Abstract
Fludarabine combinations are very affective in follicular lymphoma (FL) with high rates of complete response and prolonged survival. However, late toxicities could be a concern. The aim of the present study was to analyze the long-term impact on survival, relapse and late toxicities of a trial of treatment with fludarabine, mitoxantrone and cyclophosphamide (FCM regimen) for untreated patients with advanced stage FL. One hundred and twenty patients enrolled in a phase 2 trial of treatment with FCM regimen between 2000 and 2003 were evaluated. After a median follow-up of 12 years, 52 patients eventually relapsed/progressed with 10 year progression-free survival (PFS) of 46 %. Ten patients showed histological transformation to aggressive lymphoma with a risk of transformation of 2 and 9 % at 5 and 10 years, respectively. Three patients developed therapy-related myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) and seven solid neoplasms with an overall risk of 3 and 8 % at 5 and 10 years, respectively. Twenty-six patients eventually died during the follow-up. Overall survival at 10 years was 83 %. In conclusion, FCM regimen allows excellent long-lasting response in previously untreated patients with FL. The incidence of late events including histological transformation and secondary neoplasia is low but not negligible.
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Hallek M, Eichhorst BF (2004) Chemotherapy combination treatment regimens with fludarabine in chronic lymphocytic leukemia. Hematol J 5(Suppl 1):S20–S30
Flinn IW, Neuberg DS, Grever MR et al (2007) Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US intergroup trial E2997. J Clin Oncol 25:793–798
Czuczman MS, Koryzna A, Mohr A et al (2005) Rituximab in combination with fludarabine chemotherapy in low-grade or follicular lymphoma. J Clin Oncol 23:694–704
De la Cruz VF, Carrillo-Cruz E, Rodriguez MS et al (2014) Fludarabine, cyclophosphamide and rituximab as first-line treatment in patients with newly diagnosed follicular lymphoma. Eur J Haematol 93:469–475
Santini G, Chisesi T, Nati S et al (2004) Fludarabine, cyclophosphamide and mitoxantrone for untreated follicular lymphoma: a report from the non-Hodgkin’s lymphoma co-operative study group. Leuk Lymphoma 45:1141–1147
McLaughlin P, Hagemeister FB, Swan F et al (1994) Phase I study of the combination of fludarabine, mitoxantrone, and dexamethasone in low-grade lymphoma. J Clin Oncol 12:575–579
McLaughlin P, Hagemeister FB, Romaguera JE et al (1996) Fludarabine, mitoxantrone, and dexamethasone: an effective new regimen for indolent lymphoma. J Clin Oncol 14:1262–1268
Montoto S, Moreno C, Domingo-Doménech E et al (2008) High clinical and molecular response rates with fludarabine, cyclophosphamide and mitoxantrone in previously untreated patients with advanced stage follicular lymphoma. Haematologica 93:207–214
Federico M, Luminari S, Dondi A et al (2013) R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi. J Clin Oncol 31:1506–1513
Sacchi S, Marcheselli L, Bari A et al (2008) Secondary malignancies after treatment for indolent non-Hodgkin’s lymphoma: a 16-year follow-up study. Haematologica 93:398–404
Tam CS, Seymour JF, Prince HM et al (2006) Treatment-related myelodysplasia following fludarabine combination chemotherapy. Haematologica 91:1546–1550
Morrison VA, Rai KR, Peterson BL et al (2002) Therapy-related myeloid leukemias are observed in patients with chronic lymphocytic leukemia after treatment with fludarabine and chlorambucil: results of an intergroup study, cancer and leukemia group B 9011. J Clin Oncol 20:3878–3884
McLaughlin P, Estey E, Glassman A et al (2005) Myelodysplasia and acute myeloid leukemia following therapy for indolent lymphoma with fludarabine, mitoxantrone, and dexamethasone (FND) plus rituximab and interferon alpha. Blood 105:4573–4575
Carney DA, Westerman DA, Tam CS et al (2010) Therapy-related myelodysplastic syndrome and acute myeloid leukemia following fludarabine combination chemotherapy. Leukemia 24:2056–2062
Zhou Y, Tang G, Medeiros LJ et al (2012) Therapy-related myeloid neoplasms following fludarabine, cyclophosphamide, and rituximab (FCR) treatment in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. Mod Pathol 25:237–245
Pirani M, Marcheselli R, Marcheselli L et al (2011) Risk for second malignancies in non-Hodgkin’s lymphoma survivors: a meta-analysis. Ann Oncol 22:1845–1858
Xu Y, Wang H, Zhou S et al (2013) Risk of second malignant neoplasms after cyclophosphamide-based chemotherapy with or without radiotherapy for non-Hodgkin lymphoma. Leuk Lymphoma 54:1396–1404
Cheson BD, Horning SJ, Coiffier B et al (1999) Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol 17:1244
Gribben JG, Freedman AS, Woo SD et al (1991) All advanced stage non-Hodgkin’s lymphomas with a polymerase chain reaction amplifiable breakpoint of bcl-2 have residual cells containing the bcl-2 rearrangement at evaluation and after treatment. Blood 78:3275–3280
Estalilla OC, Medeiros LJ, Manning JT, Luthra R (2000) 5′-->3′ exonuclease-based real-time PCR assays for detecting the t(14;18)(q32;21): a survey of 162 malignant lymphomas and reactive specimens. Mod Pathol 13:661–666
Mantel NBD (1974) Evaluation of response-time data involving transient states: an illustration using heart-transplant data. J Am Stat Assoc 69:81–86
Hochster HS, Oken MM, Winter JN et al (2000) Phase I study of fludarabine plus cyclophosphamide in patients with previously untreated low-grade lymphoma: results and long-term follow-up—a report from the Eastern Cooperative Oncology Group. J Clin Oncol 18:987–994
