The most common T-cell lymphoma is cutaneous T-cell lymphoma (CTCL). The two main variants of this disease are mycosis fungoides (MF) and Sézary syndrome (SS). In CTCL, the malignant T cells often undergo migration from either the blood (SS) or the lymphatics (MF) to the skin, where they result in the appearance of lesions. As disease progression occurs, the lesions may take different shapes, forming rashes, plaques, and eventually tumors prior to spreading to other parts of the body.
Early-stage treatment of MF often involves skin-directed therapies, however, as disease progression occurs, the use of systemic therapies becomes necessary. These therapies have been wide ranging, including the use of radiation, chemotherapy, biologicals (e.g., interferon), and retinoids (vitamin A analogs).
Recently, Nathan Fowler, MD, Associate Professor in the Department of Lymphoma/Myeloma at MD Anderson Cancer Center, detailed a novel combination therapy for the treatment of a patient with advanced MF (Leuk Lymphoma 2018; doi:10.1080/10428194.2018.1516879). In this case, he utilized an off-label combination of the immunomodulatory drug lenalidomide and the anti-PD-1 antibody pembrolizumab.
“In this report, we present a case of refractory MF with large cell transformation treated with pembrolizumab and lenalidomide, which induced a near-complete response with minimal toxicity,” Fowler stated. “To our knowledge, this is the first reported case of using lenalidomide in combination with PD-1 inhibition for treatment of advanced MF.”
Cutaneous T-Cell Lymphoma
CTCL is one type of non-Hodgkin lymphoma (NHL). However, unlike most NHLs, where B cells are typically affected, CTCL is a T-cell based malignancy. The most common form of CTCL is MF, which is also known as granuloma fungoides or Alibert-Bazin syndrome.
Currently, the use of immune-mediated therapies in the treatment of MF and CTCL remains an unsettled matter. “The transition from early- to late-stage MF is characterized by loss of Th1 (a cytokine) expression and reduced anti-tumor immune response,” Fowler explained. “Lenalidomide, which is an immunomodulatory drug, upregulates the Th1 microenvironment and has been shown to have a modest 28 percent overall response rate in a small phase II clinical trial of 22 patients with advanced, refractory mycosis fungoides/Sézary syndrome (Blood 2014;123:1159-1166). Notably, all were partial responses with median progression-free survival of 8 months and no grade 4 toxicities.”
Preliminary trials evaluating PD-1 inhibitor monotherapy (nivolumab or pembrolizumab) in relapsed/refractory MF have shown promising results. Nivolumab was evaluated in a phase Ib trial (NCT01592370) in patients with advanced, refractory hematologic malignancies. In one part of the study, 13 patients with MF were treated, affording two documented partial responses and median progression-free survival of 10 weeks (J Clin Oncol 2016;34:2698-2704).
In a phase II trial (NCT02243579), pembrolizumab monotherapy was evaluated in 24 patients with advanced MF/SS who failed a median of four prior lines of systemic therapy, producing an objective response rate of 38 percent, including one complete response (Blood 2016;128:181). These responses, with 89 percent being ongoing at 32 weeks, were considered durable.
“Immunomodulatory drugs are hypothesized to act synergistically with PD-1 inhibition through several mechanisms,” Fowler noted. “In addition to direct proapoptotic and antiangiogenic effects, these immunomodulators also modify the tumor microenvironment by increasing inflammatory cytokines interferon-gamma (IFN-γ) and interleukin-2.
“In conjunction with downstream activation of the B7-CD28 costimulatory pathway,” Fowler stated, “immunomodulatory drugs functionally enhance cytotoxic T-cell and NK-cell activity.” In addition, post-treatment biopsies from MF patients receiving lenalidomide showed increased CD8 (a protein present on cytotoxic T cells) expression relative to the corresponding pretreatment samples (Blood 2014;123:1159-1166).
In a series of KEYNOTE clinical trials, combinations of the PD-1 inhibitor pembrolizumab and immunomodulatory drugs were evaluated in multiple myeloma patients. The phase I KEYNOTE-023 study (NCT02036502) evaluated the combination of pembrolizumab plus lenalidomide and low-level dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma. The phase III KEYNOTE-183 trial (NCT02576977) compared the use of the immunomodulator pomalidomide plus low-dose dexamethasone with or without pembrolizumab in patients with refractory or relapsed and refractory multiple myeloma. The combination of lenalidomide plus low-dose dexamethasone with or without pembrolizumab was evaluated in newly diagnosed, treatment-naïve multiple myeloma patients in the phase III KEYNOTE-185 clinical study (NCT02579863).
In July 2017, the FDA issued a statement, putting a clinical hold on these three trials. This was done on the basis of higher numbers of deaths being noted in the pembrolizumab arms of the KEYNOTE-183 and 185 studies. This indicated that the risks associated with the pembrolizumab-immunomodulator combination outweighed the potential benefits of that regimen.
In August 2017, the FDA issued another statement regarding these clinical trials, reminding doctors that given the serious nature of the safety issue, pembrolizumab was not approved for treating multiple myeloma patients and should not be given in combination with any immunomodulatory agents, including lenalidomide and pomalidomide, for the treatment of multiple myeloma.
