Clearance of the Janus kinase 2 (JAK2) V617F mutation after allogeneic stem cell transplantation in a patient with myelofibrosis with myeloid metaplasia

2007 ◽  
Vol 82 (5) ◽  
pp. 400-402 ◽  
Author(s):  
Guillermo J. Ruiz-Argüelles ◽  
Javier Garcés-Eisele ◽  
Virginia Reyes-Núñez ◽  
Guillermo J. Ruiz-Delgado ◽  
Carlos Rosillo ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Jak2 V617f ◽  
Janus Kinase ◽  
Jak2 V617f Mutation ◽  
Janus Kinase 2 ◽  
Myeloid Metaplasia ◽  
Myelofibrosis With Myeloid Metaplasia

Long-Term Survival of Patients with Myelofibrosis Treated with Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2704-2704
Author(s):  
Michele L. Donato ◽  
Andrew L. Pecora ◽  
STuart L. Goldberg ◽  
Jack W. Hsu ◽  
David S. Siegel ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Term Survival ◽  
Hematopoietic Stem ◽  
Myeloid Metaplasia ◽  
Myelofibrosis With Myeloid Metaplasia ◽  
Reduced Intensity

Myelofibrosis with myeloid metaplasia (MMM) is a disorder characterized by clonal myeloproliferation, ineffective erythropoiesis, extramedullary hematopoiesis and bone marrow fibrosis. Between 4/1998 and 1/2006, 17 patients with MMM were treated with allogeneic hematopoietic stem cell transplantation. Patients included 8 males and 9 females with a median age of 51.8 years (range 37–66). All patients were transfusion-dependent at the time of transplantation, 3 (18%) had abnormal cytogenetics and 4 (24%) had a prior splenectomy. Six patients (35%) received a reduced intensity conditioning regimen consisting of either fludarabine and busulfan (1 pt), fludarabine and low dose total body irradiation (1 pt), fludarabine and melphalan (3 pts) or fludarabine and cyclophosphamide (1 pt). Eleven patients (65%) received an ablative regimen of either busulfan and cyclophosphamide (10 pts) or cyclophosphamide and total body irradiation (1 pt). Patients with unrelated donors also received ATG as part of their conditioning. The hematopoietic cell source was peripheral blood in 12 pts (71%) and bone marrow in 5 pts (29%). Six pts (35%) received cells from an HLA-identical sibling, 1 pt (6%) had a 1 Antigen mismatch sibling and 10 pts (59%) received stem cells from an unrelated donor. Graft-versus-host disease prophylaxis consisted of tacrolimus in 15 pts (88%) and cyclosporine in 2 pts (12%). Transplant-related mortality was 17% (sepsis 1 pt, VOD 1 pt, acute GVHD 1 pt) all occurring in the group treated with a myeloablative regimen. Of the remaining 14 patients, all achieved hematological recovery and transfusion independence. There were 2 relapses and one patient died of disease recurrence; both relapses occurred in the group receiving a reduced intensity regimen. The other 12 patients remain alive and in remission. The 6-year actuarial survival is 67% with no statistical difference between the groups who received a reduced intensity versus a myeloablative regimen. In conclusion, Myelofibrosis with Myeloid Metaplasia can be successfully treated with allogeneic hematopoietic stem cell transplantation with a significant proportion of patients achieving long-term survival. Hematopoietic recovery can be achieved despite the presence of marrow fibrosis. The optimal preparative regimen remains to be determined with more relapses observed in the reduced intensity regimen group and a higher mortality seen in the myeloablative group. A risk-stratification strategy for regimen selection should be considered in future studies.

Rapid Regression of Bone Marrow Fibrosis after Dose-Reduced Allogeneic Stem Cell Transplantation in Patients with Myelofibrosis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 374-374
Author(s):  
Nicolaus Kroeger ◽  
Juergen Thiele ◽  
Axel Zander ◽  
Michael Kvasnicka
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Growth Factor ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Bone Marrow Fibrosis ◽  
Myeloid Metaplasia ◽  
Bone Marrow Histology ◽  
Marrow Fibrosis

