Campath and Rituximab in Early Stage CLL Gives Good Results; Improvement Needed

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[2829] Alemtuzumab and Rituximab for Therapy of Patents with Early

Stage High Risk CLL: Report of a Planned Interim Analysis. Session

Type: Poster Session, Board #58-III

Clive S. Zent, D. Bone, G. Call, Tait D. Shanafelt,

M. Geyer, Charla R. Secreto, Diane F. Jelinek, Gordon W.

Dewald, Neil E. Kay Hematology, Mayo Clinic College of Medicine,

Rochester, MN, USA

The standard of care for CLL is to treat only patients with obvious

clinical progression because earlier intervention is not of proven

benefit. The discovery of more accurate prognostic markers for CLL

could change that paradigm.

The predictors of more aggressive disease include 17p13 deletion

(17p13-), 11q22-3 deletion (11q22-), unmutated (UM) immunoglobulin

heavy-chain variable region (IgVH), and expression of ZAP-70 and

CD38. In addition, monoclonal antibody (MoAb) therapies provide

effective treatment with less toxicity than chemotherapy and are

likely to be most efficacious in early stage CLL.

The combination of alemtuzumab (ALEM) and rituximab (RIT) is of

interest because of non-overlapping mechanisms of action. ALEM is

also effective therapy for patients with defects in the p53

apoptotic pathway that are more resistance to purine analogue

therapy. We tested the hypothesis that MoAb therapy with ALEM and

RIT will eliminate/greatly decrease the high risk clone

characterized by 17p13-, 11q22-, or UM IgVH plus either ZAP70+ or

CD38+, in early stage CLL.

Methods: This trial will enroll a maximum of 30 patients and be

considered promising if 19 patients respond. All patients with

previously untreated CLL (Rai stage 0 II) not meeting NCI-WG 1996

treatment criteria and with a high risk CLL clone were evaluated for

enrollment. Treatment duration was 30 days (subcutaneous ALEM dose

escalation, 3 mg - 10 mg - 30 mg on days 1-3) then 30 mg Monday,

Wednesday and Friday for 4 weeks. RIT (375 mg/m2/dose IV x 4) was

administered weekly staring on day 8. All patients received PCP and

herpes virus prophylaxis and had CMV viral DNA testing for 7 months.

Response was evaluated using NCI-WG 1996 criteria and minimal

residual disease (MRD) was measured in peripheral blood using

sensitive flow cytometry (1:104) for CD19+/CD5+/CD79b- lymphocytes.

Results: Since January 2005, 17 patients have been enrolled and the

interim analyses are for the first 11 patients accrued. Median age

was 62 years (29 75) with 6 males and 5 females. The qualifying

high risk features were 17p13- (n = 4), 11q22- (n = 3), and UM IgVH

+ CD38+ +/- ZAP-70+ (n = 4). Median time from diagnosis to treatment

was 11 months (2-72). Clinical stage (Rai) was 0 in 3 patients, I in

5 patients and II in 3 patients. Median absolute lymphocyte count

was 25.6 x 109/L (15.9 81.8), Hgb 14.4 g/dL (12 15.8), and

platelet count 171 x 109/L (125 312). Two patients had serious

adverse reactions requiring intervention (CMV reactivation

responsive to treatment; febrile drug reaction to

sulfamethoxazole/trimethoprim). Grade 3-4 adverse reactions not

requiring interventions were leukopenia (n = 4), neutropenia (n =

2), anemia (n = 1), elevated ALT (n = 1), and skin reaction to ALEM

(n =1). There were no first dose reactions. All patients responded

to therapy with 5 CR (4 of these MRD negative), 3 nodular PR, and 3

PR. Median duration of response has not yet been reached at median

follow up of 11.7 months (6.5 14.9). Patients with a MRD negative

CR had recurrence of detectable MRD at 120 210 days after

completing therapy but all remain in CR. One patient died off study

of complications of a myeloablative allogeneic transplant for

progressive CLL.

Discussion: ALEM and RIT is effective and tolerable therapy for

early stage high risk CLL. All patients responded with 36% achieving

a MRD negative CR but serial MRD assays showed that the CLL clone

was not deleted. This promising, treatment requires further

improvement.