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bloodBLD2021012328 Suppl1
bloodBLD2021012328 Suppl1
Swantje Buchmann1*, Martin Schrappe1*§, Andre Baruchel2, Andrea Biondi3, Michael Borowitz4, Myriam Campbell5, Gunnar Cario1, Gianni
Cazzaniga3, Gabriele Escherich6, Christine J. Harrison7, Mats Heyman8, Stephen P. Hunger9, Csongor Kiss10, Hsi-Che Liu11, Franco Locatelli12,
Mignon L. Loh13, Atsushi Manabe14, Georg Mann15, Rob Pieters16, Ching-Hon Pui17, Susana Rives18, Kjeld Schmiegelow19, Lewis B. Silverman20, Jan
Stary21, Ajay Vora22 and Patrick Brown23 on behalf of the Ponte-di-Legno Consortium
Supplementary material
1
Supplementary data
1. Recommendations of COG:
2. Recommendations of AIEOP-BFM:
2
Supplementary tables
Supplement table 1: Remission and treatment failure definitions in current ALL studies
Study group Current/Recent Trial Remission (CR) Treatment Failure (TF) Additions Events Reference
definition definition timepoint(s) technique definition technique
AIEOP-BFM AIEOP-BFM ALL 2017 <5% blasts in BM ≥5% blasts in BM d33, end of induction cytomorphology Late Response Death NCT03643276
CR after d33 up to end of 3rd HR/2nd
CNS1 blasts in CSF cytomorpholgy Relapse
Blina
no localized leukemic infiltrates/
reduction of initial mass to at least 1/3 of persistent leucemic mass clinical examination, imaging, biopsy Morphological Non Response Second malignancy
initial mass
nCR after 3rd HR/2nd Blina cytomorphology Morphological Non Response
ALL-IC-BFM ALL-IC-BFM 2009 <5% blasts in BM ≥5% blasts in BM d33, end of induction cytomorphology Late Responders Death EudraCT 210-019722-13
no blasts in CSF blasts in CSF CR after d33 up to end of 2rd HR cytomorphology Relapse
no localized leukemic infiltrates/masses persistent leukemic mass clinical examination, imaging, biopsy Non Responders Second malignancy
CR regardless of timing
FCM/PCR-MRD, cytomorphology if no Resistant disease/Protocol therapy
ALLTogether ALLTogether1 <1% blasts in BM ≥1% blasts in BM end of induction (at the earliest), TF after Induction Death NCT04307576
markers (5% cut-off) failure
Cons (Down) or HR-blocks (all others)
CSF: no blasts on Cytospin 2 consecutive cytomorphology, confirmation by FCM- FCM/PCR-MRD, cytomorphology if Protocol Therapy Failure (RD)
still Cytospin pos EOC (d71) EOC (d71) ≥1% blasts in BM after 3 HR blocks
samples MRD allowed if cells are seen no markers (5% cut-off) (not "refractory")
still no reduction (viable tumour by PET-
mediastinal mass: reduction to <1/3 EOC (d71) radiology +/- PET-CT, biopsy Refractory disease (T-ALL) Relapse
CT/biopsy)
≥5% d29 and ≥0.5% day 50 or
US not normal, biopsy proven remaining FCM/PCR-MRD, cytomorphology if
testis: bilateral US normalize EOC (d71) US +/- biopsy <5% d29 and ≥0.05% d71 or Death in CR1
infiltration no markers (5% cut-off)
≥5% d29, and ≥0.01% day 71
unchanged/increasing MR-
CNS clinical/MR: MR-findings EOC (d71) clinical assessment, MR Second malignancy
findings/symptoms
eye: Ophtalmoscopy normalised remaining infiltrates EOC (d71) clinical assessment
CoALL CoALL 08-09 <5% blasts in BM ≥5% blasts in BM d 29, end of induction cytomorphology Late Response Death EudraCT 2009-012758-18
CNS1 blasts in CSF CR after d29 up to end of 2rd HR1 cytomorphology Relapse
no localized leukemic infiltrates/
reduction of initial mass to at least 1/3 of persistent leukemic mass clinical examination, imaging, biopsy Non Response Second malignancy
initial mass
nCR after 2nd HR Morphological Non Response
COG AALL1731, AALL1732 <1% blasts in BM ≥1% blasts in BM d29, end of induction (for early CR) FCM-MRD Early CR Death NCT03914625
FCM-MRD, cytomorphology and
resolution of CNS leukemia (CNS1) CNS2 or CNS3 End of consolidation (for late CR) cytomorphology achievement of CR by d29 evaluation Relapse NCT03959085
clin. examination
NOTE: end of consolidation evaluation is
resolution of other extramedullary disease non-resolution of other EM disease clinical examination/imaging Late CR Second malignancy
done after day 56 once APC>500/uL
If not early CR, achievement of CR by FCM-MRD, cytomorphology and
Consolidation failure
end-of-consolidation evaluation clin. examination
Induction Failure
d29 M3 marrow, or d29 MRD ≥5%, or FCM-MRD, cytomorphology and
residual EM disease clin. examination
