The efficacy of non-myeloablative allogeneic stem cell transplantation in ZAP-70 positive/chemo-antibody refractory patients with chronic lymphocytic leukemia (CLL)

Abstract

6559 Background and Purpose: In aggressive CLL, the presence of an unmutated IgVH gene is strongly associated with the expression of ZAP-70. We used immunohistochemical techniques and routinely fixed, paraffin-embedded tissue to survey ZAP-70 expression in chemo-refractory patients with CLL who received a non-myeloablative allogeneic transplantation (NMT). Methods: The methodology for the ZAP-70 immunostaining was previously described (Modem Pathology 17:954, 2004). Tissues were scored in evenly labeled areas. All cases were reviewed by two authors. Nuclear staining of non-neoplastic, reactive T cells served as an internal control in each case. Neoplasms demonstrating nuclear staining in greater than 20% of tumor cells were considered positive. Patients were eligible for NMT if they have failed chemo-antibody combination of therapy. The conditioning regimens consisted of fludarabine, cyclophosphamide and rituximab (Blood 98:3595, 2001). Results: Twenty five consecutive pts were treated. ZAP-70 information was available for 22. Median age of these 22 pts was 54 yrs (range, 36–73), and 16 (73%) were males. Median time from diagnosis to NMT was 69 mos. Median # of prior chemoregimens received was 4. Ten (45%) had a B2-microglobulin level of >3, and 7 (32%) had evidence of large cell transformation. Seventeen of the 22 pts (77%) tested positively for ZAP-70 and five were negative. All 22 pts had evidence of active disease prior NMT by morphological examination as well as by flow cytometry. With a median follow-up time of 20 months, overall survival at 2-years was 63% and 80% for the ZAP (+) and the ZAP(-) groups, respectively (P=0.6). Patients with ZAP(+) and who had evidence of large cell transformation faired worse: only 2 of 6 pts (33%) were alive at 9+, and 18+ mos; whereas 10 of 11 pts (91%) who were ZAP(+) but with no evidence of transformation remained alive at a median of 23+ mos post NMT (range, 7+ to 45+ mos) (P = 0.001). Conclusions: These data suggest that NMT may overcome the negative prognostic impact of ZAP-positivity in CLL, and that transplantation should be considered earlier in the course of the disease, prior to large cell transformation. No significant financial relationships to disclose.