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Rapid and sustained response to immune checkpoint inhibition in cutaneous squamous cell carcinoma after allogenic hematopoietic cell transplant for sézary syndrome

Rapid and sustained response to immune checkpoint inhibition in cutaneous squamous cell carcinoma... Background: Cutaneous squamous cell carcinoma (cSCC) is not uncommon in association with indolent malignancies that were treated with prior radiotherapy and after allogenic bone marrow transplantation. On the other hand, cutaneous T-cell lymphoma (CTCL) is a subtype of non-Hodgkin’s lymphoma which is characterized by an indolent course, with relative refractoriness to conventional chemotherapies and radiotherapy, and occasionally referred for allogeneic hematopoietic cell transplantation (allo-HCT). Recently, the use of immune checkpoint inhibitors has gained attention in the treatment of both cutaneous squamous cell carcinoma and hematological malignancies. However, many patients with hematological malignancies eventually undergo allo-HCT, raising the concern of potential adverse events (graft versus host disease) due to manipulation of the immune system with use of checkpoint inhibitors. Case presentation: We describe a patient with relapsed refractory CTCL (Sézary Syndrome) who underwent allo-HCT with persistence of disease post-transplant. The patient additionally developed a progressively worsening lesion on the right shoulder which was biopsied and showed poorly differentiated carcinoma (cSCC). Pembrolizumab was started for the treatment of cSCC. After second cycle of treatment, the cSCC lesion responded dramatically to the use of immune checkpoint inhibitor. Also, the patient experienced significant resolution of pruritus and generalized erythema. During 24 months of follow up after initial treatment with checkpoint inhibition immunotherapy, the patient showed durable response of both cSCC and CTCL, as well as restoration of full donor chimerism, without obvious worsening of graft versus host disease (GVHD). Conclusion: This is the first case to our knowledge of rapid and durable response of both cSCC and CTCL to immune checkpoint inhibition after allo-HCT. Although this report highlights the potential for significant response to this class of medication, further studies are required to confirm the efficacy and safety of this approach in patients with CTCL after allo-HCT given the potential concern of GVHD. Keywords: Cutaneous squamous cell carcinoma, Cutaneous T-cell lymphoma, Sézary syndrome, Immune checkpoint inhibitors, Allogenic hematopoietic cell transplant, Pembrolizumab, Graft versus host disease * Correspondence: gasnsstas@wustl.edu Division of Medical Oncology, Department of Medicine, Washington University in Saint Louis, 660 South Euclid Avenue, Campus Box 8056, St. Louis, MO 63110, USA Alvin J. Siteman Cancer Center, St. Louis, USA Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Khaddour et al. Journal for ImmunoTherapy of Cancer (2019) 7:338 Page 2 of 7 Background Table 1 Sequence of systemic therapies administered since diagnosis of cutaneous T-cell lymphoma/ Sézary Syndrome Conventional chemotherapies are considered not to be curative in the majority of cutaneous T-cell lymphomas Prior therapy for CTCL/ Sequence and Duration SS (CTCL) [1]. Recently, the use of immune checkpoint in- Photochemotherapy First Line of Therapy 8 months (2009) hibitors has largely expanded to include hematological (PUVA) malignancies, specifically relapsed/refractory chemoresis- Photopheresis Second Line of 31 months (2009–2012) tant Hodgkin’s Lymphoma (r/r-cHL) and primary medi- Therapy astinal large B-cell lymphoma [2, 3].The rationale relies Romidepsin Third Line of Therapy 48 months (2010–2014) on the fact that genetic alterations occurring in the Pegylated liposomal Fourth Line of 3 months (2014) microenvironment of lymphomas specifically in the pro- doxorubicin Therapy grammed death ligand receptor (PD-L1/PD-L2) loci can Gemcitabine Fifth Line of Therapy 1 month (2014) lead to overexpression of PD-L1/2 on malignant cells, Alemtuzumab Sixth Line of Therapy 2 months (2015) which helps tumor cells to evade the effective antitumor immune response [4]. Similarly, CTCL such as Mycosis Mogamulizumab Seventh Line of 1 month (2015) Therapy Fungoides (MF) and Sézary Syndrome (SS) can debilitate the immune response against malignant cells in the Total skin electron Eighth Line of 3 months (2016) beam therapy Therapy tumor microenvironment and thus could be considered Bexarotene Ninth Line of Therapy 2 months (2016) a target for therapies that can restore immune surveil- lance [5]. However, there is a concern for the use of im- Pralatrexate Tenth Line of 2 months (2016) Therapy mune checkpoint inhibitors in patients with lymphoma who undergo allogenic hematopoietic cell transplant- ICE (Ifosfamide, Eleventh Line of 3 months (2016–2017) Carboplatin, Etoposide) Therapy ation due to the possibility of triggering or aggravating Sibling allogenic stem Twelfth Line of (2017) graft versus host disease. This has led to lack of litera- cell transplantation Therapy ture regarding the safety and efficacy of immune check- point inhibitors in this population as patients with prior history of allo-HCT were excluded from clinical trials mature T-cell lymphoma (79% by flow cytometry), and which examined the efficacy of immunotherapy. More- cytogenetic studies revealed no aberrations. The patient over, advanced cutaneous squamous cell carcinoma has underwent allogeneic hematopoietic cell transplantation been shown to have a high mutational burden which (allo-HCT) using a fully matched male sibling donor. could increase the expression of tumor neoantigens [6]. The myeloablative conditioning regimen prior to trans- Also, the association with PD-L1 expression is estab- plant consisted of hyperfractionated total body irradi- lished with cutaneous squamous cell carcinoma which ation combined with high dose cyclophosphamide. Graft prompted the study of immune checkpoint inhibitors as versus host disease (GVHD) prophylaxis consisted of a potential therapy [7]. tacrolimus and methotrexate. Tacrolimus was subse- We describe the first case to our knowledge of a pa- quently changed to sirolimus due to peri-transplant tient with a history of allo-HCT who had a rapid and neurotoxicity. Shortly after