Second allogeneic hematopoietic stem cell transplantation (HSCT) results in outcome similar to that of first HSCT for patients with juvenile myelomonocytic leukemia

Yoshimi, Ayami; Mohamed, Maher; Bierings, Marc; Urban, Ch.; Korthof, Elisabeth T.; Zecca, Marco; Sykora, Karl‐Walter; Duffner, Ulrich; Trebo, Monika; Matthes‐Martin, Susanne; Sedláček, Petr; Klingebiel, Thomas; Lang, Peter; Führer, Monika; Claviez, Alexander; Wössmann, W.; Pession, Andrea; Arvidson, Johan; O'Marcaigh, Aengus; Heuvel‐Eibrink, Marry M. van den; Starý, Jan; Hasle, Henrik; Nöllke, Peter; Locatelli, Franco; Niemeyer, Charlotte M.

doi:10.1038/sj.leu.2404537

Cited by 47 publications

(50 citation statements)

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“…With respect to patients at relapse of MF after a first allo-SCT, this series suggests that a second allo-SCT is a promising approach, as 3 of 5 patients achieved stable remission with a combination of treosulfan and fludarabine. Also in other subentities such as JMML, Yoshimi et al [27] observed comparable results of a second allo-SCT in the case of relapse in comparison with those for first allo-SCT regarding relapse risk and TRM. Of course, favorable outcomes and stable remissions might be more frequent in pediatric patients after a second allo-SCT when compared with adults [7,20,26].…”

Section: Discussionmentioning

confidence: 92%

Second Allogeneic Stem Cell Transplantation in Myeloid Malignancies

et al. 2009

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For patients with myeloid malignancies who relapse after allogeneic stem cell transplantation (allo-SCT), one salvage option is a second SCT. We retrospectively analyzed outcomes of the second allo-SCT in 25 patients who received at least 2 allografts from related/unrelated donors due to relapse of acute myeloid leukemia, myelodysplastic syndrome or myelofibrosis after the first SCT. A minority of the acute myeloid leukemia/myelodysplastic syndrome patients had reached complete hematological remission before the second SCT (6/25, 24%). Reduced conditioning strategies were performed in the majority (n = 23). Complete remission was achieved in all 21 cases with available data after the second SCT, but relapse was seen in 11/25 patients (44%). After a median follow-up of 18 months (range 6–47), 8/25 patients (32%) were still alive, and of those, 6 (24%) were in stable remission. In 9 cases mortality was associated to relapse and in 8 cases to transplant-related causes (treatment-related mortality; 8/25, 32%). In conclusion, a second SCT offers the chance of stable remission for some patients relapsing with a myeloid malignancy after a first allo-SCT, although high treatment-related mortality and relapse rates remain a problem. Efforts should concentrate on an optimization of conditioning strategies, immunosuppression and post-transplant surveillance for this specific situation.

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Section: Discussionmentioning

confidence: 92%

Second Allogeneic Stem Cell Transplantation in Myeloid Malignancies

et al. 2009

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“…71,77,80 The biological/ immunologic reasons why JMML recurrence has limited sensitivity to DLI remain obscure. 72,79 Because a second HSCT can be an effective salvage therapy for children with JMML who relapse after a first grafting procedure, 71,77,80 we believe that children with JMML should not receive DLI but are to be given a second transplant as soon as possible, especially if they have already discontinued GVHD prophylaxis.…”

Section: How We Manage Children With Disease Recurrence After An Allomentioning

confidence: 99%

How I treat juvenile myelomonocytic leukemia

Locatelli

Niemeyer

2015

Blood

206

251

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Juvenile myelomonocytic leukemia (JMML) is a unique, aggressive hematopoietic disorder of infancy/early childhood caused by excessive proliferation of cells of monocytic and granulocytic lineages. Approximately 90% of patients carry either somatic or germline mutations of PTPN-11, K-RAS, N-RAS, CBL, or NF1 in their leukemic cells. These genetic aberrations are largely mutually exclusive and activate the Ras/mitogen-activated protein kinase pathway. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the therapy of choice for most patients with JMML, curing more than 50% of affected children. We recommend that this option be promptly offered to any child with PTPN-11-, K-RAS-, or NF1-mutated JMML and to the majority of those with N-RAS mutations. Because children with CBL mutations and few of those with N-RAS mutations may have spontaneous resolution of hematologic abnormalities, the decision to proceed to transplantation in these patients must be weighed carefully. Disease recurrence remains the main cause of treatment failure after HSCT. A second allograft is recommended if overt JMML relapse occurs after transplantation. Recently, azacytidine, a hypomethylating agent, was reported to induce hematologic/molecular remissions in some children with JMML, and its role in both reducing leukemia burden before HSCT and in nontransplant settings requires further studies.

