Publications by authors named "Pierre Fenaux"

382 Publications

Actinomycin D targets NPM1c-primed mitochondria to restore PML-driven senescence in AML therapy.

Cancer Discov 2021 Jul 23. Epub 2021 Jul 23.

The Campbell Family Institute for Breast Cancer Research, Princess Margaret Hospital, University of Toronto.

Acute myeloid leukemia (AML) pathogenesis often involves a mutation in the NPM1 nucleolar chaperone, but the bases for its transforming properties and overall association with favorable therapeutic responses remain incompletely understood. Here we demonstrate that an oncogenic mutant form of NPM1 (NPM1c) impairs mitochondrial function. NPM1c also hampers formation of PML nuclear bodies (NBs), which are regulators of mitochondrial fitness and key senescence effectors. Actinomycin D (ActD), an antibiotic with unambiguous clinical efficacy in relapsed/refractory NPM1c-AMLs, targets these primed mitochondria, releasing mtDNA, activating cGAS signaling and boosting ROS production. The latter restore PML NB formation to drive TP53 activation and senescence of NPM1c-AML cells. In several models, dual targeting of mitochondria by venetoclax and ActD synergized to clear AML and prolong survival through targeting of PML. Our studies reveal an unexpected role for mitochondria downstream of NPM1c and implicate a mitochondrial/ROS/PML/TP53 senescence pathway as an effector of ActD-based therapies.
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http://dx.doi.org/10.1158/2159-8290.CD-21-0177DOI Listing
July 2021

Eltrombopag for myelodysplastic syndromes or chronic myelomonocytic leukaemia with no excess blasts and thrombocytopenia: a French multicentre retrospective real-life study.

Br J Haematol 2021 Jul 20;194(2):336-343. Epub 2021 Jun 20.

Service d'Hématologie Sénior, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris (APHP), Université de Paris, Paris, France.

Despite a moderate prevalence in low-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), thrombocytopenia remains a risk of severe bleeding and therapeutic options are still limited. There are only a few studies with eltrombopag (ELT), a thrombopoietin receptor agonist, in those patients. In this retrospective multicentre study, ELT was used in 50 patients with MDS and 11 with CMML, with no excess of marrow blasts and platelet counts of <50 × 10 /l in a 'real-life' situation. Platelet response occurred in 47 (77%) patients. The median (range) duration of response was 8 (0-69) months. None of the eight still responders who discontinued ELT had relapsed, at a median (range) of 16 (6-23) months after ELT discontinuation. Although 36% of the patients were anti-coagulated or anti-aggregated only 10% of patients had Grade ≥3 bleeding events. Thrombotic events were observed in six (10%) patients, who all but one had a medical history of arterial or venous thrombosis. Progression to acute myeloid leukaemia occurred in four (7%) patients. In this first 'real-life' study, ELT was effective and generally well tolerated in patients with MDS/CMML without excess blasts.
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http://dx.doi.org/10.1111/bjh.17539DOI Listing
July 2021

In vitro assessment of the sensitivity to APR-246 + azacitidine combination predicts response to this combination in myelodysplastic/acute myeloid leukaemia patients.

Br J Haematol 2021 Jun 17. Epub 2021 Jun 17.

Assistance Publique Hopitaux de Paris (APHP), Laboratoire de Biologie Cellulaire, Hopital Saint-Louis, Paris, France.

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http://dx.doi.org/10.1111/bjh.17548DOI Listing
June 2021

Clinical relevance of clonal hematopoiesis in the oldest-old population.

Blood 2021 Jun 14. Epub 2021 Jun 14.

IRCCS Humanitas Clinical Institute, Rozzano, Italy.

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes very common in oldest-old individuals, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 oldest-old individuals enrolled in two population-based studies and investigate the relationships between CHIP and associated pathologies. Clonal mutations were observed in one third of oldest-old individuals and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, ASXL1 with additional genetic lesions) and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1 or JAK2 (most occurring as single lesion) were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was a common finding in oldest-old population, the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly-specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of oldest-old subjects with cytopenia had presumptive evidence of myeloid neoplasm. In conclusion, specific mutational patterns define different risk of developing myeloid neoplasms vs. inflammatory-associated diseases in oldest-old population. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.
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http://dx.doi.org/10.1182/blood.2021011320DOI Listing
June 2021

Targeting health-related quality of life in patients with myelodysplastic syndromes - Current knowledge and lessons to be learned.

Blood Rev 2021 May 14:100851. Epub 2021 May 14.

Sylvester Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA. Electronic address:

Using a range of health-related quality of life (HRQoL) instruments, most - but not all - studies of myelodysplastic syndromes (MDS) have reported that lower hemoglobin levels and red blood cell transfusion dependency are associated with worse HRQoL. In addition, some MDS treatments may significantly improve HRQoL, particularly among those patients who respond to therapy; however, the majority of these studies were underpowered for this secondary endpoint. Furthermore, decreased HRQoL has been associated with worse survival outcomes, and HRQoL scores can be used to refine classical prognostic systems. Despite the subjective nature of HRQoL, the importance and validity of measuring it in trials and clinical practice are increasingly being recognized, but properly validated MDS-specific instruments are required. We describe what is currently known about HRQoL in patients with MDS, and the limitations of measuring HRQoL, and we provide some recommendations to improve the measurement of this outcome in future trials.
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http://dx.doi.org/10.1016/j.blre.2021.100851DOI Listing
May 2021

Characteristics and outcome of patients with low-/intermediate-risk acute promyelocytic leukemia treated with arsenic trioxide - an international collaborative study.

