Haematology

Permanent URI for this collection

Research outputs form the Clinical Haematology service at the RD&E.

Browse

Recent Submissions

Now showing 1 - 5 of 27
  • Item
    Ruxolitinib Versus Best Available Therapy for Polycythemia Vera Intolerant or Resistant to Hydroxycarbamide in a Randomized Trial
    (American Society of Clinical Oncology, 2023-07-01) Harrison, C. N.; Nangalia, J.; Boucher, R.; Jackson, A.; Yap, C.; O'Sullivan, J.; Fox, S.; Ailts, I.; Dueck, A. C.; Geyer, H. L.; Mesa, R. A.; Dunn, W. G.; Nadezhdin, E.; Curto-Garcia, N.; Green, A.; Wilkins, B.; Coppell, J.; Laurie, J.; Garg, M.; Ewing, J.; Knapper, S.; Crowe, J.; Chen, F.; Koutsavlis, I.; Godfrey, A.; Arami, S.; Drummond, M.; Byrne, J.; Clark, F.; Mead-Harvey, C.; Baxter, E. J.; McMullin, M. F.; Mead, A. J.
    PURPOSE: Polycythemia vera (PV) is characterized by JAK/STAT activation, thrombotic/hemorrhagic events, systemic symptoms, and disease transformation. In high-risk PV, ruxolitinib controls blood counts and improves symptoms. PATIENTS AND METHODS: MAJIC-PV is a randomized phase II trial of ruxolitinib versus best available therapy (BAT) in patients resistant/intolerant to hydroxycarbamide (HC-INT/RES). Primary outcome was complete response (CR) within 1 year. Secondary outcomes included duration of response, event-free survival (EFS), symptom, and molecular response. RESULTS: One hundred eighty patients were randomly assigned. CR was achieved in 40 (43%) patients on ruxolitinib versus 23 (26%) on BAT (odds ratio, 2.12; 90% CI, 1.25 to 3.60; P = .02). Duration of CR was superior for ruxolitinib (hazard ratio [HR], 0.38; 95% CI, 0.24 to 0.61; P < .001). Symptom responses were better with ruxolitinib and durable. EFS (major thrombosis, hemorrhage, transformation, and death) was superior for patients attaining CR within 1 year (HR, 0.41; 95% CI, 0.21 to 0.78; P = .01); and those on ruxolitinib (HR, 0.58; 95% CI, 0.35 to 0.94; P = .03). Serial analysis of JAK2V617F variant allele fraction revealed molecular response was more frequent with ruxolitinib and was associated with improved outcomes (progression-free survival [PFS] P = .001, EFS P = .001, overall survival P = .01) and clearance of JAK2V617F stem/progenitor cells. ASXL1 mutations predicted for adverse EFS (HR, 3.02; 95% CI, 1.47 to 6.17; P = .003). The safety profile of ruxolitinib was as previously reported. CONCLUSION: The MAJIC-PV study demonstrates ruxolitinib treatment benefits HC-INT/RES PV patients with superior CR, and EFS as well as molecular response; importantly also demonstrating for the first time, to our knowledge, that molecular response is linked to EFS, PFS, and OS.
  • Item
    Genome sequencing and comprehensive rare-variant analysis of 465 families with neurodevelopmental disorders
    (Cell Press, 2023-08-01) Sanchis-Juan, A.; Megy, K.; Stephens, J.; Armirola Ricaurte, C.; Dewhurst, E.; Low, K.; French, C. E.; Grozeva, D.; Stirrups, K.; Erwood, M.; McTague, A.; Penkett, C. J.; Shamardina, O.; Tuna, S.; Daugherty, L. C.; Gleadall, N.; Duarte, S. T.; Hedrera-Fernández, A.; Vogt, J.; Ambegaonkar, G.; Chitre, M.; Josifova, D.; Kurian, M. A.; Parker, A.; Rankin, J.; Reid, E.; Wakeling, E.; Wassmer, E.; Woods, C. G.; Raymond, F. L.; Carss, K. J.
    Despite significant progress in unraveling the genetic causes of neurodevelopmental disorders (NDDs), a substantial proportion of individuals with NDDs remain without a genetic diagnosis after microarray and/or exome sequencing. Here, we aimed to assess the power of short-read genome sequencing (GS), complemented with long-read GS, to identify causal variants in participants with NDD from the National Institute for Health and Care Research (NIHR) BioResource project. Short-read GS was conducted on 692 individuals (489 affected and 203 unaffected relatives) from 465 families. Additionally, long-read GS was performed on five affected individuals who had structural variants (SVs) in technically challenging regions, had complex SVs, or required distal variant phasing. Causal variants were identified in 36% of affected individuals (177/489), and a further 23% (112/489) had a variant of uncertain significance after multiple rounds of re-analysis. Among all reported variants, 88% (333/380) were coding nuclear SNVs or insertions and deletions (indels), and the remainder were SVs, non-coding variants, and mitochondrial variants. Furthermore, long-read GS facilitated the resolution of challenging SVs and invalidated variants of difficult interpretation from short-read GS. This study demonstrates the value of short-read GS, complemented with long-read GS, in investigating the genetic causes of NDDs. GS provides a comprehensive and unbiased method of identifying all types of variants throughout the nuclear and mitochondrial genomes in individuals with NDD.
