Open access Original research EHA evaluation of the ESMO— Magnitude of Clinical Benefit Scale version 1.1 (ESMO-­MCBS v1.1) for haematological malignancies Barbara Kiesewetter ‍ ‍ ,1 Nathan I Cherny,2 Nicolas Boissel,3,4 Francesco Cerisoli,5 Urania Dafni,6,7 Elisabeth G E de Vries,8 Paolo Ghia,9,10 Nicola Gökbuget,11 Verónica González-­Calle,12 Brian Huntly,13 Ulrich Jäger,14 Nicola Jane Latino,15 Jean-­Yves Douillard,15 Luca Malcovati,16,17 María-­Victoria Mateos,12 Gert J Ossenkoppele,18 Kimmo Porkka,19 Markus Raderer,1 Josep-­Maria Ribera,20 Lydia Scarfò,9,10 Ruth Wester,21 Panagiota Zygoura,7 Pieter Sonneveld21,22 To cite: Kiesewetter B, Abstract Cherny NI, Boissel N, et al. Key questions Objective Value frameworks in oncology have not EHA evaluation of the ESMO— been validated for the assessment of treatments in Magnitude of Clinical Benefit What is already known about this subject? Scale version 1.1 (ESMO-­MCBS haematological malignancies, but to avoid overlaps and ►► The European Society for Medical Oncology— v1.1) for haematological duplications it appears reasonable to build up experience Magnitude of Clinical Benefit Scale (ESMO-­MCBS) malignancies. ESMO Open on existing value frameworks, such as the European v1.1 is a validated value scale for solid tumour on- 2020;5:e000611. doi:10.1136/ Society for Medical Oncology—Magnitude of Clinical cology, but it has not yet been evaluated for the use esmoopen-2019-000611 Benefit Scale (ESMO-­MCBS). in haematological malignancies. Methods Here we present the results of the first feasibility testing of the ESMO-­MCBS v1.1 for What does this study add? BK and NIC contributed equally. haematological malignancies based on the grading of ►► Here, we present the results of the first feasibility Received 5 October 2019 80 contemporary studies for acute leukaemia, chronic testing of the ESMO-­MCBS v1.1 for haematological Revised 5 November 2019 leukaemia, lymphoma, myeloma and myelodysplastic malignancies based on grading of 80 contemporary Accepted 6 November 2019 syndromes. The aims were (1) to evaluate the scorability of studies for leukaemia, lymphoma, myeloma and my- data, (2) to evaluate the reasonableness of the generated elodysplastic syndromes. grades for clinical benefit using the current version and ►► The ESMO-­MCBS v1.1 was found to be widely ap- (3) to identify shortcomings in the ESMO-­MCBS v1.1 that plicable to studies in haematological malignancies, require amendments to improve the efficacy and validity of generating scores that were judged as reasonable the scale in grading new treatments in the management of by European Hematology Association (EHA) experts; haematological malignancies. however, a small number of studies could either not Results In general, the ESMO-­MCBS v1.1 was found be graded or were not appropriately graded because to be widely applicable to studies in haematological of shortcomings related to the differences between malignancies, generating scores that were judged as haematological and solid tumour malignancies. reasonable by European Hematology Association (EHA) How might this impact on clinical practice? experts. A small number of studies could either not be ►► Based on the findings of this study, ESMO and EHA graded or were not appropriately graded. The reasons, are committed to develop a version of the score that related to the differences between haematological and is robustly validated to grade studies in malignant solid tumour malignancies, are identified and described. haematology. Conclusions Based on the findings of this study, © Author (s) (or their ESMO and EHA are committed to develop a version of employer(s)) 2020. Re-­use the ESMO-­MCBS that is validated for haematological permitted under CC BY-­NC. No malignancies. This development process will incorporate Introduction commercial re-­use. Published all of the usual stringencies for accountability of In recent years, rapid developments in by BMJ on behalf of the European Society for Medical reasonableness that have characterised the development haematology research resulted in a consid- Oncology. of the ESMO-­MCBS including field testing, statistical erable expansion of treatment options. The For numbered affiliations see modelling, evaluation for reasonableness and openness development of instruments to measure clin- end of article. to appeal and revision. Applying such a scale will support ical benefit is essential in the current scenario future public policy decision-­making regarding the value where increasing numbers of treatments Correspondence to of new treatments for haematological malignancies and Dr Barbara Kiesewetter; for haematological malignancies (HMs) are will provide insights that could be helpful in the design of ​barbara.​kiesewetter@​ becoming available, often targeting a small future clinical trials. meduniwien.​ac.​at and defined subpopulation of patients. Kiesewetter B, et al. ESMO Open 2020;5:e000611. doi:10.1136/esmoopen-2019-000611 1 Open access For this, several value frameworks have been published current version and (3) to identify shortcomings in the by different organisations and institutions taking into ESMO-­MCBS v1.1 that require amendments to improve account or emphasising different aspects contributing the efficacy and validity of the scale in grading new treat- to such an evaluation.1 These frameworks vary in terms ments in the management of HMs. of their definition of value, target audience and method- ology, and each of them has specific limitations, which should be taken into consideration when interpreting Methods their outputs.2 Until now, value frameworks developed in Study selection oncology have not been validated in the setting of HMs. The corresponding disease-­ oriented EHA scientific The European Society for Medical Oncology (ESMO) working groups identified experts who selected repre- has developed such a value framework called the ESMO— sentative treatments currently used in clinical practice Magnitude of Clinical Benefit Scale (ESMO-­ MCBS).3 with a focus on recently approved drugs and novel strat- Initially published in 2015, the scale is a validated and egies, to be evaluated for each of the common haema- reproducible tool in solid tumour oncology with a partic- tological malignancies: acute lymphoblastic leukaemia ular focus on the clinical benefit. The ESMO-­MCBS was (ALL), acute myeloid leukaemia (AML), chronic lympho- developed to generate clear, valid and unbiased grading cytic leukaemia (CLL), chronic myeloid leukaemia of the magnitude of clinical benefit demonstrated in (CML), Hodgkin and non-­Hodgkin lymphomas, multiple therapeutic studies that could be used for a number myeloma (MM) and myelodysplastic syndromes (MDS). of purposes including public health policy and health The treatments selected underwent a literature search to technology assessment (HTA), clinical decision-­making, identify corresponding clinical trials and data. medical publication and journalism. The ESMO-­MCBS grading highlights those treatments which substantially ESMO-MCBS grading improve the duration of survival and/or the quality of Identified studies were graded by members of the EHA life (QOL) of patients with cancer and aims to distin- scientific working groups according to the ESMO-­MCBS guish them from trials demonstrating more limited and v1.1 forms4 in accordance with the instructions provided sometimes even marginal benefits. The ESMO-­ MCBS by ESMO. Magnitude of clinical benefit scores