Incidence of Hemolytic Anemia after Chemotherapy in the CLL4 Trial. A Possible Protective Role for Fludarabine Plus Cyclophosphamide.
Authors: Catovsky Daniel , Richards Sue 
Published: October 2019

Abstract
In 1966, Lewis, Schwartz and Dameshek described in a landmark paper the triggering of autoimmune complications in CLL and related conditions by alkylating agents and radiotherapy (Lewis et al, Clin Exp Immunol 1, 3–11). This has been confirmed by many since and it is well known that autoimmune hemolytic anemia (AHA) is also a feature of untreated CLL but it is more common in treated cases. Review of data from MRC CLL trials in the last 20 years shows an incidence of AHA of 8.6% (1273 patients), which rises to 11% (716 patients) after therapy based largely on alkylating agents. The advent of nucleoside analogues and, in particular, fludarabine (FDR), showed that these agents could also trigger AHA. Because of the severity of this complication in some of the reported cases, there is a perception that FDR may induce AHA more often than other agents. The LRF CLL4 trial, launched in 1999, and still open, gave us the opportunity to document AHA in newly diagnosed patients with Binet stages A progressive, B and C randomised to: 1) chlorambucil 10mg/m2 x 7 days and 2) FDR alone x 5 days IV or oral or FDR plus cyclophosphamide x 3 days IV or x 5 days orally, all every 4 weeks. Information was available from follow-up forms after completion of chemotherapy on 470 randomised patients. AHA was reported in 23/218 (10.5%) after chlorambucil, 9/123 (7.3%) after FDR and 3/129 (2.3%) after FDR plus cyclophosphamide (Chi-square 7.95; p<0.02). The incidence in both FDR regimens combined was 4.8% (p<0.01 for the comparison with chlorambucil). Information on the status of the direct antiglobulin test (DAT) at entry was available on 379 patients; the overall incidence of DAT positivity was 14%. AHA developed in 20/326 DAT negative (6%) and 12/53 DAT positive (22.6%) patients (Chi-square 10.55; p<0.005). In both groups, AHA was more frequent after chlorambucil particularly in the DAT positive cases (p<0.02): 8% in DAT negative and 39% in DAT positive compared with FDR 7% in DAT negative and 18% in DAT positive cases and FDR plus cyclophosphamide 2% and 5.8%, respectively. Furthermore, of 28 patients who were DAT positive at entry we observed a change to DAT negativity in 7/9 with FDR plus cyclophosphamide, 6/13 with chlorambucil and 1/6 with FDR after completion of therapy (Chi-square 5.5 p = 0.063)We conclude that: 1) chlorambucil is more likely than FDR +/− cyclophosphamide to trigger AHA in CLL; 2) Although AHA could develop regardless of DAT status its incidence is higher in DAT positive cases; 3) The incidence of AHA is significantly lower in patients receiving FDR plus cyclophosphamide, suggesting a protective role for this combination which is supported by a higher conversion rate from DAT positive to DAT negative after therapy. A lower incidence of AHA was reported with FDR plus cyclophosphamide compared to FDR alone by the German CLL Study Group (Eichorst et al, Abstract 243, ASH 2003). We still need to establish whether the severity of AHA after FDR alone is greater than with alkylating agents, as 2 patients in our trial died of AHA after FDR.