  • Item
    Frailty subgroup analysis of isatuximab with pomalidomide and dexamethasone in a UK-wide real-world cohort of relapsed myeloma patients
    (Wiley, 2023-04-01) Djebbari, F.; Rampotas, A.; Vallance, G.; Panitsas, F.; Basker, N.; Sangha, G.; Salhan, B.; Karim, F.; Al-Kaisi, F.; Gudger, A.; Ngu, L.; Poynton, M.; Lam, H. P. J.; Morgan, L.; Yang, L.; Young, J.; Walker, M.; Tsagkaraki, I.; Anderson, L.; Chauhan, S. R.; Maddams, R.; Soutar, R.; Triantafillou, M.; Prideaux, S.; Obeidalla, A.; Eyre, T. A.; Bygrave, C.; Kothari, J.; Basu, S.; Ramasamy, K.
  • Item
    Efficacy of Isatuximab With Pomalidomide and Dexamethasone in Relapsed Myeloma: Results of a UK-Wide Real-World Dataset
    (Lippincott, Williams & Wilkins, 2022-06-01) Djebbari, F.; Rampotas, A.; Vallance, G.; Panitsas, F.; Basker, N.; Sangha, G.; Salhan, B.; Karim, F.; Al-Kaisi, F.; Gudger, A.; Ngu, L.; Poynton, M.; Lam, H. P. J.; Morgan, L.; Yang, L.; Young, J.; Walker, M.; Tsagkaraki, I.; Anderson, L.; Chauhan, S. R.; Maddams, R.; Soutar, R.; Triantafillou, M.; Prideaux, S.; Obeidalla, A.; Bygrave, C.; Basu, S.; Ramasamy, K.
    Real-world data on the efficacy and tolerability of isatuximab with pomalidomide and dexamethasone (IsaPomDex) in relapsed/refractory myeloma patients have not been reported. In this UK-wide retrospective study, IsaPomDex outcomes were evaluated across 24 routine care cancer centers. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), duration of response (DOR) for patients who achieved an objective response (≥partial response [PR]), and adverse events (AEs). In a total cohort 107 patients, median follow up (interquartile range [IQR]) was 12.1 months (10.1-18.6 mo), median age (IQR) was 69 years (61-77). Median (IQR) Charlson Comorbidity Index (CCI) score was 3 (2-4); 43% had eGFR <60 mL/min. Median (IQR) number of prior therapies was 3 (3-3). Median (IQR) number of IsaPomDex cycles administered was 7 (3-13). ORR was 66.4%, with responses categorized as ≥ very good partial response: 31.8%, PR: 34.6%, stable disease: 15.9%, progressive disease: 15%, and unknown 2.8%. Median PFS was 10.9 months. Median DOR was 10.3 months. There was no statistical difference in median PFS by age (<65: 10.2 versus 65-74 13.2 versus ≥75: 8.5 mo, log-rank P = 0.4157), by CCI score (<4: 10.2 mo versus ≥4: 13.2, log-rank P = 0.6531), but inferior PFS was observed with renal impairment (≥60: 13.2 versus <60: 7.9 mo, log-rank P = 0.0408). Median OS was 18.8 months. After a median of 4 cycles, any grade AEs were experienced by 87.9% of patients. The most common ≥G3 AEs were neutropenia (45.8%), infections (18.7%), and thrombocytopenia (14%). Our UK-wide IsaPomDex study demonstrated encouraging efficacy outcomes in the real world, comparable to ICARIA-MM trial.
  • Item
    Infections in relapsed myeloma patients treated with isatuximab plus pomalidomide and dexamethasone during the COVID-19 pandemic: Initial results of a UK-wide real-world study
    (American Society of Hematology, 2022-12-01) Djebbari, F.; Rampotas, A.; Vallance, G.; Panitsas, F.; Basker, N.; Sangha, G.; Salhan, B.; Karim, F.; Firas, A. K.; Gudger, A.; Ngu, L.; Poynton, M.; Lam, H. P. J.; Morgan, L.; Yang, L.; Young, J.; Walker, M.; Tsagkaraki, I.; Anderson, L.; Chauhan, S. R.; Maddams, R.; Soutar, R.; Triantafillou, M.; Prideaux, S.; Obeidalla, A.; Eyre, T. A.; Bygrave, C.; Basu, S.; Ramasamy, K.
    OBJECTIVES: There are no real-world data describing infection morbidity in relapsed/refractory myeloma (RRMM) patients treated with anti-CD38 isatuximab in combination with pomalidomide and dexamethasone (IsaPomDex). In this UK-wide retrospective study, we set out to evaluate infections experienced by routine care patients who received this novel therapy across 24 cancer centres during the COVID-19 pandemic. METHODS: The primary endpoint was infection morbidity (incidence, grading, hospitalization) as well as infection-related deaths. Secondary outcomes were clinical predictors of increased incidence of any grade (G2-5) and high grade (≥G3) infections. RESULTS: In a total cohort of 107 patients who received a median (IQR) of 4 cycles (2-8), 23.4% of patients experienced ≥1 any grade (G2-5) infections (total of 31 episodes) and 18.7% of patients experienced ≥1 high grade (≥G3) infections (total of 22 episodes). Median time (IQR) from start of therapy to first episode was 29 days (16-75). Six patients experienced COVID-19 infection, of whom 5 were not vaccinated and 1 was fully vaccinated. The cumulative duration of infection-related hospitalizations was 159 days. The multivariate (MVA) Poisson Regression analysis demonstrated that a higher co-morbidity burden with Charlson Co-morbidity Index (CCI) score ≥4 (incidence rate ratio (IRR) = 3, p = 0.012) and sub-optimal myeloma response less than a partial response (