The Risk of Progression in 127 Early Stage CLL Patients. Prognostic Significance of Mutational Status, ZAP-70 and CD-38.
Authors: Perego Alessandra , Rossini Fausto , Perego Daniele , Soccodato Andrea , Tramacere Pierluigi , Colombo Chiara , Rossi Fabio , Speranza Tiziana , Mocarelli Paolo , Pogliani Enrico Maria 
Published: April 2020

Abstract
The course of early stage CLL patients may be very different with patients who never need therapy and other who need therapy at different times. The presence or absence of somatic mutations in the immunoglobulin heavy-chain gene of the CLL cell (mutational status) was recently identified as one of the most predictive factors for the time from diagnosis to initial treatment. CD-38 and ZAP-70 were also shown to have a similar prognostic value and they were sometimes considerate as a “surrogate” markers of mutational state. This study was aimed to evaluate the prognostic impact of different prognostic factors on time from diagnosis to initial treatment in this subgroup of CLL patients. We studied 127 patients (71 M; 56 F); median age was 64,3 (range 42 – 84). All they had a stage A CLL at diagnosis. When Rai stage was considered, 83 had stage 0, 32 stage I and 12 patients stage II. Median follow-up was 65 months (range 6 – 232 months).
Absolute lymphocyte count was: median 19 cells × 10^9/l (range 2,5 – 99). Median hemoglobin was 13,82 g/dL (range 11,3 g/dL – 17,5 g/dL). Median platelet count was 209 × 109/L (range 102 × 109/L e 533 × 109/L.). Patients were treated when symptomatic or progressive disease developed, according to National Cancer Institute Working Group criteria.
The following cut-off values were used: CD38 &gt;20%; ZAP-70 &gt; 20%; VH unmutated: &gt;98% homology with germ-line sequence. 26% of patients were CD38 positive, 28% were ZAP-20 positive; 24% patients were VH unmutated.
39/127 patients included in the study had received one or more chemotherapy regimens. First line therapy was chlorambucil in 28 patients, fludarabine in six, different therapies (cyclophosphamyde, prednisone, rituximab) in 5.
Median interval between diagnosis and initial therapy was 30 months (range 1–96).
22 % of Rai 0 pts, 44 % of Rai 1 pts 50% of Rai 2 pts were treated.
65% of ZAP-70 positive were treated vs 18% of ZAP-70 negative. 55% of unmutated were treated vs 18% of mutated pts. 42% of CD-38 positive were treated vs 26% of CD-38 negative. When the interval from diagnosis to therapy was analyzed with a Kaplan-Meier survival curve (see figures), mutational status and ZAP-70 positivity were the most significant prognostic factors. Median treatment-free time was 35 months for ZAP-70 negative patients vs. 190 months for ZAP-70 positive patients (p= 0,001). Median treatment-free time was 40 months for unmutated vs. 190 months for mutated patients (p= 0,002). When CD-38 was analyzed, a borderline significant value was obtained (p=.0.08) with median treatment-free interval of 70 months in CD-38 positive patients vs. 98 months in CD-38 negative patients. Absolute lymphocyte count (with a cut-off at 15 cells × 10^9/l) also showed a significant impact on the need of treatment.
Time from diagnosis to initial treatment and IgVH omology Time from diagnosis to initial treatment and IgVH omology Time from diagnosis to initial therapy and ZAP 70 Time from diagnosis to initial therapy and ZAP 70