Haematologica 2021 May 27. Epub 2021 May 27.

Gemeinschaftsklinikum Mittelrhein gGmbH, Koblenz.

The aim of this study was to characterize a large series of 154 patients with acute promyelocytic leukemia (APL; median age, 53 years; range, 18-90 years) and evaluate real-life outcome after up-front treatment with arsenic trioxide (ATO) and alltrans retinoic acid (ATRA). All patients were included in the prospective NAPOLEON registry (NCT02192619) between 2013 and 2019. APL was de novo in 91% (n=140) and therapy-related in 9% (n=14); 13% (n=20) were older than 70 years. At diagnosis bleeding/hemorrhage was present in 38% and thrombosis in 3%. Complete remission was achieved in 152 patients (99%), whereas two patients (1%) experienced induction death within 18 days after start of therapy. With a median follow-up of 1.99 years (95%-CI, 1.61-2.30 years) 1-year and 2-years overall survival (OS) rates were 97% (95%-CI, 94-100%) and 95% (95%-CI, 91-99%), respectively. Age above 70 years was associated with a significantly shorter OS (P<0.001) as compared to younger patients. So far no relapses were observed. Six patients (4%) died in CR after in median 0.95 years after diagnosis (range, 0.18-2.38 years). Our data confirm the efficiency and durability of ATO/ATRA in the primary management of adult low-/ intermediate-risk APL patients in the real life setting, irrespective of age.
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http://dx.doi.org/10.3324/haematol.2021.278722DOI Listing
May 2021

Oxidized mitochondrial DNA released after inflammasome activation is a disease biomarker for myelodysplastic syndromes.

Blood Adv 2021 04;5(8):2216-2228

Raleigh, NC.

Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem cell malignancies that can phenotypically resemble other hematologic disorders. Thus, tools that may add to current diagnostic practices could aid in disease discrimination. Constitutive innate immune activation is a pathogenetic driver of ineffective hematopoiesis in MDS through Nod-like receptor protein 3 (NLRP3)-inflammasome-induced pyroptotic cell death. Oxidized mitochondrial DNA (ox-mtDNA) is released upon cytolysis, acts as a danger signal, and triggers inflammasome oligomerization via DNA sensors. By using immortalized bone marrow cells from murine models of common MDS somatic gene mutations and MDS primary samples, we demonstrate that ox-mtDNA is released upon pyroptosis. ox-mtDNA was significantly increased in MDS peripheral blood (PB) plasma compared with the plasma of healthy donors, and it was significantly higher in lower-risk MDS vs higher-risk MDS, consistent with the greater pyroptotic cell fraction in lower-risk patients. Furthermore, ox-mtDNA was significantly higher in MDS PB plasma compared with all other hematologic malignancies studied, with the exception of chronic lymphocytic leukemia (CLL). Receiver operating characteristic/area under the curve (ROC/AUC) analysis demonstrated that ox-mtDNA is a sensitive and specific biomarker for patients with MDS compared with healthy donors (AUC, 0.964), other hematologic malignancies excluding CLL (AUC, 0.893), and reactive conditions (AUC, 0.940). ox-mtDNA positively and significantly correlated with levels of known alarmins S100A9, S100A8, and apoptosis-associated speck-like protein containing caspase recruitment domain (CARD) specks, which provide an index of medullary pyroptosis. Collectively, these data indicate that quantifiable ox-mtDNA released into the extracellular space upon inflammasome activation serves as a biomarker for MDS and the magnitude of pyroptotic cell death.
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http://dx.doi.org/10.1182/bloodadvances.2020003475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095151PMC
April 2021

Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients With Lower-Risk Myelodysplastic Syndromes.

J Clin Oncol 2021 May 25;39(13):1426-1436. Epub 2021 Mar 25.

Marienhospital Düsseldorf, Düsseldorf, Germany.

Purpose: Treatment options are limited for patients with lower-risk myelodysplastic syndromes (LR-MDS). This phase III, placebo-controlled trial evaluated CC-486 (oral azacitidine), a hypomethylating agent, in patients with International Prognostic Scoring System LR-MDS and RBC transfusion-dependent anemia and thrombocytopenia.

Methods: Patients were randomly assigned 1:1 to CC-486 300-mg or placebo for 21 days/28-day cycle. The primary end point was RBC transfusion independence (TI).