Nastoupil LJ, Sinha R, Byrtek M et al (2015) Comparison of the effectiveness of frontline chemoimmunotherapy regimens for follicular lymphoma used in the United States. Leuk Lymphoma 56:1295–1302
Zinzani PL, Pulsoni A, Perrotti A et al (2004) Fludarabine plus mitoxantrone with and without rituximab versus CHOP with and without rituximab as front-line treatment for patients with follicular lymphoma. J Clin Oncol 22:2654–2661
Tsimberidou AM, McLaughlin P, Younes A et al (2002) Fludarabine, mitoxantrone, dexamethasone (FND) compared with an alternating triple therapy (ATT) regimen in patients with stage IV indolent lymphoma. Blood 100:4351–4357
Galimberti S, Luminari S, Ciabatti E et al (2014) Minimal residual disease after conventional treatment significantly impacts on progression-free survival of patients with follicular lymphoma: the FIL FOLL05 trial. Clin Cancer Res 20:6398–6405
López-Guillermo A, Cabanillas F, McLaughlin P et al (1998) The clinical significance of molecular response in indolent follicular lymphomas. Blood 91:2955–2960
López-Guillermo A, Cabanillas F, McLaughlin P et al (2000) Molecular response assessed by PCR is the most important factor predicting failure-free survival in indolent follicular lymphoma: update of the MDACC series. Ann Oncol 11(Suppl 1):137–140
Apostolidis J, Gupta RK, Grenzelias D et al (2000) High-dose therapy with autologous bone marrow support as consolidation of remission in follicular lymphoma: long-term clinical and molecular follow-up. J Clin Oncol 18:527–536
Arcaini L, Colombo N, Bernasconi P et al (2006) Role of the molecular staging and response in the management of follicular lymphoma patients. Leuk Lymphoma 47:1018–1022
Ladetto M, Lobetti-Bodoni C, Mantoan B et al (2013) Persistence of minimal residual disease in bone marrow predicts outcome in follicular lymphomas treated with a rituximab-intensive program. Blood 122:3759–3766
Rambaldi A, Carlotti E, Oldani E et al (2005) Quantitative PCR of bone marrow BCL2/IgH+ cells at diagnosis predicts treatment response and long-term outcome in follicular non-Hodgkin lymphoma. Blood 105:3428–3433
Hirayama Y, Ishitani K, Ota S et al (2014) Long-term survey of survival time, histological transformation, and secondary malignancies in Japanese patients with advanced-stage follicular lymphoma in the rituximab era: Hokkaido Hematology Study Group. Int J Hematol 100:281–289
Beiggi S, Johnston JB, Seftel MD et al (2013) Increased risk of second malignancies in chronic lymphocytic leukaemia patients as compared with follicular lymphoma patients: a Canadian population-based study. Br J Cancer 109:1287–1290
Travis LB, Gospodarowicz M, Curtis RE et al (2002) Lung cancer following chemotherapy and radiotherapy for Hodgkin’s disease. J Natl Cancer Inst 94:182–192
Moser EC, Noordijk EM, van Leeuwen FE et al (2006) Risk of second cancer after treatment of aggressive non-Hodgkin’s lymphoma; an EORTC cohort study. Haematologica 91:1481–1488
Hemminki K, Lenner P, Sundquist J, Bermejo JL (2008) Risk of subsequent solid tumors after non-Hodgkin’s lymphoma: effect of diagnostic age and time since diagnosis. J Clin Oncol 26:1850–1857
Keating MJ, O’Brien S, Lerner S et al (1998) Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy. Blood 92:1165–1171
Bains P, Al Tourah A, Campbell BA et al (2013) Incidence of transformation to aggressive lymphoma in limited-stage follicular lymphoma treated with radiotherapy. Ann Oncol 24:428–432
Conconi A, Ponzio C, Lobetti-Bodoni C et al (2012) Incidence, risk factors and outcome of histological transformation in follicular lymphoma. Br J Haematol 157:188–196
Giné E, Montoto S, Bosch F et al (2006) The Follicular Lymphoma International Prognostic Index (FLIPI) and the histological subtype are the most important factors to predict histological transformation in follicular lymphoma. Ann Oncol 17:1539–1545
Wagner-Johnston ND, Link BK, Byrtek M et al (2015) Outcomes of transformed follicular lymphoma in the modern era: a report from the National LymphoCare Study (NLCS). Blood 126:851–857
Montoto S, Davies AJ, Matthews J et al (2007) Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol 25:2426–2433
Solh M, Rai KR, Peterson BL et al (2013) The impact of initial fludarabine therapy on transformation to Richter syndrome or prolymphocytic leukemia in patients with chronic lymphocytic leukemia: analysis of an intergroup trial (CALGB 9011). Leuk Lymphoma 54:252–254
Marcus R, Imrie K, Belch A et al (2005) CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 105:1417–1423
Salles G, Seymour JF, Offner F et al (2011) Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 377:42–51
Rummel MJ, Niederle N, Maschmeyer G et al (2013) Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 381:1203–1210
Casulo C, Byrtek M, Dawson KL et al (2015) Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the National LymphoCare Study. J Clin Oncol 33:2516–2522
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Magnano, L., Montoto, S., González-Barca, E. et al. Long-term safety and outcome of fludarabine, cyclophosphamide and mitoxantrone (FCM) regimen in previously untreated patients with advanced follicular lymphoma: 12 years follow-up of a phase 2 trial. Ann Hematol 96, 639–646 (2017). https://doi.org/10.1007/s00277-017-2920-2
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DOI: https://doi.org/10.1007/s00277-017-2920-2