Pegylated Liposomal Doxorubicin in Primary Cutaneous Lymphomas: Efficacy, Safety, and Low Rate of Palmar-Plantar Erythrodysesthesia
Authors: Pulini Stefano , Rupoli Serena , Pimpinelli Nicola , Natale Annalisa , Goteri Gaia , Scortechini Anna Rita , Picardi Paola , Mulattieri Simonetta , Leoni Pietro , Fioritoni Giuseppe 
Published: April 2020

Abstract
Pegylated liposomal doxorubicin (PLD) is approved in breast cancer, ovarian cancer, Kaposi’s sarcoma. Its skin-tropism suggests a role in the therapy of primary cutaneous lymphomas (PCLs). Among the cutaneous toxicities of PLD, the palmar-plantar erythrodysesthesia (PPE) is characterized by tingling, dysesthesia, erythema, swelling and, in severe cases desquamation, crusting, ulceration and necrosis. PPE is dose- and schedule-dependent and is usually reversible. Different pathophysiologic mechanisms are suggested:
PLD, excreted from sweat glands, penetrates into the corneum stratum with local oxidative and inflammatory reactions; direct cytotoxic effect; extravasation of PLD from the deep microvessels through the local pressure.
At our knowledge no specific reports on PPE in patients (pts) with PCLs treated with PLD were presented. We report 31 PCL pts treated with PLD: 26 affected by primary cutaneous T-cell lymphomas (PCTCL) and 5 by primary cutaneous B-cell lymphomas (PCBLC). Among PCTLC, 21 pts (16 M, 5 W, median age 67 yrs) received PLD in monotherapy at the dosage of 20 mg/m2 every 3–4 weeks. They were affected by relapsed or refractory PCTCLs: Mycosis Fungoides (MF) (52%), transformed MF in large cell lymphoma (20%), Sèzary Syndrome (SS) (14%), peripheral T-cell lymphoma unspecified (PTCL–U) (14%). After 6 courses, 47% achieved a CR, with ORR of 81%. The median time to the max response was 3 mo.s. After a median follow-up of 36 months 5 pts had progression of disease (PD) and 5 relapsed. To date 9 pts are alive and 12 dead, 4 for PD and 8 for non-related causes. Median OS, EFS and PFS are 36, 17 and 19 mo.s respectively; OS, EFS and PFS rates at 66 mo.s are 33%, 16% and 37%, respectively. Among the remaining 5 PCTLC pts one with transformed MF in large cell lymphoma was treated with PLD in monotherapy and then intensified with bortezomib and dexamethasone obtaining a VGPR. Another pt with PTCL-U received PLD plus rituximab with a CR and the last 3 pts (MF, MF transformed and SS) underwent CBVD scheme obtaining a PR. Among the 5 PCBCLs a woman was affected by marginal zone lymphoma (PCMZL) and 4 men by large B-cell lymphoma (PCLBCL) (all in stage: T3,N0,M0). All pts showed a CR with PLD monotherapy, in a short period (median 2,5 mo.s), even when heavily pretreated. One of them experienced a relapse. One died for PD; to date the others are still in CR after 5, 52, 63 and 69 mo.s. PLD was well tolerated. In PCTLC adverse effects were observed in 6 pts (23%) and grade III–IV toxicity occurred in 2 (8%): capillary leakage syndrome and neutropenia. Nobody required dose modifications or delays. Grade II gastrointestinal toxicity was present in 2 pts. Only two showed a grade I PPE. In these cases we delayed the dose up to 1 week, obtaining a complete resolution, thus returning to the original interval. Even in the five pts affected by PCBCL, PLD was well tolerated and no one decreased or delayed the dose. A pt showed a reversibile grade I neurotoxicity; the hematological toxicity was mild with one case of grade III neutropenia treated with G-CSF. Nobody experienced PPE. PPE is frequently reported in pts with cancer treated with PLD: about 50% off all pts who received the currently approved dose of 50 mg/m2 every 4 weeks experienced PPE and about 20% grade III PPE. When PPE develops, PLD dose reduction, schedule modification, ultimately drug withdrawal are considered. In our pts affected by PCLs, PPE occurred rarely, with mild grade (2 case of grade I). It is probably due to low dosages of Peg-Doxo, compared to the commonly used in other solid neoplasms. Besides oral prophylaxis with pyridoxine 300 mg daily was administered from the beginning of the treatment until 1 month after its discontinuation in all pts, as suggested by some authors. This is the first report of PLD in PCBCL; as regarding the other few studies (Wollina, Cantonetti, Di Lorenzo, Lybaek, Quereux) concerning PLD in PCTLC the incidence of PPE resulted always low. In conclusion, it emerges that PLD shows a significantly high clinical activity and a good safety profile in PCLs. Our data seem to confirm the dose dependent toxicity effect of PLD, since three-four weekly schedule of PLD at the dose of 20 mg/m2 has less PPE compared to the classical schedule of 50 mg/m2 every 4 weeks. Some studies in ovarian and breast cancer demonstrated that PLD dose intensity reduction can prevent PPE. The administration of prophylactic pyridoxine seems to be useful in the reduction of the incidence and severity of PPE.