scholarly journals A Case of Myeloproliferative Neoplasm with BCR-FGFR1 Rearrangement: Favorable Outcome after Haploidentical Allogeneic Transplantation

2018 ◽  
Vol 2018 ◽  
pp. 1-4 ◽  
Author(s):  
Paola Villafuerte-Gutiérrez ◽  
Montserrat López Rubio ◽  
Pilar Herrera ◽  
Eva Arranz
Keyword(s):  
Kinase Inhibitors ◽  
Fusion Gene ◽  
Myeloproliferative Neoplasms ◽  
Therapeutic Option ◽  
Myeloproliferative Neoplasm ◽  
Allogeneic Transplantation ◽  
Term Survival ◽  
Hematopoietic Stem ◽  
Health Organization

Hematopoietic myeloproliferative neoplasms with FGFR1 rearrangement result in the 8p11 myeloproliferative syndrome that in the current Word Health Organization classification is designated as “myeloid and lymphoid neoplasm with FGFR1 abnormalities.” We report the case of a 66-year-old man who had clinical features that resembled chronic myeloid leukaemia (CML), but bone marrow cytogenetic and fluorescent in situ hybridization (FISH) studies showed t(8;22)(p11;q11) and BCR-FGFR1 fusion gene. He was initially managed with hydroxyurea, and given the aggressive nature of this disease, four months later, the patient underwent an allogeneic hematopoietic stem-cell transplantation (HSCT) from an HLA-haploidentical relative. Currently, HSCT may be the only therapeutic option for long-term survival at least until more efficacious tyrosine kinase inhibitors (TKIs) become available.

A Retrospective Analysis of Myeloproliferative Neoplasms: Treatment Approach and Outcomes at Drexel University Hospital

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5190-5190
Author(s):  
Sukhdeep Kaur ◽  
Hareesha Chakunta ◽  
Courtney Ackerman ◽  
Kristine Ward ◽  
Maneesh Jain ◽  
...  
Keyword(s):  
Median Survival ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasms ◽  
Leukemic Transformation ◽  
Term Survival ◽  
Hematopoietic Stem ◽  
Myeloid Metaplasia ◽  
Drexel University ◽  
Number Of Patients

Abstract BACKGROUND Myeloproliferative neoplasms (MPN) are a group of clonal disorders that arise from a transformation in a hematopoietic stem cell. These disorders consist of chronic myeloid leukemia (CML), essential thrombocytosis (ET), primary myelofibrosis (PMF) and polycythemia vera (PCV). Several therapeutic agents have been used in the past to treat these disorders. Treatment strategies for these patients must consider the possibility of long-term survival, morbidity from thrombotic complications, transformation into myelofibrosis with myeloid metaplasia or acute myeloid leukemia, and the effect of specific therapies on the incidence of leukemic transformation and on pregnancy. At Drexel University, a significant number of patients were treated with busulfan and were thought to have a more favorable clinical course and increased survival in comparison to other agents. Due to the perceived side effects associated with busulfan, the current preferred cytoreductive agent is hydroxyurea. In our study we analyzed the outcomes of patients treated in the practice of I. Brodsky Associates diagnosed with ET, PCV and PMF, who received a variety of treatment modalities, and compared their clinical courses to determine if there is a superior treatment. METHODS This study is a retrospective cohort study in which we have examined the medical records of patients treated for the diagnoses of ET, PCV and PMF at Hahnemann Hospital-Drexel University College Medicine in the practice of I. Brodsky Associates from January 1960 to December 2013. The following variables were measured and compared: age at diagnosis; sex; race; cytogenetics; family history of malignancy; baseline hemoglobin, hematocrit, platelet count and WBC count; Bone marrow biopsy results; thrombohemorrhagic complications; transformation to acute leukemia, progression to myelofibrosis; development of secondary malignancies; and treatment. Since the diagnostic criteria for myeloproliferative disorders has evolved over the years, information regarding JAK2 V617F mutation status, initial erythropoietin level, red cell mass, oxygen saturation, presence of splenomegaly and B12 level were also collected in order to confirm the diagnosis of each patient. The treatment categories analyzed were: Busulfan Only, Hydroxyurea Only, Aspirin with or without Plavix only, Both Busulfan and Hydroxyurea, and Phlebotomy Alone. The forms were then analyzed using Prism software and the number of observations, percentages, means, standard deviation, and minimum and maximum values were obtained for all measurements. Survival was calculated using Kaplan-Meier analysis. RESULTS 119 patients with a MPN were identified: 47 ET, 56 PCV, 8 PMF and 7 MPN NOS. Median ages were 70, 75, 63 and 67, respectively. 34 received Busulfan, 26 Hydroxyurea, 24 Busulfan and hydroxyurea, 24 Aspirin/Plavix only, 11 phlebotomy; one patient who was given Interferon and Aspirin was excluded from analysis. Table. Median survival based on treatment regimen in months: Aspirin/Plavix Busulfan+Hydroxyurea Hydroxyurea Busulfan Phlebotomy 119 178 98 173 145 Table. Number of patients with complications associated with toxicities based on treatment regimens: Complication Aspirin/ Plavix Busulfan+ Hydroxyurea Hydroxyurea Busulfan Phlebotomy Thromboses 9 14 5 9 4 Hemorrhage 3 2 2 6 0 Leukemic transformation 0 1 5 2 0 Malignancy 0 5 1 5 0 Malignancies noted: Pancreatic cancer (4), Breast cancer (4), and Non-Hodgkin's lymphoma (3). Basal and squamous cell skin cancers were excluded. CONCLUSIONS MPN have been treated in much the same way for many years although few physicians use busulfan as routinely as I. Brodsky Associates. Our study set out to discover if this uncommon treatment correlated with improved survival and less treatment toxicity. Busulfan and hydroxyurea given together proved to have the lowest rate of progression to leukemia or myelofibrosis when compared to other standard therapies. The median survival of patients treated with both busulfan and hydroxyurea was 14.8 years. More patients on busulfan developed solid tumors, which could be possibly due to their longer survival rates, but increased leukemic transformation was not observed. In conclusion, patients treated with hydroxyurea and intermittent busulfan, were shown to have the best long-term outcomes. This suggests that physicians should consider using busulfan to treat MPNs. Disclosures No relevant conflicts of interest to declare.

