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Blood, 15 June 2005, Vol. 105, No. 12, pp. 4573-4575. Prepublished online as a Blood First Edition Paper on March 1, 2005; DOI 10.1182/blood-2004-08-3035. This Article Abstract Full Text (PDF) All Versions of this Article: 2004-08-3035v1 105/12/4573    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by McLaughlin, P. Articles by Hagemeister, F. B. Search for Related Content PubMed PubMed Citation Articles by McLaughlin, P. Articles by Hagemeister, F. B. Related Collections Neoplasia Clinical Trials and Observations Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS Myelodysplasia and acute myeloid leukemia following therapy for indolent lymphoma with fludarabine, mitoxantrone, and dexamethasone (FND) plus rituximab and interferon alpha Peter McLaughlin, Elihu Estey, Armand Glassman, Jorge Romaguera, Felipe Samaniego, Ana Ayala, Kimberly Hayes, Anne Marie Maddox, H. Alejandro Preti, and Fredrick B. Hagemeister From the Departments of Lymphoma/Myeloma, Leukemia, Hematopathology, and Laboratory Medicine, University of Texas M.D. Anderson Cancer Center, Houston, TX; and University of Arkansas Medical School, Little Rock, AR.    Abstract Top Abstract Introduction Patients and methods Results Discussion References   Treatment-related myelodysplasia (t-MDS) occurs less frequently with the nucleoside analogs than with DNA-damaging agents such as alkylators or topoisomerase II inhibitors. In a chemoimmunotherapy trial conducted between 1997 and 2003 in patients with stage IV indolent lymphoma, 202 patients were treated and 8 have developed MDS between 1 and 5 years after therapy, including 4 who received only fludarabine, mitoxantrone, and dexamethasone (FND) for 6 to 8 courses, with or without rituximab, followed by interferon alpha (IFN-). Complex cytogenetic abnormalities were present in all patients. Abnormalities of chromosome 7 were present in 6 of the 8 patients, 3 of whom received only FND ± rituximab and IFN-. The abnormalities of chromosome 7 were monosomy 7 in 4 patients (1 of which had add 7p in the remaining chromosome); 1 del 7q; and 1 der 7. MDS with features classically associated with DNA-damaging agents can occur following therapy with FND, with or without rituximab, and IFN-. (Blood. 2005;105:4573-4575)    Introduction Top Abstract Introduction Patients and methods Results Discussion References   Alkylating agent therapy does not cure patients with indolent lymphoma and can result in late morbidity such as treatment-related myelodysplasia (t-MDS).1 Alternatives to alkylators include biologic agents and purine nucleoside analogs, which have a low reported frequency of t-MDS.2 The combination of fludarabine, mitoxantrone, and dexamethasone (FND) is an effective regimen for patients with indolent lymphoma.3-5 Recently, we combined rituximab with FND, either concurrently (R-FND) or sequentially (FNDR), followed by interferon alpha (IFN-) maintenance, for patients with stage IV indolent lymphoma. Preliminary reports have described good short-term safety and efficacy of this program, including a 3-year failure-free survival rate of greater than 65% and a 3-year survival rate of 95%.6,7 The current report describes the occurrence of t-MDS in 8 patients in this trial.    Patients and methods Top Abstract Introduction Patients and methods Results Discussion References   Patients From 1997 to 2003, 202 evaluable patients with stage IV indolent lymphoma were treated on this trial; all signed informed consent in accordance with the University of Texas M.D. Anderson Cancer Center institutional review board regulations and the Declaration of Helsinki. With a median follow-up of 42 months (range, 6-70 months), 8 patients have been diagnosed with t-MDS or treatment-related acute myeloid leukemia (t-AML). The lymphoma protocol included FND for the majority of patients, either concurrently with rituximab or followed by rituximab. Patients also received IFN- maintenance. The doses of FND were as follows: fludarabine 25 mg/m2 intravenously days 1 to 3, mitoxantrone 10 mg/m2 intravenously on day 1, and dexamethasone 20 mg orally or intravenously days 1 to 5, every 4 weeks for 8 cycles. In R-FND, rituximab 375 mg/m2 was given intravenously on days 1 and 8 of course 1; in courses 2 to 5, it was given on day 1 only. Responding patients received maintenance with 3 million units/m2 interferon alpha 2b subcutaneously daily on days 2 to 14 and dexamethasone 40 mg orally on days 1 to 3, given monthly for 1 year. In FNDR, rituximab 375 mg/m2 was given intravenously once monthly for 6 doses, starting at month 12. Patients with