range was revised (version 1.1) in 2017, based on feedback from A to C for treatment strategies with curative intent and queries from clinicians, patients, researchers and and 5-1 for treatments with non-­ curative intent, with representatives of the pharmaceutical industry, and a scores of A–B and 5-4 relating to a substantial level of dynamic process of internal peer review.4 Version 1.1 clinical benefit. Initial grading by the expert groups were incorporates 10 revisions and most importantly allows reviewed by the ESMO-­MCBS working group for applica- also for scoring of single-­arm studies. The ESMO-­MCBS bility and correctness. assigns categorical benefit scores to European Medicines Agency (EMA) approved drugs, based on results from Evaluations ‘positive’ randomised clinical trials: (1) superiority trials For each disease entity, we evaluated the scorability of the that have demonstrated a statistically significant result evaluated studies and the reasonableness of the derived for the primary endpoint of the study, or secondary in scores. Based on these findings, we identified shortcom- case of overall survival (OS) and (2) non-­ inferiority ings in the current version of the ESMO-­MCBS that either trials, reaching a conclusion of non-­inferiority. Primary precluded scoring or which generated grading which was or secondary endpoints included in the scoring system considered not to be a reasonable estimation of benefit are OS, progression-­free survival (PFS), QOL, treatment when such studies were identified. toxicity or response rates. In developing the ESMO-­MCBS scale, ESMO aspired to meet standards for ‘account- ability for reasonableness’,5 6 incorporating extensive Results field testing, statistical modelling7 and peer review of the The extensive research concluded in 80 studies, 5 of ‘reasonableness’ of the generated results into the devel- which had either more than two arms or different publi- opment process. The ESMO-­MCBS is currently incorpo- cations for the same trial presenting results after longer rated in ESMO’s clinical practice guidelines and is being follow-­up times (87 studies and/or comparisons in total). used as part of HTA processes.8 9 In detail, we have scored 7 studies for AML, 5 studies for The European Hematology Association (EHA) and ALL, 8 studies for CLL, 4 studies for CML, 23 studies for ESMO have developed a joint initiative to develop a non-­Hodgkin and Hodgkin lymphoma, 23 studies for MM version of the ESMO-­MCBS that is validated for HMs. As and 10 studies for MDS. The ESMO-­MCBS v1.1 tool was a first step in this process, we have field tested the current applied in all the 87 distinct studies and/or subgroups. version of the ESMO-­MCBS (version 1.1) across a wide spectrum of HMs. The aims of this evaluation were (1) to Acute myeloid leukaemia evaluate the scorability of data derived from contempo- Studies evaluated: Seven studies were evaluated,10–16 three rary clinical trials in HMs, (2) to evaluate the reasonable- in a curative setting and four in a non-­curative setting ness of the generated grades for clinical benefit using the (table 1). 2 Kiesewetter B, et al. ESMO Open 2020;5:e000611. doi:10.1136/esmoopen-2019-000611 Open access Scorability: All studies were published with endpoints Reference DFS, disease-­free survival; DOR, duration of response; EFS, event-­free survival;ESMO-­MCBS v1.1, European Society for Medical Oncology—Magnitude of Clinical Benefit Scale, version 1.1; FLT3, fms-­like tyrosine kinase 3; IDH2, isocitrate dehydrogenase 2; LDAC, low-­dose cytarabine; ORR, and data applicable to the ESMO-­MCBS v1.1. Reasonableness: The separation of studies with curative/ 10 11 12 13 14 15 16 non-­curative intent corresponds closely to the distinction ESMO-­ ESMO-­ MCBS between intensive versus non-­ intensive chemotherapy form 2a 2a 2a 1 1 1 3 regimens which are the terms usually applied in the treat- ment of AML. Grading effectively distinguished between MCBS score high benefit treatment strategies in a curative setting and A A A 5 2 3 2 stratified between higher and lower benefit treatments in Benefit (+1 Increased increased increased a non-­curative setting. Toxicity Slightly Slightly point) Shortcomings: None identified. QOL Acute lymphoblastic leukaemia Studies evaluated: Five studies were evaluated,17–23 and 40.3% (5.8 13%, gain RR (DOR) months) 31% vs 18% these included studies relating to three agents recently approved by EMA for relapsed and refractory ALL (table 2).17–20 22 49.1 months 0.78 (0.63–0.96) 0.63 (0.40–1.00) 0.69 (0.49–0.98) 0.47 (0.28–0.79) 0.82 (0.68–0.99) Scorability: Four of the five studies were published with Immature Immature endpoints and data applicable to the ESMO-­MCBS v1.1. OS HR The only not scoreable study was the single-­arm study of ponatinib as add-­on to standard of care upfront treat- 2.8 months ment with curative intent.21 8.5 months 2.7 months OS Gain Reasonableness: Both the first-­in class bispecific antibody 41.9% 2 years 11.3% 7% blinatumomab (TOWER trial)17 18 and the antibody-­drug conjugate inotuzumab ozogamicin (INO-­VATE trial)19 20 25.6 months 56% 3 years 5.2 months PFS/EFS/DFS HR OS Control 3.3 months 16 months (historical) reached high scores based on positive OS data and favour- 5 months able QOL data for blinatumomab (ESMO-­ MCBS v1.1 scores 5 and 4, respectively). The chimeric antigen Feasibility testing of the ESMO-­MCBS v1.1 for acute myeloid leukaemia (n=7) receptor (CAR) T-­ cell treatment in children/young 0.58 (0.43–0.78) 0.64 (0.45–0.91) 0.57 (0.35–0.92) adults with relapsed or refractory B-­cell ALL was graded with maximal credit of 3 for a single-­arm study in a non-­ curative setting.22 The ponatinib treatment (single-­arm overall response rate; OS, overall survival;PFS, progression-­free survival; QOL, quality of life; RR, response rate; SOC, standard of care. Across all tables, in case there is reported information for multiple endpoints, the evaluated endpoint results are indicated with bold. PACE trial)23 was assigned grade 2 based on the major PFS/EFS/DFS molecular response (MMR) in the non-­curative setting. 11.2 months 2.3 months EFS 3.3 months Reasonableness: Grading effectively distinguished 23.7% Gain 18% between high benefit treatment strategies in a curative stetting and stratified between higher and lower benefit PFS/EFS/ DFS 17.1% 2 years treatments in a non-­curative setting. 