Results: Two hundred sixteen patients received CC-486 (n = 107) or placebo (n = 109). The median age was 74 years, median platelet count was 25 × 10/L, and absolute neutrophil count was 1.3 × 10/L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI ( = .0002), with median durations of 11.1 and 5.0 months. Reductions of ≥ 4 RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months, and more CC-486 patients had ≥ 1.5 g/dL hemoglobin increases from baseline (23.4% 4.6%). Platelet hematologic improvement rate was higher with CC-486 (24.3% 6.5%). Underpowered interim overall survival analysis showed no difference between CC-486 and placebo (median, 17.3 16.2 months; = .96). Low-grade GI events were the most common adverse events in both arms. In the CC-486 and placebo arms, 90% and 73% of patients experienced a grade 3-4 adverse event. Overall death rate was similar between arms, but there was an imbalance in deaths during the first 56 days (CC-486, n = 16; placebo, n = 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 × 10/L.

Conclusion: CC-486 significantly improved RBC-TI rate and induced durable bilineage improvements in patients with LR-MDS and high-risk disease features. More early deaths occurred in the CC-486 arm, most related to infections in patients with significant pretreatment neutropenia. Further evaluation of CC-486 in MDS is needed.
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http://dx.doi.org/10.1200/JCO.20.02619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099416PMC
May 2021

A systematic review of higher-risk myelodysplastic syndromes clinical trials to determine the benchmark of azacitidine and explore alternative endpoints for overall survival.

Leuk Res 2021 05 2;104:106555. Epub 2021 Mar 2.

Hôpital Saint-Louis, Assistance Publique - Hôpitaux de Paris, Université de Paris, Paris, France.

The hypomethylating agent azacitidine can prolong overall survival (OS) in patients with higher risk-myelodysplastic syndromes (HR-MDS) compared to conventional regimens. However, outcomes differ largely between studies, making it challenging to determine the contribution of novel therapies added to azacitidine. Further, a discrepancy is seen between complete (CR) or partial (PR) response rates and OS improvement with azacitidine, making it challenging to rely on earlier endpoints than OS. We conducted a systematic literature search and study-level systematic review of 237 clinical studies to better understand outcomes for HR-MDS patients treated with azacitidine. Pooled marrow CR was 9% (N = 2654; 95% CI: 6-13 %), CR rate was 17 % (N = 6943; 95% CI: 15-20 %), and median OS (mOS) was 18.6 months (N = 2820; 95% CI: 15.3-21.9). A weak correlation to mOS was detected with CR rate (207 patient cohorts, Pearson's r = 0.315; P < 0.0005), and a much stronger correlation with median progression-free survival (mPFS) (r=0.88, P = 3 × 10). Six-months progression-free survival rates correlated with 1-year OS rates but were only infrequently reported (N = 41 patient cohorts) therefore not allowing a robust recommendation for a surrogate to the established OS endpoint. Larger patient numbers and patient-level data appear necessary, especially for designing future clinical trials using azacitidine combinations.
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http://dx.doi.org/10.1016/j.leukres.2021.106555DOI Listing
May 2021

Cytokine-like protein 1-induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML.

Blood 2021 Jun;137(24):3390-3402

INSERM U1287, Gustave Roussy Cancer Campus, Villejuif, France.

Mouse models of chronic myeloid malignancies suggest that targeting mature cells of the malignant clone disrupts feedback loops that promote disease expansion. Here, we show that in chronic myelomonocytic leukemia (CMML), monocytes that accumulate in the peripheral blood show a decreased propensity to die by apoptosis. BH3 profiling demonstrates their addiction to myeloid cell leukemia-1 (MCL1), which can be targeted with the small molecule inhibitor S63845. RNA sequencing and DNA methylation pattern analysis both point to the implication of the mitogen-activated protein kinase (MAPK) pathway in the resistance of CMML monocytes to death and reveal an autocrine pathway in which the secreted cytokine-like protein 1 (CYTL1) promotes extracellular signal-regulated kinase (ERK) activation through C-C chemokine receptor type 2 (CCR2). Combined MAPK and MCL1 inhibition restores apoptosis of monocytes from patients with CMML and reduces the expansion of patient-derived xenografts in mice. These results show that the combined inhibition of MCL1 and MAPK is a promising approach to slow down CMML progression by inducing leukemic monocyte apoptosis.
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http://dx.doi.org/10.1182/blood.2020008729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233685PMC
June 2021

Development of luspatercept to treat ineffective erythropoiesis.

Blood Adv 2021 03;5(5):1565-1575

Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital Leipzig, Leipzig, Germany.

Luspatercept (Reblozyl) was recently approved for treating patients with transfusion-dependent lower-risk myelodysplastic syndrome (MDS) with ring sideroblasts (RS) and/or SF3B1 mutation who were not eligible for erythropoiesis-stimulating agents (ESAs) or patients for whom those agents failed. Luspatercept acts as an activin receptor type IIB fusion protein ligand trap that targets the altered transforming growth factor beta pathway in MDS, which is associated with impaired terminal erythroid maturation. Treatment with luspatercept results in decreased SMAD signaling, which enables erythroid maturation by means of late-stage erythroblast differentiation and thus improves anemia. ESAs, the current standard first-line therapeutic option for anemic lower-risk patients with MDS, also improve red cell parameters mainly by expanding proliferation of early erythroid progenitor cells. However, erythropoietin (EPO) and its receptor (EPO-R) are also required for survival of late-stage definitive erythroid cells, and they play an essential role in promoting proliferation, survival, and appropriate timing of terminal maturation of primitive erythroid precursors. Thus, luspatercept joins the mechanism of ESAs in promoting erythroid maturation. Especially in the subgroup of MDS patients with RS, luspatercept showed high clinical activity for the treatment of anemia in the phase 2 (PACE-MDS) trial and subsequently in the phase 3 (MEDALIST) trial, which resulted in approval by both the US Food and Drug Administration and the European Medicines Agency in April 2020. Additional studies are needed to better understand the mechanism of action and pharmacodynamics of this novel agent in MDS.
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http://dx.doi.org/10.1182/bloodadvances.2020002177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948289PMC
March 2021

