Clinical trial NCT02990338: Multinational Clinical Study Comparing Isatuximab, Pomalidomide, and Dexamethasone to Pomalidomide and Dexamethasone in Refractory or Relapsed and Refractory Multiple Myeloma Patients
Official title: A Phase 3 Randomized, Open-label, Multicenter Study Comparing Isatuximab (SAR650984) in Combination With Pomalidomide and Low-Dose Dexamethasone Versus Pomalidomide and Low-Dose Dexamethasone in Patients With Refractory or Relapsed and Refractory Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Plasma Cell Myeloma
Keywords: Anti-CD38 monoclonal antibody
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2016-12-13
Enrollment: 307
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Primary Objective:

To demonstrate the benefit of isatuximab in combination with pomalidomide and low-dose dexamethasone in the prolongation of Progression Free Survival (PFS) as compared to pomalidomide and low-dose dexamethasone in participants with refractory or relapsed and refractory multiple myeloma (MM).

Secondary Objectives:

* To evaluate the Overall Response Rate (ORR) as per International Myeloma Working Group (IMWG) criteria in each arm.
* To compare the Overall Survival (OS) between the two arms.
* To evaluate the Time To Progression (TTP) in each arm.
* To evaluate the PFS in high risk cytogenetic population in each arm.
* To evaluate the Duration of Response (DOR) in each arm.
* To evaluate the safety in both treatment arms.
* To determine the Pharmacokinetic profile of isatuximab in combination with pomalidomide.
* To evaluate the immunogenicity of isatuximab.
* To assess disease-specific and generic health-related quality of life (HRQL), disease and treatment-related symptoms, health state utility, and health status.

Detailed description: The duration of the study for the participants included a period for screening of up to 21 days (or up to 28 days for women who can become pregnant). Participants continued study treatment until disease progression, unacceptable adverse reaction, participants' wish or other reason of discontinuation.

During follow-up, participants who discontinued the study treatment due to progression of the disease were followed every 3 months (12 weeks) for survival (or until cut-off date), and participants who discontinued the study treatment prior to documentation of disease progression were followed-up every 4 weeks until disease progression, and then every 3 months (12 weeks) for survival (or until cut-off date).

Eligibility criteria: Inclusion criteria :

* Age superior or equal to 18 years or country's legal age of majority if the legal age was superior to 18 years old.
* Participants had a documented diagnosis of multiple myeloma with evidence of measurable disease i.e. serum M protein superior or equal to 0.5 grams per decilitre (g/dL) measured using serum protein immunoelectrophoresis and or urine M protein superior or equal to 200 mg per 24 hours measured using urine protein immunoelectrophoresis.
* Participants had received at least 2 prior lines of anti-myeloma therapy, which must include at least 2 consecutive cycles of lenalidomide and a proteasome inhibitor (bortezomib, carfilzomib or ixazomib) given alone or in combination.
* Participants had failed treatment with lenalidomide and a proteasome inhibitor (bortezomib, carfilzomib, or ixazomib) alone or in combination (Intolerant, progression within 6 months after reaching Partial Response or better).
* Participants had progressed on or within 60 days after end of previous therapy before to study entry, i.e., refractory to the last line of treatment.

Exclusion criteria:

* Primary refractory multiple myeloma defined as participants who had never achieved at least a minimal response (MR) with any treatment during the disease course.
* Free Light Chain measurable disease only.
* Prior therapy with pomalidomide.
* Any anti-myeloma drug treatment within 14 days before randomization, including dexamethasone.
* Eastern Cooperative Oncology Group performance status superior to 2.
* Platelets inferior to 75 000 cells per microliter (mcL) if inferior to 50% of bone marrow (BM) nucleated cells are plasma cells, and inferior to 30 000 cells per mcL if superior or equal to 50% of BM nucleated cells are plasma cells. Platelet transfusion was not allowed within three days before the screening visit.
* Absolute neutrophil count inferior to 1000 per mcL (1\*10\^9/L).