Characterizing the Disease-Initiating Cell Population In a Murine Model of Jak2V617F+ Myeloproliferative Neoplasm

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 317-317
Author(s):  
Ann Mullally ◽  
Steven W. Lane ◽  
Luke Poveromo ◽  
Fatima Al-Shahrour ◽  
Jeffery Kutok ◽  
...  
Keyword(s):  
Cell Population ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Functional Characterization ◽  
Myeloproliferative Neoplasm ◽  
Hematopoietic Stem ◽  
Myeloid Progenitor

Abstract Abstract 317 The JAK2V617F mutation is the most common somatic mutation in BCR-ABL negative myeloproliferative neoplasms (MPN) and small molecule JAK2 kinase inhibitors are currently being evaluated in clinical trials in MPN patients. We recently reported a Jak2V617F conditional knockin mouse MPN model in which expression of Jak2V617F was under the control of the endogenous Jak2 promoter and the phenotype closely recapitulated the features of human polycythemia vera (PV) (Mullally and Lane et al, Cancer Cell 2010). In this model the MPN phenotype developed as a result of expansion and erythroid skewing of committed myeloid progenitor populations, while the hematopoietic stem cell (HSC) compartment (enriched within LineagelowSca1+cKithigh, LSK cells) was not expanded. In contrast to the expanded progenitor population, only LSK cells had the unique capacity to initiate the MPN. Notably, treatment with a JAK2 kinase inhibitor ameliorated the MPN phenotype, but did not eliminate the disease-initiating population. In light of these findings, we wished to further characterize MPN-initiating LSK cells in this model, with a view to gaining understanding of the differential molecular circuitry of JAK2V617F mutant and normal HSC. The LSK compartment, although enriched for HSC, may be further defined by immunophenotype into long-term HSC (LT-HSC, LSKCD150+CD48-), short-term HSC (ST–HSC, LSKCD150-CD48-), or multipotent progenitor cells (MPP, LSKCD150-CD48+). Gene expression analysis of total LSK cells revealed enrichment for markers of myeloid progenitor differentiation in Jak2V617F LSK cells compared to Jak2 wild-type (WT) controls, although there were no quantitative differences in the LSK sub-populations between the two groups. We therefore sought to evaluate whether the MPN-initiating cell population was contained within the LT-HSC compartment. Employing single cell sorting multi-parameter flow cytometry and limiting dilution bone marrow transplantation assays, we provide further functional characterization of the MPN-initiating population in this model. We demonstrate that Jak2V617F LT-HSCs are highly enriched for MPN-initiating activity in vivo and are able to maintain the MPN through multiple rounds of serial transplantation for periods greater than one year. The MPN phenotype remains stable during this time without evolution to myelofibrosis or leukemia. These findings provide important biological insights into MPN initiation and maintenance and have implications for the development of curative therapeutic strategies for MPN patients. Disclosures: No relevant conflicts of interest to declare.

