Successful implementation of genomically based treatment of chemotherapy refractory peripheral T-cell lymphoma (PTCL)

ABSTRACT

Background: The treatment of peripheral T-cell lymphoma (PTCL) after failure of standard therapy represents a significant clinical challenge as the best approach has not been defined. The outcomes of patients with peripheral T-cell lymphoma (PTCL) after relapse, in the absence of hematopoietic stem-cell transplantation, are poor with median overall survival is less than six months. Thus, relapsed/refractory PTCL presents an area of unmet medical need. Case presentation: Herein, we report an 84-year old woman with stage IV PTCL with extensive involvement of the bowel and abdominal pain. She was treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy which was complicated by prolonged pancytopenia, without response. Disease progression was manifested by small bowel obstruction, for which she received palliative radiation therapy, further complicated by cardiac arrhythmia and sepsis. In the meantime, clinical-grade next generation sequencing of a lymph node (406 gene panel) showed six genomic alterations: NRAS Q61R, PTEN Q17*, CREBBP R768*, EP300 R1529*, SETD2 loss exons 19–21, along with an intermediate tumor mutational burden. Tissue PD-L1 staining was low positive by immunohistochemistry. The patient was discussed in Molecular Tumor Board with consensus opinion favoring a combination of the MEK inhibitor trametinib (for the NRAS alteration) and the checkpoint inhibitor nivolumab for the elevated mutational burden and PD-L1 positivity. Her abdominal pain resolved and she achieved a complete remission ongoing at 5+ months. Side effects at five months included only low-grade rash and peripheral edema. Conclusions: Our observations suggest that matching patients with hematologic malignancies with customized combinations based on genomic sequencing warrants further study as a way to achieve and/or deepen responses, including in patients who are elderly and/or have refractory disease and significant disease-related complications.

Introduction

The treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) represents a significant clinical challenge as the best therapeutic strategy has not been determined. Historically, the outcomes of patients with PTCL after relapse, in the absence of hematopoietic stem-cell transplantation (HSCT), are poor, with a median overall survival (OS) of about 5.5 months¹ The frontline treatment of PTCL has been an anthracycline-containing chemotherapy, the cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) regimen, with the possible addition of etoposide, applied in nodal disease² This uniform treatment approach has quite divergent outcomes, with a significant proportion of patients (16% – 40%) demonstrating disease progression either during or immediately after induction³ The differential response to chemotherapy stems from heterogeneity of T-cell neoplasms, where patients with ALK-positive tumors, for example, have a 5-year failure-free survival of 60% as compared to only 36% in ALK-negative disease⁴ As the classification of PTCL is evolving, specific molecular signatures can be helpful not only in distinguishing among different histological subtypes and determining disease prognosis, but also may have a potential impact on treatment selection⁵ The optimal therapy of PTCL may need to be tailored to its unique phenotype, genetics and biology.⁶ Indeed in solid tumors, matching patients to targeted therapy has been shown to be an effective strategy in some studies^7-10

Based on a better understanding of the molecular drivers of various subtypes of PTCL, novel therapeutic strategies are emerging to match oncogenic genomic alterations with biologically-informed, targeted therapy in an effort to improve clinical outcomes. Herein, we describe an elderly patient with primary chemotherapy-refractory PTCL, who had next-generation sequencing (NGS) identifying NRAS Q61R with intermediate tumor mutational burden (TMB). For these abnormalities, she received a combination regimen that included trametinib and nivolumab that resulted in a complete response (CR).

Case report

Briefly, the patient is a 84-year old lady with stage IV PTCL involving the bowel. She initially presented with abdominal pain in late 2016. Figure 1. She underwent computed tomography (CT) imaging that showed a 6.5 cm mass involving the ileum. Figure 2. Positron emission tomography (PET) confirmed intensely hypermetabolic pathologic small bowel wall thickening with associated adjacent central mesenteric adenopathy (SUV 13.2) along with hypermetabolic splenomegaly and retroperitoneal lymphoadenopathy. Figure 2, upper left panel. CT-guided core biopsy of the mesenteric mass was consistent with PTCL as evident by pathological review at UCSD and CD2+, CD8+, CD7+ positivity by immunohistochemistry (IHC), and T-cell receptor (TCR) alpha/beta rearrangement by polymerase chain reaction (PCR). Ki67 expression was variable but noted as high as 50% (Alk1, CD30 and EBER were all negative).

Figure 1.

Time course of therapy.

Figure 2.

Imaging prior to (upper and lower left panel) and following two months of molecularly matched therapy (upper and lower right panel). Upper panels are PET scans. Lower panels are CT scans.