transplantation (week 7), the durable response of both cSCC and CTCL/SS after treat- patient developed a diffuse erythematous rash, a biopsy ment with immune checkpoint inhibitors. of which was most consistent with skin GVHD (vs CTCL vs drug rash) and received prednisone, mycophe- Case presentation nolate mofetil (MMF) with ongoing sirolimus with A 58-year-old Caucasian male with relapsed/refrac- improvement, and subsequent tapering to low dose tory Sézary Syndrome (r/r SS) stage IVA was referred prednisone (5 mg daily/ week 23). A bone marrow bi- for allogeneic hematopoietic cell transplantation (allo- opsy 4 months after allo-HCT showed persistent mar- HCT). The patient had received multiple therapies prior row (and peripheral blood) involvement with sézary cells to being assessed for a transplant (Table 1). Positron (15% bone marrow involvement by mature T-cell lymph- Emission Tomography/Computed Tomography (PET/ oma with CD4+/CD8+ ratio > 100). There was also CT) with [ F]fluorodeoxyglucose (FDG) prior to trans- mixed chimerism by short tandem repeat (STR) assay plant (1/17/2017) revealed interval development of a with 82% donor cells (Fig. 2). There was incomplete new hypermetabolic soft tissue nodule in the skin of the resolution of the skin manifestations of CTCL, which in- posterior right shoulder with maximum standard uptake cluded generalized erythema and pruritus. Repeated skin value (SUV ) of 12.3 and a hypermetabolic right para- biopsies were consistent with residual CTCL/SS. Five max tracheal lymph node (Fig. 1). Skin biopsy was consistent months after allo-HCT, STR studies again demonstrated with residual CTCL/SS, a bone marrow biopsy demon- persistent mixed chimerism, and donor lymphocyte infu- strated hypocellularity with extensive involvement of sions (DLI) in two separate doses were administered on Khaddour et al. Journal for ImmunoTherapy of Cancer (2019) 7:338 Page 3 of 7 a. b. c. Fig. 1 Anterior and posterior volume-rendered maximum activity-reprojection FDG-PET images showing (a) FDG uptake in the right shoulder (arrow) and a paratracheal lymph node. b markedly hypermetabolic lesion in the right shoulder with SUV of 26.7 (arrow), markedly max hypermetabolic right axillary and right paratracheal lymphadenopathy with SUV of 27.3 with interval development of hypermetabolic focal max cutaneous lesions, left axillary lymph node and pulmonary lesions. c near complete response of the right shoulder hypermetabolic lesion (arrow), complete resolution of paratracheal lymph node, left axillary lymph node, pulmonary and cutaneous lesions, with persistent FDG uptake of the right axillary lymph nodes weeks 26 and 31 (1 and 3 X 10e7 CD3 cells/kg, respect- and spread to the anterior chest wall (Fig. 3), a skin bi- ively) without complete resolution of skin symptoms or opsy was performed and histopathology revealed poorly erythema. Following allo-HCT, there was a gradual differentiated squamous cell carcinoma. Magnetic Res- worsening of a right shoulder skin lesion noted on PET/ onance Imaging (MRI) of the shoulder showed a right CT prior to transplant, and thought to be related to my- lesion with no bone or muscular invasion, but there was cosis fungoides secondary to CTCL. The skin mass even- extensive right axillary lymphadenopathy. FDG-PET/CT tually extended over the superior aspect of the right revealed worsening of disease with extensive markedly shoulder with ulceration and hard induration, and 3 hypermetabolic soft tissue thickening in the right shoul- months post allo-HCT, the patient underwent subse- der with SUV of 26.7 and interval development of max quent involved-field radiotherapy with a total dose of 50 markedly hypermetabolic partially necrotic right axillary Gy. The lesion persisted and grew to 17 × 10 cm in max- lymphadenopathy with SUV of 27.3, as well as wors- max imum dimension with worsening necrosis, ulceration, ening in FDG uptake of the right paratracheal lymph Fig. 2 Timeline of bone marrow chimerism performed with STR studies after bone marrow transplantation. * Donor lymphocyte infusion was administered on two separate doses on weeks 26 and 31. Pembrolizumab cycle 1 was at week 36 and last cycle (cycle 14) was at week 78 Khaddour et al. Journal for ImmunoTherapy of Cancer (2019) 7:338 Page 4 of 7 Fig. 3 Skin lesions of CTCL and cSCC before and after PD-1 inhibition. a: Generalized eruption of small confluent erythematous macules and papules on the anterior chest wall after stem cell transplant and before pembrolizumab. b: resolution of the previously mentioned erythematous maculopapular eruption after pembrolizumab. c: multiple firm nodules with partial ulceration and keratin deposition on the superior aspect of the right shoulder representing poorly differentiated squamous cell carcinoma (before pembrolizumab), also erythematous eruption can be noted around the cSCC lesion which represents cutaneous lymphoma. d & e: Granular tissue with skin regeneration replacing the nodular ulcerated lesions of cSCC (after pembrolizumab), there is complete resolution of the papular erythematous rash. CTCL: cutaneous T cell lymphoma, cSCC: cutaneous squamous cell carcinoma nd node. There was interval development of hypermetabolic were secondary to CTCL resolved completely after the 2 th focal cutaneous lesions, left axillary lymph nodes and cycle of immunotherapy. A FDG-PET/CT after the 5 cycle pulmonary lesions (T3N2B; Stage IV SCC) (Fig. 1). of pembrolizumab showed marked metabolic response and After discussion of treatment options with the patient, near-complete resolution of the superficial right shoulder intravenous pembrolizumab was started at a dose of 200 mg mass (SUV of 1.9), and complete resolution of right para- max every 3 weeks. The patient had an Eastern Cooperative On- tracheal and left axillary lymph nodes, as well as pulmonary cology Group performance of (ECOG 3) prior to beginning and cutaneous lesions. There was decreased but persistent nd of treatment. After 2 cycle of pembrolizumab, a macular FDG uptake in the necrotic right axillary lymph nodes rash appeared on the lower back. Skin biopsy demonstrated (SUV of 18.2) (Fig. 1). Given the rapid and significant re- max superficial perivascular mixed inflammatory cell infiltrate sponse, pembrolizumab was continued for another three cy- with normal CD4+/CD8+ ratio and was consistent with cles