Reduced-Intensity Conditioning Followed by Allogeneic Hematopoietic Stem Cell Transplantation in Myelofibrosis

Alchalby, Haefaa

doi:10.1007/s11899-010-0044-z

Cited by 11 publications

(8 citation statements)

References 48 publications

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“…Under 45 to 50 years of age, I use myeloablative regimens with targeted busulfan and cyclophosphamide, 77 whereas in older patients, I use reducedintensity conditioning with fludarabine and busulfan. 78 In case of massive splenomegaly, I no longer perform splenectomy before transplantation; instead, I currently give JAK inhibitors to reduce tumor burden and to improve the general status. [79][80][81] In good candidates for allo-SCT who improve under JAK inhibitors, I take advantage to proceed to transplantation in better general conditions and I do not postpone the procedure until response is lost, because this could jeopardize the success of transplantation.…”

Section: How I Decide On Transplantationmentioning

confidence: 99%

How I treat myelofibrosis

Cervantes

2014

Blood

145

118

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Myelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasm characterized by clonal myeloproliferation, dysregulated kinase signaling, and release of abnormal cytokines. In recent years, important progress has been made in the knowledge of the molecular biology and the prognostic assessment of MF. Conventional treatment has limited impact on the patients' survival; it includes a wait-and-see approach for asymptomatic patients, erythropoiesis-stimulating agents, androgens, or immunomodulatory agents for anemia, cytoreductive drugs such as hydroxyurea for the splenomegaly and constitutional symptoms, and splenectomy or radiotherapy in selected patients. The discovery of the Janus kinase (JAK)2 mutation triggered the development of molecular targeted therapy of MF. The JAK inhibitors are effective in both JAK2-positive and JAK2-negative MF; one of them, ruxolitinib, is the current best available therapy for MF splenomegaly and constitutional symptoms. However, although ruxolitinib has changed the therapeutic scenario of MF, there is no clear indication of a disease-modifying effect. Allogeneic stem cell transplantation remains the only curative therapy of MF, but due to its associated morbidity and mortality, it is usually restricted to eligible high- and intermediate-2-risk MF patients. To improve current therapeutic results, the combination of JAK inhibitors with other agents is currently being tested, and newer drugs are being investigated.

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Section: How I Decide On Transplantationmentioning

confidence: 99%

How I treat myelofibrosis

Cervantes

2014

Blood

145

118

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“…90 I will use ruxolitinib in all post-PV MF patients with splenomegaly and/or with diseaserelated symptoms, except in younger patients candidates to allogeneic hematopoietic stem cell transplantation. [92][93][94][95][96][97] AML post-PV is an aggressive phase of the disease, which is not curable in the majority of patients. 98 Experimental therapies should be considered.…”

Section: Pruritusmentioning

confidence: 99%

How I treat polycythemia vera

Passamonti

2012

Blood

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Polycythemia vera (PV) is a clonal disorder characterized by unwarranted production of red blood cells. In the majority of cases, PV is driven by oncogenic mutations that constitutively activate the JAK-STAT signal transduction pathway, such as JAK2 V617F, or exon 12 mutations or LNK mutations. Diagnosis of PV is based on the WHO criteria. Diagnosis of post-PV myelofibrosis is established according to the International Working Group for Myeloproliferative Neoplasms Research and Treatment criteria. Different clinical presentations of PV are discussed. Prognostication of PV is tailored to the most frequent complication during follow-up, namely, thrombosis. Age older than 60 years and prior history of thrombosis are the 2 main risk factors for disease stratification. Correlations are emerging between leukocytosis, JAK2(V617F) mutation, BM fibrosis, and different outcomes of PV, which need to be confirmed in prospective studies. In my practice, hydroxyurea is still the "gold standard" when cytoreduction is needed, even though pegylated IFN-alfa-2a and ruxolitinib might be useful in particular settings. Results of phase 1 or 2 studies concerning these latter agents should however be confirmed by the ongoing randomized phase 3 clinical trials. In this paper, I discuss the main problems encountered in daily clinical practice with PV patients regarding diagnosis, prognostication, and therapy. (Blood. 2012;120(2):275-284) IntroductionPolycythemia vera (PV) is a myeloproliferative neoplasm (MPN). 1 The abnormal myeloproliferation of PV is sustained by a constitutively active JAK-STAT signal transduction pathway, caused by the unique V617F mutation within exon 14 (ϳ 95% of PV) 2-5 and by different mutations within exon 12 (ϳ 4% of PV) of the JAK2 gene. 6,7 With lower prevalence, loss of negative regulation of JAK activation caused by LNK mutations (hot spot between codons 208 and 234), 8 or by SOCS mutations 9 or hypermethylation of CpG islands in SOCS1 and SOCS3, 10 have been implicated in PV pathogenesis. The current view suggests that several other cooperating genetic hits might be required. Among others, mutations involving EZH2 11 or TET2, 12 possibly interfering with epigenetic regulatory mechanisms, have been found in approximately 3% and in approximately 16% of JAK2(V617F)-positive PV, respectively.The course of PV is mainly dominated by thrombosis, with an incidence estimated at 18 ϫ 1000 person-years and accounting for 45% of all deaths, but also evolution to myelofibrosis (post-PV MF) and to acute myeloid leukemia (AML), both occurring with an incidence of 5 ϫ 1000 person-years and accounting for 13% of deaths, 13 highlighting the genetic complexity of AML after PV.In this manuscript, I discuss my approach to patients with PV with a focus on specific issues encountered in daily practice regarding diagnosis, prognosis, and treatment. DiagnosisThe median age at presentation is in the sixth decade; patients younger than 50 years of age account for one-third of PV patients. 23 Clinical presentation of PV may be rec...

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“…34–38 RIC and NMA HCTs are generally better tolerated with lower rates of toxicity and NRM than occur with MAC HCTs. 37,39–41 …”

Section: Advantages Of Ric and Nma Regimensmentioning

confidence: 99%

Pushing the envelope—nonmyeloablative and reduced intensity preparative regimens for allogeneic hematopoietic transplantation

Pingali

Champlin

2015

Bone Marrow Transplant

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Allogeneic hematopoietic cell transplantation (HCT) was originally developed to allow delivery of myeloablative doses of chemotherapy and radiotherapy. With better understanding of disease pathophysiology, the graft vs malignancy (GVM) effect of allogeneic hematopoietic transplantation and toxicities associated with myeloablative conditioning (MAC) regimens, the focus shifted to developing less toxic conditioning regimens to reduce treatment-related morbidity without compromising survival. Although HCT with MAC is preferred to reduced intensity conditioning (RIC) for most patients ≤ 60 years with AML/myelodysplastic syndrome and ALL, RIC and nonmyeloablative (NMA) regimens allow HCT for many otherwise ineligible patients. Reduced intensity preparative regimens have produced high rates of PFS for diagnoses, which are highly sensitive to GVM. Relapse of the malignancy is the major cause of treatment failure with RIC/NMA HCT. Incorporation of novel agents like bortezomib or lenalidomide, addition of cellular immunotherapy and use of targeted radiation therapies could further improve outcome. In this review, we discuss commonly used RIC/NMA regimens and promising novel regimens.

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Reduced-Intensity Conditioning Followed by Allogeneic Hematopoietic Stem Cell Transplantation in Myelofibrosis

Cited by 11 publications

References 48 publications

How I treat myelofibrosis

How I treat myelofibrosis

How I treat polycythemia vera

Pushing the envelope—nonmyeloablative and reduced intensity preparative regimens for allogeneic hematopoietic transplantation

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