We conducted a large international nested case-control study including 1881 patients with Philadelphia-negative myeloproliferative neoplasms (MPN). Cases (n = 647) were patients with second cancer (SC: carcinoma, non-melanoma skin cancer, hematological second cancer, and melanoma) and controls (n = 1234) were patients without SC, matched with cases for sex, age at MPN diagnosis, date of MPN diagnosis, and MPN disease duration. The aim was to evaluate the risk of SC after exposure to cytoreductive drugs. Patients exposed to hydroxyurea (HU) (median: 3 years) had a risk of SC similar to unexposed patients (OR = 1.06, 95% CI 0.82-1.38). In contrast, in cancer-specific stratified multivariable analysis, HU had two-fold higher risk of non-melanoma (NM) skin cancer (OR = 2.28, 95% CI 1.15-4.51). A significantly higher risk of NM-skin cancer was also documented for pipobroman (OR = 3.74, 95% CI 1.00-14.01), ruxolitinib (OR = 3.87, 95% CI 1.18-12.75), and for drug combination (OR = 3.47, 95% CI 1.55-7.75). These three drugs did not show excess risk of carcinoma and hematological second cancer compared with unexposed patients. Exposure to interferon, busulfan, and anagrelide did not increase the risk. In summary, while it is reassuring that no excess of carcinoma was documented, a careful dermatologic active surveillance before and during the course of treatments is recommended.

CRIMM Center of Research and Innovation of Myeloproliferative Neoplasms Azienda Ospedaliera Universitaria Careggi Department of Experimental and Clinical Medicine and Denothe Center University of Florence Florence Italy

Department of Hemato oncology University Hospital Olomouc Olomouc Czech Republic

Department of Hematology Oncology Fondazione IRCCS Policlinico San Matteo Pavia Pavia Italy

Department of Medicine Section of Hematology University of Verona Verona Italy

Department of Molecular Medicine University of Pavia Pavia Italy

Division of Hematology Department of Translational Medicine University of Eastern Piedmont Novara Italy

FROM Research Foundation Papa Giovanni XXIII Hospital Bergamo Italy

Guy's and St Thomas' NHS Foundation Trust London UK

HAEMOSTASIS UNIT Department of Clinical and Experimental Medicine University of Catania Policlinico Vittorio Emanuele Hospital Catania Italy

Hematology and Bone Marrow Transplantation Unit IRCCS San Raffaele Scientific Institute Milano Italy

Hematology Department Hospital Clínic Barcelona Spain

Hematology Department Hospital Clínico Universitario de Santiago de Compostela Santiago de Compostela Spain

Hematology Department Hospital Clínico Universitario Valencia Spain

Hematology Department Hospital del Mar Barcelona Spain

Hematology Department Hospital Universitario Miguel Servet Zaragoza Spain

Hematology Department Hospital Universitario Vall d'Hebron Barcelona Spain

Hematology Division Città della Salute e della Scienza Hospital Torino Italy

Hematology Division Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico and University of Milan Milan Italy

Hematology Division Ospedale San Gerardo ASST Monza Monza Italy

Hematology Division Papa Giovanni XXIII Hospital Bergamo Italy

Hematology Division San Bortolo Hospital Vicenza Italy

Hematology Institute and Blood Bank Meir Medical Center Kfar Saba Israel

Hematology Unit Azienda Unità Sanitaria IRCCS di Reggio Emilia Reggio Emilia Italy

Institute of Hematology Catholic University Fondazione Policlinico Universitario A Gemelli IRCCS Roma Italy

Institute of Hematology L and A Seràgnoli S Orsola Malpighi Hospital Bologna Italy

Oncology Unit Cardinal Massaia Hospital Asti Italy

Queen's University Belfast UK

Rete laziale MPN Roma Italy

S C Ematologia Azienda Ospedaliera S Croce e Carle Cuneo Italy

Sackler School of Medicine Tel Aviv University Tel Aviv Israel

Unit of Hematology Department of Oncology University of Torino Torino Italy

University Clinic for Hematology and Oncology Minden University of Bochum Bochum Germany

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