Usefulness of Low-Dose Splenic Irradiation prior to Reduced-Intensity Conditioning Regimen for Hematopoietic Stem Cell Transplantation in Elderly Patients with Myelofibrosis

The Janus kinase (JAK) 1 and 2 inhibitor, ruxolitinib, was recently approved in Japan and has been effective in many patients with myelofibrosis (MF). Although the inhibitor decreases splenomegaly and relieves MF-related symptoms, allogeneic hematopoietic cell transplantation (HCT) remains as the only curative therapy for MF. The presence of splenomegaly has been reported as a risk factor for graft failure, delayed engraftment, and poor survival. Here, we report two elderly MF patients with massive splenomegaly and a JAK2 V617F mutation. These patients underwent splenic irradiation to decrease splenomegaly prior to HCT with a reduced-intensity conditioning (RIC) regimen. Massive splenomegaly gradually decreased by 4 Gy splenic irradiation. The subsequent RIC regimen involved 4 Gy total body irradiation and fludarabine and intravenous busulfan. In both patients, engraftment failure did not occur, and complete remission was achieved. The splenomegaly decreased, and MF-related symptoms were resolved. Furthermore, the JAK2 V617F mutation disappeared, and fibrosis in the bone marrow regressed. We suggest that splenic irradiation prior to the RIC regimen for HCT in elderly MF patients with massive splenomegaly is safe. Furthermore, the HCT protocols with splenic irradiation should be considered for patients who have not shown clinical benefits to optimal medical management such as treatment with ruxolitinib.

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Splenic Irradiation as a Component of a Reduced-Intensity Conditioning Regimen for Hematopoietic Stem Cell Transplantation in Myelofibrosis with Massive Splenomegaly

The Tohoku Journal of Experimental Medicine ◽

10.1620/tjem.228.295 ◽

2012 ◽

Vol 228 (4) ◽

pp. 295-299 ◽

Cited By ~ 11

Author(s):

Takeshi Ito ◽

Kentaro Akagi ◽

Tadakazu Kondo ◽

Hiroshi Kawabata ◽

Tatsuo Ichinohe ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Conditioning Regimen ◽

Reduced Intensity Conditioning ◽

Massive Splenomegaly ◽

Hematopoietic Stem ◽

Splenic Irradiation ◽

Reduced Intensity Conditioning Regimen ◽

Reduced Intensity

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WP1066 Inhibits Growth of Human Cells Carrying the JAK2 V617F Mutation.

Blood ◽

10.1182/blood.v108.11.4885.4885 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4885-4885

Author(s):

Taghi Manshouri ◽

Zeev Estrov ◽

Alfonso Quintas-Cardama ◽

Jorge Cortes ◽

Francis Giles ◽

...

Keyword(s):

Cell Line ◽

Anticancer Agents ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Jak2 V617f ◽

Janus Kinase ◽

Jak2 V617f Mutation ◽

Dependent Manner ◽

Hematopoietic Stem ◽

V617f Mutation

Abstract Myeloproliferative disorders (MPDs) are characterized by proliferation of one or more myeloid cell lineages in bone marrow and peripheral blood, with relatively preserved differentiation. Recent discovery of a dominant gain-of-function mutation in the Janus kinase 2 (JAK2) gene in patients with MPDs, involving the substitution of valine for phenylalanine at position 617 of the JAK2 protein (JAK2 V617F), represents the first acquired somatic mutation in hematopoietic stem cells described in these disorders. This discovery has opened new avenues for the development of targeted therapies for MPDs. WP1066 is a small molecule, a member of a novel class of anticancer agents whose development was based upon the backbone of AG490, a tyrphostin with activity against JAK2 V617F-expressing cell lines but limited in vivo activity. We investigated the inhibitory activity of the WP1066 against the JAK2 V617F-mutant expressing erythroid leukemia HEL cell line and peripheral blood mononuclear cells from patients with polycythemia vera (PV). WP1066 significantly inhibited the phosphorylation of JAK2 and downstream signal transduction proteins STAT3, STAT5, and ERK1/2 in a dose- and time-dependent manner. It induced a time- and dose-dependent antiproliferative and pro-apoptotic effects (activation of caspase 3, release of cytochrome c, and cleavage of PARP) in the JAK2 V617F-bearing HEL cell line in the low micromolar range. Pretreatment of cells with pan-caspase inhibitor Z-VAD abolished WP1066-induced apoptosis. The expression of apoptosis related proteins bcl-2, bax, and XIAP, however, was not changed. More important, WP1066 was effective in inhibiting cell growth in clonogenic assays of mononuclear cells harboring the JAK2 V617F mutation obtained from peripheral blood of patients with PV. We conclude that WP1066 is active both in vitro and ex vivo against cells carrying the JAK2 V617F mutation and represents a solid candidate for the treatment of JAK2 V617V-expressing MPDs.

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