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A Phase III trial of fludarabine, cyclophosphamide, and rituximab vs. pentostatin, cyclophosphamide, and rituximab in B-cell chronic lymphocytic leukemia

  • PHASE III STUDIES
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Summary

Background Uncontrolled studies comparing pentostatin (P), cyclophosphamide (C), and rituximab (R) (PCR) to fludarabine plus C+R (FCR) suggest similar efficacy with fewer infectious complications with PCR. We compared FCR and PCR in previously-untreated or minimally-treated B-cell chronic lymphocytic leukemia (CLL). Treatment FCR (F 20 mg/m2 Days 1–5, C 600 mg/m2 Day 1, R 375 mg/m2 Day 1) (28-day cycles) or PCR (P 4 mg/m2 Day 1, C 600 mg/m2 Day 1, R 375 mg/m2 Day 1) (21-day cycles). Dose 1 of R: 100 mg/m2 was given on Day 8 Cycle 1 and the remainder on Day 9; in subsequent cycles the entire dose was given on Day 1. Results Ninety-two patients were randomly assigned to each group (N = 184). Groups were balanced; ~20% had received prior chemotherapy. The infection rate (FCR/PCR) was 31%/36%, the infective event rate was 38%/45%; 30 (35%)/37 (44%) patients were hospitalized; total hospitalization days was 271/404. 12 (14%)/6 (7%) patients achieved complete remissions (CR); the overall response rate (ORR) including CR+nodular PR (nPR)+PR was 59%/49%. Grade 3–4 treatment related AEs: neutropenia (69%/57%), leukopenia (34%/17%), thrombocytopenia (13%/6%). Grade 3–4 infections: febrile neutropenia (8%/6%), fever (2%/6%), infection (1%/3%), urinary tract infection (1%/0%), pneumonia (3%/1%), and sepsis (1%/2%); 5 deaths (1 FCR/4 PCR) were treatment-related. Conclusions PCR and FCR have significant activity in CLL and can be given safely in the community setting despite significant toxicity. ORRs were lower than expected; the CR rate was higher (NS) with FCR. This trial did not demonstrate a lower infection rate with PCR.

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Acknowledgments

We thank the patients who shared their experiences with US Oncology physicians (see Appendix), the site coordinators in the field (especially Lisa Mision in Columbia, MO), program manager Julie Boston, RN; project manager Mary Ann Rauch, BS; and data reviewers Tracy Locke, RHIA and Renada Guidry, BS who assured the accuracy and integrity of the data. The authors would especially like to acknowledge R. David Lauper, PharmD, for his support and guidance during the conduct of this study; David passed away as the manuscript was being finalized. He was an excellent colleague and a genuinely nice person. Just after this study was concluded, and during the preparation of the preliminary analysis, Dr. Gary Lee died in a tragic accident. Gary was a superb and caring physician and a great source of inspiration to those who worked with him in his clinic and in the community. David and Gary will be greatly missed.

Manufacturer name

Pentostatin (Nipent ®, Hospira, Inc. [formerly SuperGen, Inc.])

Cyclophosphomide—generic preparations are available and were used at the discretion of the treating physician.

Rituximab (Rituan ®, Genentech/biogen idec)

Fludarabine—generic preparations are available and were used at the discretion of the treating physician.

Author information

Authors and Affiliations

  1. US Oncology Research, LLC., The Woodlands, TX, USA

    Craig Reynolds, Nicholas Di Bella, Roger M. Lyons, William Hyman, Donald A. Richards, Gerald J. Robbins, Mark Vellek, Kristi A. Boehm, Feng Zhan & Lina Asmar

  2. Ocala Oncology, 433 SW 10th Street, Ocala, FL, 34474, USA

    Craig Reynolds

  3. Rocky Mountain Cancer Centers, Aurora, CO, USA

    Nicholas Di Bella

  4. Cancer Care Centers of South Texas, San Antonio, TX, USA

    Roger M. Lyons

  5. Texas Oncology, Tyler, TX, USA

    William Hyman & Donald A. Richards

  6. Florida Cancer Institute, New Port Richey, FL, USA

    Gerald J. Robbins

  7. Missouri Cancer Associates, Columbia, MO, USA

    Mark Vellek

Authors
  1. Craig Reynolds
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  2. Nicholas Di Bella
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  3. Roger M. Lyons
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  4. William Hyman
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  5. Donald A. Richards
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  6. Gerald J. Robbins
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  7. Mark Vellek
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  8. Kristi A. Boehm
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  9. Feng Zhan
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  10. Lina Asmar
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Corresponding author

Correspondence to Craig Reynolds.

