Prompted by advances in the biology and treatment of patients with chronic lymphocytic leukemia (CLL), the National Cancer Institute–sponsored International Workshop on CLL has issued an update to its consensus guidelines originally published in 2008.1,2
“These guidelines provided definitions intended to standardize the assessment of patients that were adopted by [regulatory agencies] for the evaluation of new drugs,” the guideline panel authors wrote. Michael Hallek, MD, of the University of Cologne in Germany, and co-authors updated the guidelines with the goal of integrating new findings into future practice and clinical trials of CLL. Their recommendations were published in Blood. Here, we review the major changes reflected in the guidelines.
Clinical Relevance of Mutations Found in CLL
Patients with del17p and TP53 mutations have an inferior prognosis, and their disease can be resistant to standard chemotherapy regimens; however, these patients often fare significantly better when treated with non-chemotherapeutic agents, such as Bruton’s tyrosine kinase inhibitors, phosphatidylinositol 3-kinase inhibitors, and BCL2 inhibitors.
The authors recommend that clinical trials include testing molecular genetics prior to treating a patient based on study protocol. Genetic abnormalities can also be acquired over the course of the disease, so genetic analyses – particularly of del17p and TP53 – should be repeated prior to any subsequent line of treatment.
Next-generation whole-exome and whole-genome sequencing have also identified NOTCH1 and SF3B1 as genomic abnormalities that have pathogenic and prognostic significance in CLL, but the guideline authors noted that prospective trials are needed to validate the importance of these mutations before advocating regular use in routine practice.
The Prognostic Role of IGHV Mutational Status
Immunoglobulin heavy chain variable (IGHV) mutational status also plays an important prognostic role in CLL: The presence of mutated IGHV genes – particularly when combined with additional prognostic factors such as favorable cytogenetics or minimal residual disease (MRD)–negative status – is associated with favorable outcomes in this patient population. However, assessment of IGHV stereotypes “is not an element of the routine prognostic workup in CLL,” the authors wrote.
Clinical Staging and New Prognostic Markers
Several prognostic scores and stratification systems have been proposed that incorporate information about newly identified prognostic markers, like the CLL International Prognostic Index, which consists of a weighted score that includes the clinical stage, patient age, IGHV status, serum ß2-microglobulin, and the presence of del17p and TP53 mutations.
However, the updated guidelines confirm the value of the “two widely accepted staging systems for use in both patient care and clinical trials: the Rai and Binet staging systems.” Because both models “rely solely on a physical examination and standard laboratory tests and do not require imaging studies,” the authors stated, these simple, inexpensive approaches should “be readily and consistently applied by physicians worldwide.”
Definition of Response
The guidelines emphasize that evaluation of treatment response should include a physical examination and the evaluation of blood and bone marrow (BM), including an assessment of the lymphoid tumor load and hematopoietic system. To establish a complete response, the authors recommend the following cutoffs:
- Lymph nodes ≥5 cm
- Spleen size <13 cm and normal liver size
- No constitutional symptoms
- Normal circulating lymphocyte count
- Platelet count ≥100,000/μL
- Hemoglobin ≥ 11.0 g/dL
- Normocellular marrow with no CLL cells and no B-lymphoid nodules
The updated consensus guidelines also outlined monitoring for lymphadenopathy, splenomegaly, and hepatomegaly to define relapsed disease and treatment failure, noting that the use of imaging in CLL does not typically add much information to the detection of progression or relapse.
Monitoring Viral Diseases and Infectious Complications
The guideline authors outlined other measurements that should be included in a complete baseline evaluation to help determine whether to treat patients according to clinical protocols. These include assessments for viral diseases and other infections, which should be tracked and reported.
Patients with HIV should be given special consideration because of the risks for immunosuppression with most anti-leukemia therapies, as well as the potential for compounded myelotoxicity of treatment with anti-retroviral therapy, the authors noted.
Because some therapies have the potential to reactivate cytomegalovirus (CMV), this should also be evaluated. However, positive CMV serology does not represent a contraindication to treatment, the researchers wrote.
“As a general recommendation, patients treated with [immunosuppressive] agents … should be monitored for CMV and be considered for anti-viral therapy if found to have increased levels of CMV in the blood … even in the absence of clinical symptoms,” the guidelines note. Hepatitis B and C can also be reactivated following immunosuppressive or myelosuppressive therapy, so patients with hepatitis virus “should receive prophylactic antiviral agents while undergoing therapy for CLL with immunosuppressive drugs.”
“The complete eradication of the leukemia is a desired endpoint,” the researchers wrote, and MRD has become an important part of CLL assessment. The updated guidelines recommend that the presence of MRD after therapy should be evaluated in clinical trials aimed at maximizing the depth of remission, and the proportion of patients achieving undetectable MRD (assessed via multicolor flow cytometry, polymerase chain reaction, or next-generation sequencing) should be reported with the total number of patients treated as the denominator, “not as a proportion of the responders or those in complete remission.”
Reporting of the clinical trial should also state clearly whether blood or BM were used for assessment. The authors noted that some therapies, such as monoclonal antibodies, preferentially clear the blood but not the BM, “therefore, it may be important to confirm that the [BM] aspirate also is MRD-negative when the blood is found to be MRD-negative.”
The authors report no financial conflicts.
- Hallek M, Cheson BD, Catovsky D, et al. Guidelines for diagnosis, indications for treatment, response assessment and supportive management of chronic lymphocytic leukemia. Blood. 2018 March 14. [Epub ahead of print]
- Hallek M, Cheson, BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111:5446-56.