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1.
Palliat Med ; 32(5): 1021-1029, 2018 05.
Article in English | MEDLINE | ID: mdl-29756557

ABSTRACT

BACKGROUND: Integrated palliative care is correlated with earlier end-of-life discussion and improved quality of life. Patients with haematological malignancies are far less likely to receive care from specialist palliative or hospice services compared to other cancers. AIM: The main goal of this study was to determine hematologists' barriers to end-of-life discussions when potentially fatal hematological malignancies recur. DESIGN: Qualitative grounded theory study using individual interviews. SETTING/PARTICIPANTS: Hematologists ( n = 10) from four hematology units were asked about their relationships with their patients and their attitudes toward prognosis and end-of-life discussions at the time of recurrence. RESULTS: As long as there are potential treatments, hematologists fear that end-of-life discussions may undermine their relationship and the patient's trust. Because of their own representations, hematologists have great difficulty opening up to their patients' end-of-life wishes. When prognosis is uncertain, negative outcome, that is, death, is not fully anticipated. Persistent hope silences the threat of death. CONCLUSION: This study reveals some of the barriers clinicians face in initiating early discussion about palliative care or patients' end-of-life care plan. These difficulties may explain why early palliative care is little integrated into the hematology care model.


Subject(s)
Communication , Physician-Patient Relations , Terminal Care , Adult , Advance Care Planning , Belgium , Female , France , Hematologic Neoplasms , Humans , Interviews as Topic , Male , Middle Aged , Palliative Care , Qualitative Research
2.
Haematologica ; 103(5): 840-848, 2018 05.
Article in English | MEDLINE | ID: mdl-29351986

ABSTRACT

JAK2 constitutive activation/overexpression is common in classical Hodgkin lymphoma, and several cytokines stimulate Hodgkin lymphoma cells by recognizing JAK1-/JAK2-bound receptors. JAK blockade may thus be therapeutically beneficial in Hodgkin lymphoma. In this phase II study we assessed the safety and efficacy of ruxolitinib, an oral JAK1/2 inhibitor, in patients with relapsed/refractory Hodgkin lymphoma. The primary objective was overall response rate according to the International Harmonization Project 2007 criteria. Thirty-three patients with advanced disease (median number of prior lines of treatment: 5; refractory: 82%) were included; nine (27.3%) received at least six cycles of ruxolitinib and six (18.2%) received more than six cycles. The overall response rate after six cycles was 9.4% (3/32 patients). All three responders had partial responses; another 11 patients had transient stable disease. Best overall response rate was 18.8% (6/32 patients). Rapid alleviation of B-symptoms was common. The median duration of response was 7.7 months, median progression-free survival 3.5 months (95% CI: 1.9-4.6), and the median overall survival 27.1 months (95% CI: 14.4-27.1). Forty adverse events were reported in 14/33 patients (42.4%). One event led to treatment discontinuation, while 87.5% of patients recovered without sequelae. Twenty-five adverse events were grade 3 or higher. These events were mostly anemia (n=11), all considered related to ruxolitinib. Other main causes of grade 3 or higher adverse events included lymphopenia and infections. Of note, no cases of grade 4 neutropenia or thrombocytopenia were observed. Ruxolitinib shows signs of activity, albeit short-lived, beyond a simple anti-inflammatory effect. Its limited toxicity suggests that it has the potential to be combined with other therapeutic modalities. ClinicalTrials.gov: NCT01877005.


Subject(s)
Drug Resistance, Neoplasm , Hodgkin Disease/drug therapy , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Neoplasm Recurrence, Local/drug therapy , Pyrazoles/therapeutic use , Salvage Therapy , Administration, Oral , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Hodgkin Disease/pathology , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Nitriles , Prognosis , Protein Kinase Inhibitors/therapeutic use , Pyrimidines , Survival Rate , Young Adult
3.
Eur J Haematol ; 100(4): 361-366, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29285836

ABSTRACT

OBJECTIVE: The current survey aimed to gather predefined disease parameters and treatment strategies to characterize the polycythemia vera (PV) patient population in Belgium. METHODS: Cross-sectional data from PV patients, seen at least once between May 2014 and May 2015 at 10 sites in Belgium, were collected in aggregated form and analyzed descriptively and quantitatively. RESULTS: Data from 343 PV patients were collected. Of these, 174 (50.7%) were male and 256 (74.6%) were ≥60 years of age. Ninety-two (26.8%) had a prior history of thrombotic events. Considerable proportions of patients had increased hematological parameters (hematocrit > 45% [31.2%], leukocytes > 10 × 109 /L [33.3%], and platelet > 400 × 109 /L [38.2%]). Most patients had non-palpable spleen (284, 87.7%) and no phlebotomies during the past 6 months (197, 57.4%). Low-dose aspirin was given as thrombosis prophylaxis in 249 (72.6%) patients, while 232 (67.6%) received hydroxyurea (HU) as cytoreductive treatment. Forty-one patients (12.0%) were reported as resistant and/or intolerant to HU. Seventeen patients (5.0%) received ruxolitinib in the context of clinical trials. CONCLUSION: This survey provides better insight into the characteristics of Belgian PV patients and currently used treatment strategies. It shows that 232 (67.6%) PV patients continue to receive HU despite being potentially HU-resistant.


