Janus kinase (JAK) inhibitors approved for myelofibrosis provide spleen and symptom improvements but do not meaningfully improve anaemia. Momelotinib, a first-in-class inhibitor of activin A receptor ...type 1 as well as JAK1 and JAK2, has shown symptom, spleen, and anaemia benefits in myelofibrosis. We aimed to confirm the differentiated clinical benefits of momelotinib versus the active comparator danazol in JAK-inhibitor-exposed, symptomatic patients with anaemia and intermediate-risk or high-risk myelofibrosis.
MOMENTUM is an international, double-blind, randomised, controlled, phase 3 study that enrolled patients at 107 sites across 21 countries worldwide. Eligible patients were 18 years or older with a confirmed diagnosis of primary myelofibrosis or post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis. Patients were randomly assigned (2:1) to receive momelotinib (200 mg orally once per day) plus danazol placebo (ie, the momelotinib group) or danazol (300 mg orally twice per day) plus momelotinib placebo (ie, the danazol group), stratified by total symptom score (TSS; <22 vs ≥22), spleen size (<12 cm vs ≥12 cm), red blood cell or whole blood units transfused in the 8 weeks before randomisation (0 units vs 1–4 units vs ≥5 units), and study site. The primary endpoint was the Myelofibrosis Symptom Assessment Form (MFSAF) TSS response rate at week 24 (defined as ≥50% reduction in mean MFSAF TSS over the 28 days immediately before the end of week 24 compared with baseline). MOMENTUM is registered with ClinicalTrials.gov, number NCT04173494, and is active but not recruiting.
195 patients were randomly assigned to either the momelotinib group (130 67%) or danazol group (65 33%) and received study treatment in the 24-week randomised treatment period between April 24, 2020, and Dec 3, 2021. A significantly greater proportion of patients in the momelotinib group reported a 50% or more reduction in TSS than in the danazol group (32 25% of 130 vs six 9% of 65; proportion difference 16% 95% CI 6–26, p=0·0095). The most frequent grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were haematological abnormalities by laboratory values: anaemia (79 61% of 130 vs 49 75% of 65) and thrombocytopenia (36 28% vs 17 26%). The most frequent non-haematological grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were acute kidney injury (four 3% of 130 vs six 9% of 65) and pneumonia (three 2% vs six 9%).
Treatment with momelotinib, compared with danazol, resulted in clinically significant improvements in myelofibrosis-associated symptoms, anaemia measures, and spleen response, with favourable safety. These findings support the future use of momelotinib as an effective treatment in patients with myelofibrosis, especially in those with anaemia.
Sierra Oncology.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Telomere biology disorder (TBD) can present within a wide spectrum of symptoms ranging from severe congenital malformations to isolated organ dysfunction in adulthood. Diagnosing TBD can be ...challenging given the substantial variation in symptoms and age of onset across generations. In this report, we present two families, one with a pathogenic variant in ZCCHC8 and another with a novel variant in TERC. In the literature, only one family has previously been reported with a ZCCHC8 variant and TBD symptoms. This family had multiple occurrences of pulmonary fibrosis and one case of bone marrow failure. In this paper, we present a second family with the same ZCCHC8 variant (p.Pro186Leu) and symptoms of TBD including pulmonary fibrosis, hematological disease, and elevated liver enzymes. The suspicion of TBD was confirmed with the measurement of short telomeres in the proband. In another family, we report a novel likely pathogenic variant in TERC. Our comprehensive description encompasses hematological manifestations, as well as pulmonary and hepatic fibrosis. Notably, there are no other reports which associate this variant to disease. The families expand our understanding of the clinical implications and genetic causes of TBD.