Consolidation Failure
d92 (d57) MRD ≥1% (CF-MRD), or FCM-MRD, cytomorphology and
residual EM disease clin. examination
DCOG DCOG ALL-11 <5% blasts in BM ≥5% blasts in BM d33, end of induction cytomorphology Non Responders Death in induction/death in CR EudraCT 2012-00006725
without extramedullary leukemia extramedullary leukemia clinical examination,imaging M2/M3 or cytomorphology, imaging, biopsy Relapse
extramedullary disease (testis and CNS: blasts in CSF after one Depocyte
imaging and biopsy cytomorphology Second malignancy
mediastinal mass) will be tested at d 85 d15 due to remaining blasts in CSF
Induction failure
<5% blasts in BM reinforced by MRD < 5x10- Treatment failure/
SFCE CAALL-F01 ≥5% blasts in BM reinforced by MRD ≥5x10-2 d35-d42, end of induction cytomorphology AND PCR-MRD Death NCT02716233
2 Induction failure at d 35
cytomorphology, confirmed by
no blasts in the CSF blasts in CSF cytomorphology ≥5% blasts in BM AND Relapse
PCR-MRD
absence of leukemic mass/reduction of MRD ≥5x10-2 (if not possible,
persistence of leukemic mass ≥30% imaging, biopsy Secondary malignancy
mass to at least 30% cytomorphology only)
Treatment failure
SJCRH TOT-XVI <5% blasts in BM ≥5% blasts in BM d38-42, end of remission induction FCM-MRD Induction failure at day 42 Death NCT00549848
cytomorphology, confirmed by
≥5% blasts in BM Relapse
FCM-MRD
Second malignancy
Induction failure
cytomorophology, confirmed by FCM-
TPOG TPOG-ALL-2013 <5% blasts in BM ≥5% blasts in BM d35-d42, end of remission induction Induction failure at day 42 Death no NCT or EudraCT
/PCR-MRD
cytomorphology, confirmed by
no blasts in CSF blasts in CSF ≥5 % blasts in BM Second malignancy
FCM-/PCR-MRD
Relapse
Induction failure
UKALL UKALL 2011 Trial <5% blasts in BM ≥5% blasts in BM d29, end of induction PCR-MRD True induction failure at day 29 Death www.isrctn.com/ISRCTN64515327
no blasts in the CSF blasts in CSF cytomorphology ≥25% blasts in BM PCR-MRD Relapse
initial testsis involvement is controlled at
week eight, without impact on risk Partial response at d 29 Secondary tumour
stratification
< 35 % reduction of mediastinal mass > 35 % reduction of mediastinal mass 5- < 25% blasts in BM PCR-MRD True induction failure
Blina: Blinatumomab, BM: bone marrow, CNS: central nervous system, CSF: cerebral spinal fluid, Cons.: Consolidation, CR: complete remission, CT: clinical trial, d: day, EM: extramedullary
sites, EOC: end of consolidation, EOI: end of induction, FCM-MRD: flow cytometric minimal residual disease, FISH: fluorescence in situ hybridization, HR: high risk, i.t.: intra thecal, MRD:
minimal residual disease, NCT: number of ‘Clinical Trial’, PB: peripheral blood, PCR-MRD: polymerase chain reaction minimal residual disease, TF: treatment failure, US: ultra sound
3
Supplement table 2: Relapse definitions in current ALL studies
reexamination in intervals of
≥ 5-50% blasts cytomorphology
one week, if increase or >25%
≥ 25% blasts in BM AND >2% in PB cytomorphology
cytomorphology AND confirmation by
≥ 25% blasts in BM
genetic tests
>5/μl nucl. cells in CSF and evidence of
Isolated CNS cytomorphology
blasts
intracranially mass excluding
imaging AND biopsy
hemorrhage
≥ 5% blasts in BM and ≥ 1 if BM relapse is diagnosed, no
Combined
extramedullary site localization biopsy needed
Other sides biopsy/imaging
cytomorphology, conf. by histochemistry,
NOPHO NOPHO-ALL 2008 Isolated BM ≥ 5% blasts
FCM-/PCR-MRD or genetics
cytomorphology, conf. by histochemistry,
Isolated CNS ≥ 5/μL blasts in CSF
FCM-/PCR-MRD or genetics
bulky CNS leukemia imaging, biopsy
Isolated testicular imaging, biopsy
Other sides clinically suspiious imaging, biopsy
BM: bone marrow, CNS: central nervous system, CSF: cerebral spinal fluid, CR: complete remission, EM: extramedullary sites, FCM-MRD: flow cytometric minimal residual disease, FISH:
fluorescence in situ hybridization, i.t.: intra thecal, MRD: minimal residual disease, PB: peripheral blood, PCR-MRD: polymerase chain reaction minimal residual disease, US: ultra sound
4
Supplement table 3: Common/currently used relapse criteria
Isolated CNS > 5/μl nucleated cells in CSF and evidence of blasts cytomorphology
OR
intracranial mass imaging, biopsy
BM: bone marrow, CNS: central nervous system, CSF: central spinal fluid, EM: extramedullary sites