ZAP-70 Status Does Not Predict Outcome after Transplant

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[3028] ZAP-70 Status Does Not Predict Outcome after Nonmyeloablative

Allogeneic Stem-Cell Transplantation (NST) in Relapsed/Refractory

Chronic Lymphocytic Leukemia (CLL) That Fails To Respond to

Conventional Chemoimmunotherapy. Session Type: Poster Session, Board

#257-III

Issa F. Khouri, Rima M. Saliba, Joan Admirand, O'Brien, Ming-S.

Lee, Barry I. s, Giralt, Marcos de Lima, J.

Keating, E. Champlin, Bueso-Ramos Blood Marrow

Transplantation, The University of Texas MD Cancer Center,

Houston, TX, USA; Hematopathology, The University of Texas MD

Cancer Center, Houston, TX, USA; Leukemia, The University of Texas MD

Cancer Center, Houston, TX, USA; Laboratory Medicine, The

University of Texas MD Cancer Center, Houston, TX, USA;

Diagnostic Radiology, The University of Texas MD Cancer

Center, Houston, TX, USA

Recent studies demonstrated that ZAP-70 is an important prognostic

factor in CLL. Patients (pts) who were ZAP-70 positive were reported

to have an early time to treatment failure and a shorter survival. We

determined the effect of ZAP-70 status on the outcome of NST in pts

with advanced relapsed CLL.

Between 1999 and 2005, 39 pts were enrolled, ranging in age from 34 to

70 years (median, 57 years). All pts had recurrent advanced CLL and

had been previously treated with fludarabine-rituximab-based regimens.

Each pt had received 2 to 8 (median, 3) chemotherapy regimens.

Thirty-four pts (87%) had active disease at the time of study entry.

Using immunohistochemical techniques on marrow biopsy samples, we

determined that 25 pts were ZAP-70 positive, 13 were ZAP-70 negative,

and 1 was of indeterminate status. All pts received a preparative

regimen of fludarabine (30 mg/m2 daily for 3 days), intravenous

cyclophosphamide (750 mg/m2 daily for 3 days), and high-dose

rituximab, as previously reported. Thirty-five pts underwent

allogeneic transplantation from a sibling donor and 4 from a matched

unrelated donor.

The median number of CD34+ cells infused ranged from 1.96 to 6.6 x 106

/kg (median, 4.7 x 106 /kg). Neutrophil counts recovered to > 0.5 x

109/L at a median of 10 days after NST. Donor cells failed to engraft

in 1 patient. The median percentage of donor T cells at day 30 was 68%

(range, 0%100%), and increased to 93% and 100% at days 90 and 180,

respectively (P < 0.001).

Fourteen pts experienced disease progression after transplantation and

required immunomanipulation. The last progressions within the whole

group and among those patients who were ZAP-70 positive occurred at 23

and 18 months, respectively after transplantation. By multivariate

analysis, chemorefractory disease (P = 0.01) and having mixed T cell

chimerism at day 90 (P = 0.02), but not ZAP-70 positivity, were

identified as the most significant factors for progression after

transplantation. Of the 14 pts who required immunomanipulation after

transplantation, 6 experienced a complete response (CR) and 1 had a

partial response. Responses occurred after therapy with rituximab and

donor lymphocyte infusion (DLI) (median, 1 dose of 1 x 107 CD3+/kg).

Overall, of the 38 evaluable patients, 27 (71%) experienced a CR. The

incidence of acute grade II-IV GVHD was 45%, whereas the incidence of

chronic extensive GVHD, pre- and post-DLI, was 58%.

With a median follow-up time of 27 months (range, 4-80 months), the

estimated overall survival (OS) and current progression-free survival

(CFPS) rates at 4 years was 48% and 44%, respectively. Pts who were

ZAP-70 positive had a median follow-up period of 41 months (range,

5-80 months). Their estimated OS and CPFS rates at 4 years were

estimated to be 56% and 53%, respectively. These results indicate that

NST can overcome the negative prognostic feature of ZAP-70 expression

in advanced CLL.