* Creatinine clearance inferior to 30 mL per minute (Modification of Diet in Renal Disease \[MDRD\] Formula).
* Total bilirubin superior to 2\*ULN (Upper Limit of Normal).
* Corrected serum calcium superior to 14 milligrams per deciliter (mg/dL) (superior to 3.5 millimoles per liter (mmol/L).
* Aspartate aminotransferase (AST) and/or Alanine Aminotransferase (ALT) superior to 3\*ULN.
* Hypersensitivity to immunomodulatory drugs (IMiDs) (thalidomide or lenalidomide) defined as any hypersensitivity reaction leading to stop IMiDs within the 2 first cycles or toxicity, which does meet intolerance definition.
* Hypersensitivity to dexamethasone, sucrose histidine (as base and hydrochloride salt), and polysorbate 80 or any of the components of study therapy that are not amenable to premedication with steroids, or H2 blockers that would prohibit further treatment with these agents.
* Significant cardiac dysfunction; myocardial infarction within 12 months; unstable, poorly controlled angina pectoris.
* Pregnant or breastfeeding woman or female who intends to become pregnant during the participation in the study.
* Male participants who disagreed to practice true abstinence or disagreed to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and at least 3 or 5 months following study treatment discontinuation, even if he had undergone a successful vasectomy.
* All participants who disagreed to refrain from donating blood while on study treatment and for 4 weeks after discontinuation from this study treatment.

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: From the date of randomization to the date of first documentation of progression, or the date of death from any cause, or initiation of further anti-myeloma treatment or data cut-off whichever comes first (maximum duration: 76.7 weeks)
Secondary outcomes:
measure: Overall Response Rate (ORR): Percentage of Participants With Disease Response as Per Independent Response Committee (IRC)
timeFrame: From the date of randomization to the date of first documentation of progression or initiation of further anti-myeloma treatment or data cut-off whichever comes first (maximum duration 76.7 weeks)
measure: Percentage of Participants With Best Overall Response (BOR) as Per Independent Response Committee
timeFrame: From the date of randomization until disease progression, or death, initiation of further anti-myeloma treatment or data cut-off whichever comes first (maximum duration 76.7 weeks)
measure: Percentage of Participants With Very Good Partial Response (VGPR) or Better as Per Independent Response Committee
timeFrame: From the date of randomization to the date of first documentation of progression, death, initiation of further anti-myeloma treatment, or data cut-off whichever comes first (maximum duration 76.7 weeks)
measure: Clinical Benefit Rate (CBR): Percentage of Participants With Clinical Benefit as Per Independent Response Committee
timeFrame: From the date of randomization to the date of first documentation of progression, death, initiation of further anti-myeloma treatment or data cut-off whichever comes first (maximum duration 76.7 weeks)
measure: Overall Survival (OS): Final Analysis
timeFrame: From the date of randomization to date of death from any cause or data cut-off date, whichever was earlier (maximum duration 245.6 weeks)
measure: Time to Progression (TTP) as Per Independent Response Committee
timeFrame: From the date of randomization to the date of first documentation of progression, or initiation of further anti-myeloma treatment or data cut-off whichever comes first (maximum duration 76.7 weeks)
measure: Progression Free Survival in High Risk Cytogenetic Population
timeFrame: From the date of randomization to the date of first documentation of progression, or the date of death from any cause, or initiation of further anti-myeloma treatment or data cut-off whichever comes first (maximum duration 76.7 weeks)
