Serum Beta-2 Microglobulin: The Universal Independent Prognostic Factor for Patients with CLL.
Authors: Wierda William G. , Wang X. , OBrien S. , Faderl S. , Ferrajoli A. , Thomas D. , Ravandi F. , Cortes J. , Giles F. , Koller C. , Kantarjian H. , Lerner S. , Keating M. 
Published: April 2020

Abstract
Prognostic factors are tools to address heterogeneity in clinical behavior and survival in patients with disease. They are particularly relevant for patients with malignancy, including chronic lymphocytic leukemia (CLL). There is striking heterogeneity in overall survival (OS) of patients with CLL as well as in response to treatment, time to treatment failure (TTF), and time to progression (TTP) following response. Serum β2 microglobulin (β2M) has previously been reported to correlate with OS and TTP in patients with CLL. We performed a retrospective analysis of 659 Rx-naïve and 1062 previously treated patients with CLL enrolled on clinical trials from 5/74 to 7/05 at MD Anderson Cancer Center evaluating for predictors for response to treatment, amount of treatment given, incidence of myelosuppression, TTF, TTP in responders, and OS. Univariate analysis was performed, then significant factors were used to develop multivariate models for these endpoints. Groups were analyzed separately. The clinical factors evaluated included: age, Rai stage, # nodal sites, liver and spleen size, β2M, WBC, ALC, HGB, PLT, serum LDH, Cr, ALB, CD38 expression, and serum Ig levels, and refractoriness to alkylating agents and fludarabine and # prior treatments for previously treated patients. In the Rx-naïve group, characteristics (median and range) were as follows: age=57 yrs(17–86); β2M=3.3 mg/L(1.1–16.4); WBC=74.7k/μL(2.1–552); ALC= 63k/μL(1–512); HGB=12.7 g/dL(5.7–18.7); PLT=156 k/μL(8–450); LDH=545 IU/L(103–3600); and IgG=754 mg/dL(45–5000). Patients with Rai stage 0=28; Rai I-II=402; and Rai III-IV=196. In the previously treated group, characteristics (median and range) were as follows: age=61 yrs(25–83); β2M= 4.4 mg/L(1.4–59.4); WBC= 43 k/μL(.6–953); ALC=36 k/μL(0–829); HGB=11.4 g/dL(3.8–17.6); PLT= 121 k/μL(2–703); LDH=597 IU/L(21–4739); and IgG=586 mg/dL(14–5000). Patients with Rai stage 0=37; Rai I-II=392; and Rai III-IV=563. Multivariate models identified the following predictors (p&lt;.05) for response to treatment for Rx-naive patients: β2M, PLT, ALC, age, and treatment regimen; for previously treated patients they were β2M, PLT, HGB, age, # prior Rx, and treatment regimen. TTF was correlated in multivariate analysis (p&lt;.05) with β2M, age, extent of bone marrow (BM) involvement, and treatment regimen for Rx-naïve patients and with β2M, HGB, IgM, # prior Rx, and treatment regimen for previously treated patients. TTP for responders correlated (p&lt;.05) in multivariate analysis with treatment regimen and BM involvement for Rx-naïve and with # prior Rx and treatment regimen for previously treated patients. Finally, Cox proportinal hazards model for OS identified the following predictors in Rx-naïve patients: β2M, age, treatment regimen; and for previously treated patients they included β2M, # prior Rx, age, treatment regimen, IgM, HGB, and PLT. Therefore, β2M and treatment regimen were consistent and significant independent predictors of outcome. In Rx-naïve patients, β2M level rose prior to initiating treatment, decreased with response to treatment for responders, and rose again with relapse in those patients with serial β2M determinations. β2M is a powerful prognostic factor for patients with CLL predicting for multiple clinical endpoints. We are currently incorporating it into our risk-stratification for clinical trials and it should be incorporated into the routine evaluation of patients with CLL.