Advanced Mycosis Fungoides Case
When asked about the procedure for treating a patient with an off-label combination therapy, Fowler replied, “Due to the lack of standard therapies for this patient, and the refractory nature of his cancer, we sought approval to use a novel combination therapy. Approval for the pembrolizumab-lenalidomide combination was granted by institutional committee and the drugs were obtained from pharmaceutical suppliers.
“Upon initial presentation,” he noted, “the patient had advanced disease and was unable to ambulate secondary to severe pain from denuded, ulcerated, and erythematous skin of the face, neck, torso, and limb covering over 60 percent of his body surface area.”
Biopsies of the skin-based tumors showed the presence of a T-cell lymphoma with large cell transformation. The patient was initially treated with low dose (24 Gy) total skin electron beam radiation (TSEB), which was completed in early February 2016, eliciting a partial response.
“One month later, the patient had disease progression, including a large ulcerating lesion of the hard palate,” Fowler noted. “A biopsy of the palate confirmed the presence of a persistent T-cell lymphoma with an immunophenotype that was consistent with that of the original diagnosis.” Systemic disease progression, including small bowel involvement, was then shown by diagnostic imaging (PET CT).
“The ulcers on the patient's palate were irradiated followed by 1 cycle of brentuximab vedotin, then 2 cycles of cyclophosphamide, epirubicin, vincristine, and prednisone,” Fowler said. “Unfortunately, the patient experienced disease progression while undergoing therapy, and he developed small bowel perforation. Subsequently, he received 2 cycles of gemcitabine, but once more developed small bowel perforation. While recovering from peritonitis, chemotherapy was withheld, which permitted rapid progression with multiple skin lesions.”
As a result of this progression, the patient received 3 cycles of brentuximab vedotin for the second time with progression, followed by 2 cycles of CMED (cyclophosphamide, etoposide, methotrexate, and dexamethasone) without response. “In December 2016, he received 1 cycle of romidepsin but was subsequently admitted to the hospital for cellulitis, deteriorating performance status, and disease progression,” Fowler noted.
“At this point, the family decided to pursue additional therapy, and on Feb. 9 2017, the patient was started on lenalidomide 15 mg daily, producing an initial response, but then resulting in progression after 2 months of single-agent therapy,” he detailed. “In April 2017, pembrolizumab therapy was initiated (150 mg, Q3W) with continued lenalidomide administration; immediately, rapid improvement was noted in his cutaneous lesions.” By May 2017, the patient was discharged from the hospital and walking with some assistance.
“In total, the patient completed 8 cycles of combination therapy by September 2017 with PET/CT demonstrating 90 percent improvement in avid lesions with resolution of all cutaneous nodules,” Fowler stated. “The patient did develop a hard palate ulcer, which was confirmed by biopsy to be T-cell lymphoma in October 2017; for this, he received local radiation with excellent response, and he has continued to improve.” Thus far the patient has shown no evidence of therapy-associated toxicity.
When queried about how the treatment combination utilized for this patient affected his outcome, Fowler replied, “While our patient continues to experience a durable response, we recognize that the sequential administration of TSEB, lenalidomide, and pembrolizumab makes it challenging to attribute his clinical improvement to immunotherapy alone.
“However, our patient demonstrated progression following TSEB and rapid progression following lenalidomide monotherapy, and only experienced dramatic skin clearing and resolution of tumor bulk following the addition of pembrolizumab.
“Prior to beginning combination therapy with pembrolizumab, the patient and his family were considering hospice care and were having end-of-life discussions,” he noted. Regarding patient's response to the combination therapy, “This was one of the most remarkable cases of combination immunotherapy I have observed in my entire career.”
When treating MF with lenalidomide (25 mg per day), rare instances of tumor flare have been noted. “This was less likely in our patient,” Fowler explained, “as he was treated at a lower 15 mg daily dose and experienced progression more than 30 days after lenalidomide initiation.
“The patient's rapid improvement within 3 weeks after initiation of pembrolizumab also suggests a combinatorial effect given a median time to response of 11 weeks (range 8-41 weeks) with published literature of single-agent pembrolizumab,” he added.
“Of equal importance to the duration of response in a chemo-refractory patient, the combination of lenalidomide with pembrolizumab was well-tolerated with no associated grade 3-4 toxicities,” Fowler noted. “In a recent phase II study (NCT02289222) of relapsed/ refractory multiple myeloma, the combination of the immunomodulatory pomalidomide with pembrolizumab and low-dose dexamethasone demonstrated an objective response rate of 60 percent with median duration of response of 14.7 months. However, grade 3-4 toxicities occurred in 40 percent of the patients, most significantly neutropenia (Blood 2017;130:1189-1197).”
“As our case report is the first to present data regarding the safety and efficacy of an immunomodulatory drug-PD-1 inhibitor combination in a T-cell disorder,” Fowler noted, “it is not clear if the side-effect profile will be comparable to multiple myeloma and will require prospective studies.
“Thus, while our patient experienced a dramatic, durable, and ongoing response to combination pembrolizumab and lenalidomide, we are cognizant of the potential significant toxicities of such therapy, given the results observed in multiple myeloma-based clinical trials,” he stated. “Clearly, additional clinical trials are required to further elucidate the role of immunotherapy in advanced MF.”
Richard Simoneaux is a contributing writer.