Surprising Lack of Correlation between CD38 and Time to First Treatment in Chronic Lympocytic Leukemia.
Authors: Kaufman Matthew S. , Damle Rajendra , Kohn Nina , Johnson Christina , Driscoll Nancy , Caramanica Angelica , Lebowicz Yehuda , Tsao Kai , Chiorazzi Nicholas , Rai Kanti 
Published: April 2020

BACKGROUND: Although IgVH gene mutation status and expression of CD38 are accepted prognostic markers of patient survival in chronic lymphocytic leukemia(CLL), the relative value of these two markers continues to vex even experts in the field.

METHODS: To address this issue we evaluated mutation status and CD38 expression in 159 patients and examined time to first treatment(TTT), as a surrogate endpoint for survival, in various combinations of factors. IgVH gene and CD38 analyses were performed according to standard practice. TTT was analyzed using the product limit method and compared using the log rank test. For these analyses, subjects who had not yet started treatment at the time of cut-off (July 2007) or were lost-to-follow-up were considered censored. A Cox proportional hazards model was used to examine the joint effects of CD38 and mutation status on starting treatment.

RESULTS: The two tables show TTT for each CD38 and mutation status independently and in combination. Median TTT for CD38- patients(n=88) was 79 months(95% CI: 60–144) vs 60 months(95% CI: 45–153) for CD38+ patients(n=71). This did not represent a statistical difference(p=0.1891). On the other hand, there was a statistical difference in TTT based on mutation(p&lt;0.0001). Median TTT for mutated patients(n=73) was 192 months(95% CI: 96-not estimable(NE)) vs 48 months(95% CI: 45–60) for unmutated patients(n=86). Cox regression showed that unmutated patients were 2.7 times more likely to start treatment than patients who were mutated(p&lt;0.006). There was a significant difference in TTT based on CD38 status and mutation status combined(p&lt;0.0009). Pair-wise comparisons indicate that: TTT was significantly longer for patients who were CD38-/mutated than for patients who were CD38+/unmutated(p=0.0013); TTT was significantly longer for patients who were CD38-/mutated than for patients who were CD38-/unmutated(p=0.0137). Although the median TTT is longer for CD38+/mutated patients(192 mo) than for the CD38-/mutated patients(120 mo), it is not statistically significant(p=0.7725) and may be effected by the relatively small sample size of the former(n=18).

CONCLUSIONS: These data confirm the significant prognostic value of mutation status and time to first treatment in CLL. Surprisingly, and in contrast to a recent report(Rassenti et al, Blood, in press), our results with CD38 expression reveal a lesser level of influence. These findings must be cautiously interpreted to avoid potentially confounding factors. First, a selection bias in patients referred to a tertiary care institution in terms of disease severity or aberrant clinical course may exist. Second, TTT decisions are, to some extent, subjective and our threshold for initiating treatment may be higher than of other hematologists-oncologists. Our data confirm that newly identified prognostic markers need further evaluation.

Univariate Analysis n Median Time to Treat(95% CI) Total unmutated 86 48 mo (45–60) Total mutated 73 192 mo (96-not estimable) Total CD38+ 71 60 mo (45–153) Total CD38– 88 79 mo (60–144) Multivariate Analysis n Median TTT(95% CI) unmutated CD38+ 54 57 mo (36–72) mutated CD38+ 17 192 mo (72-not estimable) unmutated CD38– 32 48 mo (42–66) mutated CD38– 56 120 mo (79-not estimable)