A Rare Case of Chronic Myeloid Leukemia with t(3;9;22) 3-way Translocation

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S147-S147
Author(s):  
S Elzamly ◽  
O Padilla ◽  
M McAlice ◽  
M Gohar ◽  
S Gaur ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chromosomal Abnormalities ◽  
Fusion Gene ◽  
Myeloproliferative Neoplasm ◽  
Molecular Response ◽  
Hematopoietic Stem

Abstract Introduction/Objective Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm originating from malignant clonal proliferation of a pluripotent hematopoietic stem cell. CML is characterized by a reciprocal translocation between chromosomes 9 and 22, t(9;22)(q34;q11), that gives rise to an abnormal chromosome 22 called the Philadelphia (Ph) chromosome. The translocation results in the formation of a chimeric BCR-ABL1 fusion gene, which is the molecular hallmark of the disease. However, 5-10% of CML patients present with additional chromosomal abnormalities which is often considered a sign of clonal evolution, genetic instability, and is generally thought to portend a poor prognosis. Methods We present a case of CML with a rare 3- way translocation, t(3;9;22)(q21;q34;q11.2), who achieved a major molecular response on imatinib for 18 months. A review of the literature and Mitelman database search is presented focusing on the prognostic implications of this 3 way translocation in the era of tyrosine kinase inhibitors starting in 2001 till now. Results Twenty seven cases were reported, but the patient therapeutic response to imatinib and clinical outcome were only reported in 11 cases. Nine cases achieved a cytogenetic remission while the remaining two cases had an adverse outcome. Conclusion Taken in conjunction with the favorable outcome in our patient, we suggest that t(3;9;22) is not an adverse prognostic factor in the era of tyrosine kinase inhibitors.

scholarly journals Autologous Transplantation for Older Adults with AML

Cancers ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 340 ◽  
Author(s):  
Beatrice Mueller ◽  
Katja Seipel ◽  
Ulrike Bacher ◽  
Thomas Pabst
Keyword(s):  
Autologous Transplantation ◽  
Allogeneic Transplantation ◽  
Induction Treatment ◽  
Term Survival ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Consolidation Treatment ◽  
Autologous Hct

While the majority of patients with acute myeloid leukemia (AML) are above the age of 65 years at diagnosis, the outcome of older AML patients remains disappointing. Even if standard intensive chemotherapy induces morphologic complete remission (CR1), relapses in older AML patients are common leading to poor long-term survival outcomes. Since autologous hematopoietic stem cell transplantation (HCT) offers distinct anti-leukemic effectiveness while avoiding graft-versus-host disease associated with allogeneic transplantation, it represents an option for consolidation treatment in selected older AML patients. However, prospective studies in older AML patients assessing the benefit of autologous HCT compared to chemotherapy consolidation or allogeneic transplantation are lacking. Consequently, clinicians face the dilemma that there is considerable ambiguity on the most appropriate consolidation treatment for older AML patients in CR1. This review highlights the possible role of autologous HCT for consolidation in older AML patients reaching CR1 after induction treatment.

scholarly journals Transformation of an Unclassified Myeloproliferative Neoplasm with a RareBCR-JAK2Fusion Transcript Resulting from the Translocation (9;22)(p24;q11)

2015 ◽  
Vol 2015 ◽  
pp. 1-5
Author(s):  
A. N. Chamseddine ◽  
P. Etancelin ◽  
D. Penther ◽  
F. Parmentier ◽  
C. Kuadjovi ◽  
...  
Keyword(s):  
Fusion Gene ◽  
Myeloproliferative Neoplasms ◽  
Present Report ◽  
Myeloproliferative Neoplasm ◽  
Strong Support ◽  
Fusion Transcript ◽  
Derivative Chromosome ◽  
Aggressive Clinical Course

BCR-ABL1negative myeloproliferative neoplasms (MPNs) are known to contain alterations of the tyrosine kinase JAK2 (located on 9p24) that result in constitutive activation of the encoded protein. JAK2 fusions are reported in acute and chronic leukemias of myeloid and lymphoid phenotypes. Here, we report an unclassified case of MPN (MPN-U) showing a t(9;22)(p24;q11), which generates aBCR-JAK2fusion gene by fusing theBCRat intron 13 toJAK2at intron 17 on the derivative chromosome 22. Most reported JAK2 fusions cases reveal an aggressive clinical course and long-term remissions have only been achieved after allogeneic stem cell transplantation (ASCT). To the best of our knowledge, this is the thirteenth case reported worldwide to describe aBCR-JAK2fusion transcript in MPN-U. The present report revealed a sustained complete clinical, hematologic, and cytogenetic remission 35 months after diagnosis and ~24 months after ASCT. RegardingBCR-ABL1  negativeMPN patients this case report provides strong support for a role ofJAK2activation in the oncogenesis and suggests a possible diagnostic and therapeutic target that should be investigated.