Continue rare cancers collaboration with European Reference Networks after Brexit.

Lancet 2021 Feb;397(10276):793

Radboud University Medical Centre, Nijmegen, Radboud, Netherlands.

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http://dx.doi.org/10.1016/S0140-6736(21)00264-6DOI Listing
February 2021

Clinical spectrum, outcome and management of immune thrombocytopenia associated with myelodysplastic syndromes and chronic myelomonocytic leukemia.

Haematologica 2021 05 1;106(5):1414-1422. Epub 2021 May 1.

Sorbonne Université, AP-HP, Hôpital Saint-Antoine, Service de Médecine Interne and Inflammation-Immunopathology-Biotherapy Department (DMU 3iD), F-75012, Paris.

Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are associated with systemic inflammatory or autoimmune diseases in 10-20 % of cases. Among them, immune thrombocytopenia (ITP) has been reported but large studies assessing this association are missing. Whether such patients have a particular phenotype and require particular management is unclear. This study analyzes the clinical spectrum, outcome and therapeutic management of patients with ITP associated with MDS or CMML, in comparison (i) to patients with primary ITP without MDS/CMML and (ii) to patients with MDS/CMML without ITP. Forty-one MDS/CMML-associated ITP patients were included, with chronic ITP in 26 (63%) patients, low-risk myelodysplasia in 30 (73%) patients and CMML in 24 (59%) patients. An associated autoimmune disease was noted in 10 (24%) patients. In comparison to primary ITP patients, MDS/CMML-associated ITP patients had a higher occurrence of severe bleeding despite similar platelet counts at diagnosis. First-line treatment consisted of glucocorticoids (98%) and intravenous immunoglobulin (IVIg) (56%). Response achievement with IVIg was more frequent in primary ITP than in MDS/CMML-associated ITP patients. Response rates to second-line therapies were not statistically different between primary ITP and MDS/CMMLassociated ITP patients. Ten percent (n=4) of patients with MDS/CMML-associated ITP had multirefractory ITP versus none in primary ITP controls. After a median follow-up of 60 months, there was no difference in overall survival between MDS/CMML-associated ITP and primary ITP patients. Leukemia-free-survival was significantly better in MDS/CMMLassociated ITP patients than in MDS/CMML without ITP MDS/CMML-associated ITP have a particular outcome with more severe bleeding and multirefractory profile than primary ITP, similar response profile to primary ITP therapy except for IVIg, and less progression toward acute myeloid leukemia than MDS/CMML without ITP.
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http://dx.doi.org/10.3324/haematol.2020.272559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094121PMC
May 2021

Eprenetapopt Plus Azacitidine in -Mutated Myelodysplastic Syndromes and Acute Myeloid Leukemia: A Phase II Study by the Groupe Francophone des Myélodysplasies (GFM).

J Clin Oncol 2021 May 18;39(14):1575-1583. Epub 2021 Feb 18.

GFM.

Purpose: -mutated () myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) have very poor outcome irrespective of the treatment received, including 40% responses (20% complete remission [CR]) with azacitidine (AZA) alone, short response duration, and a median overall survival (OS) of approximately 6 months. Eprenetapopt (APR-246), a novel first-in-class drug, leads to p53 protein reconformation and reactivates its proapoptotic and cell-cycle arrest functions.

Patients And Methods: This phase II study assessed the safety and efficacy of eprenetapopt in combination with AZA in untreated high or very high International Prognostic Scoring System-R MDS and AML patients.

Results: Fifty-two patients (34 MDS, 18 AML [including seven with more than 30% blasts]) were enrolled. In MDS, we observed an overall response rate (ORR) of 62%, including 47% CR, with a median duration of response at 10.4 months. In AML, the ORR was 33% including 17% CR (27% and 0% CR in AML with less than and more than 30% marrow blasts, respectively). Seventy-three percent of responders achieved next-generation sequencing negativity (ie, variant allele frequency < 5%). The main treatment-related adverse events were febrile neutropenia (36%) and neurologic adverse events (40%), the latter correlating with a lower glomerular filtration rate at treatment onset ( < .01) and higher age ( = .05), and resolving with temporary drug interruption without recurrence after adequate eprenetapopt dose reduction. With a median follow-up of 9.7 months, median OS was 12.1 months in MDS, and 13.9 and 3.0 months in AML with less than and more than 30% marrow blasts, respectively.