and repeated PET/CT showed continued response with grade I skin immune related adverse event (IRAEs) due to decreased FDG avidity in the right axilla. After cycle 14, the pembrolizumab. Prednisone 60 mg was started and tapered patient underwent right axillary lymph node dissection over a total of 4 weeks with complete resolution of the skin encompassing levels 1–3 nodes for assessment of the symptoms secondary to IRAEs. The cutaneous manifesta- residual persistent lymphadenopathy on the right side. tions including generalized erythema and pruritus which Histopathology demonstrated metastatic squamous cell Khaddour et al. Journal for ImmunoTherapy of Cancer (2019) 7:338 Page 5 of 7 carcinoma in 3 of 17 lymph nodes. His post-operative However, the previous study excluded patients with prior course was uncomplicated. The complete course of pem- allogenic hematopoietic cell transplant. A different brolizumab treatment consisted of 14 cycles, over a course study using pembrolizumab demonstrated an ORR of 38% of 9 months. Follow up 24 months after initiation of in 24 evaluable patients with MF/SS stages Ib-IV with the immune checkpoint blockade therapy (14 months after longest duration of response reported to be 46 weeks [11]. stopping pembrolizumab) revealed no evidence of re- Interestingly, there were higher response rates in retro- currence of cSCC. There was no compelling evidence spective studies examining the role of PD-1 inhibition of either progression of CTCL/SS or a flare in GVHD after allo-HCT compared to patients who received im- throughout his course of checkpoint inhibition ther- munotherapy prior to transplant for r/r-cHL [12, 13]. apy (most recent peripheral blood flow cytometry on These two previous retrospective studies showed ORR of week 120 showing no morphologic or immunopheno- 95 and 77% with 1 –year progression free survival (PFS) of typic evidence of atypical lymphocytosis or sézary 85.2% compared to ORR of 75 and 87% respectively in pa- cells and CD4+/CD8+ ration of 0.65). tients who received immune checkpoint inhibitors prior to transplant [2, 12–14]. This raises the hypothesis that Discussion immune checkpoint blockade could have a synergistic role Systemic treatment of locally advanced and metastatic after allo-HCT or a role in homing of donor T-cells lead- cutaneous squamous cell carcinoma has been limited ing to an enhanced graft versus tumor effect. Some data with the exception of recent data supporting the poten- support the previous hypothesis as immune escape is one tial role of immune checkpoint blockade specifically of the mechanisms considered to cause relapse after trans- cemiplimab [8] among other ongoing trials with other plant in hematological malignancies, and T-cell exhaus- PD-1 and PD-L1 inhibitors (Clinical Trials.gov. Identi- tion is a potential mechanism of relapse after allo-HCT fiers: NCT02978625, NCT02964559, NCT03284424 and due to overexpression of PD-1/PD-L1 receptors, which NCT03108131). Also, the data supporting the use of im- leads to inactivation of effective T-cells in the tumor mune checkpoint inhibitors in the treatment of microenvironment [15]. Norde et al. found that relapsed hematological malignancies other than classical Hodg- myeloid leukemia after allo-HCT had higher expression kin’s Lymphoma (cHL) or primary mediastinal large B- and upregulation of PD-L1 receptors on progenitor malig- cell lymphoma is limited. A new incentive of implement- nant clones. It was also observed in the same study the ing immune checkpoint blockade in the treatment of T- suppressive effect on allogenic CD3+ T-cells when there cell lymphomas is supported by preclinical studies that was high expression of PD-L1 on malignant leukemic showed programmed cell death ligand-1 (PD-L1) recep- cells. Interestingly, blockade of the PD-1/PD-L1 inter- tors to be expressed on malignant cells which contribute action can augment the expansion of effector CD8+ T- to suppression of host immunity against the malignant cells and reactivate unresponsive T-memory cells in the cells. This leads to overgrowth in T-cell clones derived microenvironment required for graft versus leukemia ef- from non-Hodgkin lymphoma [9]. Our case demon- fect [15]. Moreover, there is a small body of evidence sup- strates a rapid and durable response after treatment with porting a role of immune checkpoint inhibitors in the immune checkpoint inhibitors manifested by a reso- bone marrow microenvironment in acute myeloid lution of CTCL/SS symptoms within 6 weeks and a re- leukemia (AML), myelodysplastic syndrome (MDS) and mission period of 24 months since initiation of a PD-1 myelopthisis due to melanoma [16, 17]. inhibitor. The indication to use pembrolizumab in our Theconcern withthe useofimmunecheckpointinhibi- patient was for the treatment of poorly differentiated cu- tors after allo-HCT is the development of graft versus host taneous squamous cell carcinoma. The theoretical possi- disease (GVHD). Conflicting data exist regarding the oc- bility of a derived benefit against CTCL/SS was taken currence of this adverse event, with some studies reporting into consideration when starting treatment. Also, the increased incidence and worsening of preexisting GVHD possibility of exacerbating GVHD was also considered. with 30% (6 of 20 patients), and 26% deaths in patients Both poorly differentiated cutaneous squamous cell car- who received immune checkpoint blockade after allo-HCT cinoma (cSCC) and CTCL/SS responded rapidly within [12, 13]. In the previous two retrospective studies there 6 weeks (2 cycles) after initiation of PD-1 inhibitor, with- were 10 deaths related to GVHD in 51 patients (23 of out an evidence of GVHD flare. whom developed GVHD) [12, 13]. However, another retro- Early phase clinical trials using the PD-1 inhibitor (nivo- spective study assessing patients who were treated with im- lumab) in refractory/relapsed cutaneous T-cell lymph- mune checkpoint inhibitors after allo-HCT did not report omas demonstrated different objective response rates GVHD development in any of the 7 evaluable patients [18]. (ORR) ranging from 15% in mycosis fungoides (MF) to The largest systematic review assessing the risk of 40% in peripheral T-cell lymphoma/Sézary Syndrome (SS) GVHD with immune checkpoint inhibitors after allo- in phase I studies (number of evaluable patients = 18) [10]. HCT showed