Activity of alemtuzumab monotherapy in treatment-naive, relapsed, and refractory severe acquired aplastic anemia

Abstract

Antithymocyte globulin (ATG) + cyclosporine is effective in restoring hematopoiesis in severe aplastic anemia (SAA). We hypothesized that the humanized anti-CD52 mAb alemtuzumab might be active in SAA because of its lymphocytotoxic properties. We investigated alemtuzumab monotherapy from 2003-2010 in treatment-naive, relapsed, and refractory SAA in 3 separate research protocols at the National Institutes of Health. Primary outcome was hematologic response at 6 months. For refractory disease, patients were randomized between rabbit ATG + cyclosporine (n = 27) and alemtuzumab (n = 27); the response rate for alemtuzumab was 37% (95% confidence interval [CI], 18%-57%) and for rabbit ATG 33% (95% CI, 14%-52%; P = .78). The 3-year survival was 83% (95% CI, 68%-99%) for alemtuzumab and 60% (95% CI, 43%-85%) for rabbit ATG (P = .16). For relapsed disease (n = 25), alemtuzumab was administered in a single-arm study; the response rate was 56% (95% CI, 35%-77%) and the 3-year survival was 86% (95% CI, 72%-100%). In treatment-naive patients (n = 16), alemtuzumab was compared with horse and rabbit ATG in a 3-arm randomized study; the response rate was 19% (95% CI 0%-40%), and the alemtuzumab arm was discontinued early. We conclude that alemtuzumab is effective in SAA, but best results are obtained in the relapsed and refractory settings. The present trials were registered at www.clinicaltrials.gov as NCT00195624, NCT00260689, and NCT00065260.

Figures

Figure 1

Absolute lymphocyte count (ALC) after rabbit ATG and alemtuzumab. In the refractory study (left panel), the degree and duration of lymphopenia was similar between the rabbit ATG (red) and alemtuzumab arms (blue). The baseline ALC had not been reached for either group by 6 months. In the relapsed study (right panel), the pattern of lymphopenia was similar to that observed in the alemtuzumab arm in the refractory study. The mean ± SEM is shown.

Figure 2

EBV and CMV reactivations after immunosuppression in the refractory and relapse studies. Nearly all patients were seropositive for EBV (A), whereas CMV seropositivity ranged from 60%-80% (B). Of the seropositive patients, EBV reactivation in the rabbit ATG arm was observed in approximately 80%, with median peak copy numbers of approximately 100 000 copies per 106 mononuclear cell (MNC) genome equivalents (C). In the alemtuzumab arm, EBV reactivations were less frequent and the median peak copy numbers were much lower compared with rabbit ATG (C). There was no difference in the likelihood or degree of reactivation after alemtuzumab in the refractory and relapsed studies. CMV reactivations were less common for both rabbit ATG and alemtuzumab, with median peak copy numbers of approximately 1000/mL. Only one patient in the relapsed study had reactivated CMV after alemtuzumab. All reactivations were self-limited and subclinical with prophylactic or preemptive therapies not used in any case. A positive PCR was defined as > 250 EBV copies/106 MNC genome equivalents or > 250 CMV copies/mL of blood.

Figure 3

Increase in blood counts after immunosuppression among responders in the refractory and relapsed studies. In the refractory study, the increment in blood counts was similar in the rabbit ATG and alemtuzumab arms. In the relapsed study, the increment in blood counts after alemtuzumab was similar to the same regimen in the refractory study. Only 1 responder in the rabbit ATG arm is shown for 4- and 5-year follow-up. Blood counts after relapse are not shown because alternative therapies were sought. The mean ± SEM is shown.

Figure 4

Cumulative incidence or relapse and clonal evolution. In the refractory study (left panels), the rate of relapse was comparable between arms (A), whereas the rate of clonal evolution (C) was higher with rabbit ATG (red) compared with alemtuzumab (blue), but this difference was not statistically significant. In the relapsed study (right panels), the rate of a second relapse after alemtuzumab was 23% (B) and the clonal evolution rate 11% (D). For the relapse study panels, dotted lines represent 95% CI.

Figure 5

Overall survival. In the treatment-naive study (A), 3-year survival was 63%. In the relapsed study (B), 3-year survival was 86%. In the refractory study (C), 3-year survival in the alemtuzumab arm (blue) was approximately 20% higher than rabbit ATG (red), but this difference was not statistically significant. The dotted lines in the treatment-naïve and relapse study panels represent 95% CI. The median survival was not reached in any of the treatment arms in any of the studies.