Subject(s)
Polycythemia Vera/epidemiology , Belgium/epidemiology , Biomarkers , Biopsy , Bone Marrow/pathology , Combined Modality Therapy , Cross-Sectional Studies , Disease Management , Erythrocyte Indices , Female , Humans , Male , Polycythemia Vera/diagnosis , Polycythemia Vera/etiology , Polycythemia Vera/therapy , Public Health Surveillance , Treatment Outcome
4.
Haematologica ; 103(3): 438-446, 2018 03.
Article in English | MEDLINE | ID: mdl-29217781

ABSTRACT

We have previously described the safety and efficacy of pegylated interferon-α2a therapy in a cohort of 62 patients with myeloproliferative neoplasm-associated myelofibrosis followed in centers affiliated to the French Intergroup of Myeloproliferative neoplasms. In this study, we report their long-term outcomes and correlations with mutational patterns of driver and non-driver mutations analyzed by targeted next generation sequencing. The median age at diagnosis was 66 years old, the median follow-up since starting pegylated interferon was 58 months. At the time of analysis, 30 (48.4%) patients were alive including 16 still being treated with pegylated interferon. The median survival of patients with intermediate and high-risk prognostic Lille and dynamic International Prognostic Scoring System scores treated with pegylated interferon was increased in comparison to that of historical cohorts. In addition, overall survival was significantly correlated with the duration of pegylated interferon therapy (70 versus 30 months after 2 years of treatment, P<10-12). JAK2V617F allele burden was decreased by more than 50% in 58.8% of patients and two patients even achieved complete molecular response. Next-generation sequencing analyses performed in 49 patients showed that 28 (57.1%) of them carried non-driver mutations. The presence of at least one additional mutation was associated with a reduction of both overall and leukemia-free survival. These findings in a large series of patients with myelofibrosis suggest that pegylated interferon therapy may provide a survival benefit for patients with intermediate- or high-risk Lille and dynamic International Prognostic Scoring System scores. It also reduced the JAK2V617F allele burden in most patients. These results further support the use of pegylated interferon in selected patients with myelofibrosis.


Subject(s)
Interferon-alpha/therapeutic use , Myeloproliferative Disorders/drug therapy , Polyethylene Glycols/therapeutic use , Primary Myelofibrosis/drug therapy , Adult , Aged , Aged, 80 and over , DNA Mutational Analysis , Female , Follow-Up Studies , Humans , Male , Middle Aged , Myeloproliferative Disorders/genetics , Myeloproliferative Disorders/mortality , Primary Myelofibrosis/genetics , Primary Myelofibrosis/mortality , Prognosis , Recombinant Proteins/therapeutic use , Risk Assessment , Survival Analysis
6.
Clin Biochem ; 50(7-8): 452-454, 2017 May.
Article in English | MEDLINE | ID: mdl-28017570

ABSTRACT

This retrospective multicenter study in patients with chronic myeloid leukemia in chronic phase was undertaken to confirm the clinical relevance of imatinib plasma concentrations monitoring in daily practice. Forty-one patients, with 47 imatinib plasma measurements, were analyzed during treatment with imatinib given at a fixed 400mg daily dose. A significant inverse relationship of imatinib concentration with the patients' weight was observed (Pearson's test: p=0.02, R2=0.1). More interestingly, patients with poor response (switched to another tyrosine kinase inhibitor because of imatinib failure, or because of disease progression after an initial response) displayed a significantly lower mean imatinib concentration as compared to patients maintained on imatinib (822ng/mL vs 1099ng/mL; Student's t-test, p=0.04). Failure or disease progression occurred more often in patients in the lowest quartile of imatinib concentrations compared to patients in the highest quartile (p=0.02, logrank test). No correlation could be established with other biological or clinical parameter, including complete cytogenic response and major molecular response. IN CONCLUSION: in patients treated with imatinib at a fixed daily dose of 400mg, imatinib plasma concentrations decreased with increasing body weight and were lower in patients switched to another tyrosine kinase inhibitor due to imatinib failure. Systematic determination of imatinib plasma trough levels should be encouraged in such patients.