follicular lymphoma without BCL2 gene rearrangement8 received alternating triple therapy (ATT) with concurrent rituximab, followed by maintenance IFN-. ATT is a rotation of 3 regimens, CHOD-Bleo (cyclophosphamide, doxorubicin, vincristine, dexamethasone, bleomycin), ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin), and NOPP (mitoxantrone, vincristine, prednisone, procarbazine), for 12 courses (3-4 courses of each); doses have previously been reported.4 Six doses of rituximab (375 mg/m2) were included with ATT: 2 in courses 1 and 3 and 1 dose in courses 4 and 6. Diagnosis of t-MDS and t-AML The diagnosis of t-MDS, using World Health Organization criteria,9 was considered when the bone marrow contained excess blasts (> 5%) or was dysplastic or when unexpected cytopenias occurred. Marrow assessment was done pretreatment and every 3 to 6 months if initially positive. However, neither pretreatment nor follow-up cytogenetic monitoring was part of the study design; cytogenetics was performed only when MDS was suspected. Cytogenetic data were reported using the International System for Human Cytogenetic Nomenclature (ISCN).10 Statistical analysis The time to development of t-MDS was measured from the time of lymphoma therapy until the t-MDS diagnosis. The actuarial incidence was calculated by the method of Kaplan and Meier.11    Results Top Abstract Introduction Patients and methods Results Discussion References   Eight of 202 patients developed t-MDS or t-AML (crude incidence 4%), as categorized in Table 1. In all cases, the t-MDS was first suspected based on cytopenias (n = 7) or overt leukemia (n = 1) on routine hematology survey. The median age of the MDS patients was 57 years (range, 42-75 years), with 3 males and 5 females. MDS was diagnosed a median of 32 months after the lymphoma therapy (range, 15-59 months). Figure 1 shows the actuarial incidence of t-MDS. View this table: [in this window] [in a new window]   Table 1.. Features of myelodysplasia and/or leukemia   The initial lymphoma treatment for these 8 patients included R-FND for 5, FNDR for 1, and ATT+R for 2 (Table 1). Two R-FND patients who attained only partial remission received salvage therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) before developing t-MDS. The other 6 patients attained complete remission (CR) with the lymphoma therapy. One patient was still on IFN- maintenance when MDS was diagnosed, 5 others were off therapy 12 to 40 months. Five patients were in ongoing CR from the lymphoma standpoint when the t-MDS was diagnosed. All had cytogenetic abnormalities commonly seen following alkylating agent therapy, including abnormalities of chromosome 5 and/or 7 in 6 patients (Table 1). Two patients had del(12)(p11p12). None had abnormalities of 11q23. The median survival after the development of AML or MDS was 9 months (range, 2-17 months). View larger version (14K): [in this window] [in a new window]   Figure 1.. Actuarial incidence of t-MDS. (A) Actuarial incidence of t-MDS (and 95% confidence interval [CI]) for the entire study population. At 4 years the risk is 3% (CI 1%-7%). (B) Actuarial incidence of t-MDS by treatment arm. At 4 years the risk (and 95% CI) by regimen is ATT, 3% (0.4%-21%); FNDR, 1% (0.2%-9%); and R-FND, 4% (1%-13%). When the 2 FND arms are pooled, the risk is 3% (1%-7%).      Discussion Top Abstract Introduction Patients and methods Results Discussion References   Management options for indolent lymphoma are numerous. The risks of the lymphoma need to be weighed against those of the therapy. In our stage IV protocol, a risk-adapted approach was taken, with ATT reserved for those considered to be poor risk.8 MDS has been previously described following ATT.4 The risk of t-MDS in patients who received only FND, IFN-, and rituximab was expected to be minimal. MDS has been described rarely following IFN-,12 never with rituximab, and only infrequently with the nucleoside analogs or other antimetabolites.2,13-16 Mitoxantrone is an intercalator and a topoisomerase II inhibitor, which has only infrequently been associated with MDS.17 MDS can occur following CHOP-like therapy,18 which is a potentially confounding factor in 2 of our patients who received R-CHOP salvage therapy; it is plausible to suspect that the primary therapy contributed to the risk of MDS in those cases.19 The cytogenetic abnormalities in these patients were complex (Table 1). Six patients had abnormalities of chromosome 7, as commonly observed following exposure to DNA-damaging agents. Two patients had del(12)(p11p12). Abnormalities of chromosome 12 are seen in a broad spectrum of hematologic malignancies, including