measure: Duration of Response (DOR) as Per Independent Response Committee
timeFrame: From the date of the first IRC determined response to the date of first IRC progression or death, whichever occurred first (maximum duration 76.7 weeks)
measure: Time to First Response (TT1R) as Per Independent Response Committee
timeFrame: From the date of randomization to the date of first IRC determined response, or death or data cut-off whichever comes first (maximum duration 76.7 weeks)
measure: Time to Best Response (TTBR) as Per Independent Response Committee
timeFrame: From the date of randomization to date of first occurrence of IRC determined best overall response or data cut-off whichever comes first (maximum duration 76.7 weeks)
measure: Number of Participants With Minimal Residual Disease (MRD)
timeFrame: Up to 76.7 weeks
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: From randomization up to 30 days after last dose of study drug (maximum duration up to 241.6 weeks for Pd arm and 245.6 weeks for IPd arm)
measure: Pharmacokinetics (PK) Parameter: Plasma Concentration of Isatuximab at End of Infusion (CEOI)
timeFrame: End of infusion on Cycle(C)1 Day(D)1 and Cycle1 Day 15; Cycle 2 Day 1; and Cycle 4 Day 1
measure: Pharmacokinetic Parameter: Accumulation Ratio of Isatuximab at Concentration at the End of Infusion (CEOI)
timeFrame: End of infusion on Cycle 1 Day 1, Cycle 2 Day 1, and Cycle 4 Day 1
measure: Pharmacokinetic Parameter: Plasma Concentration of Isatuximab at 1 Hour After End of Infusion (CEOI+1 Hour)
timeFrame: Cycle 1:1 hour after End of Infusion on Day 1; Cycle 4:1 hour after End of Infusion on Day 1
measure: PK Parameter: Plasma Concentration of Isatuximab at Ctrough
timeFrame: Pre-infusion on C1D1, C1D8, C1D15, C1D22, C2D1, C2D15, C3D1, C3D15, C4D1, C4D15, C5D1, C6D1, C7D1, C8D1, C9D1, C10D1, C11D1, C12D1, C13D1, C14D1, C15D1, C16D1, C17D1, C18D1, C19D1, C20D1; End of treatment (EOT [30 days after last drug administration])
measure: PK Parameter: Accumulation Ratio of Isatuximab at Trough Concentration (Ctrough)
timeFrame: Pre-infusion on Cycle 1 Day 8, Cycle 2 Day 1, and Cycle 4 Day 1
measure: Number of Participants With Anti-drug Antibodies (ADA)
timeFrame: From randomization up to 60 days after last dose of study drug (maximum duration 76.7 weeks)
measure: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 30 Items (EORTC QLQ-C30): Global Health Status (GHS)/Quality of Life (QOL) Score
timeFrame: Baseline, Day 1 of each cycle (Cycle 3, Cycle 6, Cycle 9, and Cycle 17)
measure: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Multiple Myeloma Specific Module With 20 Items (EORTC QLQ-MY20): Disease Symptoms Domain Score
timeFrame: Baseline, Day 1 of each cycle (Cycle 3, Cycle 6, Cycle 9, and Cycle 17)
measure: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Multiple Myeloma Specific Module With 20 Items (EORTC QLQ-MY20): Side Effects of Treatment Domain Score
timeFrame: Baseline, Day 1 of each cycle (Cycle 3, Cycle 6, Cycle 9, and Cycle 17)
measure: Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions (5D), 5 Levels (5L) (EQ-5D-5L) Score: Health State Utility Index Value
timeFrame: Baseline, Day 1 of each cycle (Cycle 3, Cycle 6, Cycle 9, and Cycle 17)
measure: Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels (EQ-5D-5L) Score: Visual Analogic Scale (VAS)
timeFrame: Baseline, Day 1 of each cycle (Cycle 3, Cycle 6, Cycle 9, and Cycle 17)
Other outcomes:
Locations:
city: Plantation
country: United States
facility: BRCR Medical Center Inc. Site Number : 8400002
state: Florida
city: Boston
country: United States
facility: Dana Farber Site Number : 8400006
state: Massachusetts
city: St Leonards
country: Australia
facility: Investigational Site Number : 0360004
state: New South Wales