This study identified a variant in ZCCHC8 in a family with pulmonary fibrosis, elevated liver enzymes and short telomeres and a novel variant in the J6a‐6.1 region of TERC in a family with pulmonary fibrosis, hematological disease, and short telomeres.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Peripheral T‐Cell Lymphomas (PTCLs) are rare, aggressive lymphomas with poor outcomes, but limited‐stage disease is infrequent and not well‐described. This study reports outcomes and prognostic ...factors in limited‐stage nodal PTCLs in a binational population‐based setting. Patients were identified from the Danish and Swedish lymphoma registries. Adults diagnosed with limited‐stage nodal PTCL (stage I‐II) and treated with CHOP(−like) therapy ±radiotherapy between 2000 and 2014 were included. Medical records were reviewed by local investigators. A total of 239 patients with a median age of 62 years were included; 67% received 6–8 cycles of CHOP(−like) therapy and 22% received 3–4 cycles, of which 59% also received radiotherapy. Autologous stem cell transplant consolidation was administered to 16% of all patients. Median follow‐up was 127 months with 5‐years overall survival (OS) of 58% (95% CI: 53–65) and progression‐free survival (PFS) of 53% (95% CI: 47–59). In multivariable analysis, age ≥ 60 years and B‐symptoms were unfavorable and ALK+ anaplastic large cell T‐Cell lymphoma was favorable for survival outcomes. There was no difference in treatment‐specific outcome (3–4 cycles vs. 6–8 cycles of CHOP(−like) ± radiotherapy). Low‐risk patients (age < 60 without B‐symptoms) had a 5‐year OS of 77% (95% CI 67–89%). In the present study of limited‐stage nodal PTCL, survival after curative intent chemotherapy +/− radiotherapy was inferior to that of limited‐stage diffuse large B‐cell lymphoma, but a subgroup of young patients without B‐symptoms had very good outcomes. Treatment outcomes after 3–4 cycles versus 6–8 cycles of CHOP(−like) therapy were comparable.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Current estimates suggest that up to 10% of patients with myeloid neoplasms (MN) harbor variants associated with a germline predisposition. A pathogenic variant in the runt-related transcription ...factor 1 gene (RUNX1) is a frequent cause of germline predisposition to MN. RUNX1 variants detected in tumor tissue at a VAF close to 50% are potentially germline and causative of RUNX1 familial platelet disorder with associated myeloid malignancies. Previous studies have found germline RUNX1 variants in 3% of patients with acute myeloid leukemia; however, the frequency of germline RUNX1 variants in less advanced myeloid neoplasms has not been examined. We screened 590 patients suspected of MN, excluding myeloproliferative neoplasms, for germline variants in RUNX1. We found RUNX1 variants in 83 patients (14%) by targeted sequencing of tumor tissue. In 40 patients (6.8%), the VAF of RUNX1 was above 30%. In 32 of the 40 patients, skin biopsies were available and used for Sanger sequencing to assess the germline status. Two of the tested variants (6.3%) were confirmed as germline, and both variants were curated as variants of unknown significance. To further explore the pathogenicity of these variants, we implemented a novel CRISPR-Select functional genetic assay. The assay demonstrated a profound effect on proliferation in K562 cells for a known pathogenic variant but no effect for the two germline variants detected in the study. We therefore propose that both germline variants are classified as likely benign. In this study, we show that RUNX1 germline variants are rare in Danish patients with MN and use a novel assay for functional classification of germline RUNX1 variants.
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BFBNIB, FZAB, GIS, IJS, KILJ, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Cardiovascular diseases, especially congestive heart failure (CHF), are known complications of anthracyclines, but the risk for patients undergoing high-dose chemotherapy and autologous stem cell ...transplant (HDT-ASCT) is not well established. With T-cell therapies emerging as alternatives, studies of long-term complications after HDT-ASCT are warranted. Danish patients treated with HDT-ASCT for aggressive lymphoma between 2001 and 2017 were matched 1:5 on sex, birth year and Charlson comorbidity score to the general population. Events were captured using nationwide registers. A total of 787 patients treated with HDT-ASCT were identified. Median follow-up was 7.6 years. The risk of CHF was significantly increased in the HDT-ASCT population compared to matched comparators with an adjusted hazard ratio (HR) of 5.5 (3.8-8.1). The 10-year cumulative incidence of CHF was 8.0% versus 2.0% (p < 0.001). Male sex, ≥2 lines of therapy, hypertension and cumulative anthracycline dose (≥300 mg/m
) were risk factors for CHF. In a separate cohort of 4089 lymphoma patients, HDT-ASCT was also significantly associated with increased risk of CHF (adjusted HR of 2.6 1.8-3.8) when analysed as a time-dependent exposure. HDT-ASCT also increased the risk of other cardiac diseases. These findings are applicable for the benefit/risk assessment of HDT-ASCT versus novel therapies.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The treatment of relapsed or refractory (R/R) acute myeloid leukaemia (AML) remains challenging and outcomes extremely poor. The introduction of venetoclax has transformed the treatment of AML and ...emerging data suggest that venetoclax-based therapy may enforce salvage treatment.
In this nationwide Danish retrospective study, we analysed treatment outcomes of venetoclax-based salvage treatment for R/R AML between 2019 and 2022. Only venetoclax-naive patients who had previously received treatment with intensive chemotherapy therapy were included.
