Consensus definitions for response criteria in pediatric ALL: results from the Ponte-di-Legno consortium

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.

Methods

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.

Terminology

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:

• M1 marrow: <5% blasts
• M2 marrow: ≥5 to <25% blasts
• M3 marrow: ≥25% blasts
  • COG has historically defined M3 marrow as >25% blasts.

CNS classification by cytomorphology and/or clinical findings (+/− imaging and biopsy) is defined as follows:

• CNS1: Absence of blasts on cytospin preparation in cerebrospinal fluid (CSF) and no clinical or imaging findings of CNS leukemia
• CNS2: ≤5/µl nucleated cells in CSF, cytospin preparation positive for blasts, and no clinical or imaging findings of CNS disease
• CNS3: >5/µl nucleated cells in CSF, cytospin preparation positive for blasts, or clinical or imaging findings of CNS disease
  • COG, EsPhALL/COG, DFCI, NOPHO, SFCE, SJCRH, and TPOG defined CNS3 as ≥5/µl nucleated cells in CSF.

Treatment phases

Most protocols define treatment phases thus:

• Induction, lasting 4–6 weeks (phase Ia in BFM-type regimens)
• Consolidation (phase Ib in BFM-type regimens)
• Intensification, targeting the extramedullary space
• Re-intensification (or delayed intensification), with or without CNS irradiation

In a small number of cases, the later phases may be replaced by allogeneic hematopoietic stem cell transplantation.

Results

Complete remission

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*

Treatment failure

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*

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.

Consensus for complete remission and treatment failure

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

Regarding TF:

• Failure to achieve CR at a clearly pre-defined time point (such as EOI or EOC) should be considered as a TF event.
• There was progress toward a consensus that a TF event should be defined no earlier than EOC, allowing patients who do not achieve CR by EOI to potentially achieve CR with consolidation therapy.

Relapse

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.

Consensus for relapse

The consensus for relapse can be seen in Table 4.

Table 4. Consensus for diagnosis of relapse*

Conclusion

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.