in secondary leukemias after mutagenic agents, and are generally associated with a poor outlook.20 The 11q23 abnormality, classically observed with topoisomerase II inhibitors, was not observed in our 8 cases.21 Fludarabine inhibits the DNA repair process, thereby enhancing the antineoplastic effect of an agent like cyclophosphamide.22 This synergism has been exploited successfully in the treatment of chronic lymphocytic leukemia (CLL); an analogous synergism may exist for fludarabine and mitoxantrone. But there could also be augmented adverse effects. MDS has been reported following fludarabine plus chlorambucil for CLL.23 Antitumor synergism exists between rituximab and several chemotherapeutic agents,24 but rituximab selectively targets B cells so an impact on myeloid cells would not be expected. The risk of t-MDS is calculated variably in the literature: crude incidence figures (4% in our report) underestimate the risk, whereas Kaplan-Meier plots (as in Figure 1) overestimate the risk.25 Overall, up to 10% of lymphoma patients treated with standard chemotherapy may develop t-MDS.25 Prolonged exposure to cytotoxic agents increases the risk. Patients in the current report received 6 to 8 courses of FND or 9 to 12 courses of ATT. Shorter-duration therapy might lessen the risk. Others who use 4 to 6 courses of FND and variants in the front-line setting have not noted a high frequency of t-MDS (E. Montserrat, J. Seymour, V. Jain, P.L. Zinzani, W. Hiddemann, S. Gregory, personal communications, July 2004). Since t-MDS following FND with or without rituximab and IFN- appears to be infrequent, routine cytogenetic monitoring may not be warranted. But based on the current report, t-MDS occurring 1 to 5 years after therapy must be considered a risk of FND or R-FND plus IFN- therapy, particularly if protracted treatment is given.    Acknowledgements   The authors thank Joyce Palmer-Brown for preparation and editing of the manuscript and Mark Hess for the Kaplan-Meier curves.    Footnotes   Submitted August 5, 2004; accepted January 12, 2005. Prepublished online as Blood First Edition Paper, March 1, 2005; DOI 10.1182/blood-2004-08-3035. Supported in part by National Cancer Institute Core Grant CA16672 awarded to the University of Texas M.D. Anderson Cancer Center and by clinical grants from Genentech Inc, Integrated Therapeutics, and OSI. An Inside Blood analysis of this article appears in the front of this issue. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: Peter McLaughlin, Department of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 429, Houston, TX; e-mail address: pmclaugh{at}mdanderson.org.    References Top Abstract Introduction Patients and methods Results Discussion References   Pedersen-Bjergaard J, Ersbøll J, Sørensen HM, et al. Risk of acute nonlymphocytic leukemia and preleukemia in patients treated with cyclophosphamide for non-Hodgkin's lymphomas. Ann Intern Med. 1985;103: 195-200.[Medline] [Order article via Infotrieve] Cheson BD, Vena DA, Barrett J, Freidlin B. Second malignancies as consequence of nucleoside analog therapy for chronic lymphoid leukemias. J Clin Oncol. 1999;17: 2454-2460.[Abstract/Free Full Text] McLaughlin P, Hagemeister FB, Romaguera JE, et al. Fludarabine, mitoxantrone, and dexamethasone: an effective new regimen for indolent lymphoma. J Clin Oncol. 1996;14: 1262-1268.[Abstract/Free Full Text] Tsimberidou AM, McLaughlin P, Younes A, et al. Fludarabine, mitoxantrone, dexamethasone compared with an alternating triple therapy regimen in patients with stage IV indolent lymphoma. Blood. 2002;100: 4351-4357.[Abstract/Free Full Text] Zinzani PL, Pulsoni A, Perrotti A, et al. Fludarabine plus mitoxantrone with and without rituximab versus CHOP with and without rituximab as frontline treatment for patients with follicular lymphoma. J Clin Oncol. 2004;22: 2654-2661.[Abstract/Free Full Text] McLaughlin P, Hagemeister FB, Rodriguez MA, et al. Safety of fludarabine, mitoxantrone, and dexamethasone combined with rituximab in the treatment of stage IV indolent lymphoma. Semin Oncol. 2000;27(suppl 12): 37-41.[Medline] [Order article via Infotrieve] McLaughlin P, Rodriguez MA, Hagemeister FB, et al. Stage IV indolent lymphoma: a randomized study of concurrent vs sequential use of FND chemotherapy (fludarabine, mitoxantrone, dexamethasone) and rituximab monoclonal antibody therapy, with interferon maintenance [abstract]. Proc ASCO. 2003;22: 564. Lopez-Guillermo A, Cabanillas F, McDonnell TI, et al. Correlation of bcl-2 rearrangement with clinical characteristics and outcome in indolent follicular lymphoma. Blood. 1999;93: 3081-3087.