'Intense' Reversal of Angiogenesis After Campath

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[4985] Intense Reversal of Bone Marrow Angiogenesis after

Consolidation Therapy with Alemtuzumab in Advanced Chronic Lymphocytic

Leukemia. Session Type: Publication Only

Stefano Molica, Marco Montillo, Domenico Ribatti, nna Mirabelli,

Alessandra Tedeschi, Francesca Ricci, Silvio Veronese, Angelo Vacca,

Enrica Morra Department Hematology-Oncology, A.O. Pugliese-Ciaccio,

Catanzaro, Italy; Department Hematology, Niguarda Ca Grande Hospital,

Milan, Italy; Department of Human Anatomy and Histology, University of

Bari, Bari, Italy; Department Human Anatomy and Histology, Niguarda Ca

Grande Hospital, Milan, Italy; Department of Biomedical Sciences and

Human Oncology, University of Bari, Bari, Italy

We evaluated microvessel area of bone marrow (BM) samples from 20

patients with advanced CLL (i.e., symptomatic Binet stage A, B or C)

who received at least 8 weeks, after the end of treatment with

fludarabine, subcutaneous alemtuzumab, three times weekly for 6 weeks,

at escalating dose up to 10 mg. The patient sample included 14 males

and 6 females with a median age of 51 years (range 44-60).

After a median number of 6 cycles of fludarabine (range, 4-13), 11

(55%) patients could be classified in complete remission (CR) and 9

(45%) in partial remission (PR) (7 nodular-PR and 2 PR).

Interestingly, the rate of CR increased to 90% (18 CR; P=0.03; Fishers

exact test) after treatment with alemtuzumab.

In keeping with hematological responses, significant changes in BM

microvessel area were observed. The decrease of BM angiogenesis,

observed virtually in all patients, was a continuous process

characterizing the sequential use of fludarabine and alemtuzumab (P =

0.002; Kruskal-Wallis test). This conspicuous feature was easily

demonstrable in either ZAP-70-positive (P = 0.02) or ZAP-70-negative

(P = 0.001) patients.

Residual disease was assessed using a consensus polymerase chain

reaction (PCR) methodology to detect the clonality of IgH sequences.

Thirteen out of 20 (65%) patients changed from a monoclonal to a

polyclonal pattern of IgH after alemtuzumab consolidation. We wondered

whether molecular response could translate into a change in the BM

microvessel area. A separate evaluation carried out in patients with a

persistent monoclonal pattern and in those who changed to a polyclonal

pattern of IgH after alemtuzumab therapy showed a significant

reduction of BM microvessel area only in the latter (P = 0.0002).

New information provided by the present study concerns the impact of

the cumulative dose of alemtuzumab on either molecular response or

reduction in BM angiogenesis. Analysis carried out after setting as

cut-off the median cumulative dose of alemtuzumab (i.e., 184 mg;

range, 134-187) revealed a dose-response relationship. Only two

(15.3%) out of 13 patients who received a cumulative dose of

alemtuzumab higher than 184 mg had persistent monoclonal IgH in

comparison to 5 (71.4%) out 7 patients who had received a cumulative

dose of alemtuzumab lower than median (P = 0.007). Similarly, a

significant decrease in the extent of microvessel area was observed

among patients whose cumulative dose was equal or higher than 184 mg

(P = 0.0001) while the same did not apply for a cumulative dose of

alemtuzumab lower than 184 mg (P = 0.09).

Overall, these data demonstrate a decrease in BM vascularity after

treatment with alemtuzumab, which reflects both molecular response and

cumulative dose of this drug, and suggest a potential use of

alemtuzumab as anti-angiogenic agent in the treatment of advanced CLL.