Conclusion: In this very high-risk population of MDS and AML patients, eprenetapopt combined with AZA was safe and showed potentially higher ORR and CR rate, and longer OS than reported with AZA alone.
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http://dx.doi.org/10.1200/JCO.20.02342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099409PMC
May 2021

Time for Change? The Why, What and How of Promoting Innovation to Tackle Rare Diseases - Is It Time to Update the EU's Orphan Regulation? And if so, What Should be Changed?

Biomed Hub 2020 May-Aug;5(2):1-11. Epub 2020 Jul 17.

Imperial College London, London, United Kingdom.

Since developments are global in the healthcare arena, more should be done to align EU and other big markets' regulatory practices for rare disease patients. Notwithstanding efforts and cooperation between the US and EU aimed to harmonize their strategic plans in the field of orphan drugs, regulatory criteria and procedures to gain the designation, terms and classifications should be still harmonised. Aligning the criteria of prevalence and support to orphan medicines in the various jurisdictions internationally, would facilitate patient recruitment eventually at global level, so as to gain the data and the biological insights required to identify biomarkers and appropriate endpoints needed for progressing clinical development. A conducive regulatory environment can further support the development of medicines to treat rare diseases. Overall there is a need for joined-up regulatory process coordination. Better integration of regulatory pathways and better integration of regulatory systems, such as scientific tools and methods to generate evidence, would be helpful. There is a need to revise and agree the current frameworks to be improved which will take into account the considerations and challenges to diagnose and treat different rare diseases and improve quality of life. Deliberative processes with multi-stakeholders' involvement for reimbursement should be considered. This paper explores the successes and limitation of both the regulation and its implementation mechanisms in the current regulatory context, and suggests some improvements that could maximise its benefits and boost rare disease research even further.
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http://dx.doi.org/10.1159/000509272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841717PMC
July 2020

Classification and Personalized Prognostic Assessment on the Basis of Clinical and Genomic Features in Myelodysplastic Syndromes.

J Clin Oncol 2021 Apr 4;39(11):1223-1233. Epub 2021 Feb 4.

Department of Physics and Astronomy, University of Bologna, Bologna, Italy.

Purpose: Recurrently mutated genes and chromosomal abnormalities have been identified in myelodysplastic syndromes (MDS). We aim to integrate these genomic features into disease classification and prognostication.

Methods: We retrospectively enrolled 2,043 patients. Using Bayesian networks and Dirichlet processes, we combined mutations in 47 genes with cytogenetic abnormalities to identify genetic associations and subgroups. Random-effects Cox proportional hazards multistate modeling was used for developing prognostic models. An independent validation on 318 cases was performed.

Results: We identify eight MDS groups (clusters) according to specific genomic features. In five groups, dominant genomic features include splicing gene mutations (, , and ) that occur early in disease history, determine specific phenotypes, and drive disease evolution. These groups display different prognosis (groups with mutations being associated with better survival). Specific co-mutation patterns account for clinical heterogeneity within - and -related MDS. MDS with complex karyotype and/or gene abnormalities and MDS with acute leukemia-like mutations show poorest prognosis. MDS with 5q deletion are clustered into two distinct groups according to the number of mutated genes and/or presence of mutations. By integrating 63 clinical and genomic variables, we define a novel prognostic model that generates personally tailored predictions of survival. The predicted and observed outcomes correlate well in internal cross-validation and in an independent external cohort. This model substantially improves predictive accuracy of currently available prognostic tools. We have created a Web portal that allows outcome predictions to be generated for user-defined constellations of genomic and clinical features.

Conclusion: Genomic landscape in MDS reveals distinct subgroups associated with specific clinical features and discrete patterns of evolution, providing a proof of concept for next-generation disease classification and prognosis.
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http://dx.doi.org/10.1200/JCO.20.01659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078359PMC
April 2021

Eprenetapopt (APR-246) and Azacitidine in -Mutant Myelodysplastic Syndromes.

J Clin Oncol 2021 May 15;39(14):1584-1594. Epub 2021 Jan 15.

Malignant Hematology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.

Purpose: Approximately 20% of patients with -mutant myelodysplastic syndromes (MDS) achieve complete remission (CR) with hypomethylating agents. Eprenetapopt (APR-246) is a novel, first-in-class, small molecule that restores wild-type p53 functions in -mutant cells.

Methods: This was a phase Ib/II study to determine the safety, recommended phase II dose, and efficacy of eprenetapopt administered in combination with azacitidine in patients with -mutant MDS or acute myeloid leukemia (AML) with 20%-30% marrow blasts (ClinicalTrials.gov identifier: NCT03072043).

