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Mar 13, 2008 - Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu). Fludarabine combination therapy for ...
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1781 with leukemia using the MTT assay with improved culture conditions. Blood 1990; 76: 2327–2336. 7 Novotny JR, Nu¨ckel H, Du¨hrsen U. Correlation between expression of CD56/NCAM and severe leukostasis in hyperleukocytic acute myelomonocytic leukaemia. Eur J Haematol 2006; 76: 299–308.

8 Haferlach T, Kohlmann A, Schnittger S, Dugas M, Hiddemann W, Kern W et al. AML M3 and AML M3 variant each have a distinct gene expression signature but also share patterns different from other genetically defined AML subtypes. Genes Chromosomes Cancer 2005; 43: 113–127.

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

Fludarabine combination therapy for follicular lymphoma followed by acute myeloid leukemia: two further case records Leukemia (2008) 22, 1781–1782; doi:10.1038/leu.2008.51; published online 13 March 2008

follow-up were censored at the time of the last visit. The two cases complicated by secondary myeloid disorder were observed and briefly described.

The risk of secondary myelodysplastic syndromes/acute myeloid leukemia (tMDS/AML) after lymphoma treatment is still a matter of discussion, but a recent review concluded that it may reach 10% within 10 years of primary therapy.1 Fludarabine-containing regimens have been reported to increase the risk of secondary myeloid neoplasia, particularly when combined with alkylating agents.2 From our series of 156 lymphoma patients, we identified 19 consecutive patients who had received combination chemotherapy containing fludarabine (25 mg m2 for days 1–3), plus novantrone (10 mg m2 for day 1) and dexamethasone (20 mg for days 1–5 every 4 weeks) (FND) or fludarabine (25 mg m2 for days 1–3) and cyclophosphamide (250 mg m2 for days 1–3), with or without rituximab (r). Clinical characteristics of the selected cohort are reported in Table 1. The mean and median follow-up for the entire group was 53 and 50 months, respectively. Two patients who were lost to

Table 1

Case report Case 1. The patient, a 75-year-old man, was diagnosed as having follicular lymphoma grade II, Stage IVA, in July 2001. After informed consent, he entered in a protocol under which he received four cycles of FND-r. He attained complete (molecular) remission and was regularly followed up to June 2005, when he became febrile and was found pancytopenic. Bone marrow biopsy and cytologic examination showed hypoplasia with 20% myeloid blast cells and dysplastic erythroid features. Cytogenetic analysis showed normal karyotype in 10% of metaphases and 90% metaphases with 5,9 and 17 monosomy, extra material on short arm of chromosome 10 and 13, deletion of long arm of chromosome 20 and two markers (46, XY/45, XY; 5, 9, 17, 13p þ , 10p þ , del20q11, þ mar, þ mar). He received lowintensity antileukemic therapy and died 2 months later.

Patients’ clinical characteristics

No.

Age (years)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

55 31 45 71 65 58 59 56 51 74 63 74 65 75 54 65 76 64 67

Sex

Diagnosis

F-Therapy

Other therapies

Female Female Female Female Male Female Male Female Male Female Male Male Male Female Male Female Female Male Male

FCL FCL LPC FCL FCL FCL FCL FCL FCL SMZL FCL FCL CLL/SLL CLL SMZL LBCL CLL/SLL FCL CLL/SLL

FND  4+r  4 FND  4+r  4 FND  4 FND  4+r  4 FND  4+r  4 FND  4+r  4 FND  4+r  4 FND  4+r  4 FND  4+r  4 FND  1+r  1 FND  4+r  4 FND  4+r  4 r-FC  6 r-FC  2 FND  4+r  4 FND  6 r-FC  1 FD  3 r-FC  6

r-CHOP  6, A-INF r-CHOP  6, ABMT CVP  3, CHOP  6, A-INF CHOP  6+r  4, RT, r-CHOP  6* F CHOP  6 CHOP  6 CHOP  6, r  6, HDCTX r-CHOP  6 Splenectomy r-CHOP  4, RT F Chlor, CVP, F Chlor, F Splenectomy F Chlor, F Micep+r  4 CVP, Chlor, F, r-CHOP  8

Outcome CR, r-maintenance Relapse, W and W CR Death with FUO CR Relapse, in observation CR CR, AML PR, lost in follow-up PR CR CR, AML PR PD PR CR, lost in follow-up PD, sudden cardiac death PD, NSCLC PD

OS 96+ 80+ 80+ 76 73+ 66+ 66+ 36 18 (?) 26+ 99+ 50 56+ 32 36+ 17 (?) 23 48 49+

Abbreviations: ABMT, autologous bone marrow transplantation; A-INF, alpha interferon; AML, acute myeloid leukemia; C, cyclophosphamide; Chlor, chlorambucile; CHOP, cyclophosphamide, adryamicin, vincristine, prednisone; CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; CR, complete remission; CVP, cyclophosphamide vincristine prednisone; D, dexamethasone; F, fludarabine; FCL, follicular cell lymphoma; FUO, fever unknown origin; HDCTX, high-dose cyclophosphamide; LBCL, large cell B-lymphoma; LPC, lymphoplasmacytic lymphoma; N, novantrone; OS, overall Survival; PD, progressive disease; PR, partial remission; r, rituximab; RT, radiation therapy; SMZL, splenic marginal zone lymphoma; W and W, watch and wait. *With lyposomial doxorubicin. Data in bold indicate patients who developed acute myeloid leukemia. Leukemia

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Case 2. The patient, a 56-year-old woman, was diagnosed as having follicular lymphoma grade II, stage IVA, in April 2004. She received four FND-r cycles after which, on the basis of computed tomography and positron emission tomography restaging, residual disease was observed in the abdomen. She received further chemotherapy in an attempt to induce complete remission for stem cell collection and eventual autologous bone marrow transplantation. In September 2005, she completed four cyclophosphamide, adryamicin, vincristine and prednisone cycles plus a further four doses of rituximab, but bcl-2 bone marrow molecular positivity was induced to give two further doses of rituximab. In January 2006, molecular remission was obtained and high-dose cyclophosphamide plus growth factor were given, but the patient did not mobilize appreciable amounts of CD34 þ cells, so it was decided to continue with rituximab every 3 months. In January 2007, pancytopenia was observed with blast cells in peripheral blood. Bone marrow biopsy showed marked dysplastic changes, 20% CD34 þ blast cells and increased Factor VIII þ large elements. Cytologic examination showed 60% undifferentiated Sudan black negative blast cells. Cytogenetic analysis showed normal karyotype. She underwent induction chemotherapy without obtaining remission. Second-line chemotherapy induced response, and she underwent unrelated donor bone marrow transplantation but died of acute graft versus host disease in March 2007. Comment The reported incidence of secondary myeloid disorders following fludarabine-containing regimens, which has been reported to be 2.7%,3 4%4 and 7.3%,5 in our series, approached 11%. A period of 44 and 33 months to tAML was comparable to previous observations. Although in patient 2, cyclophosphamide, adryamicin, vincristine and prednisone, and HDCTX may have contributed to AML, in patient 1 as few as four front-line FND-r were followed by leukemic evolution with the complex cytogenetic abnormalities commonly seen in tAML.6 Base line normal hemogram and morphologic and karyotype analysis performed at the time of initial staging rule out a possible preexisting bone marrow disease. In a large randomized comparative trial of fludarabine and novantrone versus cyclophosphamide, adryamicin, vincristine and prednisone with and without rituximab, fludarabine and novantrone arm showed higher rates of complete remission and no cases of secondary myelodysplastic syndromes/acute myeloid leukaemia.7 However, this superiority did not translate into both progression-free survival and overall survival, and follow-up was too short (median 19 months, range 9–37) to detect eventual therapy-related myeloid disorders.

Follicular Lymphoma International Prognostic Index (FLIPI) is an accepted method to predict the outcome in different risk groups.8 Patient 1 had FLIPI score 3 (high risk), with an expected 5-year OS of 52.5%, whereas patient 2 had FLIPI score 2 (intermediate risk) with an expected 5-year OS of 77.6%. By literature review and in our experience, leukemic risk after FND-r is not negligible and this would stimulate the careful evaluation of the benefit/risk ratio in selecting treatment options for chronic lymphoproliferative disorders.

P Bernardeschi1, G Fiorentini1, P Dentico1, S Rossi1, G Turrisi1, A Del Conte1, PG Giannessi1, G Giustarini2 and I Montenora3 1 Oncologia e Oncoematologia, Ospedale S. Giuseppe Empoli, Empoli, Italy; 2 Anatomia Patologica, Ospedale S. Giuseppe Empoli, Empoli, Italy and 3 Laboratorio Analisi, Ospedale S. Giuseppe Empoli, Empoli, Italy E-mail: [email protected] References 1 Armitage JO, Carbone PP, Connors JM, Levine A, Bennett JM, Kroll S. Treatment-related myelodysplasia and acute leukemia in non-Hodgkin’s lymphoma patients. J Clin Oncol 2003; 21: 897–906. 2 Morrison VA, Rai KR, Peterson B, Kolitz JE, Elias L, Appelbaum FR 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. 3 Au WY, Chan LC, Liang R, Kwong YL. Myelodysplastic syndrome and acute myeloid leukemia after treatment with fludarabine, mitoxantrone, and dexamethasone. Am J Hematol 2006; 81: 471–473. 4 McLaughlin P, Estey E, Glassman A, Romaguera J, Samaniego F, Ayala A et al. Myelodysplasia and acute myeloid leukemia following therapy for indolent lymphoma with fludarabine, mitoxantrone, and dexamethasone (FND) plus rituximab and interferon alpha. Blood 2005; 105: 4573–4575. 5 Constantine S, Tam CS, Seymour JF, Prince HM, Kenealy M, Wolf M et al. Treatment-related myelodysplasia following fludarabine combination chemotherapy. Haematologica 2006; 91: 1546–1550. 6 Le Beau MM, Albain KS, Larson RA, Larson RA, Vardiman EM, Davis EM et al. Clinical and cytogenetic correlations in 63 patients with therapy-related myelodysplastic syndromes and acute nonlymphocytic leukemia: further evidence for characteristic abnormalities of chromosomes no. 5 and 7. J Clin Oncol 1986; 4: 325–345. 7 Zinzani PL, Pulsoni A, Perrotti A, Soverini S, Zaia F, De Renzo 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. 8 Solal-Celigny P, Roy P, Colombat P, White J, Armitage JO, Arranz-Saez R et al. Follicular lymphoma international prognostic index. Blood 2004; 104: 1258–1265.

Successful treatment of multicentric Castleman’s disease with combined immunochemotherapy in an AIDS patient with multiorgan failure

Leukemia (2008) 22, 1782–1785; doi:10.1038/leu.2008.54; published online 1 May 2008

Here we describe the complicated course of a 33-year-old African male with AIDS, with multiorgan failure due to multicentric Castleman’s disease (MCD). Leukemia

Multicentric Castleman’s disease is a generalized lymphoproliferative disorder with poor prognosis. It is highly associated with HIV and human herpes virus-8 (HHV-8) infection. Overall mortality in HIV-positive patients is 70–85%, with a median survival of 8–14 months. A total of 15–20% develop intermediate- to high-grade non-Hodgkin lymphoma most commonly of the immunoblastic type.1–3 MCD occurs