Superior Survival Associated with Early Lymphocyte Regeneration after Cytoreductive Chemotherapy in Childhood Acute Lymphoblastic Leukemia.

Abstract

Post autologous stem cell transplantation (ASCT) studies have demonstrated that early absolute lymphocyte count (ALC) recovery is associated with prolonged survival. A potential explanation for the survival advantage associated with ALC recovery after ASCT is the possibility that early immune reconstitution may have a protective effect against residual disease progression. This is analogous to the graft -versus-tumor effect in allogeneic bone marrow transplantation recipients whereby the donor immune system is responsible for the eradication of residual disease in the host. If true then ALC following cytoreductive chemotherapy without transplantation could help predict patients at increased risk of relapse. The relationship of ALC with clinical outcomes following cytoreductive chemotherapy for childhood acute lymphoblastic leukemia (ALL) is unknown. We evaluated all 91 children treated according to BFM 95 protocol at a single center with ALL from 1997 to 2002.We studied if the recovering ALC post induction (Day33) in all patients, post consolidation (Day79) in standard risk patients and day +28 from commencement of 1st high risk block of chemotherapy for high risk patients can predict clinical outcome. These time points correlate with minimal residual disease as per recent studies. Of the 91 patients 77 were standard risk, 7 were high risk and remaining 7 had very high risk disease as per BFM 95 criteria. Patients were analyzed according to overall and disease free survival. Mean lymphocyte counts were calculated and survival curves drawn based on a median count for all patients. The study shows that post chemotherapy recovery of ALC correlates with overall survival at all time points studied. Post induction (Day 33) mean ALC in disease free survivors v patients who had relapsed was 1.89 v 1.10 x 109/L.Similarly for these groups the recovering ALC was higher on post consolidation (Day 79) 1.28 v 0.97 x 109/L. Post 1st high risk block also showed a significant difference between survivors and relapsing high risk patients 1.47 v 0.96 x 109/L. Post Day 33 patients were split into those with ALC greater or less than 1.0 x 109/L. Overall survival was 94 % for patients with ALC greater than 1.0x 109/L on day 33 and 52 % for patients with ALC less than 1.0x 109/L on day 33 at median follow up of 3 years (median survival not reached v 20 months). If lymphocyte numbers are influencing outcome by an autologous immune anti-tumor effect, this knowledge could be used to influence and benefit future therapies to treat ALL in children. In conclusion, we confirm the association between early ALC recovery and superior survival after cytoreductive chemotherapy in children with ALL. Since the limitations of a retrospective analysis, our results should be viewed with caution and prospective studies that attempt to link specific lymphocytes subsets and outcome after cytoreductive chemotherapy in ALL are needed before any firm conclusions are drawn.