that 49% of patients who developed Khaddour et al. Journal for ImmunoTherapy of Cancer (2019) 7:338 Page 6 of 7 GVHD had a prior history of the disease [19]. Some of operated on the case and supervised the surgical peri-operative course. L.A.C & A.M prepared Fig. 3 and supervised the work. G.A & P.W supervised the en- the predictive factors of GVHD development in this pa- tire work. All authors contributed to the final version of the manuscript. All tient population were higher doses of immune check- authors read and approved the final manuscript. point inhibitors, shorter intervals between transplant and start of immunotherapy, and previous history of Funding No funding provided for this study. GVHD. This systematic review also supports other ob- servations of higher response rates when immune check- Availability of data and materials point inhibitors were administered after transplant Data was acquired through patient chart review using Washington University compared to those who received immunotherapy before in Saint Louis medical records. they underwent allo-HCT [12, 13, 19]. In our case, we did not observe GVHD after treatment Ethics approval and consent to participate Not Applicable. with PD-1 inhibitors. In fact, the patient’s erythema and pruritus which were manifestations of patient’s CTCL Consent for publication improved significantly after starting pembrolizumab. Written and verbal consent were obtained from the patient prior to Moreover, there was a dermatological immune related submission for publication. A copy of the written consent form is available at the editorial office for this journal. adverse event observed in the patient during treatment (after 2nd cycle of pembrolizumab) which correlated Competing interests with the response of both cSCC and CTCL. The previ- KK reports no conflict of interest. AM reports: kyowa kirin- advisory board, ous observation is supported by a retrospective study Helsinn- Advisory board, Elorac, Sologenix MiRagen (investigator), investigator in CITN study “embrolizymab and IFN-gamma in MF/SS and syn- showing robust immune response to PD-1/PD-L1 inhibi- ovial sarcoma”. LC reports no conflict of interest. FD reports no conflict of tors when lichenoid and spongiotic IRAEs develop dur- interest. PW reports no conflict of interest. RF reports no conflict of interest. ing treatment with PD-1/PD-L1 inhibitors [20]. GA speaker bureau for Merck. It should be noted that donor lymphocyte infusion Author details (DLI) which was performed in our patient on weeks 26 Division of Medical Oncology, Department of Medicine, Washington and 31 could have potentially led to full engraftment of University in Saint Louis, 660 South Euclid Avenue, Campus Box 8056, St. Louis, MO 63110, USA. Division of Medical Oncology, Bone Marrow allo-HCT resulting in the response observed in CTCL. Transplantation and Leukemia, Department of Medicine, Washington The median response from administration of DLI to full University in Saint Louis, St. Louis, USA. Division of Dermatology, engraftment is estimated to be 8–12 weeks [21]. How- Department of Medicine, Washington University in Saint Louis, St. Louis, USA. 4 5 Alvin J. Siteman Cancer Center, St. Louis, USA. Division of Nuclear Medicine, ever, the response of cSCC and CTCL in our case was Department of Radiology, Washington University in Saint Louis, St. Louis, observed to occur only after the administration of pem- USA. Section of Surgical Oncology, Department of Surgery, Washington brolizumab (first cycle was at week 36) and the substan- University in Saint Louis, St. Louis, USA. tial deep response was observed after the second cycle Received: 23 August 2019 Accepted: 30 October 2019 which was at week 39. In conclusion, our case is the first to describe a rapid and sustained clinical response of both CTCL/SS and References cSCC to immune checkpoint inhibition after allo-HCT, 1. Hughes CF, Khot A, McCormack C, Lade S, Westerman DA, Twigger R, Buelens O, et al. Lack of durable disease control with chemotherapy for without development of GVHD. However, this observa- mycosis fungoides and Sezary syndrome: a comparative study of systemic tion should be interpreted with caution given the non- therapy. Blood. 2015;125:71–81. trivial concern of GVHD. Further larger studies are 2. Chen R, Zinzani PL, et al. Phase II study of the efficacy and safety of Pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin needed to confirm the efficacy of immune checkpoint Oncol. 2017;35(19):2125–32. inhibitors and their safety profile in this patient 3. Zinzani PL, Ribrag V, et al. Safety and tolerability of pembrolizumab in population. patients with relapsed/refractory primary mediastinal large B-cell lymphoma. Blood. 2017;130(3):267–70. Abbreviations 4. Roemer MG, Advani RH, Ligon AH, et al. PD-L1 and PD-L2 genetic Allo-HCT: allogenic hematopoietic stem cell transplant; CTCL: Cutaneous T alterations define classical Hodgkin lymphoma and predict outcome. J Clin cell lymphoma; GVHD: Graft versus host disease; IRAEs: Immune related Oncol. 2016;34(23):2690–7. adverse events; PD-1: Programmed death receptor 1; PET/CT: Positron 5. Sivanand A, Surmanowicz P, Alhusayen R, Hull P, Litvinov IV, Zhou Y, emission tomography- computed tomography; r/r-cHL: Relapsed/refractory Gniadecki R. Immunotherapy for Cutaneous T-Cell Lymphoma: Current classical Hodgkin’s lymphoma; cSCC: Cutaneous squamous cell carcinoma; Landscape and Future Developments. J Cutan Med Surg. 2019;23(5):537–44. SS: Sézary syndrome 6. Pickering CR, et al. Mutational landscape of aggressive cutaneous squamous cell carcinoma. Clin Cancer Res. 2014;20(24):6582–92. Acknowledgments 7. Slater NA, et al. PD-L1 expression in cutaneous squamous cell carcinoma Not applicable. correlates with risk of metastasis. J Cutan Pathol. 2016;43(8):663–70. 8. Migden MR, et al. PD-1 blockade with Cemiplimab in advanced cutaneous Authors’ contributions squamous-cell carcinoma. N Engl J Med. 2018;379(4):341–51. K.K performed the chart, literature review to support conclusions of this 9. Wilcox RA, Feldman AL, et al. B7-H1 (PD-L1, CD274) suppresses host report, prepared Fig. 2 and wrote the manuscript with consultation with the immunity in T-cell lymphoproliferative disorders. Blood. 2009;114(10): other authors. F.D prepared Fig. 1 with supervision on the manuscript. R.C.F 2149–58. Khaddour et al. Journal for ImmunoTherapy of Cancer (2019) 7:338 Page 7 of 7 10. Lesokhin AM, Ansell SM, Armand P, et al. Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study. J Clin Oncol. 2016;34(23):2698–704. 11. Khodadoust M, Rook AH, Porcu P, et al. Pembrolizumab for treatment of relapsed/refractory mycosis Fungoides and Sezary syndrome: clinical efficacy in a Citn multicenter phase 2 study. Blood. 2016;128. 12. Herbaux C, Gauthier J, Brice P, et al. Efficacy and tolerability of nivolumab after allogeneic transplantation for relapsed Hodgkin lymphoma. Blood. 2017;129(18):2471–8. 13. Haverkos BM, Abbott D, Hamadani M, et al. PD-1 blockade for relapsed lymphoma postallogeneic hematopoietic cell transplant: high response rate but frequent GVHD. Blood. 2017;130(2):221–8. 14. 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. 15. Norde WJ, Maas F, et al. PD-1/PD-L1 interaction contribute to functional T- cell impairment in patients who relapse with cancer after allogenic stem cell transplantation. Cancer Res. 2011;71(15):5111–22. 16. Boddu P, Kantarjian H, et al. The emerging role of immune checkpoint based approaches in AML and MDS. Leuk Lymphoma. 2018;59(4):790–802. 17. Rosner S, Sen F, Postow M. Response after treatment with pembrolizumab in a patient with myelophthisis due to melanoma: the role of checkpoint inhibition in the bone. J Immunother Cancer. 2017;5:34. 18. Schoch LK, Borrello I, Fuchs EJ, et al. Checkpoint inhibitor therapy and graft versus host disease in allogeneic bone marrow transplant recipients of haploidentical and matched products with post-transplant cyclophosphamide [abstract]. Blood. 2016;128(22):Abstract 4571. 19. Ijaz A, Khan AY, Malik SU, et al. Significant risk of graft-versus-host disease with exposure to checkpoint inhibitors before and after allogeneic transplantation. Biol Blood Marrow Transplant. 2019;25(1):94–9. 20. Min Lee CK, Li S, Tran DC, Zhu GA, Kim J, Kwong BY, Chang ALS. Characterization of dermatitis after PD-1/PD-L1 inhibitor therapy and association with multiple oncologic outcomes: a retrospective case-control study. J Am Acad Dermatol. 2018;79(6):1047–52. 21. Deol A, Lum LG. Role of donor lymphocyte infusions in relapsed hematological malignancies after stem cell transplantation revisited. Cancer Treat Rev. 2010;36(7):528–38. 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Rapid and sustained response to immune checkpoint inhibition in cutaneous squamous cell carcinoma after allogenic hematopoietic cell transplant for sézary syndrome

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Abstract

Background: Cutaneous squamous cell carcinoma (cSCC) is not uncommon in association with indolent malignancies that were treated with prior radiotherapy and after allogenic bone marrow transplantation. On the other hand, cutaneous T-cell lymphoma (CTCL) is a subtype of non-Hodgkin’s lymphoma which is characterized by an indolent course, with relative refractoriness to conventional chemotherapies and radiotherapy, and occasionally referred for allogeneic hematopoietic cell transplantation (allo-HCT). Recently, the use of immune checkpoint inhibitors has gained attention in the treatment of both cutaneous squamous cell carcinoma and hematological malignancies. However, many patients with hematological malignancies eventually undergo allo-HCT, raising the concern of potential adverse events (graft versus host disease) due to manipulation of the immune system with use of checkpoint inhibitors. Case presentation: We describe a patient with relapsed refractory CTCL (Sézary Syndrome) who underwent allo-HCT with persistence of disease post-transplant. The patient additionally developed a progressively worsening lesion on the right shoulder which was biopsied and showed poorly differentiated carcinoma (cSCC). Pembrolizumab was started for the treatment of cSCC. After second cycle of treatment, the cSCC lesion responded dramatically to the use of immune checkpoint inhibitor. Also, the patient experienced significant resolution of pruritus and generalized erythema. During 24 months of follow up after initial treatment with checkpoint inhibition immunotherapy, the patient showed durable response of both cSCC and CTCL, as well as restoration of full donor chimerism, without obvious worsening of graft versus host disease (GVHD). Conclusion: This is the first case to our knowledge of rapid and durable response of both cSCC and CTCL to immune checkpoint inhibition after allo-HCT. Although this report highlights the potential for significant response to this class of medication, further studies are required to confirm the efficacy and safety of this approach in patients with CTCL after allo-HCT given the potential concern of GVHD. Keywords: Cutaneous squamous cell carcinoma, Cutaneous T-cell lymphoma, Sézary syndrome, Immune checkpoint inhibitors, Allogenic hematopoietic cell transplant, Pembrolizumab, Graft versus host disease * Correspondence: gasnsstas@wustl.edu Division of Medical Oncology, Department of Medicine, Washington University in Saint Louis, 660 South Euclid Avenue, Campus Box 8056, St. Louis, MO 63110, USA Alvin J. Siteman Cancer Center, St. Louis, USA Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Khaddour et al. Journal for ImmunoTherapy of Cancer (2019) 7:338 Page 2 of 7 Background Table 1 Sequence of systemic therapies administered since diagnosis of cutaneous T-cell lymphoma/ Sézary Syndrome Conventional chemotherapies are considered not to be curative in the majority of cutaneous T-cell lymphomas Prior therapy for CTCL/ Sequence and Duration SS (CTCL) [1]. Recently, the use of immune checkpoint in- Photochemotherapy First Line of Therapy 8 months (2009) hibitors has largely expanded to include hematological (PUVA) malignancies, specifically relapsed/refractory chemoresis- Photopheresis Second Line of 31 months (2009–2012) tant Hodgkin’s Lymphoma (r/r-cHL) and primary medi- Therapy astinal large B-cell lymphoma [2, 3].The rationale relies Romidepsin Third Line of Therapy 48 months (2010–2014) on the fact that genetic alterations occurring in the Pegylated liposomal Fourth Line of 3 months (2014) microenvironment of lymphomas specifically in the pro- doxorubicin Therapy grammed death ligand receptor (PD-L1/PD-L2) loci can Gemcitabine Fifth Line of Therapy 1 month (2014) lead to overexpression of PD-L1/2 on malignant cells, Alemtuzumab Sixth