The cohort consisted of 43 R/R patients with a median age of 57 years. Nine (20.9%) were primary refractory and 34 (79.1%) patients had relapsed, including 21 after previous allogeneic stem cell transplantation. The overall response rate was 76.2% including 61.9% with composite complete remission (CRc: CR + CRi). Among CRc-responders with information on measurable residual disease (MRD), 8/13 (61.5%) obtained an MRD-negativity response. The overall survival was 9.3 months for all patients with an estimated 1-year overall survival of 34%. For CRc-responders the median overall survival was 13.3 months, and the median relapse-free survival was 12.8 months.
Venetoclax-based salvage treatment for R/R AML produced high response rates; however, for most patients the response was of limited duration. This study is limited by an observational design and prone to selection bias.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Summary
Overweight patients with cancer are frequently reduced in chemotherapy dose due to toxicity concerns, although previous studies have indicated that dose reduction (DR) of overweight patients ...results in comparable toxicity but may compromise overall survival (OS). Current evidence regarding DR in patients with acute myeloid leukaemia (AML) is limited. To investigate the association between DR and outcome among overweight patients with AML we analysed a Danish nationwide cohort of overweight adult AML patients treated with remission induction chemotherapy. Among 536 patients identified, 10.1% were categorized as DR defined as 95% or less of full body surface area (BSA)‐based dose. Risk factors for DR were high body mass index (BMI) and BSA, therapy‐related AML and favourable cytogenetics. No significant differences were observed for rates of complete remission (CR), 30‐ and 90‐day mortality between DR and non‐DR patients. Furthermore, DR did not affect median relapse‐free survival (RFS) DR, 14.5 (95% confidence interval, 9.0–41.7) months; non‐DR, 15.0 (12.3–19.3) with an adjusted difference in five‐year restricted mean survival time (Δ5y‐RMST) of 0.2 (−8.4 to 8.8) months nor median OS (DR, 17.0 11.9 to 45.5 months; non‐DR, 17.5 14.8 to 20.5) with an adjusted Δ5y‐RMST of 0.8 (−5.7 to 7.3) months. In conclusion, we found no statistically significant association between DR and outcomes among overweight patients with AML. However, we acknowledge the limited sample size and encourage further studies in this important subject.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Healthcare databases can be a valuable source of epidemiological research regarding postoperative venous thromboembolism (VTE), ie, deep vein thrombosis (DVT) and pulmonary embolism (PE), following ...orthopedic procedures, but only if the diagnoses are valid. We examined the validity of VTE diagnosis codes in the Danish National Patient Registry (DNPR) by calculating their positive predictive value (PPV) and negative predictive value (NPV) versus actual medical records.
We identified patients who had undergone lower limb surgery during the period 2009-2019 at a hospital in the North Denmark Region. Of these, 420 patients had at least one VTE diagnosis registered in the DNPR within 180 days after lower limb surgery. Each patient with a VTE diagnosis was matched with two patients on age and sex, as well as type, location and period of surgery. The entire medical record and diagnostic imaging were reviewed to confirm VTE diagnosis.
The overall PPVs was 85.2% (95% CI: 81.5-88.5%) for first time VTE diagnosis following lower limb surgery, 82.6% (95% CI: 77.5-82.8%) for DVT, and 90.3% (95% CI: 84.3-94.6%) for PE. We found improvement in PPV during the study period when stratifying for three periods of the whole period. There were no significant differences when stratifying for sex, age, or surgery site. All negative predictive values were higher than 99%. A total of 113 additional VTE diagnoses were registered among 88 VTE patients during follow-up. Only four of the suspected recurrent VTEs were confirmed to be true recurrent VTEs.
The VTE diagnosis codes in the DNPR after lower limb orthopedic surgery were highly valid against the actual medical records, and we observed better PPV over recent years.
Background
The aetiology of multiple myeloma (MM) is unknown but various environmental exposures are suspected as risk factors. We present the first paper analysing the geographical distribution of ...MM in Denmark at the municipal level to investigate variations that could be explained by environmental exposures.
Methods
Patients diagnosed with MM in Denmark during 2005–2020 were identified from nationwide registries and grouped into the 98 Danish municipalities based on residence. The age‐ and sex‐standardised incidence rate (SIR) of each municipality was compared to the national incidence in a funnel plot with 95% control limits. Differences in SIRs of rural, suburban, and urban areas were evaluated with incidence rate ratios.
Results
In total, 5243 MM patients were included. Overall, we found a heterogeneous geographical distribution of MM and a potential hotspot in southern Denmark. This hotspot contains three municipalities with SIRs above the 95% control limit assuming considerably higher rate of MM compared to the national incidence rate. A significant higher SIR was found in rural areas compared to urban areas.
Conclusion
The geographical distribution of MM in Denmark indicates that the risk of developing MM depends on place of residence probably due to environmental factors.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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