city: Waratah
country: Australia
facility: Investigational Site Number : 0360001
state: New South Wales
city: Melbourne
country: Australia
facility: Investigational Site Number : 0360005
state: Victoria
city: Melbourne
country: Australia
facility: Investigational Site Number : 0360002
state: Victoria
city: Richmond
country: Australia
facility: Investigational Site Number : 0360006
state: Victoria
city: Antwerpen
country: Belgium
facility: Investigational Site Number : 0560003
city: Brussel
country: Belgium
facility: Investigational Site Number : 0560002
city: Gent
country: Belgium
facility: Investigational Site Number : 0560004
city: Leuven
country: Belgium
facility: Investigational Site Number : 0560001
city: Montreal
country: Canada
facility: Investigational Site Number : 1240001
state: Quebec
city: Montreal
country: Canada
facility: Investigational Site Number : 1240004
state: Quebec
city: Sherbrooke
country: Canada
facility: Investigational Site Number : 1240005
state: Quebec
city: Brno
country: Czechia
facility: Investigational Site Number : 2030005
city: Hradec Kralove
country: Czechia
facility: Investigational Site Number : 2030004
city: Olomouc
country: Czechia
facility: Investigational Site Number : 2030001
city: Ostrava - Poruba
country: Czechia
facility: Investigational Site Number : 2030002
city: Praha 2
country: Czechia
facility: Investigational Site Number : 2030003
city: Ålborg
country: Denmark
facility: Investigational Site Number : 2080002
city: Bayonne
country: France
facility: Investigational Site Number : 2500021
city: Caen
country: France
facility: Investigational Site Number : 2500008
city: Dijon
country: France
facility: Investigational Site Number : 2500009
city: Grenoble
country: France
facility: Investigational Site Number : 2500017
city: La Roche Sur Yon
country: France
facility: Investigational Site Number : 2500013
city: Lille
country: France
facility: Investigational Site Number : 2500003
city: Limoges
country: France
facility: Investigational Site Number : 2500023
city: Montpellier Cedex
country: France
facility: Investigational Site Number : 2500019
city: Nantes
country: France
facility: Investigational Site Number : 2500002
city: Paris
country: France
facility: Investigational Site Number : 2500015
city: Paris
country: France
facility: Investigational Site Number : 2500016
city: Pessac
country: France
facility: Investigational Site Number : 2500005
city: Pierre Benite
country: France
facility: Investigational Site Number : 2500004
city: POITIERS Cedex
country: France
facility: Investigational Site Number : 2500007
city: Reims
country: France
facility: Investigational Site Number : 2500025
city: Rennes
country: France
facility: Investigational Site Number : 2500014
city: TOULOUSE Cedex 9
country: France
facility: Investigational Site Number : 2500001
city: Tours
country: France
facility: Investigational Site Number : 2500012
city: Vandoeuvre-les-nancy
country: France
facility: Investigational Site Number : 2500018
city: Leipzig
country: Germany
facility: Investigational Site Number : 2760001
city: Athens
country: Greece
facility: Investigational Site Number : 3000002
city: Athens
country: Greece
facility: Investigational Site Number : 3000005
city: Athens
country: Greece
facility: Investigational Site Number : 3000001
city: Patra
country: Greece
facility: Investigational Site Number : 3000004
city: Thessaloniki
country: Greece
facility: Investigational Site Number : 3000003
city: Budapest
country: Hungary
facility: Investigational Site Number : 3480001
city: Budapest
country: Hungary
facility: Investigational Site Number : 3480003
city: Debrecen
country: Hungary
facility: Investigational Site Number : 3480002
city: Bologna
country: Italy
facility: Investigational Site Number : 3800001
city: Catania
country: Italy
facility: Investigational Site Number : 3800010
