International CLL Group Updates Trials Guidelines

The International Workshop on Chronic Lymphocytic Leukemia has updated its 2008 consensus guidelines for design and conduct of CLL clinical trials.

The International Workshop on Chronic Lymphocytic Leukemia recently published an update to its 2008 consensus guidelines for the design and conduct of clinical trials for patient with chronic lymphocytic leukemia (CLL). These updates were prompted by advances in the biology and treatment of patients with CLL that have been made in the last decade.

The guidelines were published in Blood. Among the major updates to the guidelines is new information about the clinical relevance of several genomic alterations, including mutations of the TP53 gene. Prospective clinical trials have shown that patients with leukemia with del(17p) and/or mutations of TP53 have worse prognosis and appear to be resistant to standard chemotherapy regimens that used alkylating drug or purine analogues. In contrast, these patients may fare better when treated with small-molecule inhibitors of BTK, PI3K, or BCL2.

“As additional genetic abnormalities may be acquired during the course of the disease, genetic analyses (in particular for del(17p)/TP53 mutations) should be repeated prior to any subsequent, second- or third-line of treatment,” the guidelines said.

The guidelines also acknowledged the important role of IGHV mutational status for patients with CLL. Specifically, patients with CLL that has an unmutated IGHV gene have outcomes inferior to those of leukemia patients with a mutated IGHV gene. In addition, the presence of IGHV-mutated genes may identify a subset of patients who could benefit from chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab.

The guidelines provided a series of updates on the use of clinical staging, novel genetic or biological prognostic markers, and prognostic scores in the management of CLL.

“There are two widely accepted staging systems for use in both patient care and clinical trials: the Rai and the Binet systems,” according to the guidelines. “The original Rai classification was modified to reduce the number of prognostic groups from five to three. As such, both systems now describe three major subgroups with distinct clinical outcomes.”

These two simple and inexpensive staging systems should be “applied by physicians worldwide,” according to the guidelines.

In its update of the definition of treatment response, as well as relapsed and refractory disease, the guidelines also addressed improved approaches for the assessment of splenomegaly, hepatomegaly, and lymphadenopathy. Response should be assessed with both a physical examination and evaluation of blood and bone marrow.

The physical exam should show no signs of splenomegaly or hepatomegaly. The guidelines proposed a recent consensus response cutoff of 13 cm for splenomegaly in craniocaudal length. In addition, there should be an absence of significant lymphadenopathy on physical exam. Lymph nodes should be less than 1.5 cm in longest diameter.

Finally, the guidelines addressed the increasing role of minimal residual disease (MRD) assessment in patients with CLL.

“Use of sensitive multicolor flow cytometry, PCR, or next-generation sequencing can detect minimal residual disease in many patients who achieved a complete clinical response,” the guidelines said. “Prospective clinical trials have provided substantial evidence that therapies that are able to eradicate MRD usually result in an improved clinical outcome.”