[Abstract/Free Full Text] Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100: 2292-2302.[Abstract/Free Full Text] Mitelman F, ed. ISCN: An International System for Human Cytogenetic Nomenclature. Basel, Switzerland: Karger; 1995. Kaplan FL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53: 457-481.[CrossRef] Kampmeier P, Spielberger R, Dickstein J, et al. Increased incidence of second neoplasms in patients treated with interferon 2b for hairy cell leukemia: a clinicopathologic assessment. Blood. 1994;83: 2931-2938.[Abstract/Free Full Text] Orchard JA, Bolam S, Oscier DG. Association of myelodysplastic changes with purine analogues. Br J Haematol. 1998;100: 677-679.[CrossRef][Medline] [Order article via Infotrieve] Kroft SH, Tallman MS, Shaw JM, Thangavelu M, Peterson LC. Myelodysplasia following treatment of chronic lymphocytic leukemia (CLL) with 2-chlorodeoxyadenosine (2CdA) [letter]. Leukemia. 1997;11: 170.[CrossRef][Medline] [Order article via Infotrieve] Todd SA, Morris TCM, Alexander HD. Myelodysplasia terminating in acute myeloid leukemia in a hairy cell leukemia patient treated with 2-deoxy-coformycin. Leuk Lymphoma. 2002;43: 1343-1344.[Medline] [Order article via Infotrieve] Abe M, Tanaka Y, Shinohara M, et al. Myelodysplastic syndrome/acute myelogenous leukaemia related to adjuvant chemotherapy with oral pyrimidine anti-metabolites. Br J Haematol. 2000;111: 711-715.[CrossRef][Medline] [Order article via Infotrieve] Saso R, Kulkarni S, Mitchell P, et al. Secondary myelodysplastic syndrome/acute myeloid leukaemia following mitoxantrone-based therapy for breast carcinoma. Br J Cancer. 2000;83: 91-94.[CrossRef][Medline] [Order article via Infotrieve] André M, Mounier N, Leleu X, et al. Second cancers and late toxicities after treatment of aggressive non-Hodgkin lymphoma with the ACVBP regimen: a GELA cohort study on 2837 patients. Blood. 2004;103: 1222-1228.[Abstract/Free Full Text] Pedersen-Bjergaard J, Pedersen M, Myhre J, Geisler C. High risk of therapy-related leukemia after BEAM chemotherapy and autologous stem cell transplantation for previously treated lymphomas is mainly related to primary chemotherapy and not to the BEAM-transplantation procedure. Leukemia. 1997;11: 1654-1660.[CrossRef][Medline] [Order article via Infotrieve] Streubel B, Sauerland C, Heil G, et al. Correlation of cytogenetic, molecular cytogenetic, and clinical findings in 59 patients with ANLL or MDS and abnormalities of the short arm of chromosome 12. Br J Haematol. 1998;100: 521-533.[CrossRef][Medline] [Order article via Infotrieve] Smith MA, Rubinstein L, Anderson JR, et al. Secondary leukemia or myelodysplastic syndrome after treatment with epipodophyllotoxins. J Clin Oncol. 1999;17: 569-577.[Abstract/Free Full Text] Yamauchi T, Nowak BJ, Keating MJ, Plunkett W. DNA repair initiated in chronic lymphocytic leukemia lymphocytes by 4-hydroperoxycyclophosphamide is inhibited by fludarabine and clofarabine. Clin Can Res. 2001;7: 3580-3589.[Abstract/Free Full Text] Morrison VA, Rai KR, Peterson BL, et al. 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. 2002;20: 3878-3884.[Abstract/Free Full Text] Demidem A, Lam T, Alas S, et al. Chimeric anti-CD20 (IDEC-C2B8) monoclonal antibody sensitizes a B cell lymphoma cell line to cell killing by cytotoxic drugs. Cancer Biother Radiopharm. 1997;12: 177-186.[Medline] [Order article via Infotrieve] Armitage JO, Carbone PP, Connors JM, et al. Treatment-related myelodysplasia and acute leukemia in non-Hodgkin's lymphoma patients. J Clin Oncol. 2003;21: 897-906.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Flu redux and RIT: friendly fire in the treatment of low-grade lymphoma Leo I. Gordon Blood 2005 105: 4543-4544. [Full Text] [PDF] This article has been cited by other articles: J. W. Friedberg Secondary malignancies after therapy of indolent non-Hodgkin's lymphoma Haematologica, March 1, 2008; 93(3): 336 - 338. [Full Text] [PDF] S. Montoto, C. Moreno, E. Domingo-Domenech, C. Estany, A. Oriol, A. Altes, J. Besalduch, C. Pedro, S. Gardella, L. Escoda, et al. 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[Abstract] [Full Text] [PDF] This Article Abstract Full Text (PDF) All Versions of this Article: 2004-08-3035v1 105/12/4573    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by McLaughlin, P. Articles by Hagemeister, F. B. Search for Related Content PubMed PubMed Citation Articles by McLaughlin, P. Articles by Hagemeister, F. B. Related Collections Neoplasia Clinical Trials and Observations Related Article in Blood Online Social Bookmarking                   What's this?

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