Since there is no standard rescue therapy for refractory CLL or relapsed to the purine analogous, our target is to carry out a rescue therapy combining several chemotherapy agents (CHOP) adding the synergistic effect of Rituximab in order to act against tumour-like CLL forms, with assessable size lymph nodes. Afterwards, based in other studies, we shall study the role of Alemtuzumab as drug for consolidation or improvement of responses obtained with the initial therapy (CHOP-R), acting by “cleaning” from peripheral blood and bone marrow the CLL lymphocytes that may have had remain as residual after chemotherapy induction therapy. More precisely, the addition of Alemtuzumab as maintenance treatment would increase the complete responses with negative residual disease number and may prolong the duration of the response. For this, it is necessary to have not only an adequate and rigorous clinical follow-up but also biological, i.e. being able to analyze minimal residual disease by molecular biology techniques. This is the reason of writing this phase II clinical trial protocol.

1 OBJECTIVES

The objectives of this clinical trial are the following:

1.1 Main objective of the study

Overall response rate obtained after R-CHOP regime followed by Alemtuzumab consolidation as second line therapy

1.2 Secondary objectives

• Determine the molecular complete response rate after R-CHOP regimen
• Determine the efficacy of Alemtuzumab in response improvement after R-CHOP regimen: conversion of PR to CR and of MRD+ to MRD-.
• Applicability (toxicity profile) of Alemtuzumab consolidation therapy.

• As additional objectives will be considered:

  • Prognostic value of several biological variables (ZAP-70 and cytogenetics) having influence on the response
  • Response duration
  • Progression free survival
  • Overall survival

• Chronic Lymphocytic Leukaemia
• Patients Resistant to a Purine Analogous
• Patients Relapsed With Purines Therapy

Four Rituximab – CHOP courses will be given The courses will be given every 21 days Drug Dose Day Rituximab (Mabthera) 500mg/m2 1(*) (**) Cyclophosphamide 750mg/m2 1 Adriamycin 50mg/m2 1 Vincristine 1,4 mg/m2 1 Prednisone 60mg/m2 1 to 5

(**) 1st course, 375 mg/m2 (*) If lymphocyte count is > 30 X 10 9/l, dose will be split up in two, which will be given in days 0 and 1

Inclusion Criteria:

1. Patient’s written informed consent before initiation of any specific procedure related with the study.
2. Age ≥ 18 years and ≤ 70 years
3. (ECOG) ≤ 2
4. Patients suffering from chronic lymphocyte leukaemia according to the established diagnostic criteria (Addendum A).

5. Active CLL defined by the presence of one or more of the following criteria:

   • Related symptoms: weight loss >10% in the 6 previous months, or fever >38ºC for 2 weeks with no evidence of infections, or extreme fatigue, or night sweats with no evidence of infection.
   • 5.2.Enlarged lymph nodes or giant node clusters (>10 cm in diameter) or progressive growth lymph nodes.
   • 5.3.Giant splenomegaly (> 6 cm under ribs border) or progressive splenomegaly.
   • 5.4.Progressive lymphocytosis (>50% increase in a period of 2 months) or lymphocyte duplication time (expected) < 6 months
   • 5.5.Proof of progressive bone marrow failure evidenced by development or worsening of anaemia and/or thrombopenia.

6. Patients previously treated in first line with purine analogous and showing:

   • Treatment failure (stable disease or progression)
   • Relapse within three years of therapy.
7. Agreement to use a high efficacy contraception method throughout all study period.

Exclusion Criteria:

1. Age > 70 years
2. Patients having received more than one therapy line
3. Patients that had not received previously purine analogous therapy.
4. CLL patients in transformation to more aggressive cytologic or pathologic forms (Pro-lymphocytic leukaemia large cell lymphoma, Hodgkin’s lymphoma)
5. Hypersensitivity shown as anaphylactic reaction to any of the DRUGS used in the trial.
6. Patients with severe heart, lung, neurological, psychiatric or metabolic diseases not due to CLL
7. Patients under systemic and continued steroid therapy.
8. Impairment of renal function (Creatinine > 2 times the upper limit of normal) non-attributable to CLL.
9. Patients suffering anaemia or thrombocytopenia of autoimmune origin as well as those with a positive Coombs test
10. Impairment of liver function (Bilirubin, ASAT/ALAT or Gamma-GT > 2 times upper limit of normal) non attributable to CLL
11. Patients with active severe infectious disease
12. Patients suffering another malignancy (with the exception of focalized skin carcinoma)
13. Patients with positive serum tests for HBsAg or CHV
14. Patients with history of HIV or other severe immune depression conditions.
15. Pregnant or breast feeding women
16. Patients unable to attend the controls under outpatient regimen
17. Patients previously treated with alemtuzumab

• Francesc Bosch, MD
• Fundacion Clinic per a la Recerca Biomédica