Line of Therapy 2 months (2015) which helps tumor cells to evade the effective antitumor immune response [4]. Similarly, CTCL such as Mycosis Mogamulizumab Seventh Line of 1 month (2015) Therapy Fungoides (MF) and Sézary Syndrome (SS) can debilitate the immune response against malignant cells in the Total skin electron Eighth Line of 3 months (2016) beam therapy Therapy tumor microenvironment and thus could be considered Bexarotene Ninth Line of Therapy 2 months (2016) a target for therapies that can restore immune surveil- lance [5]. However, there is a concern for the use of im- Pralatrexate Tenth Line of 2 months (2016) Therapy mune checkpoint inhibitors in patients with lymphoma who undergo allogenic hematopoietic cell transplant- ICE (Ifosfamide, Eleventh Line of 3 months (2016–2017) Carboplatin, Etoposide) Therapy ation due to the possibility of triggering or aggravating Sibling allogenic stem Twelfth Line of (2017) graft versus host disease. This has led to lack of litera- cell transplantation Therapy ture regarding the safety and efficacy of immune check- point inhibitors in this population as patients with prior history of allo-HCT were excluded from clinical trials mature T-cell lymphoma (79% by flow cytometry), and which examined the efficacy of immunotherapy. More- cytogenetic studies revealed no aberrations. The patient over, advanced cutaneous squamous cell carcinoma has underwent allogeneic hematopoietic cell transplantation been shown to have a high mutational burden which (allo-HCT) using a fully matched male sibling donor. could increase the expression of tumor neoantigens [6]. The myeloablative conditioning regimen prior to trans- Also, the association with PD-L1 expression is estab- plant consisted of hyperfractionated total body irradi- lished with cutaneous squamous cell carcinoma which ation combined with high dose cyclophosphamide. Graft prompted the study of immune checkpoint inhibitors as versus host disease (GVHD) prophylaxis consisted of a potential therapy [7]. tacrolimus and methotrexate. Tacrolimus was subse- We describe the first case to our knowledge of a pa- quently changed to sirolimus due to peri-transplant tient with a history of allo-HCT who had a rapid and neurotoxicity. Shortly after transplantation (week 7), the durable response of both cSCC and CTCL/SS after treat- patient developed a diffuse erythematous rash, a biopsy ment with immune checkpoint inhibitors. of which was most consistent with skin GVHD (vs CTCL vs drug rash) and received prednisone, mycophe- Case presentation nolate mofetil (MMF) with ongoing sirolimus with A 58-year-old Caucasian male with relapsed/refrac- improvement, and subsequent tapering to low dose tory Sézary Syndrome (r/r SS) stage IVA was referred prednisone (5 mg daily/ week 23). A bone marrow bi- for allogeneic hematopoietic cell transplantation (allo- opsy 4 months after allo-HCT showed persistent mar- HCT). The patient had received multiple therapies prior row (and peripheral blood) involvement with sézary cells to being assessed for a transplant (Table 1). Positron (15% bone marrow involvement by mature T-cell lymph- Emission Tomography/Computed Tomography (PET/ oma with CD4+/CD8+ ratio > 100). There was also CT) with [ F]fluorodeoxyglucose (FDG) prior to trans- mixed chimerism by short tandem repeat (STR) assay plant (1/17/2017) revealed interval development of a with 82% donor cells (Fig. 2). There was incomplete new hypermetabolic soft tissue nodule in the skin of the resolution of the skin manifestations of CTCL, which in- posterior right shoulder with maximum standard uptake cluded generalized erythema and pruritus. Repeated skin value (SUV ) of 12.3 and a hypermetabolic right para- biopsies were consistent with residual CTCL/SS. Five max tracheal lymph node (Fig. 1). Skin biopsy was consistent months after allo-HCT, STR studies again demonstrated with residual CTCL/SS, a bone marrow biopsy demon- persistent mixed chimerism, and donor lymphocyte infu- strated hypocellularity with extensive involvement of sions (DLI) in two separate doses were administered on Khaddour et al. Journal for ImmunoTherapy of Cancer (2019) 7:338 Page 3 of 7 a. b. c. Fig. 1 Anterior and posterior volume-rendered maximum activity-reprojection FDG-PET images showing (a) FDG uptake in the right shoulder (arrow) and a paratracheal lymph node. b markedly hypermetabolic lesion in the right shoulder with SUV of 26.7 (arrow), markedly max hypermetabolic right axillary and right paratracheal lymphadenopathy with SUV of 27.3 with interval development of hypermetabolic focal max cutaneous lesions, left axillary lymph node and pulmonary lesions. c near complete response of the right shoulder hypermetabolic lesion (arrow), complete resolution of paratracheal lymph node, left axillary lymph node, pulmonary and cutaneous lesions, with persistent FDG uptake of the right axillary lymph nodes weeks 26 and 31 (1 and 3 X 10e7 CD3 cells/kg, respect- and spread to the anterior chest wall (Fig. 3), a skin bi- ively) without complete resolution of skin symptoms or opsy was performed and histopathology revealed poorly erythema. Following allo-HCT, there was a gradual differentiated squamous cell carcinoma. Magnetic Res- worsening of a right shoulder skin lesion noted on PET/ onance Imaging (MRI) of the shoulder showed a right CT prior to transplant, and thought to be related to my- lesion with no bone or muscular invasion, but there was cosis fungoides secondary to CTCL. The skin mass even- extensive right axillary lymphadenopathy. FDG-PET/CT tually extended over the superior aspect of the right revealed worsening of disease with extensive markedly shoulder with ulceration and hard induration, and 3 hypermetabolic soft tissue thickening in the right shoul- months post allo-HCT, the patient underwent subse- der with SUV of 26.7 and interval development of max quent involved-field radiotherapy with a total dose of 50 markedly hypermetabolic partially necrotic right axillary Gy. The lesion persisted and grew to 17 × 10 cm in max- lymphadenopathy with SUV of 27.3, as well as wors- max imum dimension with worsening necrosis, ulceration, ening in FDG uptake of the right paratracheal lymph Fig. 2 Timeline of bone marrow chimerism performed with STR studies after bone marrow transplantation. * Donor lymphocyte infusion was administered on two separate doses