Subcutaneous Campath for Treatment of Residual Disease

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8th Congress of the European Hematology Association

abstract nr.: 0432

SUBCUTANEOUS ALEMTUZUMAB FOR THE TREATMENT OF RESIDUAL DISEASE IN

PATIENTS WITH CLL IN CLINICAL RESPONSE TO FLUDARABINE PHOSPHATE

Author: M. Montillo, Divisione Ematologia, Milan, Italy

Co-author(s): A. Tedeschi, Niguarda Ca'Granda Hospital, Milan, Italy

V. Rossi, Niguarda Ca'Granda Hospital, Milan, Italy

M. Montagna, IRCSS-Policlinico S. Matteo, Pavia, Italy

L. Intropido, Niguarda Ca'Granda Hospital, Milan, Italy

A.M. Cafro, Niguarda Ca'Granda Hospital, Milan, Italy

G. D'Avanzo, Niguarda Ca'Granda Hospital, Milan, Italy

E. Pungolino, Niguarda Ca'Granda Hospital, Milan, Italy

P. Oreste, Niguarda Ca'Granda Hospital, Milan, Italy

S. Veronese, Niguarda Ca'Granda Hospital, Milan, Italy

B. Brando, Niguarda Ca'Granda Hospital, Milan, Italy

E. Morra, Niguarda Ca'Granda Hospital, Milan, Italy

Background: Fludarabine phosphate (Fludara®) improves complete

response (CR) rate in patients with chronic lymphocytic leukaemia

(CLL), compared with alkylating agents. However, residual disease may

persist, and patients eventually relapse.

Alemtuzumab (MabCamPath®) eradicates disease from blood and bone

marrow, achieving 87% overall response (OR) in previously untreated

patients and 33% OR in patients with highly refractory CLL.

Here, we investigate the use of subcutaneous (sc) alemtuzumab for the

eradication of residual disease in the bone marrow of patients

currently in clinical response after fludarabine phosphate treatment,

as determined by National Cancer Institute criteria.

Methods: At least 8 weeks after fludarabine phosphate treatment, 17

CLL patients (4F/13M; median age 55 [range 38–62] years) received sc

alemtuzumab, three times weekly for 6 weeks, at escalating doses up

to 10 mg. Residual disease was assessed using the polymerase chain

reaction to detect the clonality of IgH sequences. Patients received

aciclovir and cotrimoxazole as infection prophylaxis. Pharmacokinetic

parameters were estimated in five patients receiving alemtuzumab.

Serum samples of alemtuzumab were assayed by indirect

immunofluorescence with target cells (HUT-78, a human T-cell line),

and antibody concentration was calculated by comparison with a

standard curve.

Results: Post-fludarabine phosphate responses were: six CR, six

nodular partial responses (PRn) and five partial responses (PR). Post-

alemtuzumab responses were: 15 CR and two PRn. Overall, 47% of

patients converted to molecular response (MR).

Of the patients in CR at baseline, five achieved MR, with a

polyclonal IgH pattern. Of the patients in PRn at baseline, five

improved to CR and one of these achieved MR. Of the five patients in

PR at baseline, all improved (one PRn, four CR) and two achieved MR.

In 14 patients, either granulocyte colony-stimulating factor (G-CSF;

5–10 µg/kg/day) or intermediate-dose Ara-C (800 mg/m2, every 12 h,

for six doses) plus G-CSF were administered to obtain peripheral

blood stem cell (PBSC) mobilization. Mobilization was successful in

13 patients.

At a median follow-up of 12 (range 2–20) months, disease progression

was observed in one patient. Subcutaneous alemtuzumab was generally

well tolerated; the most common adverse reactions were injection-site

reactions (65%, all were grades 1 and 2) and fever (29%, of which 5%

were grade 3). Two patients developed grade 2 neutropenia, which was

successfully treated with G-CSF. Eight patients developed

cytomegalovirus (CMV) reactivation, but CMV disease was prevented by

prompt treatment with oral ganciclovir. Alemtuzumab serum

concentrations (mean ± SD) measured at 2 and 3 weeks after the start

of therapy, just prior to the next dose (Ctrough), were relatively

stable: Ctrough (2 weeks) = 0.39±0.29 µg/ml; Ctrough (3 weeks) =

0.34±0.21 µg/ml.

Conclusions: Sequential treatment with fludarabine phosphate and

alemtuzumab is feasible, effective and safe. All patients improved to

CR or PRn and alemtuzumab was able to eliminate residual disease in

47% of patients. Sequential treatment did not compromise PBSC

mobilization, allowing patients to proceed to autologous

transplantation.