Sequential therapy with fludarabine, high-dose cyclophosphamide, and rituximab in previously untreated patients with chronic lymphocytic leukemia produces high-quality responses: Molecular remissions predict for durable complete responses Journal Article


Authors: Lamanna, N.; Jurcic, J. G.; Noy, A.; Maslak, P.; Gencarelli, A. N.; Panageas, K. S.; Heaney, M. L.; Brentjens, R. J.; Golde, D. W.; Scheinberg, D. A.; Zelenetz, A. D.; Weiss, M. A.
Article Title: Sequential therapy with fludarabine, high-dose cyclophosphamide, and rituximab in previously untreated patients with chronic lymphocytic leukemia produces high-quality responses: Molecular remissions predict for durable complete responses
Abstract: Purpose: Modern combination strategies are active in chronic lymphocytic leukemia (CLL) but can have significant myelosuppression and immunosuppression that may require dose attenuation for safety. We explored a sequential treatment strategy to allow safe delivery of active agents at full doses. Previously, we studied sequential therapy with fludarabine followed by cyclophosphamide (F→C). In that study, cyclophosphamide consolidation improved the frequency of complete response (CR) four-fold. Subsequently, rituximab was added to this regimen (F→C→R). Patients and Methods: Thirty-six previously untreated CLL patients received therapy with fludarabine 25 mg/m<sup>2</sup> on days 1 through 5 every 4 weeks for six cycles, followed by consolidation with cyclophosphamide 3,000 mg/m<sup>2</sup> administered every 3 weeks for three cycles, followed by consolidation with weekly rituximab 375 mg/m<sup>2</sup> for four cycles. Evaluation for minimal residual disease included flow cytometry and a highly sensitive clonotypic polymerase chain reaction (PCR). The median age was 59 years (range, 37 to 71 years), 61% of patients had high-risk disease, and 58% had unmutated IgV<sub>H</sub> genes. Results: There were 32 responses (89%), including 22 CRs (61%). Consolidation with cyclophosphamide improved responses in 13 patients (36%); nine patients (25%) further improved their response with rituximab. Twenty patients (56%) achieved flow cytometric CRs, and 12 patients (33%) achieved a molecular CR (PCR negative). Patients achieving molecular CRs had an excellent prognosis with a plateau in the response duration curve, and 90% remain in clinical CR at 5 years. For the entire group, 5-year survival rate is 71% compared with a rate of 48% with our prior F→C regimen (P = .10). Conclusion: Sequential therapy with F→C→R yields improvement in quality of response, with many patients achieving a PCR-negative state. © 2008 by American Society of Clinical Oncology.
Keywords: adult; cancer survival; clinical article; treatment outcome; aged; middle aged; survival rate; gene mutation; fludarabine; clinical trial; neutropenia; cancer combination chemotherapy; drug withdrawal; antineoplastic agents; cancer patient; rituximab; drug megadose; flow cytometry; follow-up studies; polymerase chain reaction; infection; multiple cycle treatment; anemia; thrombocytopenia; antineoplastic combined chemotherapy protocols; drug administration schedule; fluid therapy; aciclovir; cyclophosphamide; high risk patient; pneumonia; health care quality; drug fatality; survival time; antibodies, monoclonal; immunoglobulin variable region; minimal residual disease; drug response; antineoplastic agents, alkylating; ciprofloxacin; remission induction; colitis; autoimmune hemolytic anemia; bacteremia; age distribution; recombinant granulocyte colony stimulating factor; chronic lymphatic leukemia; cotrimoxazole; catheter infection; leukemia, lymphocytic, chronic, b-cell; drug dose sequence; skin infection; trisomy 12; vidarabine
Journal Title: Journal of Clinical Oncology
Volume: 27
Issue: 4
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2009-02-01
Start Page: 491
End Page: 497
Language: English
DOI: 10.1200/jco.2008.16.4459
PUBMED: 19075280
PROVIDER: scopus
PMCID: PMC2645858
DOI/URL:
Notes: --- - "Cited By (since 1996): 16" - "Export Date: 30 November 2010" - "CODEN: JCOND" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Nicole Lamanna
    57 Lamanna
  2. Mark L Heaney
    90 Heaney
  3. Ariela Noy
    205 Noy
  4. Renier J Brentjens
    189 Brentjens
  5. David Golde
    105 Golde
  6. Joseph G Jurcic
    127 Jurcic
  7. Andrew D Zelenetz
    551 Zelenetz
  8. Katherine S Panageas
    327 Panageas
  9. Peter Maslak
    166 Maslak
  10. Mark Weiss
    80 Weiss