Subject(s)
Drug Monitoring/methods , Imatinib Mesylate/pharmacokinetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/blood , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Belgium , Female , Humans , Imatinib Mesylate/administration & dosage , Male , Middle Aged , Retrospective Studies
7.
Cell Mol Life Sci ; 73(24): 4739-4748, 2016 12.
Article in English | MEDLINE | ID: mdl-27436342

ABSTRACT

Genomic instability drives cancer progression by promoting genetic abnormalities that allow for the multi-step clonal selection of cells with growth advantages. We previously reported that the IL-9-dependent TS1 cell line sequentially acquired activating substitutions in JAK1 and JAK3 upon successive selections for growth factor independent and JAK inhibitor-resistant cells, suggestive of a defect in mutation avoidance mechanisms. In the first part of this paper, we discovered that the gene encoding mutL homolog-1 (MLH1), a key component of the DNA mismatch repair system, is silenced by promoter methylation in TS1 cells. By means of stable ectopic expression and RNA interference methods, we showed that the high frequencies of growth factor-independent and inhibitor-resistant cells with activating JAK mutations can be attributed to the absence of MLH1 expression. In the second part of this paper, we confirm the clinical relevance of our findings by showing that chronic myeloid leukemia relapses upon ABL-targeted therapy correlated with a lower expression of MLH1 messenger RNA. Interestingly, the mutational profile observed in our TS1 model, characterized by a strong predominance of T:A>C:G transitions, was identical to the one described in the literature for primitive cells derived from chronic myeloid leukemia patients. Taken together, our observations demonstrate for the first time a causal relationship between MLH1-deficiency and incidence of oncogenic point mutations in tyrosine kinases driving cell transformation and acquired resistance to kinase-targeted cancer therapies.


Subject(s)
Drug Resistance, Neoplasm/genetics , Janus Kinases/genetics , MutL Protein Homolog 1/metabolism , Oncogenes , Point Mutation/genetics , Protein Kinase Inhibitors/pharmacology , Animals , Cell Line , Clone Cells , DNA Methylation/drug effects , DNA Methylation/genetics , Down-Regulation/drug effects , Drug Resistance, Neoplasm/drug effects , Gene Expression Regulation, Leukemic/drug effects , Gene Knockdown Techniques , Humans , Intercellular Signaling Peptides and Proteins/pharmacology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Mice , MutL Protein Homolog 1/genetics , Promoter Regions, Genetic/genetics , RNA, Small Interfering/metabolism
8.
Haematologica ; 100(10): 1240-53, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26432382

ABSTRACT

Constitutive JAK-STAT pathway activation occurs in most myeloproliferative neoplasms as well as in a significant proportion of other hematologic malignancies, and is frequently a marker of poor prognosis. The underlying molecular alterations are heterogeneous as they include activating mutations in distinct components (cytokine receptor, JAK, STAT), overexpression (cytokine receptor, JAK) or rare JAK2 fusion proteins. In some cases, concomitant loss of negative regulators contributes to pathogenesis by further boosting the activation of the cascade. Exploiting the signaling bottleneck provided by the limited number of JAK kinases is an attractive therapeutic strategy for hematologic neoplasms driven by constitutive JAK-STAT pathway activation. However, given the conserved nature of the kinase domain among family members and the interrelated roles of JAK kinases in many physiological processes, including hematopoiesis and immunity, broad usage of JAK inhibitors in hematology is challenged by their narrow therapeutic window. Novel therapies are, therefore, needed. The development of more selective inhibitors is a questionable strategy as such inhibitors might abrogate the beneficial contribution of alleviating the cancer-related pro-inflammatory microenvironment and raise selective pressure to a threshold that allows the emergence of malignant subclones harboring drug-resistant mutations. In contrast, synergistic combinations of JAK inhibitors with drugs targeting cascades that work in concert with JAK-STAT pathway appear to be promising therapeutic alternatives to JAK inhibitors as monotherapies.


Subject(s)
Antineoplastic Agents/therapeutic use , Hematologic Neoplasms/drug therapy , Hematologic Neoplasms/metabolism , Janus Kinases/antagonists & inhibitors , Janus Kinases/metabolism , Molecular Targeted Therapy , Protein Kinase Inhibitors/therapeutic use , Animals , Antineoplastic Agents/pharmacology , Genetic Variation , Hematologic Neoplasms/genetics , Hematopoiesis/genetics , Humans , Janus Kinases/genetics , Mutation , Protein Kinase Inhibitors/pharmacology , STAT Transcription Factors/genetics , STAT Transcription Factors/metabolism , Signal Transduction/drug effects
9.
J Biol Chem ; 290(48): 29022-34, 2015 Nov 27.
Article in English | MEDLINE | ID: mdl-26446793

