Randomized, Single-Blind, Multicenter Phase II Study of Two Doses of Imetelstat in Relapsed or Refractory Myelofibrosis

PURPOSE Patients with myelofibrosis who are relapsed or refractory (R/R) to Janus-associated kinase inhibitors (JAKis) have poor clinical outcomes including dismal overall survival (OS) that ranges between 13 and 16 months. Imetelstat, a telomerase inhibitor, was evaluated in patients with intermediate-2 or high-risk myelofibrosis R/R to JAKi in a phase II multicenter study (ClinicalTrials.gov identifier: NCT02426086 ). PATIENTS AND METHODS Patients were randomly assigned to receive either imetelstat 9.4 mg/kg or 4.7 mg/kg intravenous once every 3 weeks. Spleen response (≥ 35% spleen volume reduction) and symptom response (≥ 50% reduction in total symptom score) rates at week 24 were coprimary end points. Secondary end points included OS and safety. RESULTS Study enrollment was closed early, and patients treated with 4.7 mg/kg were permitted to continue treatment with 9.4 mg/kg. At week 24, spleen and symptom response rates were 10.2% and 32.2% in the 9.4-mg/kg arm and 0% and 6.3% in the 4.7-mg/kg arm. Treatment with imetelstat 9.4 mg/kg led to a median OS of 29.9 months and bone marrow fibrosis improvement in 40.5% and variant allele frequency reduction of driver mutations in 42.1% of evaluable patients. Fibrosis improvement and variant allele frequency reduction correlated with OS. Target inhibition was demonstrated by reduction of telomerase activity and human telomerase reverse transcriptase level and correlated with spleen response, symptom response, and OS. Most common adverse events on both arms were grade 3 or 4 reversible cytopenias. CONCLUSION In this phase II study of two imetelstat doses, 9.4 mg/kg once every 3 weeks demonstrated clinical benefits in symptom response rate, with an acceptable safety profile for this poor-risk JAKi R/R population. Biomarker and bone marrow fibrosis assessments suggested selective effects on the malignant clone. A confirmatory phase III study is currently underway.

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Phase II Study of Lenalidomide and Prednisone for Patients with Myelofibrosis.

Blood ◽

10.1182/blood.v110.11.3545.3545 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3545-3545

Author(s):

Alfonso Quintás-Cardama ◽

Ayalew Tefferi ◽

Deborah Thomas ◽

Jorge Cortes ◽

Farhad Ravandi ◽

...

Keyword(s):

