iwCLL 2017 | Revised iwCLL guidelines for the approach to a CLL patient

Session four at iwCLL 2017 took place on 14^th May 2017, and was titled “Strategies for the Evaluation and Treatment of CLL in the Front-line Setting.” The session was jointly chaired by Stephen Mulligan (University of Sydney, Royal North Shore Hospital) and Neil E. Kay (Mayo Clinic).

The second of two talks in this session was given by Michael Hallek from the University of Cologne, Germany. His talk was titled “Presentation and discussion of revised iwCLL guidelines for the approach to a CLL patient.”

The talk began by outlining the three main reasons to revise the 2008 guidelines: major innovations, genomic landscape, and therapeutics.

The principles for the revision of the 2008 guidelines include: change as little as possible to facilitate comparison with historic clinical trials, eliminate a number of inconsistencies of the 2008 paper, and incorporate the numerous innovations.

In terms of indications for first-line treatment in CLL, the recommendations remain unchanged:

Binet and Rai stages are convenient strategies to stratify patients by risk of their disease. The most relevant additional markers include IGHV mutational status, serum β2m, presence of del(17p) and/or TP53 mutation, and complex karyotype. Several scores have been proposed, such as MDACC, GCLLSG, MRC, Barcelona, CLL-IPI, using multivariate analyses to extract relevant factors from all known prognostic indicators. These models decrease the complexity of CLL prognosis and merit additional prospective evaluation in clinical trials.

Regarding second-line treatment decisions, disease relapse is not a criterion to re-initiate treatment unless the disease is progression and symptomatic. The indications used for first-line treatment should also inform second-line treatment decisions. Non-chemotherapy regimens or entrance into a clinical trial should preferentially be offered to: resistant disease, time to progression after chemo-immunotherapy of <2 years, and leukemia with del(17p)/TP53 mutations. Allogeneic hematopoietic stem cell transplant should be considered (ERIC/EBMT recommendations) in some cases.

In terms of response, relapse, and refractory disease:

• Timing of response assessment:
  • For therapies with a defined treatment duration = ≥2 months after therapy completion
  • For continued therapies = ≥2 months after the patient achieves maximum response (not necessary to interrupt therapy for response assessment)
  • For clinical trials = maximum response should be sustained for ≥2 months
• A further assessment of response (such as bone marrow assessment) may be performed ≥2 months after the patient has cleared MRD from the peripheral blood
• Lymphadenopathy, splenomegaly, hepatomegaly:
  • Coordination with lymphoma assessment (Cheson et al. 2014) where possible
  • Cut-off for splenomegaly >13cm (Cheson et al. 2014)
  • Splenomegaly persistence may not correlate with outcome (Kovacs et al. 2016)
  • Quantitative determination of hepatomegaly appears more difficult due to changes including focal or disseminated hepatic nodules support liver involvement

In the 2008 guidelines, progression was defined as an increase in the number of blood lymphocytes by 50% or more with at least 5,000 lymphocytes per µl. The new definition takes into account that some therapies (especially those disrupting BCR signaling) may cause blood lymphocytosis. Moreover, with these agents, increased lymphocyte numbers alone does not indicate increased tumor burden, however could indicate re-distribution of leukemia cells from lymphoid tissues to the blood.  This should be pre-defined in the protocol of clinical trials for therapies where such re-distribution takes place. In these cases, increased blood lymphocytosis does not indicate treatment failure or disease progression.

The strategies used to assess MRD are now fairly standard. 4-color flow cytometry or allele-specific oligonucleotide PCR are reliably sensitive to the level of <1 cell/10,000 leukocytes. Therefore, MRD negative remission is defined as blood or marrow with <1 cell/10,000 leukocytes. Blood can generally be used for making this assessment; however, for treatments that preferentially clear the blood (for example monoclonal antibodies) it is important to confirm the bone marrow is also MRD negative.

Michael Hallek also outlined the factors that required stratification at inclusion of phase III trials:

• Previous treatment vs. no previous treatment
• Purine analogue-sensitive vs. purine-analogue refractory in studies for which prior therapy is permitted
• Clinical stage
• Leukemia cells harboring del(17p) or del(11q), and TP53 mutations

The talk was concluded with a succinct summary of the major points of the 2017 guideline update: