Alemtuzumab as Consolidation after a Response to Fludarabine Is Effective To Purge Residual Disease in Patients with Chronic Lymphocytic Leukemia.
Authors: Montillo Marco , Tedeschi Alessandra , Rossi Valentina , Cafro Anna Maria , Cairoli Roberto , Veronese Silvio , Scarpati Barbara , Farioli Renata , Regazzi Mario , Gambacorta Marcello , Morra Enrica 
Published: April 2020

Although an increasing number of patients with chronic lymphocytic leukemia (CLL) may achieve complete remission (CR) relapse is almost inevitable, due to re-emergence of the malignant clone. The eradication of minimal residual disease (MRD) is associated with improved remission durability and has great potential in offering the possibility of cure in many lymphoid malignancies. The monoclonal antibody alemtuzumab is the foundation of many eradication-based treatment approaches because of its ability to achieve clinical remissions and to successfully purge MRD.

We investigate the use of subcutaneous (sc) alemtuzumab for the eradication of residual disease in the bone marrow of patients in clinical response after fludarabine treatment, as determined by NCI criteria.

At least 8 weeks after fludarabine treatment, 35 B-CLL patients (13 female, 22 male; median age 55 [range 39–64] years) received sc alemtuzumab, three times weekly for 6 weeks, at escalating doses up to 10 mg. Residual disease was assessed using a consensus polymerase chain reaction methodology to detect the clonality of IgH sequences. Patients obtaining a successfull peripheral blood stem cell (PBSC) harvest (CD34+ 2.5 x 109/l) after either granulocyte colony-stimulating factor (G-CSF) or intermediate-dose Ara-C (800 mg/m2, every 12 h, for six doses) plus (G-CSF) were considered eligible for autologous PBSC transplant.

Pharmacokinetic parameters were estimated in seven patients. Serum samples of alemtuzumab were assayed by indirect immunofluorescence with target cells (HUT-78, a human T cells line) and antibody concentration was calculated by comparison with a standard curve.

Post fludarabine responses were: 10 CRs, 11 nodular partial responses (PRn) and 14 partial responses (PR). Post alemtuzumab responses were: 29 CRs, 4 PRn, 2 PR. Overall, 51% of patients converted to polyclonal IgH pattern (MR). Of the patients in CR before alemtuzumab, 7 achieved MR; nine of the patients in PRn before immunotherapy, improved to CR, five achieving MR. Of the fourteen patients in PR before alemtuzumab, twelve improved (two PRn, ten CR) and six achieved MR. Twenty-three out of 25 patients successfully mobilized PBSC. Fourteen patients have been transplanted so far. Subcutaneous alemtuzumab was generally well tolerated; fifteen patients (57%) developed cytomegalovirus (CMV) reactivation, but CMV disease was prevented by prompt treatment with oral ganciclovir.

Alemtuzumab serum concentrations measured at second week after the start of therapy, just before the next dose (Ctrough), were relatively stable: Ctrough = 0.79±0.6 mg/ml.

Sequential treatment with fludarabine and alemtuzumab is feasible, effective and safe. Overall 83% of patients reached CR according to NCI criteria. Eighty-four percent of patients improved to CR or PRn after alemtuzumab. Residual disease was not detected in 51% of patients. Sequential treatment did not compromise PBSC mobilization, allowing patients to proceed to autologous transplantation.