ABSTRACT

JAK1 and JAK3 are recurrently mutated in acute lymphoblastic leukemia. These tyrosine kinases associate with heterodimeric cytokine receptors such as IL-7 receptor or IL-9 receptor, in which JAK1 is appended to the specific chain, and JAK3 is appended to the common gamma chain. Here, we studied the role of these receptor complexes in mediating the oncogenic activity of JAK3 mutants. Although JAK3(V674A) and the majority of other JAK3 mutants needed to bind to a functional cytokine receptor complex to constitutively activate STAT5, JAK3(L857P) was unexpectedly found to not depend on such receptor complexes for its activity, which was induced without receptor or JAK1 co-expression. Introducing a mutation in the FERM domain that abolished JAK-receptor interaction did not affect JAK3(L857P) activity, whereas it inhibited the other receptor-dependent mutants. The same cytokine receptor independence as for JAK3(L857P) was observed for homologous Leu(857) mutations of JAK1 and JAK2 and for JAK3(L875H). This different cytokine receptor requirement correlated with different functional properties in vivo and with distinct sensitivity to JAK inhibitors. Transduction of murine hematopoietic cells with JAK3(V674A) led homogenously to lymphoblastic leukemias in BALB/c mice. In contrast, transduction with JAK3(L857P) induced various types of lymphoid and myeloid leukemias. Moreover, ruxolitinib, which preferentially blocks JAK1 and JAK2, abolished the proliferation of cells transformed by the receptor-dependent JAK3(V674A), yet proved much less potent on cells expressing JAK3(L857P). These particular cells were, in contrast, more sensitive to JAK3-specific inhibitors. Altogether, our results showed that different JAK3 mutations induce constitutive activation through distinct mechanisms, pointing to specific therapeutic perspectives.


Subject(s)
Janus Kinase 3 , Mutation, Missense , Protein Kinase Inhibitors/pharmacology , Amino Acid Substitution , Animals , Cell Line, Tumor , Humans , Janus Kinase 1/genetics , Janus Kinase 1/metabolism , Janus Kinase 2/genetics , Janus Kinase 2/metabolism , Janus Kinase 3/antagonists & inhibitors , Janus Kinase 3/genetics , Janus Kinase 3/metabolism , Mice , Mice, Inbred BALB C , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/enzymology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Receptors, Cytokine/genetics , Receptors, Cytokine/metabolism
10.
Blood ; 124(26): 3924-31, 2014 Dec 18.
Article in English | MEDLINE | ID: mdl-25352124

ABSTRACT

The acquisition of growth signal self-sufficiency is 1 of the hallmarks of cancer. We previously reported that the murine interleukin-9-dependent TS1 cell line gives rise to growth factor-independent clones with constitutive activation of the Janus kinase (JAK)- signal transducer and activator of transcription (STAT) pathway. Here, we show that this transforming event results from activating mutations either in JAK1, JAK3, or in both kinases. Transient and stable expression of JAK1 and/or JAK3 mutants showed that each mutant induces STAT activation and that their coexpression further increases this activation. The proliferation of growth factor-independent TS1 clones can be efficiently blocked by JAK inhibitors such as ruxolitinib or CMP6 in short-term assays. However, resistant clones occur upon long-term culture in the presence of inhibitors. Surprisingly, resistance to CMP6 was not caused by the acquisition of secondary mutations in the adenosine triphosphate-binding pocket of the JAK mutant. Indeed, cells that originally showed a JAK1-activating mutation became resistant to inhibitors by acquiring another activating mutation in JAK3, whereas cells that originally showed a JAK3-activating mutation became resistant to inhibitors by acquiring another activating mutation in JAK1. These observations underline the cooperation between JAK1 and JAK3 mutants in T-cell transformation and represent a new mechanism of acquisition of resistance against JAK inhibitors.


Subject(s)
Drug Resistance, Neoplasm , Janus Kinase 1/genetics , Janus Kinase 3/genetics , Protein Kinase Inhibitors/chemistry , Adenosine Triphosphate/chemistry , Animals , Cell Line , Cell Proliferation , Cell Transformation, Neoplastic , HEK293 Cells , Humans , Janus Kinases/antagonists & inhibitors , Mice , Mutation, Missense , Nitriles , Point Mutation , Protein Structure, Tertiary , Pyrazoles/chemistry , Pyrimidines , Signal Transduction
11.
J Virol ; 88(7): 3874-84, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24453359

