Ruxolitinib treatment and risk of B‐cell lymphomas in myeloproliferative neoplasms

Rumi, Elisa; Zibellini, Silvia; Boveri, Emanuela; Cavalloni, Chiara; Riboni, Roberta; Casetti, Ilaria Carola; Ciboddo, Michele; Trotti, Chiara; Favaron, Cristina; Pietra, Daniela; Candido, Chiara; Cazzola, Mario; Arcaini, Luca

doi:10.1002/ajh.25489

Cited by 29 publications

(23 citation statements)

References 6 publications

(6 reference statements)

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“…The aggressive phenotype (approximately 40% of patients in primary or secondary BP) and poor prognosis (median survival without transplant <24 months) of JAK2 fusion gene positive myeloid neoplasms can possibly only be overcome by allo SCT and bridging with ruxolitinib should be considered. During follow‐up, two patients developed a Burkitt‐like B‐cell lymphoma and an early stage Hodgkin lymphoma, respectively, which is noteworthy in the context of recent reports describing the development of high‐grade B‐cell lymphomas in ruxolitinib‐treated patients 58,59 . Analysis of the Burkitt‐like B‐cell lymphoma revealed a complex karyotype including a t(8;9)(p22;p24), a rearrangement of JAK2 by FISH analysis and a PCM1‐JAK2 fusion gene by RT‐PCR, indicating lymphoid BP of the original disease.…”

Section: Discussionmentioning

confidence: 66%

Response to tyrosine kinase inhibitors in myeloid neoplasms associated with PCM1‐JAK2, BCR‐JAK2 and ETV6‐ABL1 fusion genes

et al. 2020

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We report on 18 patients with myeloid neoplasms and associated tyrosine kinase (TK) fusion genes on treatment with the TK inhibitors (TKI) ruxolitinib (PCM1‐JAK2, n = 8; BCR‐JAK2, n = 1) and imatinib, nilotinib or dasatinib (ETV6‐ABL1, n = 9). On ruxolitinib (median 24 months, range 2‐36 months), a complete hematologic response (CHR) and complete cytogenetic response (CCR) was achieved by five of nine and two of nine patients, respectively. However, ruxolitinib was stopped in eight of nine patients because of primary resistance (n = 3), progression (n = 3) or planned allogeneic stem cell transplantation (allo SCT, n = 2). At a median of 36 months (range 4‐78 months) from diagnosis, five of nine patients are alive: four of six patients after allo SCT and one patient who remains on ruxolitinib. In ETV6‐ABL1 positive patients, a durable CHR was achieved by four of nine patients (imatinib with one of five, nilotinib with two of three, dasatinib with one of one). Because of inadequate efficacy (lack of hematological and/or cytogenetic/molecular response), six of nine patients (imatinib, n = 5; nilotinib, n = 1) were switched to nilotinib or dasatinib. At a median of 23 months (range 3‐60 months) from diagnosis, five of nine patients are in CCR or complete molecular response (nilotinib, n = 2; dasatinib, n = 2; allo SCT, n = 1) while two of nine patients have died. We conclude that (a) responses on ruxolitinib may only be transient in the majority of JAK2 fusion gene positive patients with allo SCT being an important early treatment option, and (b) nilotinib or dasatinib may be more effective than imatinib to induce durable complete remissions in ETV6‐ABL1 positive patients.

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Section: Discussionmentioning

confidence: 66%

Response to tyrosine kinase inhibitors in myeloid neoplasms associated with PCM1‐JAK2, BCR‐JAK2 and ETV6‐ABL1 fusion genes

et al. 2020

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“…Five out of 966 (0.52%) patients with ET or PV developed lymphoma, but none of them received prior JAK inhibitors ( P ns). Also, in an Italian cohort, the rate of LPN among MPN patients was low (24/3069, 0.78%) but higher than expected in the general population and was not associated with previous exposure to ruxolitinib . As none of those patients showed B‐cell clonality on peripheral blood before ruxolitinib treatment, we suggest that in the absence of B‐cell clones, ruxolitinib treatment may be considered reasonably safe and can be initiated with close monitoring .…”