Results: Fifty-five patients (40 MDS, 11 AML, and four MDS/myeloproliferative neoplasms) with at least one mutation were treated. The overall response rate was 71% with 44% achieving CR. Of patients with MDS, 73% (n = 29) responded with 50% (n = 20) achieving CR and 58% (23/40) a cytogenetic response. The overall response rate and CR rate for patients with AML was 64% (n = 7) and 36% (n = 4), respectively. Patients with only mutations by next-generation sequencing had higher rates of CR (69% 25%; = .006). Responding patients had significant reductions in variant allele frequency and p53 expression by immunohistochemistry, with 21 (38%) achieving complete molecular remission (variant allele frequency < 5%). Median overall survival was 10.8 months with significant improvement in responding versus nonresponding patients by landmark analysis (14.6 7.5 months; = .0005). Overall, 19/55 (35%) patients underwent allogeneic hematopoietic stem-cell transplant, with a median overall survival of 14.7 months. Adverse events were similar to those reported for azacitidine or eprenetapopt monotherapy, with the most common grade ≥ 3 adverse events being febrile neutropenia (33%), leukopenia (29%), and neutropenia (29%).

Conclusion: Combination treatment with eprenetapopt and azacitidine is well-tolerated yielding high rates of clinical response and molecular remissions in patients with -mutant MDS and oligoblastic AML.
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http://dx.doi.org/10.1200/JCO.20.02341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099410PMC
May 2021

Multicenter Next-Generation Sequencing Studies between Theory and Practice: Harmonization of Data Analysis Using Real-World Myelodysplastic Syndrome Data.

J Mol Diagn 2021 03 23;23(3):347-357. Epub 2020 Dec 23.

Institute of Medical Informatics, University of Münster, Münster, Germany.

In the age of personalized medicine, genetic testing by means of targeted sequencing has taken a key role. However, when comparing different sets of targeted sequencing data, these are often characterized by a considerable lack of harmonization. Laboratories follow their own best practices, analyzing their own target regions. The question on how to best integrate data from different sites remains unanswered. Studying the example of myelodysplastic syndrome (MDS), we analyzed 11 targeted sequencing sets, collected from six different centers (n = 831). An intersecting target region of 43,076 bp (30 genes) was identified; whereas, the original target regions covered up to 499,097 bp (117 genes). Considering a region of interest in the context of MDS, a target region of 55,969 bp (31 genes) was identified. For each gene, coverage and sequencing data quality was evaluated, calculating a sequencing score. Analyses revealed huge differences between different data sets as well as between different genes. Analysis of the relation between sequencing score and mutation frequency in MDS revealed that most genes with high frequency in MDS could be sequenced without expecting low coverage or quality. Still, no gene appeared consistently unproblematic for all data sets. To allow for comparable results in a multicenter setting analyzing MDS, we propose to use a predefined target region of interest and to perform centralized data analysis using harmonized criteria.
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http://dx.doi.org/10.1016/j.jmoldx.2020.12.001DOI Listing
March 2021

Low dose IL-2 in patients with steroid-dependent dysimmune manifestations associated with myelodysplastic syndromes: a three-case report.

Rheumatology (Oxford) 2021 Jul;60(7):3404-3408

Service de Médecine Interne, IUCT Oncopôle, Centre Hospitalier Universitaire de Toulouse, Toulouse.

Objectives: Systemic inflammatory and autoimmune diseases can be associated with myelodysplastic syndromes. Current treatments (steroids, immunosuppressive agents, biologics) are unsatisfactory because of their low response rate, dependence or adverse events. We aimed at evaluating the effects of low doses of IL-2 (ld-IL2) as a regulatory T-cell inducer in this context.

Methods: We treated three patients with ld-IL2 with myelodysplastic syndromes and an associated dysimmune disorder (polymyalgia rheumatic, relapsing polychondritis associated with Sweet's syndrome and vasculitis with cutaneous and joint involvement, respectively). All three patients were dependent on steroids and refractory to biologics or azacitidine. They received doses of 1-1.5 million units of proleukin/day during 5 days and then every fortnight.

Results: The treatment led to a clinical improvement and steroid sparing in 2/3 patients with no serious adverse events, and no progression of the disease.

Conclusion: Our results support the investigation of ld-IL2 in MDS associated with immune disorders in controlled clinical studies.
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http://dx.doi.org/10.1093/rheumatology/keaa696DOI Listing
July 2021

Imetelstat Achieves Meaningful and Durable Transfusion Independence in High Transfusion-Burden Patients With Lower-Risk Myelodysplastic Syndromes in a Phase II Study.

J Clin Oncol 2021 01 27;39(1):48-56. Epub 2020 Oct 27.

Department of Hematology and Cell Therapy, University Clinic Leipzig, Leipzig, Germany.

Purpose: Patients with lower-risk (LR) myelodysplastic syndromes (MDS) who are RBC transfusion dependent and have experienced relapse after or are refractory to erythropoiesis-stimulating agent (ESA) have limited treatment options. High telomerase activity and human telomerase reverse-transcription expression in clonal hematopoietic cells have been reported in patients with MDS. Imetelstat, a first-in-class competitive inhibitor of telomerase enzymatic activity, targets cells with active telomerase. We report efficacy, safety, and biomarker data for patients with LR MDS who are RBC transfusion dependent and who were relapsed/refractory to ESAs.

Patients And Methods: In this two-part phase II/III study (MDS3001), the primary end point was 8-week RBC transfusion independence (TI) rate, with key secondary end points of 24-week RBC TI rate, TI duration, and hematologic improvement-erythroid.

