Letter to the Editor

Bone Marrow Transplantation (2016) 51, 850–852; doi:10.1038/bmt.2015.346; published online 1 February 2016

Major clinical response to nivolumab in relapsed/refractory Hodgkin lymphoma after allogeneic stem cell transplantation

J A Yared1, N Hardy1, Z Singh2, S Hajj3, A Z Badros1, M Kocoglu1, S Yanovich1, E A Sausville1, C Ujjani4, K Ruehle1, C Goecke1, M Landau1 and A P Rapoport1

  1. 1Division of Hematology/Oncology, Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA
  2. 2Department of Pathology, University of Maryland, Baltimore, MD, USA
  3. 3Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland, Baltimore, MD, USA
  4. 4Division of Hematology/Oncology, Lombardi Cancer Center, Georgetown University, Washington DC, WA, USA

Correspondence: JA Yared, E-mail: jyared@umm.edu

The immunotherapeutic contribution to allogeneic stem cell transplantation's (SCT’s) curative potential in hematological diseases is well recognized, with alloreactive donor T and NK lymphocytes mediating a graft-versus-tumor (GVT) effect.1 Recent advances in our understanding of immune regulatory pathways have identified immune check-point exploitation by cancer cells in the tumor microenvironment as a ‘druggable’ mechanism of immune evasion. The programmed death-1 (PD-1) regulatory pathway is active in several tumors and a potent immunotherapeutic target, with PD-1 inhibitors eliciting antitumor responses.2, 3, 4 Nivolumab, an anti-PD-1 monoclonal antibody (Ab), is approved therapy for melanoma5 and non-small squamous cell lung cancer;6 it also exhibits robust clinical activity in refractory/relapsed Hodgkin lymphoma (HL).7 Although PD-1 inhibition may effectively unleash GVT responses in relapsed HL after allogeneic SCT, the risks of graft-versus-host disease (GvHD)or graft rejection are unknown. We report herein the effective and safe use of nivolumab in a patient with relapsed/refractory HL progression after allogeneic SCT.

A 52-year-old female with classical HL involving lymph nodes, bones and breast, refractory to ABVD, brentuximab vedotin (BV), combination chemotherapy and investigational lenalidomide/temsirolimus (NCT01076543) underwent allogeneic SCT 16 months after diagnosis. She received myeloablative cyclophosphamide and total body irradiation (TBI) and a peripheral blood allograft from her HLA-matched sister in October 2014, with tacrolimus and low-dose methotrexate for alloprophylaxis. Clinical and radiographic disease progression was evident by day 100 and continued in spite of withdrawal of immunosuppression; there was no evidence of GvHD. A lymph node biopsy confirmed relapse, whereas immunohistochemistry showed strong programmed death-ligand 1 (PD-L1) expression on the Hodgkin Reed–Sternberg (HRS) cells and PD-1 expression on abundant tumor-infiltrating CD3+ T cells (Figure 1). Retreatment with four cycles of BV yielded no response, with PET-CT confirming further progression (Figures 2a and b). She was then treated with nivolumab 1mg/kg IV, reduced from conventional 3mg/kg dosing to mitigate potential risks of graft rejection and GvHD; this treatment started ~7 months after her allogeneic SCT. One week later, she presented with cough, shortness of breath and low-grade fever; evaluation identified hepatitis (AST and ALT 5 × ULN) and chest CT scan demonstrated bilateral diffuse ground-glass opacities. She was admitted for bronchoscopy and afterward briefly received oxygen supplementation (3L/min by nasal cannula); microbial tests were negative. Pneumonitis and hepatitis responded promptly to oral prednisone, 2mg/kg per day for 1 week and tapered over 5 weeks to 10mg/day. Significant clinical response was noted within 3 weeks of nivolumab, with significant reductions in her breast mass and axillary nodes, reduced sternal bone pain and decrease in the serum LDH from 1027 to 722 units/L (ULN: 618). Upon complete resolution of pneumonitis and hepatitis (7 weeks after the initial dose), she received a second dose of nivolumab, further reduced to 0.5mg/kg, whereas continuing on prednisone 10mg daily. There was no recurrence of hepatitis nor pneumonitis. PET/CT 2 weeks after the second dose of nivolumab demonstrated marked decrease in the size and metabolic activity of all lesions (Figures 2c–e). At last follow-up, 5 months after initial treatment, she had received four additional injections of nivolumab at escalating doses of 1, 2 and 3mg/kg and continued to do well without progression nor recurrent side effects; a subsequent PET/CT scan after the sixth injection showed further improvement in the size and metabolic activity of the residual left axillary adenopathy with no new abnormality. At this time, she has no signs of GvHD, the bone marrow allograft function remains robust, and serial chimerism assessments demonstrate continued full-donor engraftment. Biweekly maintenance nivolumab therapy is ongoing. In addition, based on the success of our first experience, we treated a second patient with relapsed and refractory HL after haploidentical allogeneic SCT using nivolumab at a dose level of 1mg/kg. Although follow-up is very short for this second patient (2.5 months), after four treatments, repeat imaging studies showed a partial nodal response including ~50% reduction in SUV values with no immunologic complications, cytopenias nor GvHD.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Composite images of pretreatment tumor biopsy (× 400). (a) H&E, numerous Hodgkin Reed–Sternberg (HRS) cells (arrow) in a background of small lymphocytes and granulocytes. Immunohistochemistry marks (b) CD30+ and (c) CD15+ (mainly Golgi zone distribution) HRS cells; (d) HRS cells are PD-L1+; (e) CD3+ lymphocytes surround HRS cells (arrow marks negative HRS cell) and (f) most express PD-1 (arrows marks negative HRS cells).