22% 3 years 15.5 months Shortcomings: One shortcoming was identified: Control (DFS) 1. The ESMO-­MCBS v1.1 does not have a form to grade single-­arm treatments with curative intent. This short- coming precluded scoring in one study21 and may also Outcome Primary have been relevant to the grading of CAR T-­cell salvage ORR ORR EFS EFS OS OS OS therapy which could also be considered as curative.22 Upfront elderly, low relapsed/refractory intermediate/poor Chronic lymphocytic leukaemia Upfront, elderly, Upfront, FLT3-­ Upfront, 50–70 IDH2 mutated, Upfront, unfit Studies evaluated: Eight studies were evaluated (table 3).24–35 blast count mutated Setting Upfront Scorability: CLL is generally a relatively indolent disease years risk with a very long survival—often decades long—and many patients do not need intervention for many years and Trial Name ALFA-0701 DACO-016 SORAML when treatment is initiated it commonly generates very AZA-001 RATIFY long periods of remission. For these reasons, PFS is gener- ally the most relevant and measurable primary endpoint. SOC±gemtuzumab Azacitidine versus Decitabine versus SOC±midostaurin Since CLL is generally not considered to be a curable LDAC ±Volasertib (+maintenance) SOC±sorafenib disease, all scoring was performed using scales for non-­ ozogamicin Medication Enasidenib curative disease. One study27 could not be scored because Table 1 the primary objective of non-­inferiority with regard to PFS SOC SOC was not met. Moreover, the published results limited to a Kiesewetter B, et al. ESMO Open 2020;5:e000611. doi:10.1136/esmoopen-2019-000611 3 4 Open access Table 2 Feasibility testing of the ESMO-­MCBS v1.1 for acute lymphoblastic leukaemia (n=5) ESMO-­ ESMO-­ Primary PFS/EFS PFS/EFS PFS/EFS MCBS MCBS Reference Medication Trial name Setting outcome control gain HR OS control OS gain OS HR RR (DOR) QOL Toxicity score form (s) 17 18 Blinatumomab TOWER Relapsed/refractory OS 12% EFS 6 19% 0.55 (0.43– 4 months 3.7 months 0.71 44% vs 25% Improved (+1 5 2a versus SOC months 0.71) (0.55– CRR, gain 19% point) 0.93) 19 20 Inotuzumab INO-­VATE Relapsed/refractory OS/CRR 1.8 months 3.2 months 0.45 (97.5% 6.7 months 1 month 0.77 81% vs 29% Improved Veno-­occlusive 4* 2a ozogamicin CI: 0.34 to (10% gain (13% gain (97.5% CRR, gain 52% disease 11% in versus SOC 0.61) in 2-­year in 2-­year CI: 0.58 experimental arm survival) survival) to 1.03) p=0.04 21 Hyper-­CVAD Philadelphia EFS 81% 2 years 80% 2 years Not +ponatinib chromosome-­ EFS scoreable positive, upfront. Phase II single arm 22 CAR T-­cell Relapsed/refractory, ORR at 3 76% 1 year 81% ORR >30% grade 3/4 3 3 tisagenlecleucel age <21 years, months cytokine release single arm syndrome 23 Ponatinib PACE Philadelphia positive Major 7% at 12 40% at 12 Major 2 3 resistant to or haematological months months haematological side effects with response within response: 41% dasatinib or nilotinib, the first 6 (3 months) or T315I mutation months after TKI *Based on >10% increase in 2 years of OS improvement. CAR T- cell, chimeric antigen receptor T-­cell therapy; CRR, complete remission rate; DOR, duration of response; EFS, event-­free survival;ESMO-­MCBS v1.1, European Society for Medical Oncology—Magnitude of Clinical Benefit Scale, version 1.1; Hyper-­CVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone; ORR, overall response rate; OS, overall survival;PFS, progression-­free survival; QOL, quality of life; RR, response rate; SOC, standard of care; TKI, tyrosine kinase inhibitor. Kiesewetter B, et al. ESMO Open 2020;5:e000611. doi:10.1136/esmoopen-2019-000611 Table 3 Feasibility testing of the ESMO-­MCBS v1.1 for chronic lymphocytic leukaemia (n=8) ESMO-­ Primary ESMO-­MCBS MCBS Medication Trial name Setting outcome PFS control PFS gain PFS HR OS control OS gain OS HR RR QOL Toxicity score form Reference(s) 24–26 FC±R CLL8 Upfront, chemofit PFS 32.9 months 23.9 months 0.59 (0.50– 86 months >10% gain 0.68 (0.54–0.89) No Increased 4 2a 0.69) (66.9% 5 at 5 years difference years) 27 FC-­R versus CLL10 Upfront, focus elderly Non- 55.2 months −13.5 months Non-­inferiority     Not significant Less toxicity in Not significant, 2c R-­ subgroup >65 years inferiority not met experimental arm not eligible for bendamustine in PFS neither scoring overall, nor in the >65 years post hoc subgroup 28 29 Ibrutinib versus RESONATE-2 Upfront elderly PFS 18.9 months 8 months 0.16 (0.09– 85% at 24 13% 0.16 (0.05–0.56) Improved 3 2b chlorambucil 0.28) months Immature (abstract only) 30 Obinutuzumab± CLL11 Upfront elderly PFS 11.1 months 15.6 months 0.18 (0.13– NR NA 0.41 (0.23–0.74) Increased but not 3 2b Kiesewetter B, et al. ESMO Open 2020;5:e000611. doi:10.1136/esmoopen-2019-000611 chlorambucil not eligible for 0.24) Immature meeting criteria for fludarabine downgrading 31 32 Ibrutinib versus RESONATE Relapsed/refractory PFS 8.1 months 4+ months 0.11 (0.08– 81% at 12 9% at 12 0.43 (0.24–0.79) Pending >10% SAE increase 3 2b ofatumumab (cross-­over allowed) 0.15) months months Immature (−1 point) (>10% gain at 12 months with plateau) 33 R-­Venetoclax MURANO Relapsed/refractory PFS 17 months 6+ months 0.17 (0.11– 87% at 24 5.30% 0.48 (0.25–0.90)   4 2b versus R-­ 0.25) months Immature bendamustine (>10% gain at 12 months with plateau) 34 Ibrutinib RESONATE-17 Relapsed/refractory ORR 63% at 24 75% at 24 64% No new safety flags 3 3 with del17p months months 35 Venetoclax M13-982 Relapsed/refractory ORR 72% at 12 87% at 12 79%   No new safety flags 3 3 with del17p months months del17p, 17 p deletion;ESMO-­MCBS v1.1, European Society for Medical Oncology—Magnitude of Clinical Benefit Scale, version 1.1; FC, fludarabine, cyclophosphamide; NA, not applicable; NR, not reached; ORR, overall response rate; OS, overall survival;PFS, progression-­free survival; QOL, quality of life; R, rituximab; RR, response rate; SAE, serious adverse event. Open access 5 Open access subcohort of patients older than 65 years, which are rele- grade of 2 for non-­curable intent to be too low for the vant for clinical practice (particularly in view of presented benefits observed. toxicity data) did not show non-­inferiority and they were The remaining studies of nilotinib, dasatinib and bosu- derived from a post hoc exploratory analysis. tinib show minor improvements in complete molecular Reasonableness: Overall scoring was considered reason- response rates when compared with imatinib (grade 2) able with the highest grades being achieved by studies in a non-­curative setting.39–43 None of these agents had demonstrating either mature OS data24–26 or PFS gains mature data beyond 5 years and consequently they were with long-­term plateauing of PFS,33 or compelling PFS not graded for curative intent. gains.28 29 Grading of the phase III study of ibrutinib versus Shortcomings: These relatively low scores for imatinib ofatumumab (RESONATE trial)31 32 was considered to be in the non-­curative grading appear to indicate two short- low; it was credited for PFS advantage including gain in comings in the ESMO-­MCBS v1.1: the tail of the curve but was penalised for toxicity associ- 1. When PFS (or EFS) is very long, there is no mechanism ated with the more prolonged drug exposure in contin- to credit strong interim gains when the median PFS of uous treatment (ESMO-­MCBS v1.1 score 3). However, the the control arm has not yet been reached. 9% improvement in OS at 12 months was not credited as 2. The surrogacy of complete cytogenic response and level these results are deemed immature by the ESMO-­MCBS 4–5 MMR, defined as 4 to 5-­log reduction in BCR–ABL1 criteria. The benefit of novel agents in populations with transcript levels from a standardised baseline, are much high unmet need, like relapsed and refractory patients stronger surrogates for survival than pathological com- with CLL carrying deletion in chromosome 17 p, was plete response and response rate in solid tumours.44 45 graded reasonably using form 3 for single-­arm studies in Consequently, form 2 c needs to be amended to incor- a non-­curative setting.34 35 porate evaluation of deep molecular responses. Shortcomings: One shortcoming was identified: 1. The EHA scientific working group members felt that Indolent non-Hodgkin’s, relapsed/refractory setting of non- compelling immature survival benefit ought to be diffuse large B-cell lymphoma (non-DLBCL) and Hodgkin’s credited even when the median survival of the control lymphoma arm has not been reached. Studies evaluated: Twelve studies of recently approved drugs for indolent non-­ Hodgkin’s, relapsed/refractory Chronic myeloid