Additional information

Research support was provided, in part, by Hospira, Inc., Lake Forest, IL

Appendix

Appendix

The following medical oncologists from the US Oncology Research network also participated in this study: Robert J. Belt, Shawnee Mission, KS; Paul D. Richards, Salem, VA; Peter J. Schlegel, Spokane, WA; Raymond Taetle, Tucson, AZ; Patrick V. Acevedo, Ocala, FL; Robert L. Anderson, Waco, TX; Arvind Bhandari, Sugar Land, TX; Ernest W. Cochran Jr., Paris, TX; Philip Y. Dien, Burnsville, MN; David C. Faragher, Aurora, CO; Maria Regina Carrillo Flores, Winter Park/Orlando, FL; Yousuf A. Gaffar, Westminster, MD; Matthew T. Gall, Burnsville, MN; Edward R. George, Norfolk, VA; Timothy K. George, Odessa, TX; Robert H. Gersh, Spokane, WA; Houston E. Holmes, III, Dallas, TX; Pankaj Khandelwal, Odessa, TX; Kathryn S. Kolibaba, Vancouver, WA; Peter X. Lamparello, Latham, NY; Deborah L. Lindquist, Sedona, AZ; Robert L. Marsh, Fairfax, VA; Joseph J. Muscato, Columbia, MO; Rajesh Nahar, Kingston, PA; Sucharu Prakash, Paris, TX; Robert N. Raju, Dayton/Kettering, OH; Michael S. Roberts, Scottsdale, AZ; Steven R. Rousey, Edina, MN; Robert L. Ruxer Jr., Fort Worth, TX; Michael A. Savin, Dallas, TX; Russell C. Tolley, Thornton, CO; Frank T. Ward, Tyler, TX; Ira L. Zackon, Latham, NY; Rony Abou Jawde, St. Joseph, MO; Radhika C. Acharya-Leon, Littleton, CO; Jose M. Acostamadiedo, Elizabeth City, NC; Carlos A. Alemany, Ocoee, FL; Stephen P. Anthony, Spokane, WA; David N. Barrera, Fort Worth, TX; Rebecca E Barrington, Kerrville, TX; Stephen B. Beck, Birmingham, AL; Sridhar Beeram, San Antonio, TX; Maury B. Berger, Ocala, FL; William R. Berry, Raleigh, NC; Anil K.V. Bhogaraju, Lewisville, TX; Michael A. Boxer, Tucson, AZ; Thomas E. Boyd, Yakima, WA; Barry D. Brooks, Dallas, TX; Donald J. Brooks, Minneapolis, MN; Elizabeth E. Campbell, Raleigh, NC; Karen M. Carr, Midland, TX; Ashis K. Chakrabarti, Terre Haute, IN; Benjamin L. Cho, Eugene, OR; Jolanta U. Cichon, Denton, TX; Paul R. Conkling, Norfolk, VA; Linda S. Couch, Longview, TX; Jay G. Courtright, Dallas, TX; John M. Davis II, Lee’s Summit, MO; Yuhoe Gia Dice, San Antonio, TX; Harry G. Dunn, Latham, NY; Charles F. Eisenbeis, Cary, NC; Maha A. Elkordy, Cary, NC; James B. Ellis, San Antonio, TX; William A. Fintel, Salem, VA; Thomas P. Flynn, Minneapolis, MN; Elke K. Friedman, Norfolk, VA; Sandeep S. Gill, Bedford, TX; William L. Gluck, Greenville, SC; Allen Greenberg, Plantation, FL; Manish Gupta, Garland, TX; Elizabeth A Harden, Newport News, VA; James W. Hathorn, Durham, NC; Lanny I. Hecker, Phoenix, AZ; John D. Hunter, Seneca, SC; Sharad K Jain, Denton, TX; John F. Kessler, Newport News, VA; Steven J. Ketchel, Tucson, AZ; Darren M. Kocs, Austin, TX; Peter A. Kovach, Eugene, OR; Flavio Kruter, Owings Mills, MD; Aparna R. Kumar, Tyler, TX; Douglas J. Lee, Seattle, WA; Gary L. Lee, (deceased) Eugene, OR; Jae H. Lee, Eugene, OR; Lixin Liao, Arlington, TX; Keith W. Logie, Fishers, IN; Regan M. Look, Portland, OR; Jose A. Lopez, Fredericksburg, TX; Jeffrey V. Matous, Denver, CO; Kristi J. McIntyre, Dallas, TX; Scott A. McKenney, Beaumont, TX; Richard J. McKittrick, Kansas City, MO; Anton M. Melnyk Jr., Abilene, TX; Mathew Miceli, Ocala, FL; Mohammed K. Nashawaty, Edina, MN; Jairo R. Olivares, Garland, TX; Alvin L. Otsuka, Thornton, CO; Mrugesh P. Patel, Bedford, TX; Kelly B Pendergrass, Kansas City, MO; James B Puckett, Asheville, NC; Syed N. Raza, Abilene, TX; Randy S. Rich, Arlington Hts., IL; Robert M. Rifkin, Denver, CO; Bruce H. Saidman, Kingston, PA; Robert L. Sayre, Colorado Springs, CO; Mark D. Sborov, Edina, MN; John F. Schwerkoske, St. Paul, MN; John E. Seng, Minneapolis, MN; John M. Shaw, Chicago, IL; Mark Sienko, Spokane, WA; Paramjeet Singh, Cary, NC; Mark A. Sitarik, Boulder, CO; David A. Smith, Vancouver, WA; Gary Spitzer, Greenville, SC; Valiant D. Tan, Elizabeth City, NC; Dina J. Tebcherany, Austin, TX; Stephen J. Tremont, Raleigh, NC; Michael C. Trendle, Columbia, MO; Kent A. Tucker, Birmingham, AL; Jeffery C. Ward, Edmonds, WA; Robert S. Wehbie, Raleigh, NC; Eric L. Weinshel, Edina, MN; Charles S. White, III, Dallas, TX; Gary M. Wright, Ocala, FL; Hillary H. Wu, Fishers, IN.

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Reynolds, C., Di Bella, N., Lyons, R.M. et al. A Phase III trial of fludarabine, cyclophosphamide, and rituximab vs. pentostatin, cyclophosphamide, and rituximab in B-cell chronic lymphocytic leukemia. Invest New Drugs 30, 1232–1240 (2012). https://doi.org/10.1007/s10637-011-9737-y

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