on weeks 26 and 31. Pembrolizumab cycle 1 was at week 36 and last cycle (cycle 14) was at week 78 Khaddour et al. Journal for ImmunoTherapy of Cancer (2019) 7:338 Page 4 of 7 Fig. 3 Skin lesions of CTCL and cSCC before and after PD-1 inhibition. a: Generalized eruption of small confluent erythematous macules and papules on the anterior chest wall after stem cell transplant and before pembrolizumab. b: resolution of the previously mentioned erythematous maculopapular eruption after pembrolizumab. c: multiple firm nodules with partial ulceration and keratin deposition on the superior aspect of the right shoulder representing poorly differentiated squamous cell carcinoma (before pembrolizumab), also erythematous eruption can be noted around the cSCC lesion which represents cutaneous lymphoma. d & e: Granular tissue with skin regeneration replacing the nodular ulcerated lesions of cSCC (after pembrolizumab), there is complete resolution of the papular erythematous rash. CTCL: cutaneous T cell lymphoma, cSCC: cutaneous squamous cell carcinoma nd node. There was interval development of hypermetabolic were secondary to CTCL resolved completely after the 2 th focal cutaneous lesions, left axillary lymph nodes and cycle of immunotherapy. A FDG-PET/CT after the 5 cycle pulmonary lesions (T3N2B; Stage IV SCC) (Fig. 1). of pembrolizumab showed marked metabolic response and After discussion of treatment options with the patient, near-complete resolution of the superficial right shoulder intravenous pembrolizumab was started at a dose of 200 mg mass (SUV of 1.9), and complete resolution of right para- max every 3 weeks. The patient had an Eastern Cooperative On- tracheal and left axillary lymph nodes, as well as pulmonary cology Group performance of (ECOG 3) prior to beginning and cutaneous lesions. There was decreased but persistent nd of treatment. After 2 cycle of pembrolizumab, a macular FDG uptake in the necrotic right axillary lymph nodes rash appeared on the lower back. Skin biopsy demonstrated (SUV of 18.2) (Fig. 1). Given the rapid and significant re- max superficial perivascular mixed inflammatory cell infiltrate sponse, pembrolizumab was continued for another three cy- with normal CD4+/CD8+ ratio and was consistent with cles and repeated PET/CT showed continued response with grade I skin immune related adverse event (IRAEs) due to decreased FDG avidity in the right axilla. After cycle 14, the pembrolizumab. Prednisone 60 mg was started and tapered patient underwent right axillary lymph node dissection over a total of 4 weeks with complete resolution of the skin encompassing levels 1–3 nodes for assessment of the symptoms secondary to IRAEs. The cutaneous manifesta- residual persistent lymphadenopathy on the right side. tions including generalized erythema and pruritus which Histopathology demonstrated metastatic squamous cell Khaddour et al. Journal for ImmunoTherapy of Cancer (2019) 7:338 Page 5 of 7 carcinoma in 3 of 17 lymph nodes. His post-operative However, the previous study excluded patients with prior course was uncomplicated. The complete course of pem- allogenic hematopoietic cell transplant. A different brolizumab treatment consisted of 14 cycles, over a course study using pembrolizumab demonstrated an ORR of 38% of 9 months. Follow up 24 months after initiation of in 24 evaluable patients with MF/SS stages Ib-IV with the immune checkpoint blockade therapy (14 months after longest duration of response reported to be 46 weeks [11]. stopping pembrolizumab) revealed no evidence of re- Interestingly, there were higher response rates in retro- currence of cSCC. There was no compelling evidence spective studies examining the role of PD-1 inhibition of either progression of CTCL/SS or a flare in GVHD after allo-HCT compared to patients who received im- throughout his course of checkpoint inhibition ther- munotherapy prior to transplant for r/r-cHL [12, 13]. apy (most recent peripheral blood flow cytometry on These two previous retrospective studies showed ORR of week 120 showing no morphologic or immunopheno- 95 and 77% with 1 –year progression free survival (PFS) of typic evidence of atypical lymphocytosis or sézary 85.2% compared to ORR of 75 and 87% respectively in pa- cells and CD4+/CD8+ ration of 0.65). tients who received immune checkpoint inhibitors prior to transplant [2, 12–14]. This raises the hypothesis that Discussion immune checkpoint blockade could have a synergistic role Systemic treatment of locally advanced and metastatic after allo-HCT or a role in homing of donor T-cells lead- cutaneous squamous cell carcinoma has been limited ing to an enhanced graft versus tumor effect. Some data with the exception of recent data supporting the poten- support the previous hypothesis as immune escape is one tial role of immune checkpoint blockade specifically of the mechanisms considered to cause relapse after trans- cemiplimab [8] among other ongoing trials with other plant in hematological malignancies, and T-cell exhaus- PD-1 and PD-L1 inhibitors (Clinical Trials.gov. Identi- tion is a potential mechanism of relapse after allo-HCT fiers: NCT02978625, NCT02964559, NCT03284424 and due to overexpression of PD-1/PD-L1 receptors, which NCT03108131). Also, the data supporting the use of im- leads to inactivation of effective T-cells in the tumor mune checkpoint inhibitors in the treatment of microenvironment [15]. Norde et al. found that relapsed hematological malignancies other than classical Hodg- myeloid leukemia after allo-HCT had higher expression kin’s Lymphoma (cHL) or primary mediastinal large B- and upregulation of PD-L1 receptors on progenitor malig- cell lymphoma is limited. A new incentive of implement- nant clones. It was also observed in the same study the ing immune checkpoint blockade in the treatment of T- suppressive effect on allogenic CD3+ T-cells when there cell lymphomas is supported by preclinical studies that was high expression of PD-L1 on malignant leukemic showed programmed cell death ligand-1 (PD-L1) recep- cells. Interestingly, blockade of the PD-1/PD-L1 inter- tors to be expressed on malignant cells which contribute action can augment the expansion of effector CD8+ T- to suppression of host immunity against the malignant cells and reactivate unresponsive T-memory cells in the cells. This leads to overgrowth in T-cell clones derived microenvironment