Bone Marrow ◽

Growth Factors ◽

Phase Ii ◽

Phase Ii Study ◽

Jak2 V617f ◽

Prior Therapy ◽

Grade 3 ◽

Wbc Count ◽

Bone Marrow Blasts ◽

Marrow Fibrosis

Abstract Prompted by the activity of lenalidomide (Revlimid®) in pts with chronic idiopathic myelofibrosis (CIMF), we sought to evaluate the safety and efficacy of the combination of lenalidomide and prednisone in a phase II study for pts with CIMF. The rationale for this combination is that the anti-angiogenic and anti-TNFa effects of lenalidomide may be potentiated by the effects of prednisone to reduce marrow fibrosis and improve hematopoiesis in CIMF. Initial therapy consisted of lenalidomide 10 mg/d (dose level [DL] 0) on days 1–21 of a 28–day cycle for 6 cycles, in combination with prednisone 30 mg/d orally during cycle 1, 15 mg/d orally during cycle 2, and 15 mg/d every other day during cycle 3. The lenalidomide dose could be reduced to 5 mg/d (DL -1) or to 5 mg/d every other day (DL -2), or increased to 15 mg/d (DL +1) or 20 mg/d (DL +2) depending upon toxicity or lack of response, respectively. A total of 40 pts (23 male, 17 female) have been enrolled. The median age was 62 years (range, 41–86), time from CIMF diagnosis to the study treatment 10 months (range, 0–269), WBC count 87x109/L (range, 1.1–89), hemoglobin 9.8 g/dL (range, 7.8–17.3), platelets 137x109/L (range, 8–1183). Pts had received a median of 1 prior therapy (range 0–4): hydroxyurea (HU; n=14), anagrelide (AG; n=4), azacitidine (n=6), steroids (n=5), thalidomide (n=4), and interferon (n=3). Ten (25%) pts had not received any prior therapy. JAK2 V617F mutation was detected in 18 (50%) of 36 tested pts and 20 (50%) of 40 had abnormal cytogenetics. A total of 260 cycles have been administered. All 40 pts are evaluable for response and toxicity. Responses have been observed in 12 (30%) pts, including complete response (CR) in 2 (normal blood counts and <5% bone marrow blasts, off HU, AG, growth factors, and no transfusions); partial response (PR) in 7 (at least 2 of the following: Hb increase by ≥2 g/dL, 50% increase in platelets, decrease of bone marrow blasts or organomegaly by ≥50%, normalization of WBC count without blasts, or reduction in bone marrow fibrosis; off HU, AG, growth factors, and transfusion independence); and hematologic improvement (HI) in 3 (at least 2 of the following: decrease by ≥25% of pretreatment leukocytosis, splenomegaly, or marrow blasts, or increase of Hb by ≥1g/dl without growth factor or transfusion support or platelets by ≥25%; off HU, AG, growth factors). Median time to response was 12 weeks (range, 2–32). Responses have been sustained for a median of 15 wks (range, 5–36) and are ongoing in all 12 responders. Overall, 21 (53%) pts experienced grade 3–4 toxicity, being the most frequent neutropenia, anemia, musculoskeletal pain, and fatigue. Twenty-four (60%) pts have required dose reduction to DL -1, of which 5 (12.5%) further reduced to DL -2. One (2.5%) pt dose-escalated to DL +1, while 15 (25%) remained at DL 0. Twenty-one (53%) pts discontinued lenalidomide due to: lack of response (n=8), pt’s decision (n=7), grade 3–4 toxicity (n=5), and poor compliance (n=1). No deaths or transformation to acute myeloid leukemia occurred. In summary, the combination of lenalidomide and prednisone is an active and generally well-tolerated regimen for pts with CIMF. Longer follow-up is warranted to evaluate the durability of ongoing responses. Updated results will be presented at the meeting.

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Genetic Background of Idiopathic Bone Marrow Failure Syndromes in Children

Blood ◽

10.1182/blood.v126.23.3610.3610 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3610-3610 ◽

Cited By ~ 1

Author(s):

Atsushi Narita ◽

Yusuke Okuno ◽

Hideki Muramatsu ◽

Kenichi Yoshida ◽

Yuichi Shiraishi ◽

...

Keyword(s):

