Iatrogenic Kaposi's sarcoma in a myelofibrosis patient treated with ruxolitinib: <scp>Case‐report</scp>, literature review, and French pharmacovigilance data
Authors: Marin Moutel, Violaine Noel, Aude Jary, Quoc‐Hung Le, Clément Lier, Manuelle Viguier, Céleste Lebbe, Brahim Azzouz, Firouzé Bani‐Sadr
Journal: American Journal of Hematology (2021)

Kaposi's sarcoma (KS) is a rare lympho-angioproliferative disorder associated with human herpesvirus 8, also known as KS-associated herpesvirus (KSHV).1 The epidemiological classification describes five presentations of KS, namely: AIDS-associated KS, classic KS in older European men, endemic KS in younger men and children in sub-Saharan Africa, nonepidemic KS in men who have sex with men (MSM) with no identifiable immunodeficiency and iatrogenic KS.1 Apart from well-described iatrogenic KS occurring among organ transplant recipients, an increasing incidence of KS has been observed in patients on long-term immunosuppression for other diseases.1, 2 We report here a case of KS in a patient who had received ruxolitinib, a Janus kinase (JAK) inhibitor, for myelofibrosis (MF). We then conducted a literature review for ruxolitinib-induced KS, and second, reviewed spontaneous reports recorded in the French national pharmacovigilance database (FPVD) up to April 14, 2021. To identify articles reporting KS in patients receiving ruxolitinib, we searched the PubMed database using the equation "ruxolitinib" AND "Sarcoma, Kaposi" [MeSH]. A 71-year-old heterosexual Caucasian man, born in Italy, was hospitalized in April 2020 for deterioration of his general status. He had a history of MF that reported 7 years of biannual surveillance from diagnosis in 2009 to 2016, when the occurrence of splenomegaly justified introduction of ruxolitinib 10 mg twice a day, leading to improvement of splenomegaly over the subsequent year. In 2018, the dose of ruxolitinib was increased to 15 mg twice a day due to recurrence of splenomegaly. Physical examination at admission revealed multiple purple papular cutaneous lesions on the left leg and no oral lesions. Thoracic computed tomography scan did not show KS lesions. KSHV serology was positive, with a KSHV viral load of 2799 copies/mL (3.45 log/mL). The KSHV-strain subtype was Subtype C, C3 variant. The skin biopsy confirmed the KS diagnosis. Lymphocyte and CD4 cell counts were 100/μL and 32/μL, respectively. HIV, Hepatitis B, and Hepatitis C serologies were negative. The ruxolitinib dose was reduced to 5 mg twice daily, but the KS lesions worsened on the skin and began to appear on the patient's palate. In August 2020, the KSHV viral load rose to 12 131 copies/mL (4.08 log/mL), while the CD4 cell count decreased to 21/μL. Ruxolitinib was stopped and doxorubicin chemotherapy was initiated. Unfortunately, the patient's condition continued to deteriorate due to the extent of KS, and the patient died 2 weeks after ruxolitinib discontinuation. In addition to the case presented here, three other cases have been described in the literature since 2017 and one patient was reported in the FPVD in 2018.2-4 The main characteristics of the five patients are presented in Table 1. All were male, with a median age of 71 years (range, 56–81 years). Four of them had MF and one had essential thrombocytopenia. The KS diagnosis was based on pathology exams of skin biopsies in all patients. In one patient, non-HIV endemic KS was diagnosed 1 month before ruxolitinib initiation and followed by rapid aggravation. In the other patients, the median time from ruxolitinib initiation to KS diagnosis was 2.2 years (range, 9 months to 7 years). Three patients had a cutaneous presentation of KS, whereas two had a muco-cutaneous form at diagnosis. The CD4 cell count was only known for two patients, one at 412/μL at diagnosis and the other at 32/μL. Therapeutic management of KS led to initial ruxolitinib dose reduction before discontinuation in one case, with no improvement of KS progression, and discontinuation for all patients. The time from KS diagnosis to ruxolitinib discontinuation was available for four out of five patients (median 2.2 months; range, 2 weeks to 18 months). The two patients who had early ruxolitinib discontinuation after KS diagnosis (2 and 6 weeks) had favorable outcomes, with disappearance of the KS lesions; one with almost total regression of the lesions 10 months after ruxolitinib discontinuation and the other with complete remission 4 months after discontinuation, associated with surgical resection and intralesional vincristine.3, 4 KS-related death was observed in two patients; in one case, at 1 month after ruxolitinib discontinuation, and in the other, at 5 months after discontinuation, despite specific treatment with radiotherapy and paclitaxel. One patient died 4 months after ruxolitinib discontinuation due to cytopenia and kidney damage; no improvement in the KS lesions was observed in that patient.2 No ruxolitinib discontinuation syndrome was reported in any patient. Lesions did not improve. Died 4 months after ruxolitinib discontinuation. Death related to cytopenia and kidney damage. Ruxolitinib discontinuation. Surgical resection Intralesional vincristine. Ruxolitinib dose reduction for 3 months before total discontinuation. Doxorubicin chemotherapy. Cutaneous lesions worsened 3 months after dose reduction, appearance of lesion on the palate. Died 2 weeks after ruxolitinib discontinuation, secondary