Low-dose fludarabine and cyclophosphamide combined with rituximab in the first-line treatment of elderly/comorbid patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL): long-term results of project Q-lite by the Czech CLL Study Group
Corresponding Author
Lukáš Smolej
4th Department of Internal Medicine – Haematology, Faculty of Medicine, University Hospital, Hradec Králové, Czech Republic
Correspondence: Lukáš Smolej, 4th Department of Internal Medicine – Haematology, University Hospital and Faculty of Medicine, Sokolská 581, 50005 Hradec Králové, Czech Republic.
E-mail: [email protected]
Search for more papers by this authorYvona Brychtová
Department of Internal Medicine – Haematology and Oncology, University Hospital, Brno, Czech Republic
Search for more papers by this authorEduard Cmunt
First Department of Medicine – Haematology, General University Hospital, Prague, Czech Republic
Search for more papers by this authorMichael Doubek
Department of Internal Medicine – Haematology and Oncology, University Hospital, Brno, Czech Republic
Search for more papers by this authorMartin Špaček
First Department of Medicine – Haematology, General University Hospital, Prague, Czech Republic
Search for more papers by this authorDavid Belada
4th Department of Internal Medicine – Haematology, Faculty of Medicine, University Hospital, Hradec Králové, Czech Republic
Search for more papers by this authorMartin Šimkovič
4th Department of Internal Medicine – Haematology, Faculty of Medicine, University Hospital, Hradec Králové, Czech Republic
Search for more papers by this authorLukáš Stejskal
Haematology/Tranfusiology Department, Silesian Hospital Opava, Opava, Czech Republic
Search for more papers by this authorIrena Zygulová
Haematology/Tranfusiology Department, Silesian Hospital Opava, Opava, Czech Republic
Search for more papers by this authorRenata Urbanová
Department of Haematology – Oncology, University Hospital, Olomouc, Czech Republic
Search for more papers by this authorJana Zuchnická
Department of Haematology, University Hospital, Ostrava, Czech Republic
Search for more papers by this authorHeidi Móciková
Department of Haematology, University Hospital Královské Vinohrady, Prague, Czech Republic
Search for more papers by this authorTomáš Kozák
Department of Haematology, University Hospital Královské Vinohrady, Prague, Czech Republic
Search for more papers by this authorfor the Czech CLL Study Group
Search for more papers by this authorCorresponding Author
Lukáš Smolej
4th Department of Internal Medicine – Haematology, Faculty of Medicine, University Hospital, Hradec Králové, Czech Republic
Correspondence: Lukáš Smolej, 4th Department of Internal Medicine – Haematology, University Hospital and Faculty of Medicine, Sokolská 581, 50005 Hradec Králové, Czech Republic.
E-mail: [email protected]
Search for more papers by this authorYvona Brychtová
Department of Internal Medicine – Haematology and Oncology, University Hospital, Brno, Czech Republic
Search for more papers by this authorEduard Cmunt
First Department of Medicine – Haematology, General University Hospital, Prague, Czech Republic
Search for more papers by this authorMichael Doubek
Department of Internal Medicine – Haematology and Oncology, University Hospital, Brno, Czech Republic
Search for more papers by this authorMartin Špaček
First Department of Medicine – Haematology, General University Hospital, Prague, Czech Republic
Search for more papers by this authorDavid Belada
4th Department of Internal Medicine – Haematology, Faculty of Medicine, University Hospital, Hradec Králové, Czech Republic
Search for more papers by this authorMartin Šimkovič
4th Department of Internal Medicine – Haematology, Faculty of Medicine, University Hospital, Hradec Králové, Czech Republic
Search for more papers by this authorLukáš Stejskal
Haematology/Tranfusiology Department, Silesian Hospital Opava, Opava, Czech Republic
Search for more papers by this authorIrena Zygulová
Haematology/Tranfusiology Department, Silesian Hospital Opava, Opava, Czech Republic
Search for more papers by this authorRenata Urbanová
Department of Haematology – Oncology, University Hospital, Olomouc, Czech Republic
Search for more papers by this authorJana Zuchnická
Department of Haematology, University Hospital, Ostrava, Czech Republic
Search for more papers by this authorHeidi Móciková
Department of Haematology, University Hospital Královské Vinohrady, Prague, Czech Republic
Search for more papers by this authorTomáš Kozák
Department of Haematology, University Hospital Královské Vinohrady, Prague, Czech Republic
Search for more papers by this authorfor the Czech CLL Study Group
Search for more papers by this authorSummary
Therapeutic options used to be very limited for treatment-naïve elderly/comorbid patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) before the introduction of chemo-immunotherapy. Because dose-reduced fludarabine-based regimens yielded promising results, the Czech CLL Study Group initiated a prospective observational study to assess safety and efficacy of low-dose fludarabine and cyclophosphamide combined with rituximab (FCR) in elderly/comorbid patients. Between March 2009 and July 2012, we enrolled 107 patients considered ineligible for full-dose FCR (median age, 70 years; median Cumulative Illness Rating Scale score, 5; median creatinine clearance, 69 ml/min). Notably, 77% patients had unfavourable biological prognosis [unmutated immunoglobulin heavy-chain variable-region gene (IGHV), 74%; deletion 17p, 9%). Fludarabine was reduced to 12 mg/m2 intravenously (iv) or 20 mg/m2 orally on days 1–3 and cyclophosphamide to 150 mg/m2 iv/orally on days 1–3. Grade 3–4 neutropenia occurred in 56% of the patients, but there were serious infections in only 15%. The median progression-free survival was 29 months, but was markedly longer in patients with mutated IGHV (median 53 months), especially in absence of del 11q or 17p (median 74 months). Low-dose FCR is a well-tolerated and effective first-line regimen for selected elderly/comorbid patients with CLL/SLL with favourable biology. The study was registered at clinicaltrials.gov (NCT02156726).