ABSTRACT

UNLABELLED: We examined the antiviral response promoted by type I interferons (IFN) in primary mouse neurons. IFN treatment of neuron cultures strongly upregulated the transcription of IFN-stimulated genes but conferred a surprisingly low resistance to infection by neurotropic viruses such as Theiler's murine encephalomyelitis virus (TMEV) or vesicular stomatitis virus (VSV). Response of primary mouse neurons to IFN treatment was heterogeneous, as many neurons failed to express the typical IFN response marker Mx1 after IFN treatment. This heterogeneous response of primary neurons correlated with a low level of basal expression of IFN-stimulated genes, such as Stat1, that are involved in signal transduction of the IFN response. In addition, transcriptomic analysis identified 15 IFN-responsive genes whose expression was low in IFN-treated primary neurons compared to that of primary fibroblasts derived from the same mice (Dhx58, Gvin1, Sp100, Ifi203 isoforms 1 and 2, Irgm2, Lgals3bp, Ifi205, Apol9b, Ifi204, Ifi202b, Tor3a, Slfn2, Ifi35, Lgals9). Among these genes, the gene coding for apolipoprotein L9b (Apol9b) displayed antiviral activity against Theiler's virus when overexpressed in L929 cells or in primary neurons. Accordingly, knocking down Apol9b expression in L929 cells increased viral replication. Therefore, we identified a new antiviral protein induced by interferon, ApoL9b, whose lack of expression in primary neurons likely contributes to the high sensitivity of these cells to viral infection. IMPORTANCE: The type I interferon (IFN) response is an innate immune defense mechanism that is critical to contain viral infection in the host until an adaptive immune response can be mounted. Neurons are a paradigm for postmitotic, highly differentiated cells. Our data show that primary mouse neurons that are exposed to type I interferon remain surprisingly susceptible to viral infection. On one hand, the low level of basal expression of some factors in neurons might prevent a rapid response of these cells. On the other hand, some genes that are typically activated by type I interferon in other cell types are expressed at much lower levels in neurons. Among these genes is the gene encoding apolipoprotein L9, a protein that proved to have antiviral activity against the neurotropic Theiler's murine encephalomyelitis virus. Our data suggest important functional differences in the IFN response mounted by specific cell populations.


Subject(s)
Apolipoproteins/biosynthesis , Gene Expression , Interferon Type I/immunology , Neurons/immunology , Neurons/virology , Theilovirus/immunology , Vesiculovirus/immunology , Animals , Cells, Cultured , Fibroblasts/immunology , Fibroblasts/virology , Gene Expression Profiling , Gene Knockdown Techniques , Mice
12.
Blood ; 123(12): 1833-5, 2014 Mar 20.
Article in English | MEDLINE | ID: mdl-24443442

ABSTRACT

The international prognostic scoring system (IPSS) provides reliable risk assessment in patients with primary myelofibrosis (PMF). Recent clinical trials in PMF patients with intermediate-2 or high IPSS risk have shown a survival advantage of ruxolitinib over placebo (COMFORT-1) or best available therapy (COMFORT-2). Because crossover was allowed in these studies, we analyzed the cohort of ruxolitinib-naive patients used for developing the dynamic IPSS (DIPSS). By adopting ad hoc statistical analyses, we compared survival from diagnosis of 100 PMF patients receiving ruxolitinib within COMFORT-2 with that of 350 patients of the DIPSS study. Subjects were properly matched, and both left-truncation and right-censoring were accounted in order to compare higher IPSS risks exclusively. Patients receiving ruxolitinib had longer survival (5 years, 95% confidence interval [CI]: 2.9-7.8 vs 3.5 years, 95% CI: 3.0-3.9) with a hazard ratio of 0.61 (95% CI: 0.41-0.91; P = .0148). This observation suggests that ruxolitinib may modify the natural history of PMF.


Subject(s)
Primary Myelofibrosis/drug therapy , Pyrazoles/therapeutic use , Adult , Aged , Aged, 80 and over , Cohort Studies , Female , Humans , Janus Kinases/antagonists & inhibitors , Kaplan-Meier Estimate , Male , Middle Aged , Nitriles , Primary Myelofibrosis/mortality , Prognosis , Protein Kinase Inhibitors/therapeutic use , Pyrimidines
13.
Haematologica ; 99(2): 292-8, 2014 Feb.
Article in English | MEDLINE | ID: mdl-23911705

ABSTRACT

Prior to Janus kinase inhibitors, available therapies for myelofibrosis were generally supportive and did not improve survival. This analysis compares efficacy outcomes of patients with myelofibrosis in the control arms (placebo [n=154] and best available therapy [n=73]) from the two phase 3 COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment (COMFORT) studies. Spleen volume was assessed by magnetic resonance imaging/computed tomography at baseline and every 12 weeks through week 72; spleen length was assessed by palpation at each study visit. Health-related quality of life and symptoms were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Items at baseline and in weeks 4, 8, 12, 16 and 24 in COMFORT-I and in weeks 8, 16, 24 and 48 in COMFORT-II. The demographic and baseline characteristics were similar between the control arms of the two studies. One patient who received placebo and no patients who received best available therapy had a ≥35% reduction in spleen volume from baseline at week 24. At 24 weeks, neither placebo nor best available therapy had produced clinically meaningful changes in global quality of life or symptom scales. Non-hematologic adverse events were mostly grade 1/2; the most frequently reported adverse events in each group were abdominal pain, fatigue, peripheral edema and diarrhea. These data suggest that non-Janus kinase inhibitor therapies provide little improvement in splenomegaly, symptoms or quality of life as compared with placebo. Both COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544) studies have been appropriately registered with clinicaltrials.gov.