Abstract Myelofibrosis with myeloid metaplasia [MMM] is a myeloproliferative disease of which bone marrow histology is characterized by substantial collagen fibrosis and osteosclerosis. Bone marrow histology changes in MMM are reactive and cytokine mediated. Studies suggested a pathogenic role of transforming growth factor β [TGF-β], platelet derived growth factor, and basic fibroblast growth factor. In the current study we investigated the dynamic and kinetic of fibrosis regression in 18 patients with myelofibrosis who underwent allogeneic stem cell transplantation after a dose-reduced conditioning. The conditioning regimen consisted of Busulfan 10 mg/kg, Fludarabin 180 mg/m2, and Antithymocyte globulin 30 – 60 mg/kg followed by peripheral stem cell transplantation (SCT). 18 patients with a median age of 45 [range 35 to 64] were included and bone marrow histology was investigated prior SCT, between day+30 and +40 after engraftment, on day+100, and 1 year after stem cell transplantation. The grading of myelofibrosis [MF] was performed according to the recently published European Consensus on Grading Bone Marrow Fibrosis [Thiele et al., Haematologica2005;90:1125–1132]. This consensus distinguishes between: MF - 0 Scattered linear reticulin with no intersections [cross-overs] corresponding to normal bone marrow MF - 1 Loose network of reticulin with many intersections, especially in perivascular areas MF - 2 Diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis MF - 3 Diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis At time of transplantation all patients suffered from advanced myelofibrosis 2° [39 %] or 3° [61 %], resulting in a median MF grade of 3 [range 2–3]. After engraftment on day+30 a regression of MF grade to a median of 2 [range 0–3] was observed. Grade 2 or less was observed in 80 % and grade 1 or 0 in 40 % of the patients. On day+100 the median grade of MF was 1 [range 0–3] and 93 % of the patients had an MF-grade of 2 or less, while 73 % of the patients had MF grade-1 or 0. One year after transplantation the median MF-grade was 0 [range 0–2] and 100 % of the patients had a MF-grade of 2 or less and 92 % of the patients had MF grade 1 or 0. We conclude that allogeneic stem cell transplantation after a dose-reduced conditioning induces a rapid and nearly complete regression of bone marrow fibrosis within the first year after transplantation.

Allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning in intermediate- or high-risk patients with myelofibrosis with myeloid metaplasia

Blood ◽  
2005 ◽  
Vol 105 (10) ◽  
pp. 4115-4119 ◽  
Author(s):  
Damiano Rondelli ◽  
Giovanni Barosi ◽  
Andrea Bacigalupo ◽  
Josef T. Prchal ◽  
Uday Popat ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Chronic Gvhd ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Myeloid Metaplasia ◽  
Myelofibrosis With Myeloid Metaplasia ◽  
Reduced Intensity

AbstractA total of 21 patients with myelofibrosis with myeloid metaplasia (MMM), with a median age of 54 years (range, 27-68 years), were prepared with a reduced-intensity conditioning (RIC) regimen. The patients received an allogeneic marrow (n = 3) or peripheral blood stem-cell (n = 18) transplant from HLA-matched related (n = 18) or unrelated (n = 2), or 1 Ag-mismatched related (n = 1), donors. RIC regimens included fludarabine/total body irradiation 200 cGy (n = 5) or 450 cGy (n = 1), fludarabine/melphalan (n = 7), thiotepa/cyclophosphamide (n = 7), and thiotepa/fludarabine (n = 1). At the time of transplantation, all of the patients were at intermediate (n = 13) or high (n = 8) risk, according to the Dupriez classification. Of the patients, 19 had grade III or IV marrow fibrosis. All of the patients achieved full engraftment but one. Posttransplantation chimerism analysis showed more than 95% donor cells in 18 patients, while 2 patients achieved complete donor chimerism after donor leukocyte infusion (DLI). Acute graft-versus-host disease (GVHD) grades II to IV was observed in 7 patients, grades III to IV in 2, and extensive chronic GVHD in 8 of 18 evaluable patients. There were 3 patients who died from acute GVHD, infection, and relapse. There are 18 patients alive 12 to 122 months (median, 31 months) after transplantation, and 17 are in remission (1 after a second transplantation). The use of RIC regimens in allogeneic stem cell transplantation results in prolonged survival in intermediate/high-risk MMM patients.

Monitoring of the JAK2-V617F mutation by highly sensitive quantitative real-time PCR after allogeneic stem cell transplantation in patients with myelofibrosis

Blood ◽  
2006 ◽  
Vol 109 (3) ◽  
pp. 1316-1321 ◽  
Author(s):  
Nicolaus Kröger ◽  
Anita Badbaran ◽  
Ernst Holler ◽  
Joachim Hahn ◽  
Guido Kobbe ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Real Time ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Real Time Pcr ◽  
Residual Disease ◽  
Jak2 V617f ◽  
Highly Sensitive

Abstract The JAK2-V617F mutation occurs in about 50% of patients with myelofibrosis and might be a reliable marker to monitor residual disease after allogeneic stem cell transplantation. We describe a new, highly sensitive (≥ 0.01%) real-time polymerase chain reaction (PCR) to monitor and quantify V617F-JAK2–positive cells after dose-reduced allogeneic stem cell transplantation. After 22 allogeneic stem cell transplantation procedures in 21 JAK2-positive patients with myelofibrosis, 78% became PCR negative. In 15 of 17 patients (88%), JAK2 remained negative after a median follow-up of 20 months. JAK2 negativity was achieved after a median of 89 days after allograft (range, 19-750 days). A significant inverse correlation was seen for JAK2 positivity and donor-cell chimerism (r: −0.91, P < .001). Four of 5 patients who never achieved JAK2 negativity fulfilled during the entire follow-up all criteria for complete remission recently proposed by the International Working Group, suggesting a major role for JAK2 measurement to determine depths of remission. In one case, residual JAK2-positive cells were successfully eliminated by donor lymphocyte infusion. In conclusion, allogeneic stem cell transplantation after dose-reduced conditioning induces high rates of molecular remission in JAK2-positive patients with myelofibrosis, and quantification of V617F-JAK2 mutation by real-time PCR allows the detection of minimal residual disease to guide adoptive immunotherapy.

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