scholarly journals Long-term outcome after allogeneic stem cell transplantation in multiple myeloma

2021 ◽  
Author(s):  
Sini Luoma ◽  
Raija Silvennoinen ◽  
Auvo Rauhala ◽  
Riitta Niittyvuopio ◽  
Eeva Martelin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Term Survival ◽  
Hematopoietic Stem ◽  
Long Term Outcome ◽  
Significant Difference ◽  
Relapse Group

AbstractThe role of allogeneic hematopoietic stem cell transplantation (allo-SCT) in multiple myeloma is controversial. We analyzed the results of 205 patients transplanted in one center during 2000–2017. Transplantation was performed on 75 patients without a previous autologous SCT (upfront-allo), on 74 as tandem transplant (auto-allo), and on 56 patients after relapse. Median overall survival (OS) was 9.9 years for upfront-allo, 11.2 years for auto-allo, and 3.9 years for the relapse group (p = 0.015). Progression-free survival (PFS) was 2.4, 2.4, and 0.9 years, respectively (p < 0.001). Non-relapse mortality at 5 years was 8% overall, with no significant difference between the groups. Post-relapse survival was 4.1 years for upfront-allo and auto-allo, and 2.6 years for the relapse group (p = 0.066). Survival of high-risk patients was reduced. In multivariate analysis, the auto-allo group had improved OS and chronic graft-versus-host disease was advantageous in terms of PFS, OS, and relapse incidence. Late relapses occurred in all groups. Allo-SCT resulted in long-term survival in a small subgroup of patients. Our results indicate that auto-allo-SCT is feasible and could be considered for younger patients in the upfront setting.

scholarly journals Long-term complete remission of early hematological relapse after discontinuation of immunosuppressants following allogeneic transplantation for Sezary syndrome

2018 ◽  
Vol 10 (3) ◽  
Author(s):  
Hiroki Hosoi ◽  
Kazuo Hatanaka ◽  
Shogo Murata ◽  
Toshiki Mushino ◽  
Kodai Kuriyama ◽  
...  
Keyword(s):  
Stem Cell ◽  
Complete Remission ◽  
Clinical Course ◽  
Cell Lymphoma ◽  
Allogeneic Transplantation ◽  
Sézary Syndrome ◽  
Sezary Syndrome ◽  
Cutaneous T Cell Lymphoma ◽  
Hematopoietic Stem

Sezary syndrome (SS) is a leukemic form of cutaneous T-cell lymphoma and is chemo-resistant. Allogeneic hematopoietic stem cell transplantation is a promising therapy for SS; however, relapse is common. Therapeutic options after relapse have not been established. We managed an SS patient with hematological relapse within one month after transplantation. After discontinuation of immunosuppressants, she achieved complete remission and remained relapse-free. The chimeric analyses of Tcells showed that the full recipient type became complete donor chimera after immunological symptoms. This clinical course suggested that discontinuation of immunosuppressants may result in a graftversus- tumor effect, leading to the eradication of lymphoma cells.

scholarly journals Loss of Atg2b and Gskip impairs the maintenance of the hematopoietic stem cell pool size

2021 ◽  
Author(s):  
Shun-suke Sakai ◽  
Atsushi Hasegawa ◽  
Ryosuke Ishimura ◽  
Naoki Tamura ◽  
Shun Kageyama ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasm ◽  
Pool Size ◽  
Double Knockout ◽  
Hematopoietic Stem ◽  
Cell Pool ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Differentiation Efficiency ◽  
Stem Cell Pool

A germline copy number duplication of chromosome 14q32, which contains ATG2B and GSKIP , was identified in families with myeloproliferative neoplasm (MPN). Herein, we show that mice lacking both Atg2b and Gskip , but not either alone, exhibited decreased hematopoiesis, resulting in death in utero accompanied by anemia. In marked contrast to MPN patients with duplication of ATG2B and GSKIP , the number of hematopoietic stem cells (HSCs), in particular long-term HSCs, in double knockout fetal livers were significantly decreased due to increased cell death. Although the remaining HSCs still had the ability to differentiate into hematopoietic progenitor cells, the differentiation efficiency was quite low. Remarkably, mice with knockout of Atg2b or Gskip alone did not show any hematopoietic abnormality. Mechanistically, while loss of both genes had no effect on autophagy, it increased the expression of genes encoding enzymes involved in oxidative phosphorylation. Taken together, our results indicate that Atg2b and Gskip play a synergistic effect in maintaining the pool size of HSCs.

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