Subject(s)
Protein Kinase Inhibitors/administration & dosage , Quality of Life , Spleen , Adult , Aged , Aged, 80 and over , Double-Blind Method , Female , Humans , Male , Middle Aged , Organ Size , Primary Myelofibrosis/drug therapy , Primary Myelofibrosis/pathology , Primary Myelofibrosis/physiopathology , Spleen/pathology , Spleen/physiopathology , Splenomegaly/drug therapy , Splenomegaly/pathology , Splenomegaly/physiopathology , Time Factors
14.
Leuk Lymphoma ; 55(5): 1176-80, 2014 May.
Article in English | MEDLINE | ID: mdl-23885837

ABSTRACT

Abstract Considering the recent impact of tyrosine kinase inhibitors in the treatment of myeloproliferative disorders carrying a recurrent JAK2 mutation not identified in multiple myeloma (MM), this study aimed to search for mutations in kinase and pseudokinase domains of the JAK1 gene in an attempt to define any critical and recurring change that can be used as a therapeutic target. We obtained CD138 + purified cells from 27 bone marrow aspirates of untreated MM, four normal controls and four MM cell lines. After amplification of kinase and pseudokinase domains of JAK1 in cDNA samples, the fragments were automatically sequenced. Seventy-eight percent of MM cases showed at least one polymorphism, all being synonymous single nucleotide polymorphisms (SNPs), with allele frequencies consistent with previous studies in normal European, African American and Asian populations. The four cell lines also showed only synonymous SNPs. Mutations in the kinase and pseudokinase domains of the JAK1 gene do not seem to be important for activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway because we were not able to find any recurrent mutation in a case series of 27 patients and four MM cell lines.


Subject(s)
Janus Kinase 1/genetics , Janus Kinases/genetics , Janus Kinases/metabolism , Multiple Myeloma/genetics , Multiple Myeloma/metabolism , Point Mutation , STAT Transcription Factors/metabolism , Signal Transduction , Adult , Aged , Aged, 80 and over , Alleles , Cell Line, Tumor , Female , Gene Frequency , Genotype , Humans , Janus Kinase 1/chemistry , Janus Kinase 1/metabolism , Male , Middle Aged , Multiple Myeloma/pathology , Neoplasm Staging , Polymorphism, Single Nucleotide , Protein Interaction Domains and Motifs/genetics
15.
Leuk Res Rep ; 2(2): 64-6, 2013.
Article in English | MEDLINE | ID: mdl-24371784

ABSTRACT

While in RARS-T, JAK2V617F mutation is common and associated with good prognosis, the clinical and prognostic impact of this mutation in other MDS is unknown. We collected data from 132 non-RARS-T MDS with known JAK2V617F mutation status. JAK2V617F mutation was significantly correlated with lower progression to AML (p<.0011) and better overall survival (OS, p=.011). OS difference persisted after matching on age, sex, IPSS and % marrow blast (p=.031). Thus, in MDS other than RARS-T, JAK2V617F mutation may be associated with favorable outcome.

16.
Blood ; 122(25): 4047-53, 2013 Dec 12.
Article in English | MEDLINE | ID: mdl-24174625

ABSTRACT

Ruxolitinib is a potent Janus kinase (JAK)1/JAK2 inhibitor that has demonstrated rapid reductions in splenomegaly and marked improvement in disease-related symptoms and quality of life in patients with myelofibrosis (MF). The present analysis reports the 3-year follow-up (median, 151 weeks) of the efficacy and safety of Controlled Myelofibrosis Study With Oral Janus-associated Kinase (JAK) Inhibitor Treatment-II (the COMFORT-II Trial), comparing ruxolitinib with the best available therapy (BAT) in 219 patients with intermediate-2 and high-risk MF. In the ruxolitinib arm, with continued therapy, spleen volume reductions of ≥35% by magnetic resonance imaging (equivalent to approximately 50% reduction by palpation) were sustained for at least 144 weeks, with the probability of 50% (95% confidence interval [CI], 36-63) among patients achieving such degree of response. At the time of this analysis, 45% of the patients randomized to ruxolitinib remained on treatment. Ruxolitinib continues to be well tolerated. Anemia and thrombocytopenia were the main toxicities, but they were generally manageable, improved over time, and rarely led to treatment discontinuation (1% and 3.6% of patients, respectively). No single nonhematologic adverse event led to definitive ruxolitinib discontinuation in more than 1 patient. Additionally, patients randomized to ruxolitinib showed longer overall survival than those randomized to BAT (hazard ratio, 0.48; 95% CI, 0.28-0.85; log-rank test, P = .009).


