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Pediatric patients with newly diagnosed acute lymphoblastic leukemia (ALL) are often treated in clinical trials, and it is important to have uniform consensus on definitions of response criteria, as these criteria—including complete remission (CR), treatment failure (TF), minimal residual disease (MRD), and relapse—are germane to treatment decisions.
It is necessary to be able to compare results from protocol to protocol as there are many therapeutic options being investigated, and the goal of each of these investigational studies is to increase event-free survival (EFS) and overall survival (OS) rates and to improve the patient’s quality of life. But which of these parameters are most relevant in ALL clinical trials? EFS is the most widely accepted parameter and is advantageous over OS in that it considers, in addition to death, other clinically important outcomes such as TF, relapse, therapy-related mortality, and second malignancies. OS also may not provide information about the efficacy of first-line therapy, as it is influenced by the efficacy of salvage therapy.
Relapse, primary TF, and CR must be defined consistently for time-to-event from diagnosis to be accurately calculated. Buchmann and colleagues,1 referred to herein as the Ponte-di-Legno (PDL) group representatives, collected and summarized the current definitions of CR, TF, relapse, and other events, and created consensus definitions for use in future trials.
This was a collaborative project between the PDL group and the following study groups: AIEOP-BFM, ALL-IC-BFM, ALLTogether, CoALL, COG, DCOG, DFCI ALL Consortium, EsPhALL/COG, JCCG, NOPHO, SEHOP-PETHEMA, SFCE, SJCRH, TPOG, and UKALL. Recent protocols from these study groups were reviewed for the definitions of CR, TF, relapse, and events, and a summary was provided to participating study groups. An overview of all definitions was prepared, and the first classifications were established prior to a face-to-face meeting of the PDL group in May 2019.
The morphologic classifications of bone marrow (BM) and central nervous system (CNS) involvement are long-standing and are defined here, as they will be referred to in the discussion of the results.
BM classification by cytomorphology is defined as follows:
CNS classification by cytomorphology and/or clinical findings (+/− imaging and biopsy) is defined as follows:
Most protocols define treatment phases thus:
In a small number of cases, the later phases may be replaced by allogeneic hematopoietic stem cell transplantation.
There were large differences between the groups’ definitions of CR regarding timing of CR assessment, threshold levels of leukemic cells to define CR, and detection method, as seen in Table 1.
Table 1. Remission assessment in current treatment protocols for pediatric ALL*
ALL, acute lymphoblastic leukemia; BM, bone marrow; CNS, central nervous system; EM, extramedullary; EOC, end of consolidation; EOI, end of induction; FCM-MRD, flow cytometric minimal residual disease; MRD, minimal residual disease; PCR-MRD, polymerase chain reaction minimal residual disease. |
||||
Anatomic sites |
Methods |
Study group |
Timepoint |
Exceptions |
---|---|---|---|---|
BM |
||||
<5% blasts in BM |
Cytomorphology |
AIEOP-BFM |
Day 33, EOI |
|
ALL-IC BFM |
Day 33, EOI |
|||
CoALL |
Day 29, EOI |
|||
DCOG |
Day 33, EOI |
|||
DFCI |
Day 32, EOI |
|||
JCCG |
Day 33, EOI |
|||
TPOG |
Day 35‒42, EOI |
|||
<5% blasts in BM |
Cytomorphology + confirmation by FCM-/PCR-MRD/genetics |
NOPHO |
Day 29, EOI |
SJCRH mainly uses FCM-MRD |
SEHOP-PETHEMA |
EOI |
|||
SFCE |
Day 35‒42, EOI |
|||
SJCRH |
Day 38‒42, EOI |
|||
<5% blasts in BM |
PCR-MRD +/− cytomorphology |
UKALL |
Day 29, EOI
|
|
<1% blasts in BM |
FCM-/PCR-MRD +/− cytomorphology |
ALLTogether |
EOI as the earliest |
|
COG |
EOI for early CR, EOC for late CR |
|||
EsPhALL/COG |
EOC block 3 |
|||
CNS |
||||
CNS1 |
Cytomorphology, imaging, clinical examination |
Every participating study group |
See above for respective study group |
|
CNS1 |
Cytomorphology + confirmation by FCM-MRD |
ALLTogether |
See above for respective study group |
If suspect cells are seen, evaluation at EOC (Day 71) |
EM |
||||
Resolution of leukemic infiltrates |
Clinical examination, imaging, histology |
ALL-IC |
See above for respective study group |
DCOG: Retesting of testicular involvement after Prot. M; NOPHO: Retesting |
COG |
||||
DCOG |
||||
JCCG |
||||
EsPhALL/COG |
||||
Reduction of initial leukemic mass to 1/3 |
Clinical examination, imaging, histology |
AIEOP-BFM |
See above for respective study group |
UKALL: Retesting of testicular involvement at Week 8 |
ALLTogether |
||||
CoALL |
||||
DFCI |
||||
SEHOP-PETHEMA |
||||
SFCE |
||||
UKALL |
Significant differences between groups were also identified regarding definitions of TF as events, as shown in Table 2.