Bone Marrow ◽

Allele Frequency ◽

Genetic Background ◽

Somatic Mutations ◽

Bone Marrow Failure ◽

Variant Allele ◽

Variant Allele Frequency ◽

Target Sequencing ◽

Bone Marrow Failure Syndromes ◽

The Mean

Abstract Introduction Pancytopenia with a severe decrease in bone marrow (BM) cellularity in children may be caused by a broad variety of underlying disorders. The appropriate classification of bone marrow failure syndromes in children is challenging, particularly with respect to the histological distinction between aplastic anemia (AA), refractory cytopenia of childhood (RCC), and refractory cytopenia with multilineage dysplasia (RCMD). Inherited bone marrow failure syndromes (IBMFS) further defy accurate diagnosis. Clonal hematopoiesis in AA is indicated by the presence of paroxysmal nocturnal hemoglobinuria (PNH) cells and by the identification of uniparental disomies involving chromosome 6p. In addition, "clonal transformation," as defined by the development of myelodysplastic syndromes (MDS) or acute myelogenous leukemia has been noted in about 15% of AA patients. In adult patients with AA, somatic mutations were frequently detected in myeloid malignancy-related genes such as DNMT3A, BCOR, and ASXL1. We aimed to characterize the genetic background of childhood AA/RCC/RCMD. Patients and Methods We studied 168 patients with idiopathic AA/RCC/RCMD in children. Diagnosis with AA, RCC, and RCMD was made on the basis of the 2008 World Health Organization classification criteria. Blood, bone marrow, and buccal samples were obtained from the patients after written informed consent was received according to protocols approved by the ethics committee of Nagoya University Graduate School of Medicine. Target sequencing (n = 168) was performed for 88 IBMFS-associated genes and 96 myeloid malignancy-related genes. Furthermore, whole-exome sequencing (WES, n = 25) was performed with matched tumor/normal samples. The mean depth for targeted sequencing was 451x, and the mean depth for WES was 103x. Somatic mutations were detected with the use of a frequency threshold of 0.07 (WES) or 0.02 (targeted sequencing) for variant allele frequency and were individually validated with the use of deep sequencing of polymerase-chain-reaction-amplified targets. Results Only one germline mutation that was diagnostic of IBMFS was detected in our cohort (0.6%). It was a RTEL1 mutation, which supported the diagnosis of dyskeratosis congenita. Telomere length of the patient with a RTEL1 mutation was shorter compared with that of age-matched healthy individuals (−3.2 Standard Deviation). WES, performed in 25 patients, detected only three somatic mutations, all of which affected BCOR. In target sequencing, 20 somatic mutations were detected in 19 patients (11.3%). BCOR (n = 9) and PIGA (n = 4) were recurrently mutated. The mutational frequency of DNMT3A and ASXL1 was very low (0.6%) in our cohort and was clearly different from that of an adult cohort. The majority of somatic mutations carried low variant allele frequency. In case of BCOR mutations, the variant allele frequency tended to be low, suggesting subclonal composition. In case of U2AF1 mutations, the variant allele frequency tended to be high, which suggests that the U2AF1 -mutated clone was dominant in the bone marrow. The difference in the frequency of somatic mutations in AA, RCC, and RCMD was not statistically significant (p = 0.49). However, with regard to the mutated genes, two patients with RCMD carried U2AF1 plus SETBP1 and TP53 mutations, respectively, which are well-known predictors of poor prognosis in adult MDS. The patient who carried U2AF1 plus SETBP1 developed MDS later and underwent bone marrow transplantation. Of the 19 patients with mutated genes, 15 patients were treated with immunosuppressive therapy (IST). The response rate to IST at 6 months was 60% in the patients with somatic mutations, which was equivalent to those without mutations. Conclusions In our cohort of children who were clinically diagnosed with AA/RCC/RCMD, the frequency of cryptic IBMFS was considered low. Furthermore, the frequency of detectable somatic mutations in childhood AA was low compared with that in adult AA. No novel mutational target was identified with WES. Idiopathic bone marrow failure syndromes in children were characterized by a paucity of gene mutations irrespective of the histopathological classification. Mutations in adult MDS-related genes suggest molecular pathogenesis is different between RCMD and AA/RCC. In conclusion, our study clarified the yet unrevealed genetic background of idiopathic bone marrow failure syndromes in children. Disclosures No relevant conflicts of interest to declare.

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Sezary's syndrome: report of a case showing peripheral neuropathy and bone marrow fibrosis

Archives of Dermatology ◽

10.1001/archderm.114.9.1360 ◽

1978 ◽

Vol 114 (9) ◽

pp. 1360-1362 ◽

Cited By ~ 2

Author(s):

H. Bargman

Keyword(s):

Bone Marrow ◽

Peripheral Neuropathy ◽

Bone Marrow Fibrosis ◽

Marrow Fibrosis ◽

Syndrome Report

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Faculty Opinions recommendation of Gli1+ mesenchymal stromal cells are a key driver of bone marrow fibrosis and an important cellular therapeutic target.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727567167.793534871 ◽

2017 ◽

Author(s):

Timothy Campbell

Keyword(s):

Bone Marrow ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Therapeutic Target ◽

Bone Marrow Fibrosis ◽

Key Driver ◽

Marrow Fibrosis

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Prolonged Myelosuppression due to Progressive Bone Marrow Fibrosis in a Patient with Acute Promyelocytic Leukemia

Case Reports in Hematology ◽

10.1155/2019/1616237 ◽

2019 ◽

Vol 2019 ◽

pp. 1-7

Author(s):

Yuta Inagawa ◽

Yukiko Komeno ◽

Satoshi Saito ◽

Yuji Maenohara ◽

Tetsuro Yamagishi ◽

...

