes HM, Brickner AG. Targeting minor histocompatibility antigens in graft versus tumor or graft versus leukemia responses. Trends Immunol. 2008;29(12):624–32. doi: 10.1016/j.it.2008.09.004. [DOI] [PMC free article] [PubMed] [Google Scholar]

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Data Availability Statement

Not applicable.


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