Supporting Information
| Filename | Description |
|---|---|
| bjh17373-sup-0001-FigS1.bmpWindows BMP image, 2.1 MB | Figure S1. Patient flow diagram. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Dores GM, Anderson WF, Curtis RE, Landgren O, Ostroumova E, Bluhm EC, et al. Chronic lymphocytic leukaemia and small lymphocytic lymphoma: overview of the descriptive epidemiology. Br J Haematol. 2007; 139: 809–19.
- 2Dreger P, Ghia P, Schetelig J, van Gelder M, Kimby E, Michallet M, et al. High-risk chronic lymphocytic leukemia in the era of pathway inhibitors: integrating molecular and cellular therapies. Blood. 2018; 132: 892–902.
- 3Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010; 376: 1164–74.
- 4Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016; 17: 928–42.
- 5Shvidel L, Shtalrid M, Bairey O, Rahimi-Levene N, Lugassy G, Shpilberg O, et al. Conventional dose fludarabine-based regimens are effective but have excessive toxicity in elderly patients with refractory chronic lymphocytic leukemia. Leuk Lymphoma. 2003; 44: 1947–50.
- 6Ferrajoli A, O’Brien S, Wierda W. Treatment of patients with CLL 70 years old and older: a single center experience of 142 patients. Leuk Lymphoma. 2005; 46(Suppl 1): S86 (abstract P95).
- 7Bouvet E, Borel C, Obéric L, Compaci G, Cazin B, Michallet AS, et al. Impact of dose intensity on outcome of fludarabine, cyclophosphamide, and rituximab regimen given in the first-line therapy for chronic lymphocytic leukemia. Haematologica. 2013; 98(1): 65–70.
- 8Thurmes P, Call T, Slager S, Zent C, Jenkins G, Schwager S, et al. Comorbid conditions and survival in unselected, newly diagnosed patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2008; 49: 49–56.
- 9Goede V, Fischer K, Engelke A, Schlag R, Lepretre S, Montero LF, et al. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015; 29: 1602–4.
- 10Hillmen P, Robak T, Janssens A, Babu KG, Kloczko J, Grosicki S, et al. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet. 2015; 385: 1873–83.
- 11Fabbri A, Lenoci M, Gozzetti A, Marotta G, Raspadori D, Forconi F, et al. Low-dose oral fludarabine plus cyclophosphamide in elderly patients with chronic lymphoproliferative disorders. Hematol J. 2004; 5: 472–4.
- 12Foon KA, Boyiadzis M, Land SR, Marks S, Raptis A, Pietragallo L, et al. Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009; 27: 498–503.
- 13Forconi F, Fabbri A, Lenoci M, Sozzi E, Gozzetti A, Tassi M, et al. Low-dose oral fludarabine plus cyclophosphamide in elderly patients with untreated and relapsed or refractory chronic lymphocytic leukaemia. Hematol Oncol. 2008; 26(4): 247–51.
- 14Marotta G, Bigazzi C, Lenoci M, Tozzi M, Bocchia M, Lauria F. Low-dose fludarabine and cyclophosphamide in elderly patients with B-cell chronic lymphocytic leukemia refractory to conventional therapy. Haematologica. 2000; 85: 1268–70.
- 15Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008; 111: 5446–56.