leukaemia setting of non-­DLBCL and Hodgkin’s lymphoma were Studies evaluated: Four landmark trials addressing the evaluated (table 5).46–62 use of tyrosine kinase inhibitors imatinib, nilotinib, Scorability: In one of the studies,46 PFS/EFS gains could dasatinib and bosutinib upfront for chronic phase CML not be graded because the PFS of the control arm was very were graded.36–43 Only one of these had mature OS data long, the median PFS was not reached and only interim (table 4).38 gains were reported. The BRIGHT study could not be Scorability: CML is generally considered an incurable scored because form 2 c makes no provision for scoring disease, but in a small proportion of cases with deep molec- of non-­ inferiority studies based on response rates.49 50 ular responses the disease may be eradicated. Thus, when The remaining 10 studies were published with endpoints mature survival data were available, CML was scored for and data applicable to the ESMO-­MCBS v1.1 and were all both curative and non-­curative intent.36–38 Contemporary evaluable. studies in CML treatments are conventionally evaluated Reasonableness: The grading was applicable and was using molecular response evaluations.44 45 This differs judged by the EHA working group to be reasonable in the from the concepts of ‘pathological complete response’ or evaluated trials, endorsing relatively high benefit grades, ‘response rate’ which are terms used in the ESMO-­MCBS that is, ESMO-­MCBS v1.1. scores of 4–5 for 7 of the 10 v1.1. Scoring of these studies was only possible by inter- evaluable studies. preting deep molecular responses (MMR 4–5) as patho- Shortcomings: Two shortcomings were observed: logical complete responses (form 1) or major responses 1. The ESMO-­MCBS v1.1 has no mechanism for scoring (form 2 c).39–43 In one study,36–38 PFS/event-­free survival non-­inferiority studies based on response rate. (EFS) gains could not be credited because the PFS of the 2. When PFS (or EFS) is very long, there is no mechanism control arm was very long and had not reached median to credit strong interim gains when the median PFS of PFS after 11 years of follow-­up. the control arm has not yet been reached. Reasonableness: In the IRIS study of imatinib versus former standard interferon plus cytarabine, initial scoring Diffuse large B-cell lymphoma at 18 months was credited on the basis of complete cyto- Studies evaluated: Eleven studies were evaluated63–75; two genic response for curative intent with a grade of C and in the first-­line setting with curative intent,63–66 two inten- improvement in molecular response rate with grade sified therapies for first-­line and salvage setting, respec- 2.36–38 At 10-­year follow-­up, the imatinib scores B for cura- tively, with both curative and non-­curative intent,67 68 two tive intent based on survival improvement. While the single-­arm studies of CAR T-­cell salvage therapy70 71 and grades for curative intent were considered reasonable, five in a non-­curative setting for relapsed and refractory the EHA working group considered the ESMO-­ MCBS disease (table 6).69 72–75 6 Kiesewetter B, et al. ESMO Open 2020;5:e000611. doi:10.1136/esmoopen-2019-000611 Table 4 Feasibility testing of the ESMO-­MCBS v1.1 for chronic myeloid leukaemia (n=4) PFS/ Major ESMO-­ ESMO-­ Primary EFS/PFS EFS/PFS EFS OS OS CytRR/ Complete MCBS MCBS Medication Trial name Setting outcome control gain HR control gain OS HR MMR CytRR MMR MR4 MR4.5 QOL Toxicity score form Reference(s) 36–38 Imatinib versus IRIS Newly Initial: PFS/EFS Improved Less toxicity interferon/ diagnosed long term: OS cytarabine chronic 18 months PFS 73.5% 18.6% 87% vs 76% vs 15%, C/2 1/2 c phase 35%, gain 62% (cross-­ gain over 52% allowed) 10 years EFS 56.6% 23% 78.8% 4.5% 0.74 B/2 1/2 c (0.56– 0.99) 39 40 Nilotinib 600 or ENESTnd Newly Initial primary: More 800 mg versus diagnosed MMR at 12 cardiovasc. imatinib chronic months, events for phase secondary: nilotinib complete cytRR 800 mg 12 months 80% vs 65%, 44% vs 2 2c 600 mg gain 15% 22%, gain 22% 12 months 78% vs 65%, 43% vs 2 2c 800 mg gain 13% 22%, gain Kiesewetter B, et al. ESMO Open 2020;5:e000611. doi:10.1136/esmoopen-2019-000611 21% 5 years 600 mg 92.6% 2.4% NS 91.7% 2.0% NS 77% vs 66% vs 54% vs 2 2c 60%, 42%, 31%, gain gain gain 17% 24% 22% 5 years 800 mg 4.3% 0.37 4.5% 0.44 63% vs 52% vs 2 2c (0.15– (0.21– 42%, 31%, 0.88) 0.93) gain gain 21% 21% 41 42 Dasatinib versus DASISION Newly Complete imatinib diagnosed cytRR chronic phase 12 months 77% vs 66%, 46% vs 1 2c gain 11% 28%, gain 18% 5 years 90% 1% NS 76% vs 42% vs 64%, 33%, gain gain 12% 9% 43 Bosutinib versus BFORE Newly MMR at 12 77% vs 66%, 47% vs 1 2c imatinib diagnosed months gain 11% 37%, chronic gain phase 10% cardiovasc., cardiovascular; CytRR, cytogenetic response rate;EFS, event-­free survival;ESMO-­MCBS v1.1, European Society for Medical Oncology—Magnitude of Clinical Benefit Scale, version 1.1; MMR, major molecular response; MR, molecular response; NS, not significant; OS, overall survival; PFS, progression-­free survival; QOL, quality of life. Open access 7 8 Table 5 Feasibility testing of the ESMO-­MCBS v1.1 for indolent non-­Hodgkin and relapsed/refractory setting of non-­DLBCL and Hodgkin’s lymphoma (n=12) ESMO-­ Primary PFS PFS ESMO-­MCBS MCBS Open access Medication Trial name Setting outcome control gain PFS HR OS control OS gain OS HR RR (DOR) QOL Toxicity score form Reference(s) 46 Obinutuzumab-­Chemo GALLIUM Follicular lymphoma, PFS 73% 7% 0.66 (0.51– Not scoreable 2b versus R-­Chemo first line (3 0.85) years) 47 48 VR-­CAP versus R-­CHOP LYM-3002 Mantle cell PFS 14.4 10.3 0.63 (0.5–0.79) 55.7 35 months 0.66 (0.51– Increased in A/4 1/2a lymphoma first months months months (7 year 0.85) experimental line, not eligible for survival arm transplant gain >5% with plateau) 49 50 R-­Bendamustine versus R-­ BRIGHT study Indolent and mantle Non-­       Non-­inferiority Improved Not scoreable 2c CHOP/R-­CVP cell lymphoma, inferiority met first line in CRR 1.26 (0.93– (margin: 1.73) 0.88) 31% versus 25%, 6% gain 51 R-­Bendamustine versus STiL Trial NHL Indolent and mantle Non-­ 31.2 38.3 0.58 (0.44– Less adverse 4 2c R-­CHOP 1-2003 cell lymphoma, inferiority months months 0.74) events in first line in PFS Non-­inferiority experimental (margin: met arm 1.32) 52–54 Bendamustine± GADOLIN Rituximab-­refractory PFS 14.9 NA 0.55 (0.40– NR >10% at 5 0.67 (0.47– Delayed 5 2a Obinutuzumab indolent non-­ months 0.74) years 0.96) deterioration Hodgkin’s lymphoma in QOL 55 Ibrutinib versus Temsirolimus Relapsed/refractory PFS 6.2 8.4 0.43 (0.32– Improved (+1 4 2b mantle cell months months 0.58) point) lymphoma 56 Lenalidomide versus MCL-002 Relapsed/refractory PFS 5.2 3.5 0.61 (0.44– Improved (+1 4 2b Investigator’s choice SPRINT mantle cell months months 0.84) point) lymphoma 57 Ibrutinib PCYC-1104-­ Relapsed/refractory ORR 13.9   68% 3 3 CA mantle cell months lymphoma 58 Ibrutinib Relapsed/refractory ORR 14.2   48% Relevant 3 3 marginal zone months toxicity but lymphoma not meeting criteria for downgrading 59 Idealisib DELTA (101- Relapsed/refractory ORR 11   57% (12.5 3 3 09) indolent lymphoma months months) 60 Pembrolizumab KEYNOTE- Relapsed/refractory ORR     69% Improved (+1 4 3 087 Hodgkin lymphoma point) 61 62 Nivolumab Check Relapsed/refractory ORR 14.7   69% Improved (+1 4 3 Mate 205 Hodgkin lymphoma months point) chemo, chemotherapy; CRR, complete response rate;DLBCL, non-­diffuse large B-­cell lymphoma; DOR, duration of