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Highlights in Myelodysplastic Syndromes KYMRIAHCART T CONGRESS HIGHLIGHTS 27 Hospital Price 0.2 to 5 x 106 CAR positive viable T cells/kg body weight € 320.000 SPECIAL EDITION 0.1 to 2.5 x 108 CAR positive viable T cells € 320.000 0.6 to 6 x 108 CAR positive viable T cells € 320.000 Highlights in myelodysplastic syndromes KYMRIAHCART T. Feys, MSC, MBA In this article, a selection of interesting abstracts related to myelodysplastic syndromes (MDS) will be discussed. In lower-risk MDS, most attention goes to therapies that address anaemia. In this respect updated results of THE TRANSFORMATION OF a phase III trial evaluating luspatercept were presented, while also the hydroxylase inhibitor roxadustat showed promising results. In addition to this, interesting data were presented on the restoration of erythropoietin CANCER TREATMENT IS HERE sensitivity by lenalidomide. In higher-risk MDS, an abstract will be discussed looking at the optimal schedule for the administration of hypomethylating agents (HMA) next to a study evaluating the safety and efficacy of an oral HMA formulation. In addition to this, several new therapeutic options are being explored in higher-risk the 4-1BB CAR-T cell therapy MDS. This includes combinations of novel agents (e.g. venetoclax, rigosertib, telaglenastat) with azacitidine and the use of targeted agents, specifically directed against mutations in MDS e.g.( olutasidenib, APR-246 approved in two distinct patient and enasidenib). population, ALL and DLBCL (BELG J HEMATOL 2020;11(1):27-34) LOWER-RISK MDS reduced the transfusion burden compared to placebo.3 During LUSPATERCEPT FOR LOW-RISK MDS PATIENTS ASH 2019, updated results of this study were presented. WITH RING SIDEROBLASTS, REQUIRING Eligible patients were ≥18 years of age with IPSS-R-defined RED BLOOD CELL TRANSFUSIONS: UPDATED Very low-, Low-, or Intermediate-risk MDS with ring sidero- ANALYSIS OF MEDALIST blasts (RS). In total, 229 patients (refractory, intolerant, or Anaemia is the most common cytopenia in patients with unlikely to respond to and requiring regular RBC trans- low-risk (LR) MDS and is associated with a number of com- fusions) were randomised (2:1) to luspatercept (1.0 mg/kg plications, such as fatigue, falls and a decreased quality of titrated up to 1.75 mg/kg, if needed) or placebo, subcutane- life. The standard of care to treat this anaemia consists of ously every 3 weeks. The updated results indicate that 47.7% erythropoiesis-stimulating agents (ESAs) and red-blood cell of patients treated with luspatercept achieved RBC trans- transfusions (RBC). However, RBC dependence is associated fusion independence (RBC-TI) ≥8 weeks at any time during with a reduced survival and responses to ESAs are limited.1 the treatment period as compared to only 15.8% in the For patients with transfusion-dependent LR-MDS for whom placebo arm (OR[95%CI]: 5.978[2.840-12.581]; p< 0.0001) ESAs have become ineffective (or who are not candidates (Figure 1).4 This higher RBC-TI ≥8 weeks with luspatercept for ESA therapy), the treatment options are limited. Luspa- vs. placebo was seen regardless of baseline transfusion tercept is a first-in-class erythroid maturation agent that burden. Interestingly, approximately 70% of responders in binds select TGF-β superfamily ligands to reduce aberrant the luspatercept arm had multiple response periods during Smad2/3 signalling and enhance late-stage erythropoiesis.2 the treatment. The median cumulative duration of RBC-TI This agent is already FDA approved for the treatment of ≥8 weeks in all responders was substantially longer with anaemia in adult patients with β-thalassemia. In the ran- luspatercept than with placebo (79.9 vs. 21.0 weeks; HR[95%- domised phase III MEDALIST trial, luspatercept significantly CI]: 0.485[0.205-1.149]). The median treatment duration Ariez International BV, Ghent, Belgium. KYMRIAH is the fi rst CAR-T cell therapy reimbursed in Belgium Please send all correspondence to: T. Feys, MSc, MBA, Ariez International, Oude Houtlei 118, 9000 Ghent, E-mail: [email protected], for the treatment of: Tel: 0479/567890. Conflict of interest: The selection of the abstracts discussed in this overview are the sole responsibility of the author and was not influenced • Adult patients with relapsed or refractory diffuse large B-cell by third parties. lymphoma (DLBCL) after two or more lines of systemic therapy. Keywords: anaemia, ring sideroblasts, azacitidine, decitabine, enasidenib, ESA, hypomethylating, IDH, lenalidomide, luspatercept, MDS, olutasidenib, rigosertib, roxadustat, telaglenastat, TP53, venetoclax. • Paediatric and young adult patients up to 25 years of age with B-cell acute lymphoblastic leukaemia (ALL) that is refractory, in relapse post-transplant or in second or later relapse. TREATMENT