Pralatrexate in Relapsed/Refractory HTLV-1 Associated Adult T-Cell Lymphoma/Leukemia: A New York City Multi-Institutional Experience.
Authors: Lunning Matthew A , Gonsky Jason , Ruan Jia , Phillips Adrienne A. , Pulitzer Melissa , Moskowitz Alison , Querfeld Christiane , Myskowski Patricia L , Noy Ariela , Horwitz Steven M. 
Published: October 2019

Abstract 2735

Introduction:

Adult T-cell lymphoma/leukemia (ATLL) is a mature T-cell malignancy associated with human T-cell lymphotropic virus -1 (HTLV-1) infection, which presents as aggressive (acute/lymphomatous) or indolent (chronic/smouldering) subtypes. The aggressive subtypes have a median survival of 6 months. Further, there is no established therapy for patients with relapsed/refractory disease. Pralatrexate is a dihydro-folate reductase inhibitor with high affinity for the reduced folate carrier type 1, a protein involved in trafficking of native folates. Pralatrexate given weekly at 30 mg/m2 for six of seven weeks was the first drug approved for use in relapsed/refractory peripheral T-cell lymphoma (PTCL) after demonstrating an overall response rate (ORR) of 29%. However, only one patient in the pivotal PROPEL study had ATLL. Approaches for relapsed/refractory PTCL are often applied to ATLL, as there is little data for this subtype. Here, we report a multi-institutional retrospective experience of pralatrexate in relapsed/refractory ATLL focusing on efficacy, durability, and toxicity.

Methods:

To investigate the therapeutic benefit and toxicity profile of pralatrexate we reviewed all patients with relapsed/refractory ATLL treated with pralatrexate on published trials or treated off study between 2005 and 2012 at three New York City institutions. Individual chart review was performed to report clinicopathologic features, treatment outcomes, and toxicity assessments. An event was defined as toxicity from pralatrexate resulting in discontinuation, progression, or death.

Results:

We identified 21 patients with relapsed/refractory ATLL treated with pralatrexate. Patient characteristics were: median age 52 (range 37–74); male:female 9:12; Region of origin was Caribbean-18, non-Caribean-3. Subtype at diagnosis of ATLL was: Acute/Lymphomatous-17 and Smouldering/Chronic-4. The median number prior treatments were 1 (range 0–5). Seven patients were treated on pralatrexate developmental clinical trials with one patient on the pivotal phase II PROPEL study. The median dose and number of treatments administered were 30 mg/m2 (range 15–45) and 4 (range 1–53) respectively. The ORR in patients evaluable for response (N=16) was 19% (2:PR; 1:CR) with an intent-to-treat (N=20) ORR was12% in patients with any exposure to pralatrexate. The median duration of response was 15 weeks (range 11–83). The median event free survival (EFS) was 6 weeks (range 1 to 90). One patient continues on pralatrexate without toxicity and has yet to be evaluated for response. Four patients (19%) developed findings consistent with Stevens-Johnson Syndrome (SJS) after 1 (N=2) or 2 (N=2) doses of pralatrexate. One additional patient developed a papular rash after pralatrexate; no biopsy was obtained. In the four patients with SJS, one had skin involvement of ATLL at diagnosis and at the time of pralatrexate, two had cutaneous ATLL lesions at the time of pralatrexate, and one did not have any cutaneous ATLL. Dermal apoptosis of tumor was not assessed in any of the cases. Seven patients (33%) developed clinically significant mucositis with two cases in patients with SJS.

Conclusion:

ATLL is a rare and difficult disease to manage. In our retrospective experience in relapsed/refractory ATLL, pralatrexate appears to have inferior ORR and much shorter EFS when compared to other PTCL subtypes. Notably, the risk of SJS, even without cutaneous involvement by lymphoma, may be higher in ATLL. In early phase studies of pralatrexate skin erosions were also seen in patients with PTCL with cutaneous involvement, including one cases of an ATLL patient with in vivo evidence of apoptosis of cutaneous tumor cells, but no cases of SJS were reported. A dedicated phase II study of pralatrexate in relapsed/refractory ATLL is planned by the Japan Clinical Oncology Group.

Disclosures:

Horwitz: Seattle Genetics: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Genzyme: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy; Johnson & Johnson: Consultancy; Infinity Pharmaceuticals, Inc.: Research Funding.