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“…123 The principal cause for failure is relapse, which approaches 50%, though 50% of these patients can be rescued with a second allograft. 124,125 It has been speculated that the high relapse rate might be related to an underlying fundamental immune defect or incomplete eradication of resistant disease prior to myeloablation. Strategies to rescue children post relapse remain suboptimal, with limited success of donor lymphocyte infusions (DLI).…”

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confidence: 99%

An International MDS/MPN Working Group's perspective and recommendations on molecular pathogenesis, diagnosis and clinical characterization of myelodysplastic/myeloproliferative neoplasms

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o n MDS/MPN: cytogenetic, molecular genetics and signaling abnormalitiesChromosome analysis using conventional cytogenetics and high-resolution single nucleotide polymorphism array karyotyping (SNP-A) reveals chromosome abnormalities in 70% of MDS/MPN patients. 7 Most of these are aneuploidies (trisomy 8, monosomy 7) or deletions (del7q, del13q, del20q); a minority have reciprocal translocations involving diverse tyrosine kinase (TK) fusion genes. 8,9 Some of these fusions are listed separately within the current WHO classification: 'myeloid and lymphoid neoplasms with eosinophilia' (MLN-eo) and abnormalities of PDGFRA, PDGFRB and FGFR1. Fusions involving other kinases are also seen in patients with MDS/MPN or MPNs. 10 Fusions involving PDGFRA, PDGFRB and ABL1 are important to recognize as they confer sensitivity to TK inhibitors (TKIs), such as imatinib. 11 Other fusions involving FGFR1 or JAK2 are insensitive to imatinib but may respond to ponatinib or ruxolitinib, respectively. [12][13][14][15][16] Most mutant genes fall into four functional classes: signaling, epigenetic, splicing and transcription ( Figure 2). [17][18][19][20] Signaling mutations result in aberrant activation of proliferative and anti-apoptotic pathways normally induced by growth factors (GFs). In addition to the TK gene fusions mentioned above, mutations have been described in GF receptors (CSF3R), downstream cytokine receptor signaling intermediates (JAK2, NRAS, KRAS) and negative regulators of signaling pathways (PTPN11, CBL, NF1). [21][22][23][24][25][26][27] Mutations involving RAS are demonstrable in 90% of JMML cases and may emerge as a defining feature of this condition. 28 Signaling mutations occur in approximately 50% of CMML patients and correlate with a myeloproliferative phenotype and enhancement of in vitro sensitivity to GM-CSF. 29 Up to 80% of patients with RARS-T have activated JAK-STAT signaling as a consequence of the presence of JAK2 V617F or mutations in MPL [encoding for the thrombopoietin receptor (Tpo-R)]. 30 In mice, abrogation of Notch signaling leads to a MDS/MPN phenotype, but its relevance in humans is unknown. 31 MDS/MPN: nuclear events -epigenetics, spliceosomes and transcription factorsMutations in genes encoding epigenetic regulators are common in MDS/MPN. [32][33][34][35] The most frequently mutated genes are TET2 and ASXL1, followed by SRSF2, IDH1/2, EZH2, SUZ12, EED and UTX. 36 The interaction between epigenetic mutations is complex, and apart from the general mutual exclusivity of TET2 and IDH1/2 mutations, no clear patterns have emerged. 37,38 Mutations in elements involved in the recognition and processing of 3'-mRNA splice sites are also common in MDS/MPN. 39 Around 50% of CMML patients have mutations involving SRSF2, with a further 20% exhibiting mutations in other splicing complex genes (SF3B1, U2AF35, U2AF65 and SF3A1). 34,35,40,41 In addition, SF3B1 mutations are present in 72% of patients with RARS-T. 42,43 These SF3B1 mutations are...

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Second allogeneic hematopoietic stem cell transplantation (HSCT) results in outcome similar to that of first HSCT for patients with juvenile myelomonocytic leukemia

Cited by 47 publications

References 8 publications

Second Allogeneic Stem Cell Transplantation in Myeloid Malignancies

Second Allogeneic Stem Cell Transplantation in Myeloid Malignancies

How I treat juvenile myelomonocytic leukemia

An International MDS/MPN Working Group's perspective and recommendations on molecular pathogenesis, diagnosis and clinical characterization of myelodysplastic/myeloproliferative neoplasms

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