Full figure and legend (456K)

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

(a) Pre-treatment FDG PET 3D maximum intensity projection shows focal increased activity in bilateral axilla (black arrows), sternum (red arrows) and left breast (green arrow), corresponding to bilateral axillary lymph nodes, sternal lytic lesions and left breast lesion. (b) Pre-treatment axial and coronal FDG PET, CT and fused FDG PET/CT images show metabolically active bilateral axillary lymph nodes (upper axial and coronal images black and white arrows), lytic sternal osseous lesions (axial images red arrows and lower coronal images arrows) and left breast lesion (axial images green arrows). (c) Post-treatment FDG PET 3D maximum intensity projection shows interval resolution of the FDG activity in the right axilla, sternum and left breast regions with residual activity in the left axilla. (d) Post-treatment axial and coronal FDG PET, CT and fused PET/CT images show interval resolution of the metabolically active right axillary lymph nodes and decrease in the size and activity of the left axillary lymph nodes with only residual metabolically active left axillary lymph node (arrows). (e) Post-treatment axial and coronal FDG PET, CT and fused PET/CT images show complete resolution of the metabolic activity within the sternal lytic osseous lesions (arrows) and resolution of the left breast lesion.

Full figure and legend (215K)

Our patient exhibited a limited GVT effect after allogeneic SCT, with disease progression and no evidence of GvHD. Following treatment with nivolumab, a major clinical response was observed in her highly refractory HL. It is reassuring that her response, presumably immune mediated by donor tumor-infiltrating lymphocytes, could be achieved without GvHD or graft rejection. In HL, constitutive PD-L1/PD-L2 expression in HRS cells8 may render them exquisitely sensitive to disruption of the PD-1 pathway, accounting for a tumor-specific immune response. Although PD-1 has been implicated in regulating alloreactivity, our patient appears to have maintained allogeneic tolerance. Grade 2 pneumonitis and hepatitis responded to corticosteroid therapy, and subsequent administration with dose escalation has been well tolerated thus far. The durability of this response remains to be seen and thus the optimal duration of therapy is unclear. Nonetheless, this first reported case suggests that immunotherapy targeting PD-1 may be safe and effective in patients with HL progression after allogeneic SCT and warrants prospective study.

Top

Conflict of interest

The authors declare no conflict of interest.

Top

References

  1. Kolb HJ. Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood 2008; 112: 4371–4383. | Article | PubMed | ISI | CAS |
  2. Green MR, Rodig S, Juszczynski P, Ouyang J, Sinha P, O'Donnell E et al. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res 2012; 18: 1611–1618. | Article | PubMed | CAS |
  3. Wilcox RA, Feldman AL, Wada DA, Yang ZZ, Comfere NI, Dong H et al. B7-H1 (PD-L1, CD274) suppresses host immunity in T-cell lymphoproliferative disorders. Blood 2009; 114: 2149–2158. | Article | PubMed | ISI |
  4. Andorsky DJ, Yamada RE, Said J, Pinkus GS, Betting DJ, Timmerman JM. Programmed death ligand 1 is expressed by non-hodgkin lymphomas and inhibits the activity of tumor-associated T cells. Clin Cancer Res 2011; 17: 4232–4244. | Article | PubMed | ISI | CAS |
  5. Larkin J, Lao CD, Urba WJ, McDermott DF, Horak C, Jiang J et al. Efficacy and safety of nivolumab in patients with BRAF V600 mutant and BRAF wild-type advanced melanoma: a pooled analysis of 4 clinical trials. JAMA Oncol 2015; 1: 433–440. | Article | PubMed |
  6. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E et al. Nivolumab versus Docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; 373: 123–135. | Article | PubMed | CAS |
  7. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med 2015; 372: 311–319. | Article | PubMed | ISI | CAS |
  8. Green MR, Monti S, Rodig SJ, Juszczynski P, Currie T, O'Donnell E et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 2010; 116: 3268–3277. | Article | PubMed | ISI | CAS |