response;ESMO-­MCBS v1.1, European Society for Medical Oncology—Magnitude of Clinical Benefit Scale, version 1.1; NA, not applicable; NR, not reached; ORR, overall response rate; OS, overall survival;PFS, progression-­free survival; QOL, quality of life; R, rituximab; R-­CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; R-­CVP, rituximab, cyclophosphamide, vincristine and prednisone; RR, response rate; VR-­CAP, bortezomib, rituximab, cyclophosphamide, doxorubicin and prednisone. Kiesewetter B, et al. ESMO Open 2020;5:e000611. doi:10.1136/esmoopen-2019-000611 Table 6 Feasibility testing of the ESMO-­MCBS v1.1 for DLBCL (n=11) Primary PFS/EFS/DFS PFS/EFS/DFS PFS/EFS/DFS OS ESMO-­MCBS ESMO-­ Medication Trial name Setting outcome control gain HR control OS gain OS HR RR (DOR) QOL Toxicity score MCBS form Reference(s) 63 64 CHOP±R MInT study First-­line DLBCL, EFS 55.8% (6 years) 18.5% p<0.0001 80% (6 10.1% p=0.0004 A 1 stage II–IV or I with years) bulky disease, IPI 0–1 65 66 CHOP±R LNH-98.5 First-­line DLBCL, PFS 20% at 10 16.5% p<0.0001 27.6% 15.9% p<0.0001 A 1 stage II–IV, age years (10 60–80 years) EFS 38% at 2 years 19% p<0.001 67 R-­CHOP REMARC First-­line DLBCL, PFS 58.9 months 4+ months 0.71 (0.54–0.93) NS A/3 1/2b ±lenalidomide stage II–IV, age maintenance 60–80 68 R-­GDP+ASCT NCIC-­CTG Relapsed/refractory Non- No difference No difference ORR Improved B/not 1/2 c versus R-­DHAP LY12 aggressive inferiority difference: scoreable +ASCT lymphoma (ORR) −1.2 (-9, 6.7) (margin: 44% vs −10%) 45% (non- inferiority met) 69 Pixantrone versus Relapsed/refractory CRR 2.6 months 2.7 months 0.60 (0.42–0.86) 20% vs 6%, 3 2b investigators’ choice aggressive gain 14% lymphoma >10% gain at 12 months, no Kiesewetter B, et al. ESMO Open 2020;5:e000611. doi:10.1136/esmoopen-2019-000611 plateau 70 CAR T-­cell ZUMA-1 Relapsed/refractory ORR 82% Toxicity but 3 3 Axicabtagene aggressive non-­ not meeting ciloleucel Hodgkin’s lymphoma criteria for downgrading 71 CAR T-­cell Tisagen-­ JULIET Relapsed/refractory ORR 52% (not Toxicity not 3 3 lecleucel DLBCL reached, >10 meeting months) criteria for downgrading 72 Lenalidomide versus DLC-001 Relapsed/refractory ORR   2 months   1.4 months 0.64 (0.41–0.99) 28% vs 12%, More PFS-­ 2 2b investigators’ choice DLBCL gain 16% improvement in ABC subtype 73 Panobinostat with or Relapsed/refractory ORR 28% (15 3 3 without R DLBCL months) 74 Brentuximab vedotin Relapsed/refractory ORR 4 months 44% 2 3 DLBCL 75 Ibrutinib   Relapsed/refractory ORR 2 months         37% (4.8     1 3 DLBCL, subgroup months) ABC subtype ASCT, autologous stem cell transplantation; CART- cell, chimeric antigen receptor T-­cell therapy; CHOP, cyclophosphamide, doxorubicin, vincristine and prednisone; CRR, complete response rate; DFS, disease-­free survival; DLBCL, diffuse large B-­cell lymphoma; DOR, duration of response; EFS, event-­free survival;ESMO-­MCBS v1.1, European Society for Medical Oncology—Magnitude of Clinical Benefit Scale, version 1.1; IPI, International Prognostic Index; NS, not significant; ORR, overall response rate; OS, overall survival;PFS, progression-­free survival; QOL, quality of life;R-­CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; R-­DHAP, rituximab, dexamethasone, cytarabine and cisplatin; R-­GDP, rituximab, gemcitabine, dexamethasone and cisplatin; RR, response rate. Open access 9 Open access Scorability: All studies incorporated required data 3. The EHA working group members felt that the capita- for evaluation using the ESMO-­MCBS v1.1. Single-­arm tion of PFS at a maximal preliminary grade of 3, with studies of CAR T-­cell therapy for refractory or resistant provision for an upgrade based on tail of the curve disease70 71 could not be evaluated for curative intent. The only if there is a plateau in the study medication PFS NCIC-­CTG LY12 trial could not be graded in the non-­ with gain of >10% at 12 months, may have undervalued curative setting because non inferiority was evaluated on some MM treatments.96 97 The plateau requirement for the basis of overall response rate.68 this adjustment precludes credit for substantial pro- Reasonableness: The grading was applicable and was longed gains in PFS in this disease entity. judged by the EHA working group to be reasonable in the evaluated trials, endorsing high benefit grades for Myelodysplastic syndrome first-­line therapies with curative intent.63–67 Lower benefit Studies evaluated: Ten studies were evaluated in this scores for trials in the relapsed and refractory therapies setting.105–114 Of these, two studies were evaluated based were considered reasonable. on OS or PFS and the remaining eight studies were evalu- Shortcomings: One shortcoming was identified: ated based on response rate (table 9). 1. The ESMO-­MCBS v1.1 does not have a form to grade Scorability: All studies incorporated required data for single-­ arm treatments with curative intent and this evaluation using the ESMO-­MCBS v1.1. Clinical benefit shortcoming does not allow for the representation of measure was, however, partly confounded by the hetero- the full potential benefit of CAR T-­cell salvage thera- geneity of the available definitions of haematological py.70 71 response and their clinical meaningfulness. Reasonableness: In the two studies evaluating Multiple myeloma hypomethylating agents in intermediate-­ risk/high-­ risk Studies evaluated: Table 7 describes results from eight patients,105 106 the ESMO-­MCBS v1.1 graded them with studies in the first-­line setting.76–84 Of these, three were substantial benefit based on either PFS gain or OS gain conducted for autologous stem cell transplantation with improved QOL. In lower risk patients, the remaining (ASCT) eligible76–78 patients and five are for ASCT ineli- eight studies included randomised trials investigating gible patients.79–84 Table 8 describes the results of a further erythropoietin-­stimulating agents, lenalidomide in MDS 15 studies with relapsed or refractory myeloma.85–104 with del(5q) or non-­ del(5q) and immunosuppressive Scorability: Most studies incorporated required data for therapy with antithymocyte globulin plus cyclosporine, evaluation using the ESMO-­MCBS v1.1. The PETHEMA/ compared with best supportive care.107–114 All studies GEM study comparing VTD (bortezomib, thalidomide were evaluated based on response rates, but they used and dexamethasone) to TD (thalidomide and dexa- a range of different and inconstant criteria, some using methasone) or VBMCP/VBAD/B (vincristine, BCNU, International Working Group, or modifications thereof, melphalan, cyclophosphamide, prednisone/vincris- and other study-­ specific criteria such as transfusion tine, BCNU, doxorubicin, dexamethasone/bortezomib) requirements. All these studies resulted in a final ESMO-­ as induction therapies did not report HRs for the PFS, MCSB v1.1 score of 2. In one of these studies108 QOL resulting in precluded scoring with non-­curative intent was evaluated and demonstrated to have improved but using form 2b.76 The GIMEMA 2005 study could not this was not reflected in grading since there is no QOL be scored for non-­curative intent because the median bonus for studies in which response rate is the primary PFS of the control arm had not yet been reached.77 The outcome. MM5 non- inferiority study78 could not be scored for Shortcomings: The EHA working group identified one non-­curative intent because non-­inferiority was based on shortcoming derived from these evaluations: response rate. 