Clinically, the patient complained of severe abdominal pain. Based on rapidly progressive symptoms and concern for impending bowel obstruction, she started CHOP therapy (full dose); this was complicated with protracted pancytopenia and ongoing pain. Three weeks later, the patient was re-admitted with acute nausea/vomiting, secondary to small bowel obstruction (SBO). Indeed, CT scan demonstrated a 10 cm segment of marked small bowel wall thickening likely representing lymphomatous involvement, fecalization of this segment indicative of delayed transit time, and multiple loops of dilated bowel proximal to this area consistent with SBO. The patient was started on palliative radiation therapy (RT) receiving a total dose 3,000cGy (given in 15 fractions); this was complicated by acute atrial fibrillation in the setting of Klebsiella urinary tract infection. She completed treatment with successful resolution of small bowel obstruction, but still persistent abdominal pain and ongoing atrial fibrillation. Post radiation CT scan demonstrated improved yet persistent abdominal mass measuring about 5 cm and unchanged mesenteric lymphoadenopathy.

In the meantime, NGS sequencing of the patient’s tumor (lymph node) (Foundation Medicine Heme panel, 406 genes; https://www.foundationmedicine.com/genomic-testing/foundation-one-heme; clinical-grade comprehensive genomic profiling) was completed and revealed six genomic alterations: NRAS Q61R, PTEN Q17*, CREBBP R768*, EP300 R1529*, SETD2 loss exons 19–21, tumor mutational burden (TMB) -Intermediate; 6 mutations per megabase. (Alterations likely or known to be bona fide oncogenic drivers and germline polymorphisms are excluded from the TMB count.) Tissue was PD-L1 tumor low positive (at least 1+, 1%), PD-L1 tumor infiltrating lymphocytes negative (Ventana, PD-L1 (SP142) antibody); PD-1 tumor infiltrating lymphocytes low positive (at least 1+, 5%) (Cell Marque PD-1 (NAT105) antibody by immunohistochemistry performed by Foundation Medicine). The patient was discussed in Molecular Tumor Board with consensus opinion favoring a combination of the MEK inhibitor trametinib (for the NRAS alteration). In addition, anakinra, an endogenous interleukin-1 receptor antagonist (IL-1ra), was also suggested since IL-1 has been shown to mediate some of the growth effects of RAS¹¹. Additionally, nivolumab was recommended for PD-L1 (low) positivity and intermediate TMB. The patient signed consent for UCSD Internal Review Board approved protocol (NCT02478931) (Center for Personalized Cancer Therapy).

Based on the genomic profile, the patient was given the combination of trametinib 2 mg by mouth daily plus anakinra 100 mg subcutaneously daily plus nivolumab 3 mg/kg intravenously every two weeks. Notably, the patient’s abdominal pain resolved. She continues on treatment at 5+ months with the main side effects being Grade 2 rash and edema (in the setting of hypoalbuminemia), both mitigated with dose reduction of trametinib to 0.5 mg by mouth daily. Two months after starting, PET and CT scans showed a complete resolution of disease Figure 2, right panels. Repeat CT imaging, two months later confirmed sustained complete remission (CR).

Discussion

Historically, T-cell non-Hodgkin lymphoma (NHL) has been challenging to treat with standard regimens. Extrapolated from the B-cell NHL studies, CHOP has been used and has a response rate of approximately 50% in T-cell NHL.¹² In the relapsed setting, the response rate declines to about 25–30% in T-cell NHL, with typical second-line regimens being histone deacetylase (HDAC) inhibitors (romidepsin, vorinostat, belinostat) or antifolates (pralatrexate).^13–16 More recently, novel agents including brentuximab vedotin (an anti-CD30 drug-conjugated monoclonal antibody), duvelisib/copanlisib (PI3K antagonists) and others have begun to emerge³ A number of clinical trials have also tested adding more agents to the CHOP backbone, including alemtuzumab (an anti-CD52 antibody), brentuximab vedotin or an HDAC inhibitor¹⁷ While promising, the results of these combination regimens in PTCL are associated with significant toxicity and relatively short duration of response. Beyond that, the data are sparse and clinical trials are indicated; these often have stringent eligibility criteria and performance status that only few octogenarian patients with advanced disease can meet. Further, given the rarity of T–cell histology, as compared to B-cell neoplasms, such trials are not widely available.

