Results of a prospective phase II trial with oral low-dose bexarotene plus photochemotherapy (PUVA) in refractory and/or relapsed patients with mycosis fungoides.

INTRODUCTION: Bexarotene is a synthetic retinoid effective in early and advanced stages of mycosis fungoides (MF)/Sezary Syndrome (SS) both in monotherapy and combination schemes. We aimed to assess disease response to low-dose bexarotene and PUVA in maintenance in refractory and/or resistant patients with early and advanced stage MF/SS. METHODS: We followed prospectively 21 patients (stages IB-IV): 15 with early stage MF and 6 with advanced disease. "Mini" and standard protocols were respectively applied to patients who failed PUVA or several systemic regimens. The dose of bexarotene and the administration of PUVA were titrated individually and tailored during induction and maintenance according to previous therapy, disease stage and toxicity. We evaluated overall response (OR) at the end of maintenance, safety and event-free survival (EFS). RESULTS: After induction phase, OR was 85.6%, higher in early MF (93.4%) than in advanced disease (66.6%). At the end of maintenance, OR was 76.2%, including 33.3% of CR. Median EFS for the whole group was 31 months. Bexarotene was well tolerated regarding the side effects, with prophylaxis and progressive drug increase in the induction phase of the protocol. Side effects were mainly of low and moderate grades. CONCLUSIONS: We observed a favorable rate of therapeutic effects and few, generally mild, side effects with low doses of bexarotene combined with PUVA.

Thrombosis in essential thrombocytemia and early/prefibrotic primary myelofibrosis: the role of the WHO histological diagnosis.

BACKGROUND: Vascular events represent the most frequent complications of thrombocytemias. We aimed to evaluate their risk in the WHO histologic categories of Essential Thrombocytemia (ET) and early Primary Myelofibrosis (PMF). METHODS: From our clinical database of 283 thrombocytemic patients, we selected those with available bone marrow histology performed before any treatment, at or within 1 year from diagnosis, and reclassified the 131 cases as true ET or early PMF, with or without fibrosis, according to the WHO histological criteria. Vaso-occlusive events at diagnosis and in the follow-up were compared in the WHO-groups. RESULTS: Histologic review reclassified 61 cases as ET and 72 cases as early PMF (26 prefibrotic and 42 with grade 1 or 2 fibrosis). Compared to ET, early PMF showed a significant higher rate of thrombosis both in the past history (22% vs 8%) and at diagnosis (15.2% vs 1.6%), and an increased leukocyte count (8389 vs 7500/mmc). Venous thromboses (mainly atypical) were relatively more common in PMF than in ET. Patients with prefibrotic PMF, although younger, showed a significant higher 15-year risk of developing thrombosis (48% vs 16% in fibrotic PMF and 17% in ET). At multivariate analysis, age and WHO histology were both independent risk-factors for thrombosis during follow-up; patients >60 yr-old or with prefibrotic PMF showed a significantly higher risk at 20 years than patients <60 yr-old with ET or fibrotic PMF (47% vs 4%, p = 0.005). CONCLUSIONS: Our study support the importance of WHO histologic categories in the thrombotic risk stratification of patients with thrombocytemias. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2020211863144412 .

Cerebral vein thrombosis in patients with Philadelphia-negative myeloproliferative neoplasms. An European Leukemia Net study.

To investigate the characteristics and clinical course of cerebral vein thrombosis (CVT) in patients with myeloproliferative neoplasms (MPN) we compared 48 patients with MPN and CVT (group MPN-CVT) to 87 with MPN and other venous thrombosis (group MPN-VT) and 178 with MPN and no thrombosis (group MPN-NoT) matched by sex, age at diagnosis of MPN (±5 years) and type of MPN. The study population was identified among 5,500 patients with MPN, from January 1982 to June 2013. Thrombophilia abnormalities were significantly more prevalent in the MPN-CVT and MPN-VT than in MPN-NoT group (P = 0.015), as well as the JAK2 V617F mutation in patients with essential thrombocythemia (P = 0.059). Compared to MPN-VT, MPN-CVT patients had a higher rate of recurrent thrombosis (42% vs. 25%, P = 0.049) despite a shorter median follow-up period (6.1 vs. 10.3 years, P = 0.019), a higher long-term antithrombotic (94% vs. 84%, P = 0.099) and a similar cytoreductive treatment (79% vs. 70%, P = 0.311). The incidence of recurrent thrombosis was double in MPN-CVT than in MPN-VT group (8.8% and 4.2% patient-years, P = 0.022), and CVT and unprovoked event were the only predictive variables in a multivariate model including also sex, blood count, thrombophilia, cytoreductive, and antithrombotic treatment (HR 1.97, 95%CI 1.05-3.72 and 2.09, 1.09-4.00, respectively).

Lesional skin chemokine CTACK/CCL27 expression in mycosis fungoides and disease control by IFN-alpha and PUVA therapy.

Recruitment of neoplastic T cells to skin is a critical step in the pathogenesis of mycosis fungoides (MF) lesions. Cutaneous T-cell attracting chemokine (CTACK)/CCL27 attracts memory T cells to skin, resulting in increased cutaneous expression. The interactions between neoplastic cells and skin immune system require further elucidation. CTACK/CCL27 expression and density of dendritic cells (DC), CD8+ and CD4+ lymphocytes were investigated in skin lesions of 52 early-stage MF patients treated by interferon (IFN)-alpha in combination with photochemotherapy (psoralen plus ultraviolet A, PUVA). Skin lesion biopsies obtained at diagnosis and after treatment were studied by immunohistochemistry. Initial CTACK/CCL27 expression was abnormal/suprabasal in 36 patients. Normal/basal CTACK/CCL27 expression tended to correlate with a high DC density and low CD4+ cell density in the neoplastic infiltrate. Treatment induced a significant increase in CTACK/CCL27 expression (chi(2) test: P=0.004). Overall, 33 patients relapsed [median event-free survival (EFS), 46 months] during follow-up (median, 92.5 months, range, 43-165). Normal/basal CTACK/CCL27 expression at the end of treatment correlated with lower rates of recurrence and a longer median EFS (111 months vs. 39 months with suprabasal expression; log rank test: P=0.031). CTACK/CCL27 overexpression in early-stage MF might thus be related to a balance between neoplastic cells and immunomodulant DC. Normal CTACK/CCL27 expression after treatment designates a subset of patients with favorable disease behavior. The mechanisms underpinning CTACK/CCL27 overexpression after therapy in the remaining patients, who are at greater risk of recurrence, warrant further investigation.