Results: Data from the phase II part of the study are reported. Of 57 patients enrolled and treated (overall population), 38 were non-del(5q) and hypomethylating agent and lenalidomide naïve (subset population). The 8- and 24-week RBC TI rates in the overall population were 37% and 23%, respectively, with a median TI duration of 65 weeks. In the subset population, 8- and 24-week RBC TI rates were 42% and 29%, respectively, with a median TI duration of 86 weeks. Eight-week TI rate was observed across all subgroups evaluated. Cytogenetic and mutational data revealed a reduction of the malignant clones, suggesting disease modification activity. The most common adverse events were cytopenias, typically reversible within 4 weeks.

Conclusion: Imetelstat treatment results in a meaningful, durable TI rate across a broad range of heavily transfused patients with LR MDS who are ineligible for or relapsed/refractory to ESAs. Biomarker analyses indicated effects on the mutant malignant clone.
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http://dx.doi.org/10.1200/JCO.20.01895DOI Listing
January 2021

Vasculitis associated with myelodysplastic syndrome and chronic myelomonocytic leukemia: French multicenter case-control study.

Semin Arthritis Rheum 2020 10 11;50(5):879-884. Epub 2020 Jul 11.

Department of Internal Medicine, Assistance Publique-Hôpitaux de Marseille, Hôpital La Timone, Marseille, France.

Introduction: Our objective was to evaluate characteristics, treatment and outcome of vasculitis associated with myelodysplastic syndrome (MDS) and chronic myelomonicytic leukemia (CMML) PATIENTS AND METHODS: Retrospective descriptive analysis of MDS/CMML-related vasculitis and comparison with MDS/CMML patients without dysimmune features.

Results: Seventy patients with vasculitis and MDS/CMML were included, with median age of 71.5 [21-90] years and male/female ratio of 2.3. Vasculitis was diagnosed prior to MDS/CMML in 31 patients (44%), and after in 20 patients. In comparison with MDS/CMML without autoimmune/inflammatory features, vasculitis with MDS/MPN showed no difference in MDS/CMML subtypes distribution nor International Prognostic Scoring System and CMML-specific prognostic (IPSS/CPSS) scores. Vasculitis subtypes included Giant cell arteritis in 24 patients (34%), Behçet's-like syndrome in 11 patients (20%) and polyarteritis nodosa in 6 patients (9%). Glucocorticoids (GCs) were used as first-line therapy for MDS/CMML vasculitis in 64/70 patients (91%) and 41 (59%) received combined immunosuppressive therapies during the follow-up. After a median follow-up of 33.2 months [1-162], 31 patients (44%) achieved sustained remission. At least one relapse occurred in 43 patients (61%). Relapse rates were higher in patients treated with conventional Disease Modifying Anti-Rheumatic Drug (DMARDs) (odds ratio 4.86 [95% CI 1.38 - 17.10]), but did not differ for biologics (odds ratio 0.59 [95% CI 0.11-3.20]) and azacytidine (odds ratio 1.44 [95% CI 0.21-9.76]) than under glucocorticoids. Overall survival in MDS/CMML vasculitis was not significantly different from MDS/CMML patients without autoimmune/inflammatory features (p = 0.5), but acute leukemia progression rates were decreased (log rank <0.05).

Conclusion: This study shows no correlation of vasculitis diagnoses with subtypes and severity of MDS/CMML, and no significant impact of vasculitis on overall survival. Whereas conventional DMARDs seem to be less effective, biologics or azacytidine therapy could be considered for even low-risk MDS/CMML vasculitis.
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http://dx.doi.org/10.1016/j.semarthrit.2020.07.002DOI Listing
October 2020

Guideline-based indicators for adult patients with myelodysplastic syndromes.

Blood Adv 2020 08;4(16):4029-4044

Department of Tumor Immunology, Nijmegen Center for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.

Myelodysplastic syndromes (MDSs) represent a heterogeneous group of hematological stem cell disorders with an increasing burden on health care systems. Evidence-based MDS guidelines and recommendations (G/Rs) are published but do not necessarily translate into better quality of care if adherence is not maintained in daily clinical practice. Guideline-based indicators (GBIs) are measurable elements for the standardized assessment of quality of care and, thus far, have not been developed for adult MDS patients. To this end, we screened relevant G/Rs published between 1999 and 2018 and aggregated all available information as candidate GBIs into a formalized handbook as the basis for the subsequent consensus rating procedure. An international multidisciplinary expert panel group (EPG) of acknowledged MDS experts (n = 17), health professionals (n = 7), and patient advocates (n = 5) was appointed. The EPG feedback rates for the first and second round were 82% (23 of 28) and 96% (26 of 27), respectively. A final set of 29 GBIs for the 3 domains of diagnosis (n = 14), therapy (n = 8), and provider/infrastructural characteristics (n = 7) achieved the predefined agreement score for selection (>70%). We identified shortcomings in standardization of patient-reported outcomes, toxicity, and geriatric assessments that need to be optimized in the future. Our GBIs represent the first comprehensive consensus on measurable elements addressing best practice performance, outcomes, and structural resources. They can be used as a standardized instrument with the goal of assessing, comparing, and fostering good quality of care within clinical development cycles in the daily care of adult MDS patients.
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http://dx.doi.org/10.1182/bloodadvances.2020002314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448599PMC
August 2020

Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia.

