ESMO Consensus Conference on Malignant Lymphoma: Recommendations for Prognostic Tools in CLL

On June 20^th 2015 in Lugano, Switzerland, a multidisciplinary panel of 25 leading experts met at the European Society of Medical Oncology (ESMO) consensus conference on mature B-cell lymphomas and Chronic Lymphocytic Leukemia (CLL). The panel suggested and voted on recommendations in important subjects that are difficult to consider and include in detail within the ESMO Clinical Practice Guidelines (CPGs). These subjects were: elderly patients, prognostic factors suitable for clinical use, and the ‘ultra-high-risk’ group.

In an article¹ published in Annals of Oncology in August 2016 by M. Ladetto of the Azienda Ospedaliera Santi Antonio e Biagio e Cesare Arrigo, Alessandria, Italy, and colleagues, the recommendations for the second subject (prognostic factors suitable for clinical use) were reported and focused on four areas of interest:

1. Interim PET (Front-Runner Entities [FREs] – HL, DLBCL)
2. TP53 mutations and deletions (FRE – CLL)
3. COO determination by GEP or IHC (FRE – DLBCL)
4. Molecular-based MRD evaluation (FREs – MCL, FL, CLL)

The level or evidence and strength of each recommendation were noted, which were defined based on the ‘Infectious Diseases Society of America-United States Public Health Service Grading System’.² Below are the recommendations for CLL which were scored IA and IB (I = Evidence from at least one large randomized, controlled trial of good methodological quality [low potential for bias] or meta-analyses of well-conducted randomized trials without heterogeneity; A = Strong evidence for efficacy with a substantial clinical benefit, strongly recommended; B = Strong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended)

IA recommendations

Both of the recommendations which scored IA fell into the ‘TP53 mutations and deletions’ category.

Recommendation 2.1

• The use of TP53 screening before the start of treatment is highly encouraged in CLL
• The panel strongly recommends the inclusion of TP53 analysis, both by FISH and DNA sequencing, in clinical trials of CLL for intervention and monitoring purposes
• The availability of new drugs that overcome TP53-mediated chemorefractory disease demands the assessment of TP53 status for all CLL patients at the time of screening in trials in which ≥1 arms may be using drugs known to be ineffective in TP53-disrupted CLL

Recommendation 2.3

• The panel supports analysis of TP53 disruption at the time of treatment requirement, both in first-line and subsequent lines of therapy
• Re-examining TP53 status in formerly TP53 wild-type CLL at relapse requiring treatment is advisable as TP53 disruption may occur or become measurable only at relapse
• TP53 screening by FISH and mutational analysis for monitoring and intervention in clinical practice is encouraged in CLL, as long as treatments which overcome TP53-mediated resistance [e.g. BCR inhibitors and allo-SCT) are available and accessible

IB recommendations

The one recommendation which scored IB fell into the ‘potential role of molecular-based MRD evaluation as a prognostic tool’ category.

Recommendation 4.1(v)

• The use of MRD evaluation in clinical trials is encouraged in CLL for monitoring (depends on the drug used)
• The panel does not support MRD evaluation for monitoring or intervention in routine practice outside of clinical trials as there is no general recommendation for treatment modification currently published

The panel advise that these additional recommendations should be read in conjunction with the already-published ESMO CPGs for the diagnosis, treatment and follow-up of CLL.

Abstract

The European Society for Medical Oncology (ESMO) consensus conference on mature B-cell lymphomas and chronic lymphocytic leukaemia (CLL) was held on 20 June 2015 in Lugano, Switzerland, and included a multidisciplinary panel of 25 leading experts. The aim of the conference was to develop recommendations on critical subjects difficult to consider in detail in the ESMO Clinical Practice Guidelines. The following areas were identified: (i) the elderly patient, (ii) prognostic factors suitable for clinical use and (iii) the 'ultra-high-risk' group. Before the conference, the expert panel was divided into three working groups; each group focused on one of these areas in order to address four clinically relevant questions relating to that topic. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, each working group developed recommendations to address each of the four questions assigned to their group. These recommendations were then presented to the entire panel and a consensus was reached. This manuscript presents recommendations dedicated to the second area of interest, i.e. prognostic factors suitable for clinical use. The four topics [i.e. interim positron emission tomography (PET), TP53 mutations, cell of origin (COO) and minimal residual disease (MRD)] were primarily chosen because of the bulk of available data together with the lack of clear guidance regarding their use in clinical practice and within clinical trials. Results, including a summary of evidence supporting each recommendation, are detailed in this manuscript. The panel acknowledged that detection of TP53 inactivation by deletion or mutation in CLL should be implemented in clinical practice (level of evidence I, strength of recommendation A). Due to their potentially high prognostic value, at least in some lymphoma entities, implementation of interim PET, COO and MRD was highly recommended in the context of clinical trials. All expert panel members approved this final article.