1. In studies evaluating response rate as a primary end- Reasonableness: First-­ line treatments for patients who point, there is no provision of QOL bonus if improved are ASCT eligible are graded both for curative and non-­ QOL is demonstrated as a secondary outcome. curative intent. The relatively low grades of C for curative intent achieved in two of the ASCT eligible studies76 77 reflect the prevailing consensus that MM is rarely cured. Discussion In most studies evaluated, the scale was feasible and the The EHA with currently more than 5000 members is results were consistent with clinical practice. the largest European-­based haematology association. In Shortcomings: Three previously described shortcomings addition to its educational mission, it has a public policy influenced scoring for a small number of these studies. and advocacy role that engages stakeholders, including 1. The ESMO-­MCBS v1.1 has no mechanism for scoring patient representatives, to improve patient care and to non-­inferiority studies in a non-­curative setting based raise awareness for haematology as a distinct medical on response rate. discipline with specific needs.115 Reflecting these goals, 2. When PFS (or EFS) is very long, the ESMO-­MCBS v1.1 EHA has observed the development of the ESMO-­MCBS has no mechanism to credit strong interim gains when and its broad utility in solid tumour oncology with great the median PFS of the control arm has not yet been interest, and in the absence of a value tool validated for reached. malignant haematology, we sought to investigate the 10 Kiesewetter B, et al. ESMO Open 2020;5:e000611. doi:10.1136/esmoopen-2019-000611 Table 7 Feasibility testing of the ESMO-­MCBS v1.1 for first-­line multiple myeloma (n=8) ESMO-­ ESMO-­ PFS/DFS MCBS MCBS Medication Trial name Setting Primary outcome control PFS/DFS gain PFS/DFS HR OS control OS gain OS HR RR QOL Toxicity score form Reference(s) 76 VTD versus TD or GEM2005-­less65 ASCT eligible CR post ASCT More neuropathy 1/2b VBMCP/VBAD/B PETHEMA/GEM (PFS) but not meeting criteria for TD 28.2 months 28.0 months p=0.01 65% at 4 9% NS CRR 46% vs C/not downgrading years 24%, gain 22% scoreable VBMCP/VBAD/B 35.3 months 20.9 months p=0.01 70% at 4 4% NS CRR 46% vs NEB/not years 38%, gain 8% scoreable 77 VTD versus TD GIMEMA 2005 ASCT eligible CR post induction 56% at 3 12% 0.63 (0.45– 84% at 3 2% NS (near) CRR 31% More neuropathy C/not 1/2b (PFS) years 0.88) years vs 11%, gain but not meeting scoreable 20% criteria for downgrading 78 VCD versus PAD MM5 ASCT eligible Non-­inferiority of VGPR SAEs higher in the Not 1/2 c ≥VGPR rates difference: 2.8% control arm scoreable (margin: −10%) (−6.8% to 12.3%) non-­ inferiority met 79 80 VMP versus MP VISTA ASCT TTP 16.6 months 7.4 months 0.48 43.1 months 13 months 0.70 4 2a ineligible (p<0.001) (0.57– Kiesewetter B, et al. ESMO Open 2020;5:e000611. doi:10.1136/esmoopen-2019-000611 0.85) 81 VMPT versus VMP GIMEMA VMPT ASCT PFS 27 months >13 months 0.67 (0.50– 87% at 3 2% NS – Vascular and 2 2b ineligible 41% at 3 15% 0.90) years cardiac events years increased in experimental arm (−1 point) 82 Lenalidomide-­d FIRST ASCT PFS continuous versus ineligible x18 or MPT x12 Len-­d x18 20.7 months 4.8 months 0.70 (0.60– 56% at 4 3% gain at 4 NS 3 2b 0.82) years years MPT 21.2 months 4.3 months 0.72 (0.61– 47 months 7 months 0.78 4 2a 0.85) 51% at 4 8% gain at 4 (0.64– years years 0.96) 83 VMP ALCYONE ASCT PFS 18 months 9+ months 0.50 (0.38– More infections but 3 2b ±daratumumab ineligible 50% at 18 21% at 18 0.65) not meeting criteria months months for penalty 84 Lenalidomide-­d SWOG S07777 ASCT PFS 30 months 13 months 0.71 (0.56– 64 months 11 months 0.71 Slightly increased 4 2a ±bortezomib ineligible 0.91) (0.52– 0.96) ASCT, autologous stem cell transplantation; CR, complete remission; CRR, complete remission rate; d, dexamethasone; DFS, disease-­free survival;ESMO-­MCBS v1.1, European Society for Medical Oncology—Magnitude of Clinical Benefit Scale, version 1.1; Len-­d, lenalidomide-­d; MP, melphalan and prednisone; MPT, melphalan, prednisone and thalidomide; NEB, no evaluable benefit; NS, not significant; OS, overall survival; PAD, bortezomib, doxorubicin, dexamethasone;PFS, progression-­free survival; QOL, quality of life; RR, response rate; SAE, serious adverse event; TD, thalidomide and dexamethasone; TTP, time to progression; VBMCP/VBAD/B, vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, doxorubicin, dexamethasone/bortezomib; VCD, bortezomib, cyclophosphamide, dexamethasone; VGPR, very good partial response rate; VMP, bortezomib, melphalan and prednisone; VMPT, bortezomib, melphalan, prednisone and thalidomide; VTD, bortezomib, thalidomide and dexamethasone. Open access 11 12 Table 8 Feasibility testing of the ESMO-­MCBS v1.1 for relapsed/refractory multiple myeloma (n=15) ESMO-­ ESMO-­ Open access Primary PFS MCBS MCBS Medication Trial name Setting outcome control PFS gain PFS HR OS control OS gain OS HR RR (DOR) QOL Toxicity score form Reference(s) 85 Dexamethasone CC-5013- MM- Relapsed/refractory TTP 4.7 6.6 months 0.35 (0.27– 20.6 NA 0.66 (0.45– 3 2b ±lenalidomide 010 months 0.46) months 0.96) 86 87 Lenalidomide-­d ASPIRE Relapsed/refractory PFS 17.6 8.7 months 0.69 (0.57– 40.4 7.9 0.79 (0.67– Improved (+1 Slightly increased 4 2a ±carfilzomib months 0.83) months months 0.95) point) 88 Lenalidomide-­d ±ixazomib TOURMALINE-­ Relapsed/refractory PFS 14.7 5.9 months 0.74 (0.59– Immature Not improved 3 2b MM1 (interim) months 0.94) 89 Lenalidomide-­d POLLUX Relapsed/refractory PFS 18.4 16+months 0.37 (0.27– Immature Higher 3 2b ±daratumumab (interim) months 0.52) haematological toxicities 90 91 Lenalidomide-­d ELOQUENT-2 Relapsed/refractory Coprimary 14.9 4.5 months 0.70 (0.57– 39.6 8.7 0.78 (0.63– No difference Slightly higher 3 2a ±elotuzumab PFS and months 11% at 12 0.85) months months 0.96) SAEs ORR 57% months (interim) at 12 months 92 93 Dexamethasone APEX Relapsed/refractory TTP 3.5 2.7 months 0.55 23.7 6.1 months 0.77 (p=0.027) 3 2b ±bortezomib months (p=0.001) months 94 95 Carfilzomib-­d versus ENDEAVOR Relapsed/refractory PFS 9.4 9.3 months 0.53 (0.44– 40 months 7.6 0.79 (0.65– Improved Slightly higher 3 2a bortezomib-­d months 0.65) months 0.96) (abstract only) SAEs 96 97 Bortezomib-­d CASTOR Relapsed/refractory PFS 7.1 9.6 months 0.31 (0.24– Immature Higher 3 2b ±daratumumab months 33.8% at 12 0.39) haematological 26.9% months toxicity at 12 months 98 Bortezomib-­d PANORAMA1 Relapsed/refractory PFS 8.1 3.9 months 0.63 (0.52– 30.4 3.25 Immature 3% increase in PN 2 2b ±panobinostat months 0.76) months months grade ≥3 (−1 point) 99 Dexamethasone MM-003 Relapsed/refractory PFS 1.9 2.1 months 0.48 (0.39– 8.1 months 4.6 0.74 (0.56– 4 2a ±pomalidomide months 0.60) months 0.97) 100 Pomalidomide-­d MMC-16705 Relapsed/refractory ORR 4.4 5.1 months NS 64.7% vs 2 2c ±cyclophosphamide ≥2 prior lines of months 38.9%, gain treatment 25.8% 101 Daratumumab SIRIUS Relapsed/refractory ORR 3.7 29% (7.4 2 3 months months) 102 Daratumumab GEN501 Relapsed/refractory Safety 5.6 36% (NR) 2 3 (16 mg/kg) months 103 Daratumumab MMY1001 Relapsed/refractory Safety 8.8 17.5 60% (>13 3 3 +pomalidomide + d ≥2 prior lines of months months months) treatment 104 Pomalidomide +bortezomib MC1082 Relapsed/refractory ORR 13.7 86% 3 3 +d months d, dexamethasone; DOR, duration of response;ESMO-­MCBS v1.1, European Society for Medical Oncology—Magnitude of Clinical Benefit Scale, version 1.1; NA, not applicable;NR, not