Alemtuzumab can be Incorporated Into Front-Line Therapy of Adult Acute Lymphoblastic Leukemia (ALL): Final Phase I Results of a Cancer and Leukemia Group B Study (CALGB 10102).

Eradication of minimal residual disease (MRD) during the first months of ALL treatment is associated with improved disease-free survival (DFS). We hypothesized that alemtuzumab, a humanized anti-CD52 monoclonal antibody, might be an effective, novel agent for eradication of MRD. In CALGB 10102, we tested dose escalation of alemtuzumab in sequential cohorts of CD52+ cases to a target dose of 30 mg administered SC 3 times/week for 4 weeks (12 doses) during post-remission therapy. Dose limiting toxicity (DLT) was defined as the inability to proceed with protocol treatment within 6 weeks after the last dose of alemtuzumab. Eligible patients (pts) had ≥10% lymphoblast CD52 expression at diagnosis determined in a CALGB reference laboratory. Antimicrobial prophylaxis for cytomegalovirus (CMV) and Pneumocystis carinii was mandated. The 10102 therapy consisted of 6 monthly chemotherapy modules followed by maintenance therapy for a total of 2 years (Stock et al. ASH 2005, abstr 145); 299 untreated ALL pts were eligible and enrolled from 2003–2007. We previously reported (Lozanski et al. ASH 2007, abstr 2386) that 70% were CD52+ and eligible to receive Alemtuzumab (70% of B-cell ALL; 53% of T-cell ALL; 100% of Ph+ cases).

Twenty-four pts in remission (CR1) received Alemtuzumab as their fourth treatment module during the Phase I portion of the study. The median age was 37 years (18-77 years); 18 (80%) had B-cell ALL; 5 (19%) had T-cell ALL. 17/24 cases had evaluable cytogenetics after central review: 5 had favorable, 8 intermediate-risk, 2 poor-risk cytogenetics (neither were Ph+), and 2 were not classifiable (miscellaneous abnormalities). Non-hematologic toxicities were mild. SC alemtuzumab was well tolerated. Grade 3-4 myelosuppression was reported during 4 weeks of alemtuzumab treatment in 4 pts; 2 pts had Grade 3-4 lymphopenia. 4 pts had DLT: subsequent treatment was delayed in 2 due to transient CMV viremia; 1 developed Staph aureus empyema; and 1 had prolonged myelosuppression but did not receive G-CSF support as recommended by the protocol. 3 pts relapsed with ALL immediately following completion of the alemtuzumab module. Serial assessment of MRD using quantitative clone-specific PCR was possible in 11/24 cases. There was a median 1-log decrease in MRD during alemtuzumab therapy in the 20 and 30 mg cohorts. However, there was a 2-log rise during alemtuzumab therapy in one pt who relapsed 6 weeks later. Pharmacokinetic analysis revealed rising alemtuzumab serum levels during treatment in all dose cohorts, and levels were still detectable in some pts 10 weeks after completing alemtuzumab. During subsequent post-remission therapy, 8 pts developed CMV viremia, 2 had Herpes simplex infections, and 3 had Herpes zoster reactivation. There was not a significant correlation between serum alemtuzumab level and change in MRD or risk of viral infection. The median follow-up time for the 14 surviving pts is 51 months (49-54 months). Median DFS is 53 months (95% CI, 39 – not reached); median overall survival is 55 months (95% CI, 42- not reached).

CD52 is expressed in the majority of adult ALL cases. Addition of alemtuzumab to front-line therapy is feasible and provides reduction in MRD, but is associated with viral infections. Dose escalation of alemtuzmab was not associated with DLT. Based on these results, the 30 mg dose of alemtuzumab was explored in an additional 70 patients in the Phase II portion of the study. The encouraging DFS results reported here require confirmation from longer follow-up of the larger Phase II cohort of patients.

Stock:Genzyme: Research Funding. Off Label Use: The testing of alemtuzumab for treatment of ALL in adults. Lozanski:Genzyme: Research Funding. Vij:CELGENE: Honoraria, Research Funding, Speakers Bureau. Powell:Antisoma: Research Funding. Sher:invivoscribe: Employment. Richards:Genzyme: Employment. Sung:genzyme: Employment.