Keyword(s):

Bone Marrow ◽

Acute Promyelocytic Leukemia ◽

Bone Marrow Biopsy ◽

Gastric Fluid ◽

Promyelocytic Leukemia ◽

Consolidation Therapy ◽

Bone Marrow Fibrosis ◽

All Trans Retinoic Acid ◽

Phlegmonous Gastritis ◽

Marrow Fibrosis

A 34-year-old woman was diagnosed with acute promyelocytic leukemia. Chemotherapy was administered following the JALSG APL204 protocol. Induction therapy with all-trans retinoic acid resulted in complete remission on day 49. She developed coccygeal pain from day 18, which spread to the spine and cheekbones and lasted 5 weeks. She had similar bone pain on days 7–10 of the first consolidation therapy and on days 4–12 of the second consolidation therapy. Oral loxoprofen was prescribed for pain relief. On day 33 of the third consolidation, white blood cell and neutrophil counts were 320/μL and 20/μL, respectively. After she developed epigastralgia and hematemesis, she developed septic shock. Gastroendoscopy revealed markedly thickened folds and diffusely damaged mucosa with blood oozing. Computed tomography revealed thickened walls of the antrum and the pylorus. Despite emergency treatments, she died. Bacterial culture of the gastric fluid yielded Enterobacter cloacae and enterococci growth. Collectively, she was diagnosed with phlegmonous gastritis. Retrospective examination of serial bone marrow biopsy specimens demonstrated progressive bone marrow fibrosis, which may have caused prolonged myelosuppression. Thus, evaluation of bone marrow fibrosis by bone marrow biopsy after each treatment cycle might serve as a predictor of persistent myelosuppression induced by chemotherapy.

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Examination of the predicted prevalence of Gitelman syndrome by ethnicity based on genome databases

Scientific Reports ◽

10.1038/s41598-021-95521-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Atsushi Kondo ◽

China Nagano ◽

Shinya Ishiko ◽

Takashi Omori ◽

Yuya Aoto ◽

...

Keyword(s):

Allele Frequency ◽

Carrier Frequency ◽

Japanese Population ◽

Autosomal Recessive ◽

Disease Prevalence ◽

Gitelman Syndrome ◽

Variant Allele ◽

Variant Allele Frequency ◽

Genome Databases ◽

Heterozygous Carriers

AbstractGitelman syndrome is an autosomal recessive inherited salt-losing tubulopathy. It has a prevalence of around 1 in 40,000 people, and heterozygous carriers are estimated at approximately 1%, although the exact prevalence is unknown. We estimated the predicted prevalence of Gitelman syndrome based on multiple genome databases, HGVD and jMorp for the Japanese population and gnomAD for other ethnicities, and included all 274 pathogenic missense or nonsense variants registered in HGMD Professional. The frequencies of all these alleles were summed to calculate the total variant allele frequency in SLC12A3. The carrier frequency and the disease prevalence were assumed to be twice and the square of the total allele frequency, respectively, according to the Hardy–Weinberg principle. In the Japanese population, the total carrier frequencies were 0.0948 (9.5%) and 0.0868 (8.7%) and the calculated prevalence was 0.00225 (2.3 in 1000 people) and 0.00188 (1.9 in 1000 people) in HGVD and jMorp, respectively. Other ethnicities showed a prevalence varying from 0.000012 to 0.00083. These findings indicate that the prevalence of Gitelman syndrome in the Japanese population is higher than expected and that some other ethnicities also have a higher prevalence than has previously been considered.

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