reached; NS, not significant; ORR, overall response rate; OS, overall survival;PFS, progression-­free survival; PN, polyneuropathy; QOL, quality of life; RR, response rate; SAEs, serious adverse events; TTP, time to progress. Kiesewetter B, et al. ESMO Open 2020;5:e000611. doi:10.1136/esmoopen-2019-000611 Table 9 Feasibility testing of the ESMO-­MCBS v1.1 for myelodysplastic syndrome (n=10) PFS PFS OS OS ESMO-­MCBS ESMO-­ Medication Trial name Setting Primary outcome control gain PFS HR control gain OS HR RR (DOR) QOL Toxicity score MCBS form Reference 105 Azacitidine versus SOC AZA-­MDS-001 High-­risk MDS OS 15 9.5 0.58 (0.43– 4 2a months months 0.77) 106 Decitabine versus SOC   MDS FAB (IPSS ≥0.5) Coprimary ORR and 7.8 4.3 0.58 (0.37– Improved 4 2b PFS months months 0.91) (+1 point) 107 Lenalidomide (10 mg/5 mg) LEN-­MDS-004 Transfusion-­dependent RR (RBC-­TI) versus SOC patients with low-­risk/ intermediate-­risk MDS 10 mg 56% vs 6%, gain 2 2c del5q (IPSS ≤1) 50% 5 mg 43% vs 6%, gain 2 2c 37% 108 Lenalidomide versus SOC LEN-­MDS-005 MDS-­WHO (IPSS ≤1) RR (RBC-­TI at ≥8 26.9% vs 2.5%, Improved 2 2c weeks) gain 24.4% Kiesewetter B, et al. ESMO Open 2020;5:e000611. doi:10.1136/esmoopen-2019-000611 109 Antithymocyte globulin SAKK 33/99 MDS <10% bone marrow RR at 6 months 29% vs 9%, gain 2 2c versus SOC blasts 20% 110 rHuEPO versus SOC ICSG MDS <10% bone marrow RR (TI) 37% vs 11%, gain 2 2c blasts 26% 111 rHuEPO versus ±GCSF   MDS-­FAB (IPSS ≤0.5) RR (TI) 73% vs 40%, gain 2 2c 33% 112 EPO versus SOC E1996 MDS <10% bone marrow RR (IWG 2000 36% vs 10%, gain 2 2c blasts modified) 26% 113 rHuEPO +GCSF versus GFM MDS <10% bone marrow RR (IWG 2006 42% vs 0%, gain 2 2c SOC blasts stringently modified) 42% 114 Darbepoetin versus SOC   MDS-­WHO IPSS ≤1 RBC transfusion 59% vs 36%, gain 2 2c incidence 23% del5q, 5 q deletion; DOR, duration of response;ESMO-­MCBS v1.1, European Society for Medical Oncology—Magnitude of Clinical Benefit Scale, version 1.1; FAB, French–American–British classification for MDS; GCS-­F, granulocyte-­stimulating factor; IPSS, International Prognostic Scoring System; IWG, International Working Group; MDS, myelodysplastic syndrome;ORR, overall response rate; OS, overall survival;PFS, progression-­free survival; QOL, quality of life; RBC-­TI, red blood cell transfusion independency; rHuEPO, recombinant human erythropoietin; RR, response rate; SOC, standard of care; TI, transfusion independency. Open access 13 Open access applicability of the ESMO-­MCBS v1.1 as a first step to the 5. The scale does not make provision for the grading of development of a version validated for HMs. non-­inferiority studies based on response rate criteria. There are several major differences in the behaviour 6. In studies evaluating response rate as a primary end- of HMs as compared with solid tumour cancers. These point, there is no provision of QOL bonus if improved differences arise largely from the more variable natural QOL is demonstrated as a secondary outcome. history of HMs which can range from fulminant (acute Finally, it must be acknowledged that the results of the leukaemia and high-­grade lymphomas) to almost benign scale may not be reasonable for some of the least malig- (low-­grade MDS). Furthermore, many of these malignant nant of the HMs such as low-­risk MDS. Most of the studies haematological diseases, even when they are not cured, for MDS were evaluated based on response rates, but there they are characterised by very long PFS and OS that are was heterogeneity of the available definitions of haemato- rarely seen among incurable solid tumour malignancies. logical response and their clinical meaningfulness. This Finally, the endpoints used in the studies of treatments underlines the need for a stand-­alone form regarding for HMs are sometimes different to those used in solid studies with such heterogeneity in their response rates. tumours and in some instances, such as CML, they are ESMO and the EHA are committed to the develop- even disease-­specific. Consequently, at the outset of this ment of a version of the ESMO-­MCBS that is validated project we did not know if ESMO-­MCBS v1.1 could be for HMs. Based on the findings of this study, a revised applied to studies in HMs, and if the grading of studies version of the ESMO-­MCBS will be developed to address would generate grades considered reasonable by experts the identified shortcomings in the current version of the in the relevant diseases. scale regarding the assessment of HMs. This develop- This evaluation of the behaviour of the ESMO-­MCBS ment process will incorporate all the usual stringencies v1.1 in the grading of 80 studies across the full spectrum for accountability of reasonableness that have character- of HMs has demonstrated that the ESMO-­MCBS v1.1 is ised the development of the ESMO-­MCBS. This, thus far, widely applicable for the overwhelming majority of anal- included field testing, statistical modelling, evaluation ysed studies (90% scoreable studies) and that the gener- for reasonableness and openness to appeal and revision. ated scores were generally adjudicated by clinical experts Applying such a scale will support future decision-­making to reasonably accord with their evaluation of the magni- and will provide insights that could be helpful in the tude of clinical benefit. In 5 of the 80 studies (6%), the design of future clinical trials. ESMO-­MCBS could not be applied at all21 27 46 49 50 78 and in 3 more studies (4%), it could not be applied to one of the Author affiliations evaluable parameters.68 76 77 In the evaluation of imatinib 1 Department of Medicine I, Clinical Division of Oncology, Medical University of in CML,36–38 it generated scores that were considered to Vienna, Vienna, Austria 2 under-­represent the true value of the intervention in the Cancer Pain and Palliative Medicine Service, Department of Medical Oncology, Shaare Zedek Medical Center, Jerusalem, Israel opinion of experts in the evaluated diseases. 3 Department of Hematology, Hospital Saint-­Louis, Paris, Île-­de-­France, France Based on the analysis of the scorability of studies and 4 Adolescent and Young Adult Hematology Unit, Diderot University Paris Faculty of the reasonableness of the generated results, this field Medicine, Paris, Île-­de-­France, France testing identified six shortcomings in the current version 5 European Hematology Association, Den Haag, Zuid-­Holland, The Netherlands 6 of the ESMO-­MCBS that will require redress to improve Laboratory of Biostatistics, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece the applicability and reasonableness of ESMO-­ MCBS 7 Frontier Science Foundation-­Hellas, Frontier Science Foundation-­Hellas, Athens, scoring for malignant haematological conditions. Greece 1. Regarding single-­arm studies with curative intent, such 8 Department of Medical Oncology, University Medical Center Groningen, Groningen, as CAR T-­cell salvage therapies, the ESMO-­MCBS v1.1 The Netherlands 9 does not have a form to grade single-­arm treatments Strategic Research Program on CLL, Division of Experimental Oncology, IRCCS with curative intent. Ospedale San Raffaele, Milano, Lombardia, Italy 10 Universita Vita e Salute San Raffaele, Milano, Lombardia, Italy 2. Regarding relatively indolent conditions with a very 11 Department of Hematology/Oncology, Goethe University, Frankfurt am Main, long PFS (or EFS) or OS such as CLL, CML, indolent Hessen, Germany lymphoma and MM, there is no mechanism to credit 12 Department of Hematology and Instituto de Investigación Biomédica de strong interim gains when the median of the control Salamanca-­IBSAL, University Hospital of Salamanca, Salamanca, Castilla y León, arm has not yet been reached. Spain 13 3. The capitation of PFS at a maximal preliminary grade Cambridge Stem Cell Institute, Department of Haematology, University of Cambridge, Cambridge, UK of 3, with provision for an upgrade based on tail of 14 Department of Medicine I, Clinical Division of Hematology and Hemostaseology, the curve only when there is a plateau in the arm with Medical University of Vienna, Vienna, Austria the study medication, may undervalue treatments with 15 Head Office, European Society for Medical Oncology, Lugano, Switzerland 16 substantial late PFS gain but with no plateauing of the Department of Molecular Medicine, University of Pavia, Pavia, Lombardia, Italy 17 curves. Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Lombardia, Italy 4. Regarding the standard molecular surrogate endpoints 18 Department of Hematology, VU University Medical Centre Amsterdam, Amsterdam, used for CML, the surrogacy of complete cytogenic re- Noord-­Holland, The Netherlands sponse and level 4–5 MMR must be acknowledged and 19 Department of Hematology, Helsinki University Hospital Comprehensive Cancer incorporated. Center, Helsinki, Finland 14 Kiesewetter B, et al. ESMO Open 2020;5:e000611. doi:10.1136/esmoopen-2019-000611 Open access 20 Clinical Hematology Department, ICO-­Hospital Germans Trias i Pujol, Josep 5 Daniels N. Accountability for Reasonableness. BMJ Carreras Research Institute, Universitat Autònoma de Barcelona, Barcelona, 2000;321:1300–1. Catalunya, Spain 6 Daniels N. Decisions about access to health care and accountability 21 for Reasonableness. J Urban Health 1999;76:176–91. Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Zuid-­ 7 Dafni U, Karlis D, Pedeli X, et al. Detailed statistical assessment of Holland, The Netherlands the characteristics of the ESMO magnitude of clinical benefit scale 22 Department of Radiation Oncology, Erasmus MC Cancer Institute, Rotterdam, (ESMO-­MCBS) threshold rules. ESMO Open 2017;2:e000216. Zuid-­Holland, The Netherlands 8 Hammerman A, Greenberg-­Dotan S, Feldhamer I, et al. The ESMO-­Magnitude of clinical benefit scale for novel oncology drugs: correspondence with three years of reimbursement Contributors Design of the study: BK, NIC, FC, EGEdV, NJL, J-­YD, PS. Collection of decisions in Israel. Expert Rev Pharmacoecon Outcomes Res trials/data: BK, NB, PG, NG, VG-­C, BH, UJ, LM, M-­VM, GJO, KP, MR, J-­MR, LS, RW, 2018;18:119–22. PS. Scoring, analysis and interpretation of data: BK, NIC, NB, UD, EGEdV, PG, NG, 9 Wild C, Grössmann N, Bonanno PV, et al. Utilisation of the ESMO-­ VG-­C, BH, UJ, LM, M-­VM, GJO, KP, MR, J-­MR, LS, RW, PZ, PS. Statistical analysis: MCBS in practice of HTa: table 1. Ann Oncol 2016;27:2134–6. UD, PZ. Manuscript design and writing: BK, NIC, FC, EGEdV. Manuscript editing and 10 Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus final approval: all authors. chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 2017;377:454–64. The authors have not declared a specific grant for this research from any funding 11 Castaigne S, Pautas C, Terré C, et al. Effect of gemtuzumab agency in the public, commercial or not-­for-­profit sectors. ozogamicin on survival of adult patients with de-­novo acute myeloid leukaemia (ALFA-0701): a randomised, open-­label, phase 3 study. Competing interests BK has received honoraria for lectures from Celgene and The Lancet 2012;379:1508–16. Novartis; NB has received honoraria for consulting and advisory role from Ariad, 12 Röllig C, Serve H, Hüttmann A, et al. Addition of sorafenib versus Amgen, Novartis and Pfizer; EGEdV declares advisory role for Daiichi Sankyo, placebo to standard therapy in patients aged 60 years or younger Merck, NSABP, Pfizer, Sanofi and Synthon, and institutional financial support with newly diagnosed acute myeloid leukaemia (SORAML): a for clinical trials or contracted research for Amgen, AstraZeneca, Bayer, Chugai, multicentre, phase 2, randomised controlled trial. Lancet Oncol CytomX Therapeutics, G1 Therapeutics, Genentech, Nordic Nanovector, Radius 2015;16:1691–9. Health, Roche and Synthon; PG has received honoraria for lectures/advisory boards 13 Fenaux P, Mufti GJ, Hellström-­Lindberg E, et al. Azacitidine and research funding from AbbVie/Pharmacyclics, Acerta/AstraZeneca, BeiGene, prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid Janssen, Gilead, Novartis, Sunesis and Verastem; NG has received honoraria for leukemia. JCO 2010;28:562–9. lectures, advisory boards and research support from Amgen, Pfizer and Incyte; VG-­C 14 Kantarjian HM, Thomas XG, Dmoszynska A, et al. Multicenter, has received honoraria for lectures from Janssen and for participation in advisory randomized, open-­label, phase III trial of decitabine versus patient boards from Prothena; BH has received honoraria for lectures from Novartis, Pfizer choice, with physician advice, of either supportive care or low-­dose and BMS, and for participation in advisory boards from Novartis, GlaxoSmithKline, cytarabine for the treatment of older patients with newly diagnosed Abbvie, Pfizer, BMS and Incyte; UJ has declared honoraria from Abbvie, BMS, acute myeloid leukemia. JCO 2012;30:2670–7. Celgene, Amgen, Roche, Novartis, Gilead, Bioverativ, Janssen, MSD, Sandoz, Takeda 15 Döhner H, Lübbert M, Fiedler W, et al. Randomized, phase 2 trial of and Pfizer; M-­VM has received honoraria for lectures from Janssen, Celgene, low-­dose cytarabine with or without volasertib in AML patients not suitable for induction therapy. Blood 2014;124:1426–33. Takeda and Amgen, and for participation in advisory boards from Janssen, Celgene, 16 Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant Takeda, Amgen, AbbVie, GlaxoSmithKline and PharmaMar; MR has received IDH2 relapsed or refractory acute myeloid leukemia. Blood honoraria for lectures from Novarits, Ipsen, Celgene and Eisai; LS has received 2017;130:722–31. honoraria for lectures from Janssen, AbbVie, AstraZeneca, and for participation in 17 Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus advisory boards from Janssen; PS has received honoraria for lectures and advisory chemotherapy for advanced acute lymphoblastic leukemia. N Engl boards from Celgene, Janssen, Takeda and Amgen, and research support from J Med 2017;376:836–47. Celgene, Janssen and Amgen. 18 Topp MS, Zimmerman Z, Cannell P, et al. Health-­Related quality of life in adults with relapsed/refractory acute lymphoblastic leukemia Patient consent for publication Not required. treated with blinatumomab. Blood 2018;131:2906–14. Provenance and peer review Not commissioned; externally peer reviewed. 19 Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab Ozogamicin versus standard therapy for acute lymphoblastic Data availability statement Data sharing not applicable as no datasets generated leukemia. N Engl J Med 2016;375:740–53. and/or analysed for this study. 20 Kantarjian HM, Su Y, Jabbour EJ, et al. Patient-­Reported outcomes from a phase 3 randomized controlled trial Open access This is an open access article distributed in accordance with the of inotuzumab ozogamicin versus standard therapy for Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which relapsed/refractory acute lymphoblastic leukemia. 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