Durable response to pralatrexate for aggressive PTCL subtypes

Case 2

A 64-year-old white man with a medical history of myasthenia gravis (in remission) and invasive thymoma (after thymectomy) presented with diffuse bulky lymphadenopathy and lung lesions to outpatient clinic at the Abramson Cancer Center at the University of Pennsylvania. His LDH was elevated (278 U/L, reference range 98-192 U/L). Excisional biopsy of a left inguinal lymph node revealed sheets of mitotically active large cells with oval to irregular nuclei, clumped chromatin, conspicuous and sometimes multiple nucleoli, and ample eosinophilic cytoplasm. Immunohistochemical staining showed that the neoplastic cells were positive for CD3, CD4, CD30, BCL2 (variable), and MUM1; and negative for ALK 1, CD5, CD8, CD15, CD43, and CD56. Proliferation index (Ki67) was 90% (Figure 2). PET-CT scan showed widespread hypermetabolic lymphoma in the chest, neck, abdomen, and pelvis with pulmonary metastases. Imaging also demonstrated FDG-avid lesions in the gastric and sinus area. The findings were consistent with ALK-negative, anaplastic large cell lymphoma. He was stage IVA; had gastric, lung, and sinus involvement; and disease above and below the diaphragm.

The patient was initially treated with 6 cycles of CHOP and intrathecal methotrexate injections. His post-treatment PET–CT scan showed persistent FDG-avid disease and his LDH level remained elevated. He underwent 1 cycle of ICE and then BCV (busulfan, cyclophosphamide, etoposide) autologous stem cell transplant. Post-transplant PET–CT scan showed improvement from previous 2 scans but still showed several hypermetabolic lymph nodes consistent with persistent disease.

The patient was started on a pralatrexate regimen of 30 mg/m² once weekly for 6 weeks of a 7-week treatment cycle. After 5 doses, he developed thrombocytopenia and mucositis, which were deemed pralatrexate related. The dosage was reduced to 20 mg/m² once weekly with variable frequency depending on tolerability. His response assessment with PET–CT scan demonstrated radiographic complete response with resolution of hypermetabolic lesions (Figure 3B).

He then proceeded with pralatrexate for 4 more doses. PET-CT imaging 2 months after the last dose of pralatrexate was consistent with metabolic complete response, and he opted to hold further therapy. His last imaging at 4 years after completion of therapy showed continued remission. At press time, he had been clinically disease free for more than 6 years after his last dose of pralatrexate.
 

Discussion

PTCL is a rare and heterogeneous lymphoma with poor prognosis. Only 3 agents – pralatrexate, belinostat, and romidespin – have been approved specifically for the treatment of PTCL and all of them have an ORR of less than 30%, based on findings from phase 2 studies.^2,6,7 In the PROPEL study, pralatrexate showed an ORR of 29% and a median DoR of 10 months.² Those results could be considered discouraging, but some PTCL patients may have durable response to pralatrexate monotherapy.

In this case series, each of the patients presented with a particularly aggressive subtype of PTCL, and 1 suffered from a notably rare subtype for which there was scant clinical data to guide treatment. Both patients went through several lines of aggressive treatment that were ineffective and resulted in minimal response. However, both were able to achieve complete resolution of their disease and maintained remission for a significant duration of time after treatment with pralatrexate. In addition, each patient has maintained his remission – one for 6 years after the last dose. These are noteworthy results, and give both patients and clinicians hope that this therapy can be highly effective in some settings.

A better understanding at the molecular level of the oncogenic mechanisms in PTCL patients will be necessary to guide our therapy choices. In these 2 cases, it is likely that the tumor demonstrated superior sensitivity to dihydrofolate reductase inhibition by pralatrexate. In the future, we hope that analysis of the tumor tissue from PTCL patients will allow us to better categorize the tumor sensitivities to particular therapeutic agents. We believe that individualized treatment will lead to better overall outcomes in this challenging group of lymphomas.