Multivariable model for time to first treatment in patients with chronic lymphocytic leukemia

Abstract

Purpose: The clinical course for patients with chronic lymphocytic leukemia (CLL) is diverse; some patients have indolent disease, never needing treatment, whereas others have aggressive disease requiring early treatment. We continue to use criteria for active disease to initiate therapy. Multivariable analysis was performed to identify prognostic factors independently associated with time to first treatment for patients with CLL.

Patients and methods: Traditional laboratory, clinical prognostic, and newer prognostic factors such as fluorescent in situ hybridization (FISH), IGHV mutation status, and ZAP-70 expression evaluated at first patient visit to MD Anderson Cancer Center were correlated by multivariable analysis with time to first treatment. This multivariable model was used to develop a nomogram-a weighted tool to calculate 2- and 4-year probability of treatment and estimate median time to first treatment.

Results: There were 930 previously untreated patients who had traditional and new prognostic factors evaluated; they did not have active CLL requiring initiation of treatment within 3 months of first visit and were observed for time to first treatment. The following were independently associated with shorter time to first treatment: three involved lymph node sites, increased size of cervical lymph nodes, presence of 17p deletion or 11q deletion by FISH, increased serum lactate dehydrogenase, and unmutated IGHV mutation status.

Conclusion: We developed a multivariable model that incorporates traditional and newer prognostic factors to identify patients at high risk for progression to treatment. This model may be useful to identify patients for early interventional trials.

Fig 1.

Time to first treatment (N = 930). Previously untreated patients with chronic lymphocytic leukemia who presented to MD Anderson Cancer Center from January 2004 through December 2009 had traditional clinical and laboratory features as well as newer prognostic factors characterized. Patients who did not require treatment within first 3 months of evaluation and had 3 months or more of follow-up were included in analyses of time to first treatment. Kaplan-Meier estimate of treatment-free survival is shown with 95% CI.

Fig 2.

Time to first treatment by fluorescent in situ hybridization (FISH; n = 835). Previously untreated patients with chronic lymphocytic leukemia had bone marrow aspirate samples evaluated for chromosome abnormalities by FISH at initial presentation to MD Anderson Cancer Center. Patients were observed for time to first treatment. Kaplan-Meier estimates of treatment-free survival are shown for each of following FISH categories according to Dohner hierarchic categorization: 17p deletion, 11q deletion, trisomy 12, no abnormality, and 13q deletion as sole abnormality.

Fig 3.

Time to first treatment by (A-E) IGHV mutation status and (F-J) ZAP-70 expression for each fluorescent in situ hybridization (FISH) category. Previously untreated patients with chronic lymphocytic leukemia had bone marrow samples evaluated for chromosome abnormalities by FISH, IGHV mutation status, and ZAP-70 expression by flow cytometry or immunohistochemistry at initial presentation to MD Anderson Cancer Center. Patients were observed for time to first treatment. Kaplan-Meier estimates of treatment-free survival are shown for (A-E) unmutated (UM; gold) versus mutated (M; blue) IGHV status or (F-J) positive (Pos; gold) versus negative (Neg; blue) ZAP-70 expression for each FISH category.

Fig 3.

Time to first treatment by (A-E) IGHV mutation status and (F-J) ZAP-70 expression for each fluorescent in situ hybridization (FISH) category. Previously untreated patients with chronic lymphocytic leukemia had bone marrow samples evaluated for chromosome abnormalities by FISH, IGHV mutation status, and ZAP-70 expression by flow cytometry or immunohistochemistry at initial presentation to MD Anderson Cancer Center. Patients were observed for time to first treatment. Kaplan-Meier estimates of treatment-free survival are shown for (A-E) unmutated (UM; gold) versus mutated (M; blue) IGHV status or (F-J) positive (Pos; gold) versus negative (Neg; blue) ZAP-70 expression for each FISH category.

Fig 4.

Nomogram for time to first treatment. Nomogram used by totaling points identified at top scale for each of four independent variables. Point score for lactate dehydrogenase (LDH) identified based on IGHV mutation status. This summed point score then identified on total point scale to identify 2- and 4-year treatment-free probability (prob) and estimate treatment-free survival. Fluorescent in situ hybridization (FISH) was categorized by Dohner hierarchic categorization. LN, lymph node.

Fig A1.

Time to first treatment by IGHV mutation status and ZAP-70 expression. Previously untreated patients with chronic lymphocytic leukemia had leukemia cells evaluated for IGHV mutation status and ZAP-70 expression by flow cytometry or immunohistochemistry at initial presentation to MD Anderson Cancer Center. Patients were observed for time to first treatment. Kaplan-Meier estimates of treatment-free survival are shown for following categories: unmutated IGHV, ZAP-70 positive; unmutated IGHV, ZAP-70 negative; mutated IGHV, ZAP-70 positive; and mutated IGHV, ZAP-70 negative.

Fig A2.

Classification and regression tree (CART) analysis for time to first treatment. Included in each oval or rectangle is hazard ratio (HR) and number of patients who went on to treatment (events) followed by total number of patients falling into category, defined by covariate above. On basis of CART analysis, cut point for lactate dehydrogenase (LDH) was different for IGHV-mutated versus unmutated group. Fluorescent in situ hybridization (FISH) was characterized by Dohner hierarchic categorization. Cv, cervical; LN, lymph node.