TRANSFORMED VOLUME11FEBRUARY20201 Kymriah_Pub A4.indd 1 14/10/2019 9:37:22 28 P < 0.0001a OR (95% CI):a 5.978 (2.840-12.581) 60% 50% 47.7% 40% 30% N = 73 8 Weeks Any Time ≥ 20% 15.8% Patients Achieving Patients 10% N = 12 RBC-TI During the Period Treatment (%) 0% Luspatercept Placebo (N = 153) (N = 76) Primary endpoint previously reported: 37.9% luspatercept versus 13.2% placebo patients achieved RBC-TI ≥ 8 weeks during Weeks 1-24 (P < 0.0001) FIGURE 1. RBC-TI ≥8 weeks at any time during the treatment with luspatercept vs. placebo in the phase III MEDALIST trial.4 with luspatercept was 50.9 weeks as compared to 24 weeks trials, treatment with lenalidomide (LEN) monotherapy gave with placebo (109 vs. 53.9 weeks in patients with RBC-TI rise to RBC-TI in 26% of TD LR, non-del(5q) MDS patients ≥ 8 weeks). Of the 153 luspatercept-treated patients, 7.8% for a median of 10.2 and 7.75 months, respectively.5,6 In a remained transfusion-free after the first dose of luspatercept pilot study of Epo-refractory LR-MDS patients, the addition throughout week 48. The percentage of patients experiencing of epoetin alfa (EA) to LEN treatment yielded erythroid at least 1 treatment-related adverse event (TRAE) during responses in 28% of patients who were unresponsive to the study was comparable for both arms at 87.6% with lus- LEN alone. This indicates that LEN may overcome clinical patercept and 82.9% with placebo. However, the incidence resistance and augment the response to Epo.7 To further test of TRAEs leading to treatment discontinuation was higher this hypothesis, a randomised phase III trial was performed with luspatercept (13.7% vs. 7.9%). AEs occurring more fre- comparing LEN to LEN + EA in LR non-del(5q) MDS patients quently with luspatercept vs. placebo (fatigue, diarrhoea, who were refractory to, or ineligible for treatment with Epo.8 asthenia, dizziness) occurred early (cycles 1–4), were mainly In the study at hand, 215 patients with low- or intermediate-1 grade 1 or 2, decreased over time, and were not associated IPSS MDS with ESA failure, or a low response profile were with a higher dose level. Progression to high-risk (HR) MDS randomly assigned to LEN (10mg/d x21d q28d) or LEN or acute myeloid leukaemia (AML) was similar in patients + EA (60.000 SC/week). The primary endpoint was major receiving luspatercept or placebo (3.3% vs. 2.6% and 2.0% erythroid response (MER) at week 16, which was defined vs. 2.6% for HR-MDS and AML, respectively).4 according to the transfusion status at baseline: (I) achieve- As such, luspatercept is a potential new therapy to treat ment of RBC-TI for ≥8 consecutive weeks AND a sustained anaemia in patients with LR-MDS and RS. The COMMANDS ≥1 g/dL haemoglobin rise compared to mean pre-transfusion trial is currently comparing luspatercept to epoetin alfa (EA) baseline value in TD patients; and (II) a >2 g/dL rise in in transfusion-dependent (TD) patients with LR-MDS. haemoglobin without transfusion for ≥ 8 consecutive weeks in non-TD patients (<4U RBC/8 weeks). In case of a non- LENALIDOMIDE RESTORES SENSITIVITY TO response to LEN alone, patients were allowed to cross-over ERYTHROPOIETIN IN LR-MDS PATIENTS to the combination treatment. The median age of patients WITHOUT A DEL(5Q) in the study was 74 years, 93% received prior Epo and at Only a small subset of LR- MDS patients benefit from treat- baseline patients received a median of 4 RBC transfusions ment with Erythropoietin (Epo). In the MDS-002 and -005 over an 8-week period. In an intent to treat analysis, 28/99 VOLUME11FEBRUARY2020 CONGRESS HIGHLIGHTS 29 SPECIAL EDITION patients (28.3%) in the combination arm achieved MER HIGHER-RISK MDS compared to 11/96 (11.5%) in the LEN monotherapy arm WHAT IS THE OPTIMAL AZACITIDINE SCHEDULE (p= 0.004). Of the 44 patients who crossed over from LEN FOR PATIENTS WITH HR-MDS: to the combination, 11 (25%) obtained a MER. Of note, the 7-DAY SCHEDULE SEEMS BETTER THAN 5 DAYS MER rate was independent of the RBC transfusion burden Azacitidine (AZA) is a HMA that significantly prolongs the at baseline. Interestingly, the modulation of the Epo respon- overall survival (OS) of patients with HR-MDS. However, siveness by LEN also led to a longer, clinically meaningful the optimal treatment schedule of AZA for HR-MDS has not response duration with a median MER duration of approxi- yet been prospectively determined. As a 7-day treatment mately 2 years compared to 13 months with LEN mono- schedule includes weekends, a 5-day administration is often therapy (p= 0.24). There was no significant difference in the applied, although solid evidence for this has not been frequency or distribution of grade ≥3, non-haematologic established. To address this issue, a prospective clinical trial AEs between treatment arms.8 was set up.
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