Section: Is There a Role For Cytoreductive Drugs For The Concomitant mentioning

confidence: 63%

“…Also, in an Italian cohort, the rate of LPN among MPN patients was low (24/3069, 0.78%) but higher than expected in the general population and was not associated with previous exposure to ruxolitinib. 77 As none of those patients showed B-cell clonality on peripheral blood before ruxolitinib treatment, 77 we suggest that in the absence of B-cell clones, ruxolitinib treatment may be considered reasonably safe and can be initiated with close monitoring. 78 In this regard, the best way to screen for a B-cell clone (either flow cytometry or polymerase chain reaction for detection of immunoglobulin gene rearrangements) or the most informative sample (bone marrow and/or peripheral blood) is still debated.…”

Section: Is There a Role For Cytoreductive Drugs For The Concomitanmentioning

confidence: 83%

Myeloproliferative and lymphoproliferative disorders: State of the art

Rumi

Baratè

Benevolo

et al. 2019

Hematological Oncology

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Myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are clonal disorders complicated mainly by vascular events and transformation to myelofibrosis (for PV and ET) or leukemia. Although secondary malignancies, in particular, lymphoproliferative disorders (LPNs), are rare, they occur at a higher frequency than found in the general population, and there has been recent scientific discussion regarding a hypothetical relationship between treatment with JAK inhibitors in MPN and the risk of development of LPN. This has prompted increased interest regarding the coexistence of MPN and LPN. This review focuses on the role of JAK2 and the JAK/STAT pathway in MPN and LPN, whether there is a role for the genetic background in the occurrence of both MPN and LPN and whether there is a role for cytoreductive drugs in the occurrence of both MPN and LPN. Furthermore, whether an increased risk of lymphoma development is limited to patients who receive the JAK inhibitor ruxolitinib, is a more general phenomenon that occurs following JAK1/2 inhibition or is associated with preferential JAK1 or JAK2 targeting is discussed.

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“…A recent publication raised considerable concern regarding the possibly increased risk of developing aggressive lymphoproliferative disorders in MPN patients treated with JAK inhibitors, especially in the presence of a pre-existing B-cell clone 73. Subsequent analyses of large academic datasets did however not confirm such data 74,75. A nested case–control study including 37 ruxolitinib-treated MF patients experiencing a second cancer, revealed an increased risk of developing a non-melanoma skin cancer with respect to ruxolitinib-naive patients, without however disclosing an increased risk of developing a lymphoid neoplasm 76…”

Section: Management Of Splenomegaly and Constitutional Symptomsmentioning

confidence: 99%

Standard care and investigational drugs in the treatment of myelofibrosis

Barraco¹,

Maffioli²,

Passamonti³

2019

DIC

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Myelofibrosis (MF) is a heterogeneous disorder characterized by splenomegaly, constitutional symptoms, ineffective hematopoiesis, and an increased risk of leukemic transformation. The ongoing research in understanding the pathophysiology of the disease has allowed for the development of targeted drugs optimizing patient management. Furthermore, disease prognostication has significantly improved. Current therapeutic interventions are only partially effective with only allogeneic stem cell transplant potentially curative. Ruxolitinib is the only approved therapy for MF by the US Food and Drug Administration. However, despite efficacy in reducing splenomegaly and controlling symptomatology, it is not associated with consistent molecular or pathologic responses. Drug discontinuation is associated with a dismal outcome. The therapeutic landscape in MF has significantly improved, and emerging drugs with different target pathways, alone or in combination with ruxolitinib, seem promising.

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Ruxolitinib treatment and risk of B‐cell lymphomas in myeloproliferative neoplasms

Cited by 29 publications

References 6 publications

Response to tyrosine kinase inhibitors in myeloid neoplasms associated with PCM1‐JAK2, BCR‐JAK2 and ETV6‐ABL1 fusion genes

Response to tyrosine kinase inhibitors in myeloid neoplasms associated with PCM1‐JAK2, BCR‐JAK2 and ETV6‐ABL1 fusion genes

Myeloproliferative and lymphoproliferative disorders: State of the art

Standard care and investigational drugs in the treatment of myelofibrosis

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