required for graft versus leukemia ef- from non-Hodgkin lymphoma [9]. Our case demon- fect [15]. Moreover, there is a small body of evidence sup- strates a rapid and durable response after treatment with porting a role of immune checkpoint inhibitors in the immune checkpoint inhibitors manifested by a reso- bone marrow microenvironment in acute myeloid lution of CTCL/SS symptoms within 6 weeks and a re- leukemia (AML), myelodysplastic syndrome (MDS) and mission period of 24 months since initiation of a PD-1 myelopthisis due to melanoma [16, 17]. inhibitor. The indication to use pembrolizumab in our Theconcern withthe useofimmunecheckpointinhibi- patient was for the treatment of poorly differentiated cu- tors after allo-HCT is the development of graft versus host taneous squamous cell carcinoma. The theoretical possi- disease (GVHD). Conflicting data exist regarding the oc- bility of a derived benefit against CTCL/SS was taken currence of this adverse event, with some studies reporting into consideration when starting treatment. Also, the increased incidence and worsening of preexisting GVHD possibility of exacerbating GVHD was also considered. with 30% (6 of 20 patients), and 26% deaths in patients Both poorly differentiated cutaneous squamous cell car- who received immune checkpoint blockade after allo-HCT cinoma (cSCC) and CTCL/SS responded rapidly within [12, 13]. In the previous two retrospective studies there 6 weeks (2 cycles) after initiation of PD-1 inhibitor, with- were 10 deaths related to GVHD in 51 patients (23 of out an evidence of GVHD flare. whom developed GVHD) [12, 13]. However, another retro- Early phase clinical trials using the PD-1 inhibitor (nivo- spective study assessing patients who were treated with im- lumab) in refractory/relapsed cutaneous T-cell lymph- mune checkpoint inhibitors after allo-HCT did not report omas demonstrated different objective response rates GVHD development in any of the 7 evaluable patients [18]. (ORR) ranging from 15% in mycosis fungoides (MF) to The largest systematic review assessing the risk of 40% in peripheral T-cell lymphoma/Sézary Syndrome (SS) GVHD with immune checkpoint inhibitors after allo- in phase I studies (number of evaluable patients = 18) [10]. HCT showed that 49% of patients who developed Khaddour et al. Journal for ImmunoTherapy of Cancer (2019) 7:338 Page 6 of 7 GVHD had a prior history of the disease [19]. Some of operated on the case and supervised the surgical peri-operative course. L.A.C & A.M prepared Fig. 3 and supervised the work. G.A & P.W supervised the en- the predictive factors of GVHD development in this pa- tire work. All authors contributed to the final version of the manuscript. All tient population were higher doses of immune check- authors read and approved the final manuscript. point inhibitors, shorter intervals between transplant and start of immunotherapy, and previous history of Funding No funding provided for this study. GVHD. This systematic review also supports other ob- servations of higher response rates when immune check- Availability of data and materials point inhibitors were administered after transplant Data was acquired through patient chart review using Washington University compared to those who received immunotherapy before in Saint Louis medical records. they underwent allo-HCT [12, 13, 19]. In our case, we did not observe GVHD after treatment Ethics approval and consent to participate Not Applicable. with PD-1 inhibitors. In fact, the patient’s erythema and pruritus which were manifestations of patient’s CTCL Consent for publication improved significantly after starting pembrolizumab. Written and verbal consent were obtained from the patient prior to Moreover, there was a dermatological immune related submission for publication. A copy of the written consent form is available at the editorial office for this journal. adverse event observed in the patient during treatment (after 2nd cycle of pembrolizumab) which correlated Competing interests with the response of both cSCC and CTCL. The previ- KK reports no conflict of interest. AM reports: kyowa kirin- advisory board, ous observation is supported by a retrospective study Helsinn- Advisory board, Elorac, Sologenix MiRagen (investigator), investigator in CITN study “embrolizymab and IFN-gamma in MF/SS and syn- showing robust immune response to PD-1/PD-L1 inhibi- ovial sarcoma”. LC reports no conflict of interest. FD reports no conflict of tors when lichenoid and spongiotic IRAEs develop dur- interest. PW reports no conflict of interest. RF reports no conflict of interest. ing treatment with PD-1/PD-L1 inhibitors [20]. GA speaker bureau for Merck. It should be noted that donor lymphocyte infusion Author details (DLI) which was performed in our patient on weeks 26 Division of Medical Oncology, Department of Medicine, Washington and 31 could have potentially led to full engraftment of University in Saint Louis, 660 South Euclid Avenue, Campus Box 8056, St. Louis, MO 63110, USA. Division of Medical Oncology, Bone Marrow allo-HCT resulting in the response observed in CTCL. Transplantation and Leukemia, Department of Medicine, Washington The median response from administration of DLI to full University in Saint Louis, St. Louis, USA. Division of Dermatology, engraftment is estimated to be 8–12 weeks [21]. How- Department of Medicine, Washington University in Saint Louis, St. Louis, USA. 4 5 Alvin J. Siteman Cancer Center, St. Louis, USA. Division of Nuclear Medicine, ever, the response of cSCC and CTCL in our case was Department of Radiology, Washington University in Saint Louis, St. Louis, observed to occur only after the administration of pem- USA. Section of Surgical Oncology, Department of Surgery, Washington brolizumab (first cycle was at week 36) and the substan- University in Saint Louis, St. Louis, USA. tial deep response was observed after the second cycle Received: 23 August 2019 Accepted: 30 October 2019 which was at week 39. In conclusion, our case is the first to describe a rapid and sustained clinical response of both CTCL/SS and References cSCC to immune checkpoint inhibition after allo-HCT, 1. Hughes CF, Khot A, McCormack C, Lade S, Westerman DA, Twigger R, Buelens O, et al. Lack of durable disease control with chemotherapy for without development of GVHD. 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