N Engl J Med 2020 08;383(7):617-629

From the Department of Leukemia, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston (C.D.D., M.K.); the Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis School of Medicine, Sacramento (B.A.J.), the Department of Hematology and Hematopoietic Cell Transplantation and Gehr Family Center for Leukemia Research, City of Hope Comprehensive Cancer Center, Duarte (V. Pullarkat), and Genentech, South San Francisco (W.-J.H.) - all in California; the Section of Hematology and Oncology, Department of Medicine, University of Chicago Medicine, Chicago (M.J.T.), and AbbVie, North Chicago (Y.Z., J.P.) - both in Illinois; the Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston (J.S.G., A.L.); the Australian Centre for Blood Diseases, Alfred Hospital and Monash University, Melbourne, VIC (A.H.W.); the Department of Internal Medicine III, Ulm University Hospital, Ulm, Germany (H.D.); Hôpital St. Louis, Assistance Publique-Hôpitaux de Paris and Université de Paris, Paris (P.F.); the Third Medical Department for Hematology and Oncology, Hanusch Hospital, Vienna (E.K.); the Department of Hematology, Cliniques Universitaires Saint-Luc, Brussels (V.H.); the Department of Medicine, McMaster University, Hamilton, ON, Canada (B.L.); the Department of Hematology, Hospital Clinic, August Pi i Sunyer Biomedical Research Institute, Barcelona (J.E.); the Institute of Hematology and Hospital of Blood Disease, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, China (J.W.); the Department of Hematology, University Hospital Dubrava, University of Zagreb School of Medicine, Zagreb, Croatia (V. Pejsa); the Department of Clinic Subjects, University Hospital Ostrava-Poruba, Ostrava, Czech Republic (R.H.); Helsinki University Hospital Comprehensive Cancer Center, University of Helsinki, Helsinki (K.P.); the Faculty of Medicine, Department of Hematology, University of Debrecen, Debrecen, Hungary (A.I.); Hadassah Medical Center, Jerusalem (D.L.); the Clinic of Hematology, Department of Internal Medicine, University of Genoa, and San Martino Hospital IRCCS - both in Genoa, Italy (R.M.L.); the Department of Hematology and Cell Therapy, Aichi Cancer Center, Nagoya, Japan (K.Y.); the Department of Internal Medicine, Seoul National University College of Medicine (S.-S.Y.), and the Department of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine (J.-H.J.) - both in Seoul, South Korea; the Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan (S.-P.Y.); the Faculty of Medicine, Department of Internal Medicine, Division of Hematology, Ondokuz Mayıs University, Samsun, Turkey (M.T.); and Abramson Cancer Center, University of Pennsylvania, Philadelphia (K.W.P.).

Background: Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine added to venetoclax had promising efficacy in a previous phase 1b study.

Methods: We randomly assigned previously untreated patients with confirmed AML who were ineligible for standard induction therapy because of coexisting conditions, because they were 75 years of age or older, or both to azacitidine plus either venetoclax or placebo. All patients received a standard dose of azacitidine (75 mg per square meter of body-surface area subcutaneously or intravenously on days 1 through 7 every 28-day cycle); venetoclax (target dose, 400 mg) or matching placebo was administered orally, once daily, in 28-day cycles. The primary end point was overall survival.

Results: The intention-to-treat population included 431 patients (286 in the azacitidine-venetoclax group and 145 in the azacitidine-placebo [control] group). The median age was 76 years in both groups (range, 49 to 91). At a median follow-up of 20.5 months, the median overall survival was 14.7 months in the azacitidine-venetoclax group and 9.6 months in the control group (hazard ratio for death, 0.66; 95% confidence interval, 0.52 to 0.85; P<0.001). The incidence of complete remission was higher with azacitidine-venetoclax than with the control regimen (36.7% vs. 17.9%; P<0.001), as was the composite complete remission (complete remission or complete remission with incomplete hematologic recovery) (66.4% vs. 28.3%; P<0.001). Key adverse events included nausea of any grade (in 44% of the patients in the azacitidine-venetoclax group and 35% of those in the control group) and grade 3 or higher thrombocytopenia (in 45% and 38%, respectively), neutropenia (in 42% and 28%), and febrile neutropenia (in 42% and 19%). Infections of any grade occurred in 85% of the patients in the azacitidine-venetoclax group and 67% of those in the control group, and serious adverse events occurred in 83% and 73%, respectively.

Conclusions: In previously untreated patients who were ineligible for intensive chemotherapy, overall survival was longer and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone. The incidence of febrile neutropenia was higher in the venetoclax-azacitidine group than in the control group. (Funded by AbbVie and Genentech; VIALE-A ClinicalTrials.gov number, NCT02993523.).
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http://dx.doi.org/10.1056/NEJMoa2012971DOI Listing
August 2020
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