city: Firenze
country: Italy
facility: Investigational Site Number : 3800009
city: Genova
country: Italy
facility: Investigational Site Number : 3800008
city: Milano
country: Italy
facility: Investigational Site Number : 3800007
city: Milano
country: Italy
facility: Investigational Site Number : 3800002
city: Padova
country: Italy
facility: Investigational Site Number : 3800006
city: Terni
country: Italy
facility: Investigational Site Number : 3800004
city: Torino
country: Italy
facility: Investigational Site Number : 3800003
city: Nagoya-shi
country: Japan
facility: Investigational Site Number : 3920001
state: Aichi
city: Shibukawa-shi
country: Japan
facility: Investigational Site Number : 3920005
state: Gunma
city: Sapporo-shi
country: Japan
facility: Investigational Site Number : 3920004
state: Hokkaido
city: Kyoto-shi
country: Japan
facility: Investigational Site Number : 3920006
state: Kyoto
city: Suwa-shi
country: Japan
facility: Investigational Site Number : 3920008
state: Nagano
city: Okayama-shi
country: Japan
facility: Investigational Site Number : 3920003
state: Okayama
city: Sunto-gun
country: Japan
facility: Investigational Site Number : 3920007
state: Shizuoka
city: Shibuya-ku
country: Japan
facility: Investigational Site Number : 3920002
state: Tokyo
city: Hwasun-gun
country: Korea, Republic of
facility: Investigational Site Number : 4100007
state: Jeollanam-do
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number : 4100001
state: Seoul-teukbyeolsi
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number : 4100002
state: Seoul-teukbyeolsi
city: Incheon
country: Korea, Republic of
facility: Investigational Site Number : 4100006
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number : 4100005
city: Takapuna
country: New Zealand
facility: Investigational Site Number : 5540001
state: Auckland
city: Dunedin
country: New Zealand
facility: Investigational Site Number : 5540004
state: Otago
city: Hamilton
country: New Zealand
facility: Investigational Site Number : 5540003
state: Waikato
city: Auckland
country: New Zealand
facility: Investigational Site Number : 5540002
city: Oslo
country: Norway
facility: Investigational Site Number : 5780001
city: Lublin
country: Poland
facility: Investigational Site Number : 6160003
state: Lubuskie
city: Krakow
country: Poland
facility: Investigational Site Number : 6160005
state: Malopolskie
city: Warszawa
country: Poland
facility: Investigational Site Number : 6160001
state: Mazowieckie
city: Chorzow
country: Poland
facility: Investigational Site Number : 6160002
state: Slaskie
city: Coimbra
country: Portugal
facility: Investigational Site Number : 6200004
city: Lisboa
country: Portugal
facility: Investigational Site Number : 6200002
city: Porto
country: Portugal
facility: Investigational Site Number : 6200001
city: Moscow
country: Russian Federation
facility: Investigational Site Number : 6430004
city: Moscow
country: Russian Federation
facility: Investigational Site Number : 6430001
city: Moscow
country: Russian Federation
facility: Investigational Site Number : 6430002
city: Bratislava
country: Slovakia
facility: Investigational Site Number : 7030001
city: Santiago de Compostela
country: Spain
facility: Investigational Site Number : 7240005
state: A Coruña [La Coruña]
city: Barcelona
country: Spain
facility: Investigational Site Number : 7240001
state: Barcelona [Barcelona]
city: Santander
country: Spain
facility: Investigational Site Number : 7240006
state: Cantabria
city: Pamplona
country: Spain
facility: Investigational Site Number : 7240002
state: Navarra
city: Madrid
country: Spain
facility: Investigational Site Number : 7240003
city: Salamanca
country: Spain
facility: Investigational Site Number : 7240004
city: Luleå
country: Sweden
facility: Investigational Site Number : 7520004
city: Uddevalla
country: Sweden
