Rituximab and subcutaneous 2-chloro-2'-deoxyadenosine combination treatment for patients with Waldenstrom macroglobulinemia: clinical and biologic results of a phase II multicenter study.
OBJECTIVE
To assess the efficacy of 2-chloro-2'-deoxyadenosine (2-CdA) given subcutaneously (SC) in combination with rituximab in the treatment of newly diagnosed/pretreated patients with Waldenström macroglobulinemia (WM) and to correlate the response to treatment with biologic findings (immunophenotypic and pharmacogenomic analysis).


METHODS
From December 2003 to February 2007, 29 patients were enrolled. Intended therapy consisted of a combination of rituximab (375 mg/m(2)) on day 1 followed by 2-CdA 0.1 mg/kg (SC injection) for 5 consecutive days, administered monthly for four cycles. Anemia (n = 16), neurologic symptoms (n = 6), symptomatic cryoglobulinemia (n = 4), and thrombocytopenia (n = 3) represented the reasons for starting treatment. The expression of zeta chain-associated protein kinase 70 (Zap-70) and of seven genes involved in 2-CdA metabolism as markers of response to the combination treatment was evaluated.


RESULTS
With a median follow-up of 43 months, the overall response rate observed was 89.6%, with seven complete responses (CR), 16 partial responses, and three minor response, without any difference between newly or pretreated patients (P = .522). The therapy was well tolerated, except for transitory cardiac toxicity (n = 2) and intolerance to rituximab (n = 2). No major infections were observed despite the lack of antimicrobial prophylaxis. No patients developed transformation to high-grade non-Hodgkin's lymphoma nor myelodysplasia. Low expression levels of human concentrative nucleoside transporter 1 (hCNT1) were correlated with the failure to achieve a CR (P = .024), whereas no association with Zap-70 expression was found.


CONCLUSIONS
The combination of rituximab and SC 2-CdA is safe and effective in patients with WM requiring treatment. The pharmacogenomic analysis associated with the study suggests hCNT1 might be beneficial in predicting clinical response to such a combination treatment.
Laszlo
Daniele
D
Department of Hematology, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy. daniele.laszlo@ieo.it
Andreola
Giovanna
G
Rigacci
Luigi
L
Fabbri
Alberto
A
Rabascio
Cristina
C
Mancuso
Patrizia
P
Pruneri
Giancarlo
G
Radice
Davide
D
Pinto
Antonello
A
Frigeri
Ferdinando
F
Calabrese
Liliana
L
Billio
Atto
A
Bertolini
Francesco
F
Martinelli
Giovanni
G
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D017338:Cladribine / Q000008:administration & dosage; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005838:Genotype; D006801:Humans; D016130:Immunophenotyping; D007279:Injections, Subcutaneous; D007558:Italy; D053208:Kaplan-Meier Estimate; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D018579:Patient Selection; D010641:Phenotype; D011446:Prospective Studies; D000069283:Rituximab; D013997:Time Factors; D016896:Treatment Outcome; D008258:Waldenstrom Macroglobulinemia / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics / Q000378:metabolism
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D026901:Membrane Transport Proteins; C065171:cif nucleoside transporter; D017338:Cladribine; D000069283:Rituximab; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human