to overall deterioration related to KS. Ruxolitinib discontinuation Radiotherapy and paclitaxel. Ruxolitinib is a potent and selective JAK1 and 2 inhibitor indicated for the treatment of myeloproliferative neoplasms such as MF.2 The JAK signal transducer and activator of transcription (JAK–STAT) pathway have a central role in intracellular signaling of cytokines by regulating cell proliferation. It is critical to blood formation and immune response.2 JAK2 is associated with hematopoiesis and its activation leads to myeloproliferative syndromes, while JAK1 plays a role in proinflammatory cytokines and type I interferon production.5 Ruxolitinib is predominantly selective for JAK2, whereas other JAK inhibitors used in inflammatory diseases (e.g. filgotinib, tofacitinib, baricitinib, and upadacitinib) are preferentially selective for JAK1.5 To the best of our knowledge, this is the first review of iatrogenic KS in patients treated with ruxolitinib. Several other opportunistic infections, such as HBV reactivation, EBV-associated lymphoproliferative disorders, VZV meningo-encephalitis, CMV retinitis, multifocal progressive leukoencephalopathy, pneumocystis, and tuberculosis have previously been reported.2-4 Salivary and sexual transmissions are the major modes of KSHV transmission.1 However, KSHV could also be transmitted through transplantation of infected organs and blood transfusion, although systematic leucocyte-depletion of red blood cell units reduces the risk of transmission.1 KSHV establishes a lifelong latency in B-lymphocytes and endothelial cells.1 The occurrence of KS during ruxolitinib treatment may be due to reactivation of latent KSHV or through acquisition. Apart from one patient with a diagnosis of non-HIV endemic KS established before ruxolitinib introduction, KSHV serology status was unknown before ruxolitinib onset in the other patients. However, all patients were from regions with an intermediate to high frequency of KSHV carriers, such as Italy, North Africa, and the Okinawa region of Japan.1, 2 Among HIV patients, although KSHV diseases can occur at any CD4 cell count, the risk increases when CD4 cell count decreases.1 Treatment with ruxolitinib may also cause absolute reduced CD4 and/or CD8 cell counts.5 In this series of cases, only two patients had CD4 assessment at KS diagnosis; one had a very low CD4 cell count (32/μL), and the other had a CD4 cell count at 412/μL.3 The median time from ruxolitinib initiation to KS diagnosis was 2.2 years (range 9 months to 7 years). The impairment of natural killer (NK) cell function by ruxolitinib could also explain the increasing risk of viral infections.4 Indeed, CMV retinitis and progressive multifocal leukoencephalopathy have been described in patients treated with ruxolitinib, despite normal CD4 cell count.4 Furthermore, substantial alterations in the NK cell receptor repertoire in healthy KSHV carriers, and impaired NK-cell lytic capacity in patients with active KS have been reported.4 In addition, KSHV deploys several mechanisms to inhibit interferon synthesis, which could explain the efficacy of interferon-alpha in the treatment of AIDS-associated KS.1 Reduction or withdrawal of immunosuppressants is the first-line therapy in iatrogenic KS.1 Despite reducing the ruxolitinib dose, KS lesions progressed rapidly in one patient. Early interruption of ruxolitinib after KS diagnosis (at 2 and 6 weeks) enabled remission in two patients. In contrast, KS worsened in the other patients who had a longer time between KS diagnosis and ruxolitinib withdrawal. KS has not been described in patients treated JAK inhibitors that are preferentially selective for JAK-1, suggesting the major role of JAK2 inhibition in KS occurrence. This is consistent with in vitro studies showing that JAK2/STAT3 pathway inhibition enhances KSHV replication through reductions in pro-inflammatory cytokines IL-6 and TNF.6 Because ruxolitinib is a recent treatment that is increasingly being used for its efficiency in myeloproliferative disorders, detecting and preventing potentially harmful infectious side effects of this drug is essential. KSHV serology screening for all patients initiating ruxolitinib treatment could help to identify patients at risk of KS. In patients with positive KSHV serology, close follow-up should be performed with regular cutaneous examination, CD4 cell count, and KSHV viral load assessment. In patients with negative KSHV serology, follow-up of KSHV serology could be useful, particularly in patients with iterative blood transfusions, those living in regions with intermediate/high prevalence of KSHV, and those at higher risk of acquisition. Early interruption of ruxolitinib after KS diagnosis may facilitate spontaneous disease regression. We thank Fiona Ecarnot, PhD (EA3920, University Hospital Besancon, France) for editorial assistance. None. Violaine Noel, Quoc-Hung Le, Firouzé Bani-Sadr, Marin Moutel, and Clément Lier cared for the patients. Marin Moutel and Firouzé Bani-Sadr wrote the first manuscript draft. All authors critically reviewed the manuscript and gave final approval. Firouzé Bani-Sadr was responsible for the overall supervision of the study. The data that support the findings of this study are available from the corresponding author upon reasonable request. The data that support the findings of this study are available from the corresponding author upon reasonable request.