facility: Investigational Site Number : 7520005
city: Kaohsiung
country: Taiwan
facility: Investigational Site Number : 1580004
city: Taichung
country: Taiwan
facility: Investigational Site Number : 1580002
city: Taipei
country: Taiwan
facility: Investigational Site Number : 1580001
city: Taoyuan
country: Taiwan
facility: Investigational Site Number : 1580003
city: Ankara
country: Turkey
facility: Investigational Site Number : 7920001
city: Antalya
country: Turkey
facility: Investigational Site Number : 7920002
city: Istanbul
country: Turkey
facility: Investigational Site Number : 7920005
city: Istanbul
country: Turkey
facility: Investigational Site Number : 7920006
city: Istanbul
country: Turkey
facility: Investigational Site Number : 7920003
city: Istanbul
country: Turkey
facility: Investigational Site Number : 7920004
city: Izmir
country: Turkey
facility: Investigational Site Number : 7920008
city: Izmir
country: Turkey
facility: Investigational Site Number : 7920010
city: Kayseri
country: Turkey
facility: Investigational Site Number : 7920009
city: Kocaeli
country: Turkey
facility: Investigational Site Number : 7920007
city: London
country: United Kingdom
facility: Investigational Site Number : 8260002
state: London, City Of
city: London
country: United Kingdom
facility: Investigational Site Number : 8260003
state: London, City Of
city: London
country: United Kingdom
facility: Investigational Site Number : 8260001
state: London, City Of
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: Attal M, Richardson PG, Rajkumar SV, San-Miguel J, Beksac M, Spicka I, Leleu X, Schjesvold F, Moreau P, Dimopoulos MA, Huang JS, Minarik J, Cavo M, Prince HM, Mace S, Corzo KP, Campana F, Le-Guennec S, Dubin F, Anderson KC; ICARIA-MM study group. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019 Dec 7;394(10214):2096-2107. doi: 10.1016/S0140-6736(19)32556-5. Epub 2019 Nov 14.
citation: Richardson PG, Perrot A, San-Miguel J, Beksac M, Spicka I, Leleu X, Schjesvold F, Moreau P, Dimopoulos MA, Huang JS, Minarik J, Cavo M, Prince HM, Malinge L, Dubin F, van de Velde H, Anderson KC. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): follow-up analysis of a randomised, phase 3 study. Lancet Oncol. 2022 Mar;23(3):416-427. doi: 10.1016/S1470-2045(22)00019-5. Epub 2022 Feb 10.
citation: Sunami K, Ikeda T, Huang SY, Wang MC, Koh Y, Min CK, Yeh SP, Matsumoto M, Uchiyama M, Iyama S, Shimazaki C, Lee JH, Kim K, Kaneko H, Kim JS, Lin TL, Campana F, Tada K, Iida S, Suzuki K; ICARIA-MM study group. Isatuximab-Pomalidomide-Dexamethasone Versus Pomalidomide-Dexamethasone in East Asian Patients With Relapsed/Refractory Multiple Myeloma: ICARIA-MM Subgroup Analysis. Clin Lymphoma Myeloma Leuk. 2022 Aug;22(8):e751-e761. doi: 10.1016/j.clml.2022.04.005. Epub 2022 Apr 8.
citation: Wilmoth J, Colson K, Dubin F, Kellam C. Isatuximab: Nursing Considerations for Use in the Treatment of Multiple Myeloma. Clin J Oncol Nurs. 2021 Dec 1;25(6):706-712. doi: 10.1188/21.CJON.706-712.
citation: Bringhen S, Pour L, Vorobyev V, Vural F, Warzocha K, Benboubker L, Koh Y, Maisnar V, Karlin L, Pavic M, Campana F, Le Guennec S, Menas F, van de Velde H, Richardson PG. Isatuximab plus pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma according to prior lines of treatment and refractory status: ICARIA-MM subgroup analysis. Leuk Res. 2021 May;104:106576. doi: 10.1016/j.leukres.2021.106576. Epub 2021 Mar 29.
citation: Schjesvold FH, Richardson PG, Facon T, Alegre A, Spencer A, Jurczyszyn A, Sunami K, Frenzel L, Min CK, Guillonneau S, Lin PL, Le-Guennec S, Campana F, van de Velde H, Bensfia S, Bringhen S. Isatuximab plus pomalidomide and dexamethasone in elderly patients with relapsed/refractory multiple myeloma: ICARIA-MM subgroup analysis. Haematologica. 2021 Apr 1;106(4):1182-1187. doi: 10.3324/haematol.2020.253450. No abstract available.