- 16Dohner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000; 343: 1910–6.
- 17Ghia P, Stamatopoulos K, Belessi C, Moreno C, Stilgenbauer S, Stevenson F, et al. ERIC recommendations on IGHV gene mutational status analysis in chronic lymphocytic leukemia. Leukemia. 2007; 21: 1–3.
- 18Salvi F, Miller MD, Grilli A, Giorgi R, Towers AL, Morichi V, et al. A manual of guidelines to score the modified cumulative illness rating scale and its validation in acute hospitalized elderly patients. J Am Geriatr Soc. 2008; 56: 1926–31.
- 19Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976; 16: 31–41.
- 20 Common Terminology Criteria for Adverse Events (CTCAE). https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Accessed 6 December 2020.
- 21 Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. https://www.fda.gov/media/71195/download. Accessed 6 December, 2020.
- 22Shuster JJ. Median follow-up in clinical trials. J Clin Oncol. 1991; 9: 191–2.
- 23Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, Ding W, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018; 379: 2517–28.
- 24Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019; 20: 43–56.
- 25Fischer K, Al-Sawaf O, Bahlo J, Fink AM, Tandon M, Dixon M, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019; 380: 2225–36.
- 26Gozzetti A, Candi V, Fabbri A, Schiattone L, Cencini E, Lauria F, et al. Chemoimmunotherapy with oral low-dose fludarabine, cyclophosphamide and rituximab (old-FCR) as treatment for elderly patients with chronic lymphocytic leukaemia. Leuk Res. 2014; 38: 891–5.
- 27Herishanu Y, Tadmor T, Braester A, Bairey O, Aviv A, Rahimi-Levene N, et al. Low-dose fludarabine and cyclophosphamide combined with standard dose rituximab (LD-FCR) is an effective and safe regimen for elderly untreated patients with chronic lymphocytic leukemia: The Israeli CLL study group experience. Hematol Oncol. 2019; 37: 185–92.
- 28Mulligan SP, Gill DS, Turner P, Renwick WE, Latimer M, Mackinlay N, et al. A randomised dose de-escalation safety study of oral fludarabine +/- oral cyclophosphamide and intravenous rituximab (OFOCIR) as first-line therapy of fit patients with chronic lymphocytic leukaemia (CLL) aged >=65 years - end of recruitment analysis of response and toxicity of the Australasian Leukaemia and Lymphoma Group (ALLG) and CLL Australian Research Consortium (CLLARC) CLL5 Study. ASH Ann Meet Abstr. 2012; 120: 436.
- 29Nikitin E, Kisilichina D, Zakharov O, Lugovskaya S, Varlamova E, Obukhova T, et al. Randomised comparison of FCR-Lite and ClbR (chlorambucil plus rituximab) regimens in elderly patients with chronic lymphocytic leukemia. Haematologica. 2013; 98(Suppl 1): 473.
- 30Michallet AS, Aktan M, Hiddemann W, Ilhan O, Johansson P, Laribi K, et al. Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study. Haematologica. 2018; 103: 698–706.
- 31Spacek M, Obrtlikova P, Hrobkova S, Cmunt E, Karban J, Molinský J, et al. Prospective observational study in comorbid patients with chronic lymphocytic leukemia receiving first-line bendamustine with rituximab. Leuk Res. 2019; 79: 17–21.
- 32Cuneo A, Mato AR, Rigolin GM, Piciocchi A, Gentile M, Laurenti L, et al. Efficacy of bendamustine and rituximab in unfit patients with previously untreated chronic lymphocytic leukemia. Indirect comparison with ibrutinib in a real-world setting. A GIMEMA-ERIC and US study. Cancer Med. 2020; 9: 8468–79.
- 33Rotbain EC, Frederiksen H, Hjalgrim H, Rostgaard K, Egholm GJ, Zahedi B, et al. IGHV mutational status and outcome for patients with chronic lymphocytic leukemia upon treatment: a Danish nationwide population-based study. Haematologica. 2020; 105: 1621–9.
- 34Patel KK, Isufi I, Kothari S, Davidoff AJ, Gross CP, Huntington SF. Cost-effectiveness of first-line vs third-line ibrutinib in patients with untreated chronic lymphocytic leukemia. Blood. 2020; 136: 1946–55.
- 35Niemann CU. Cost-effectiveness targeting CLL. Blood. 2020; 136: 1896–8.
- 36Eichhorst B, Robak T, Montserrat E, Ghia P, Niemann CU, Kater AP, et al. ESMO Guidelines Committee. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021; 32: 23–33.
Citing Literature