Table 2. Definitions of treatment failure events*
BM, bone marrow; CR, complete remission; EOI, end of induction; FCM-MRD, flow cytometric minimal residual disease; PCR-MRD, polymerase chain reaction minimal residual disease. |
||
Event |
Methods |
Study group |
---|---|---|
Induction failure (EOI) |
Cytomorphology and/or FCM-/PCR-MRD or genetics |
JCCG, SEHOP-PETHEMA, SFCE, SJCRH, TPOG |
Induction failure (EOI) |
Cytomorphology and/or FCM-/PCR-MRD or genetics |
DFCI, UKALL |
No induction failure events; TF is an event if CR has not been achieved at later timepoints |
Different combinations of methods |
AIEOP-BFM, ALLTogether, ALL-IC-BFM, CoALL, COG, DCOG, EsPhALL-COG, NOPHO |
There was a broad consensus among the groups that TF is defined as failure to achieve CR by a pre-specified time point, though the groups do not agree on that time point. Some of the study groups consider failure to achieve CR at end of induction (EOI) as a TF event, while others use a later time point after stratifying the patient to more intensive post-induction therapy, and COG trials define TF as failure to achieve CR at end of consolidation (EOC); these differences are important when trying to compare EFS results from different trials.
Each study group should define EOI and EOC for their protocols. The consensus was that MRD measurement is the gold standard to assess CR; all available methods for MRD assessment are acceptable if quality standards have been established. CR is defined in Table 3.
Table 3. Definition of CR
BM, bone marrow; CNS, central nervous system; CR, complete remission; CSF, cerebrospinal fluid; EM, extramedullary; FCM, flow cytometric; MRD, minimal residual disease. |
|
Timing |
CR is to be assessed no earlier than EOI |
---|---|
Anatomic site requirements |
BM: MRD <1% and/or M1 cytomorphology |
CNS: CNS1 |
|
Testes: Normalization of clinical examination (negative biopsy if clinical examination is not considered normal) |
|
EM: No evidence of leukemic infiltrates as evaluated clinically and by imaging; a pre-existing leukemic mass (mediastinal mass included) must have decreased to at least 1/3 of the initial tumor volume |
|
Methods |
BM: MRD measurement; if MRD is not available, response is assessed by cytomorphology |
CNS: CSF cytomorphology (FCM or genetic analysis may be used in unclear cases), clinical neurological exam, and imaging (in case of clinical findings) |
|
Non-CNS EM disease: Physical examination, imaging, or histologic examination of tissue biopsy |
Regarding TF:
A patient can only have a relapse event after CR has been previously achieved, and relapse should be subclassified by anatomic sites of involvement at the time of relapse: isolated BM relapse, isolated CNS relapse, isolated testicular relapse, isolated other EM relapse, and combinations of these sites.
The consensus for relapse can be seen in Table 4.
Table 4. Consensus for diagnosis of relapse*
BM, bone marrow; CNS, central nervous system; CSF, cerebrospinal fluid; FCM, flow cytometric; FISH, fluorescence in situ hybridization; MRD, minimal residual disease; NGS, next-generation sequencing; PCR, polymerase chain reaction. |
||
BM relapse (MRD available) |
||
---|---|---|
BM #1 |
BM #2‡ |
|
MRD |
Others |
|
≥25% |
† |
† |
5 to <25% |
1 other test§ with 1% blasts |
† |
5 to <25% |
None |
2 tests§ with 1% blasts |
1 to <5% |
2 other tests§ with 1% blasts |
† |
1 to <5% |
0 or 1 other test§ with 1% blasts |
2 tests§ with 1% blasts |
BM relapse (MRD unavailable) |
||
BM #1 |
BM #2‡ |
|
Cytomorphology |
Others |
|
M3 |
† |
† |
M2 |
1 other test‖ with 1% blasts |
† |
M2 |
None |
M2 |
M1 |
2 other tests‖ with 1% blasts |
† |
CNS relapse |
||
CSF #1 |
CSF #2‡ |
|
Cytomorphology |
Cytomorphology |
|
CNS3¶ |
† |
† |
CNS2 |
CNS2 |
1 other positive test |
While the implementation of these new consensus criteria will require serious effort from most of the study groups, it is of utmost importance that common response and relapse assessment criteria are established in pediatric ALL as current endpoints are poorly defined, creating significant challenges when comparing efficacy between trials and hindering consistency in defining EFS and eligibility criteria for enrollment in relapsed/refractory ALL trials.
References
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