Subject(s)
Primary Myelofibrosis/drug therapy , Primary Myelofibrosis/mortality , Protein Kinase Inhibitors/administration & dosage , Pyrazoles/administration & dosage , Anemia/chemically induced , Anemia/drug therapy , Anemia/enzymology , Anemia/mortality , Disease-Free Survival , Female , Follow-Up Studies , Humans , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Male , Nitriles , Primary Myelofibrosis/enzymology , Protein Kinase Inhibitors/adverse effects , Pyrazoles/adverse effects , Pyrimidines , Survival Rate , Thrombocytopenia/chemically induced , Thrombocytopenia/drug therapy , Thrombocytopenia/enzymology , Thrombocytopenia/mortality , Time Factors
17.
Br J Haematol ; 162(6): 783-91, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23848933

ABSTRACT

Myeloproliferative neoplasm-related myelofibrosis is associated with cytopenic or proliferative phases, splenomegaly and constitutional symptoms. Few effective treatments are available and small series suggested that interferon could be an option for myelofibrosis therapy. We performed a retrospective study of pegylated-interferon α-2a (Peg-IFNα-2a) therapy in myelofibrosis. Sixty-two patients treated with Peg-IFNα-2a at 17 French and Belgian centres were included. Responses were determined based on the criteria established by the International Working Group for Myelofibrosis Research and Treatment. Mean follow-up was 26 months. Sixteen of 25 anaemic patients (64%) (eight concomitantly receiving recombinant erythropoietin) achieved a complete response and transfusion-independence was obtained in 5/13 patients (38·5%). Constitutional symptoms resolved in 82% of patients. All five leucopenic patients normalized their leucocyte counts, whereas a normal platelet count was obtained in 5/8 thrombocytopenic patients. Splenomegaly was reduced in 46·5% of patients, and complete resolution of thrombocytosis and leucocytosis were observed in 82·8% and 68·8% of patients, respectively. Side effects (mostly haematological) were mainly of grade 1-2. The only factor independently associated with treatment failure was a spleen enlargement of more than 6 cm below the costal margin. In conclusion, Peg-IFNα-2a induced high response rates with acceptable toxicity in a large proportion of patients with primary and secondary myelofibrosis, especially in early phases.


Subject(s)
Interferon-alpha/adverse effects , Interferon-alpha/therapeutic use , Polyethylene Glycols/adverse effects , Polyethylene Glycols/therapeutic use , Primary Myelofibrosis/drug therapy , Adult , Aged , Aged, 80 and over , Humans , Middle Aged , Primary Myelofibrosis/pathology , Recombinant Proteins/adverse effects , Recombinant Proteins/therapeutic use , Retrospective Studies , Treatment Outcome , Young Adult
18.
Br J Haematol ; 162(2): 229-39, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23672349

ABSTRACT

Patients with myelofibrosis (MF) have significant debilitating symptoms, physical disabilities, and poor health-related quality of life (HRQoL). Here, we report post-hoc analyses of the impact of ruxolitinib, a potent and selective JAK1 and JAK2 inhibitor, on disease-related symptoms and HRQoL in MF patients from the large phase 3 COMFORT-II study (N = 219). During the follow-up period of 48 weeks, HRQoL and MF-associated symptoms improved from baseline for ruxolitinib-treated patients but remained the same or worsened for best available therapy (BAT)-treated patients. Based on the European Organization for Research and Treatment of Cancer QoL Questionnaire core 30 items (EORTC QLQ-C30), treatment-induced differences in physical and role functioning, fatigue, and appetite loss significantly favoured ruxolitinib versus BAT from week 8 (P < 0·05) up to week 48 (P < 0·05). Ruxolitinib resulted in significantly higher response rates in global health status/QoL and Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) summary scores versus BAT at most time points (P < 0·05). Significant improvements in the Lymphoma subscale (including symptoms of pain, fever, itching, fatigue, weight loss, loss of appetite, and other patient concerns), FACT-General, FACT-Lym trial outcome index, and FACT-Lym total were also observed with ruxolitinib versus BAT starting at week 8 and continuing thereafter. Overall, these data demonstrated that ruxolitinib improved HRQoL in MF patients and further support the use of ruxolitinib for the treatment of symptomatic MF.