Thus, innovative approaches to tailor therapy to each individual’s tumor are needed. Herein, we present a case of an elderly patient with primary chemotherapy refractory PCTL who was successfully treated with genomically matched combination therapy and attained a CR. Figure 2, This regimen was selected based on the patient’s genomic sequencing (Foundation Medicine, 406 gene panel). The patient was found to have mutations in NRAS Q61R, PTEN Q17, CREBP R768, EP300 R1529 and SETD2 genes; tumor mutational burden was measured as intermediate. Immunologic profile demonstrated PD-1 expression on tumor infiltrating lymphocytes (TIL) at 5%, PD-L1 tumor = 1%; TIL – negative. To target the dominant NRAS mutation (mutation allelic frequency (MAF) = 36%), the MEK inhibitor trametinib was suggested by the multidisciplinary Molecular Tumor Board (along with an IL-1 antagonist anakinra, since IL-1 has previously been shown to mediate RAS effects)¹¹ The checkpoint inhibitor nivolumab was suggested based on the finding of a modestly elevated TMB. Previously anti-PD1 therapy has been safely combined with trametinib, as well as the BRAF inhibitor dabrafenib, in melanoma with high response rate In hematologic malignancies,¹⁸ MEK inhibition appears to be a promising strategy for MLL-rearranged acute lymphoblastic leukemia (ALL) patients carrying RAS mutations. RAS mutations are found in 14–24% of infant ALL patients. Targeting the RAS signaling pathway with MEK inhibitors trametinib, selumetinib and MEK162 reduced p-ERK levels, and induced apoptosis and severely impaired primary RAS-mutant MLL-rearranged infant ALL cells in vitro. Furthermore, MEK inhibition synergistically enhanced prednisolone sensitivity and thus may represent a promising therapeutic strategy in carefully selected RAS mutant ALL¹⁹ Furthermore, a recent report of a patient with KRAS-mutant Rosai Dorfman (a non-Langerhans histiocytosis) demonstrated a remarkable response to a MEK inhibitor, cobimetinib, thus lending further support to rational use of this targeted therapy²⁰ MEK inhibition has not previously been used, to our knowledge in PTCL. Checkpoint blockade with nivolumab has been successfully used in Hodgkin lymphoma with increased PD-L1 expressio⁴ and has a potential benefit in both NK- and T-cell NH²¹albeit with response rates (mostly partial) of up to 40% in PTCL.

While the strategy used herein is novel and to our knowledge not previously reported in lymphoma, it serves as a proof of concept that matching agents to oncogenic pathways in hematologic malignancies can constitute an effective therapeutic strategy, particularly in an elderly patient with chemotherapy-refractory disease. By interrogating each patient’s individual tumor molecular signature, comprehensive genomic profiling can pave a path to truly personalized therapy, whereby a matched treatment is selected by a multidisciplinary team of experts, an approach that we used for this patient. In our institutional experience, a molecular tumor board comprised of clinicians, basic scientists, geneticists, and bioinformatics/pathway scientists provide expert multidisciplinary input and access to appropriate selection of cognate agents which makes genomically matched therapy possible^22,23 As a biologially informed approach in T-cell NHL is still in its fledgling phase, concerns will inevitably arise about whether to target a single or multiple pathways. In the current patient, the Molecular Tumor Board felt that both the MEK pathway and the immune system should be targeted, based on the presence of an intermediate mutational burden and an NRAS aberration. Our current case demonstrates that, despite the many challenges with genomically informed therapy, further investigation into individualized, matched treatments is warranted, particularly for patients without effective or well-tolerated standard options.

Funding Statement

Funded in part by National Cancer Institute [grant NCI P30 CA023100] and the Joan and Irwin Jacobs Fund philanthropic fund.

Abbreviations

CHOP

cyclophosphamide, hydroxyl-doxorubicin, oncovin, prednisone

CR

complete response

CT

computed tomography

EGD

endoscopic gastro-duodenoscopy

GI

gastrointestinal

PET

positron emission tomography

PTCL

peripheral T-cell lymphoma

RT

radiation therapy

Acknowledgments

We express our sincere gratitude to the patient and her family for willingness to participate in this study. We thank the Moores Cancer Center staff for providing support.

Authors’ contributions

N.G. wrote the manuscript; R.K. leads molecular tumor board. All authors edited the manuscript.

Authors’ information

R.K. is the Director of the Center for Personalized Cancer Therapy and Team Lead of the Experimental Therapeutics Program at the University of California San Diego, Moores Cancer Center. N.G. is the treating physician of the aforementioned patient.

Availability of data and material

All data generated or analyzed during this study are included in this published article. If any questions arise or additional information is needed, it can be provided by the corresponding author on reasonable request.

Conflict of interests

R.K. receives research funding from Incyte, Genentech, Merck, Serono, Pfizer, Sequenom, Foundation Medicine, and Guardant, as well as consultant fees from X Biotech, Loxo, and Actuate Therapeutics, speaker fees from Roche, and has an ownership interest in Curematch Inc. N.G. has no disclosures.

Consent for publication

Consent to publish this report was obtained from the patient.

Ethics approval and consent to participate

The study was conducted in accordance with the Declaration of Helsinki and with UCSD Institutional Review Board-approved study guidelines. Written informed consent was obtained from the patient.