A Single Center Experience With Pralatrexate Alone Or In Combination With Bexarotene:  Long Term Responses In Advanced Stage Relapsed/Refractory Cutaneous T-Cell Lymphoma

  Pralatrexate is an anti-folate approved for relapsed/refractory peripheral Tcell lymphoma.  Pralatrexate also had high activity and acceptable toxicity when used as a single agent in a dose finding phase 1/II study of 54 patients with relapsed/refractory cutaneous T-cell lymphoma (CTCL).  The response rate was 45% in 29 patients treated at an optimal dose of 15 mg/m²/week for 3 of 4 weeks.  In a second international multicenter Phase I/II dose finding trial, the optimal dose of praletrexate from the first trial was combined 150- 300 mg/m² bexarotene.  Eligibility was based on ECOG < 2 and MF stage > IB with ≥ one prior systemic therapy.  Pralatrexate was administered at 15 mg/m² weekly via intravenous push for 3 of 4 weeks each cycle.  The MTD for bexarotene was 150 mg/m2 taken orally daily with food and supplemented with both levothyroxine and atovastatin.  All patients on praletrexate received bi-monthly vitamin B₁₂ and daily folic acid supplementation.   Response to therapy was determined by a composite score consisting of the  modified skin assessment tool (mSWAT), lymph nodes by CT scan, and blood flow cytometry.

  The ORR for both trials at our site was 42% (11/26).  The ORR in the Phase I dose finding trial of praletrexate alone was 4/12 (33%).  The ORR in the pralatrexate plus bexarotene trial was 7/14 (50%).  Ten of 26 patients enrolled in both trials received more than 9 cycles of praletrexate: 3 on pralatrexate and 7 on the pralatrexate/bexatotene combination (Table 1). There were 4 females and 6 males with median age of 71 years (range 41-82 years). Their clinical stagies were 4 with IIB, 1 with IIIB, 4 with IVA, and 1 with IVB.  They received a median of 13 cycles (range 9-23).  The median number of prior therapies was 4 (range, 2–5).    Median time to response was 15.75 weeks (range 4-24 weeks) and the median duration of response was 26.75 weeks (range 8.5-49.5 weeks). Because there are still 4 responding subjects in ongoing therapy, the mean duration of response underestimates the true duration.  Two patients (Table 1*) presented with lower leg tumors that responded to therapy leaving residual chronic leg ulcers and are on long term active treatment.

The most common related adverse events of any grade were stomatitis (Grade 1-2) (n=8), neutropenia (n=5), headaches (n=3), dizziness (n=3), nausea (n=3), fatigue (n=2).  The dosing frequency of three out of four weeks was reduced to every other week at 10 mg/m2 in three of 10 long term responders.

Praletrexate alone or in combination with low dose oral bexarotene is active and capable of long term durable responses in CTCL patients with advanced age and stage.  The combination of 150 mg/m2 of bexarotene with 15 mg/m2 of praletrexate was well tolerated and had a better profile than praletrexate alone at our center.

Off Label Use: Off label study. Duvic:Spectrum: Research Funding.