Subject(s)
Primary Myelofibrosis/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/therapeutic use , Aged , Female , Humans , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Male , Nitriles , Primary Myelofibrosis/enzymology , Primary Myelofibrosis/pathology , Pyrimidines , Quality of Life , Surveys and Questionnaires , Treatment Outcome
19.
Blood ; 119(20): 4625-35, 2012 May 17.
Article in English | MEDLINE | ID: mdl-22378845

ABSTRACT

The constitutively active JAK2 V617F mutant is the major determinant of human myeloproliferative neoplasms (MPNs). We show that coexpression of murine JAK2 V617F and the murine thrombopoietin (Tpo) receptor (TpoR, c-MPL) in hematopoietic cell lines or heterozygous knock-in of JAK2 V617F in mice leads to down-modulation of TpoR levels. Enhanced TpoR ubiquitinylation, proteasomal degradation, reduced recycling, and maturation are induced by the constitutive JAK2 V617F activity. These effects can be prevented in cell lines by JAK2 and proteasome inhibitors. Restoration of TpoR levels by inhibitors could be detected in platelets from JAK2 inhibitor-treated myelofibrosis patients that express the JAK2 V617F mutant, and in platelets from JAK2 V617F knock-in mice that were treated in vivo with JAK2 or proteasome inhibitors. In addition, we show that Tpo can induce both proliferative and antiproliferative effects via TpoR at low and high JAK2 activation levels, respectively, or on expression of JAK2 V617F. The antiproliferative signaling and receptor down-modulation by JAK2 V617F were dependent on signaling via TpoR cytosolic tyrosine 626. We propose that selection against TpoR antiproliferative signaling occurs by TpoR down-modulation and that restoration of down-modulated TpoR levels could become a biomarker for the treatment of MPNs.


Subject(s)
Janus Kinase 2/antagonists & inhibitors , Janus Kinase 2/physiology , Proteasome Inhibitors , Protein Kinase Inhibitors/pharmacology , Receptors, Thrombopoietin/genetics , Amino Acid Substitution/genetics , Amino Acid Substitution/physiology , Animals , Cell Membrane/drug effects , Cell Membrane/metabolism , Cells, Cultured , Down-Regulation/drug effects , Drug Evaluation, Preclinical , HEK293 Cells , Humans , Janus Kinase 2/genetics , Janus Kinase 2/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mutation, Missense/physiology , Phenylalanine/genetics , Receptor Cross-Talk/drug effects , Receptor Cross-Talk/physiology , Receptors, Thrombopoietin/metabolism , Signal Transduction/drug effects , Valine/genetics
20.
N Engl J Med ; 366(9): 787-98, 2012 Mar 01.
Article in English | MEDLINE | ID: mdl-22375970

ABSTRACT

BACKGROUND: Treatment options for myelofibrosis are limited. We evaluated the efficacy and safety of ruxolitinib, a potent and selective Janus kinase (JAK) 1 and 2 inhibitor, as compared with the best available therapy, in patients with myelofibrosis. METHODS: We assigned 219 patients with intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis to receive oral ruxolitinib or the best available therapy. The primary end point and key secondary end point of the study were the percentage of patients with at least a 35% reduction in spleen volume at week 48 and at week 24, respectively, as assessed with the use of magnetic resonance imaging or computed tomography. RESULTS: A total of 28% of the patients in the ruxolitinib group had at least a 35% reduction in spleen volume at week 48, as compared with 0% in the group receiving the best available therapy (P<0.001); the corresponding percentages at week 24 were 32% and 0% (P<0.001). At 48 weeks, the mean palpable spleen length had decreased by 56% with ruxolitinib but had increased by 4% with the best available therapy. The median duration of response with ruxolitinib was not reached, with 80% of patients still having a response at a median follow-up of 12 months. Patients in the ruxolitinib group had an improvement in overall quality-of-life measures and a reduction in symptoms associated with myelofibrosis. The most common hematologic abnormalities of grade 3 or higher in either group were thrombocytopenia and anemia, which were managed with a dose reduction, interruption of treatment, or transfusion. One patient in each group discontinued treatment owing to thrombocytopenia, and none discontinued owing to anemia. Nonhematologic adverse events were rare and mostly grade 1 or 2. Two cases of acute myeloid leukemia were reported with the best available therapy. CONCLUSIONS: Continuous ruxolitinib therapy, as compared with the best available therapy, was associated with marked and durable reductions in splenomegaly and disease-related symptoms, improvements in role functioning and quality of life, and modest toxic effects. An influence on overall survival has not yet been shown. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT00934544.).


Subject(s)
Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Primary Myelofibrosis/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/therapeutic use , Splenomegaly/drug therapy , Adult , Aged , Aged, 80 and over , Cause of Death , Female , Follow-Up Studies , Humans , Male , Middle Aged , Nitriles , Organ Size , Primary Myelofibrosis/mortality , Primary Myelofibrosis/pathology , Protein Kinase Inhibitors/adverse effects , Pyrazoles/adverse effects , Pyrimidines , Quality of Life , Spleen/drug effects , Spleen/pathology , Survival Analysis
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