The clinical course of patients with recently diagnosed early stage chronic lymphocytic leukemia (CLL) is highly variable. We examined the relationship between CLL-cell birth rate and treatment-free survival (TFS) in 97 patients with recently diagnosed, Rai stage 0–II CLL in a blinded, prospective study, using in vivo 2H2O labeling. Birth rates ranged from 0.07 to 1.31% new cells per day. With median follow-up of 4.0 years, 33 subjects (34%) required treatment by NCI criteria. High-birth rate was observed in 44% of subjects and was significantly associated with shorter TFS, unmutated IGHV status and expression of ZAP70 and of CD38. In multivariable modeling considering age, gender, Rai stage, expression of ZAP70 or CD38, IGHV mutation status and FISH cytogenetics, only CLL-cell birth rate and IGHV mutation status met criteria for inclusion. Hazard ratios were 3.51 (P=0.002) for high-birth rate and 4.93 (P<0.001) for unmutated IGHV. The association between elevated birth rate and shorter TFS was observed in subjects with either mutated or unmutated IGHVs, and the use of both markers was a better predictor of TFS than either parameter alone. Thus, an increased CLL birth rate in early stage disease is a strong predictor of disease progression and earlier treatment.
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We would like to thank the study participants, referring physicians and study coordinators at all six clinical sites where patients were recruited. We also acknowledge Robert Bush for important guidance in the development of protocols for CLL cell isolation necessary for this work, Dan Holquist for cell processing, and Mohammed Awada and Tim Riff for IRMS analyses. This work was supported in whole by federal funding from the National Cancer Institute, NIH, R44 CA100506 (E Murphy and G Hayes, PI) and PO1 CA081534 for the CLL Research Consortium (T Kipps, PI).
This work was a collaboration between KineMed Inc. and the CRC and was funded entirely by NIH grants to both institutions. MH is on the board of directors at KineMed, Inc. MH is on the Board of Directors of KineMed Inc. No other authors have a current financial conflict of interest.
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Murphy, E., Neuberg, D., Rassenti, L. et al. Leukemia-cell proliferation and disease progression in patients with early stage chronic lymphocytic leukemia. Leukemia 31, 1348–1354 (2017). https://doi.org/10.1038/leu.2017.34
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