Epstein–barr virus-associated b-cell lymphoproliferative disorder in cll patients after treatment with fludarabine and cyclophosphamide followed by high-dose chemotherapy with autologous stem cell transplantation

Access through your institution Buy or subscribe Epstein–Barr virus (EBV)-associated B-lymphoproliferative disorder (BLPD) in the setting of autologous stem cells transplantation (ASCT) is

described mainly as case histories.1,2,3,4,5,6 The purine analogues as new treatment modalities with enhanced immunosuppressive effect have the capacity to promote EBV reactivation and

transformation to lymphoproliferative disorder as recently demonstrated.7,8,9 Moreover, this risk could theoretically be even more pronounced if ASCT follows the treatment with purines. We

report on two patients with CLL in whom EBV-BLPD developed after therapy with fludarabine monophosphate (Flu) and cycloclophosphamide (Cy) followed directly by ASCT. From 1998, in our

department, all patients with CLL with risk factors–defined as Rai stage III–IV or adverse cytogenetics, rapid doubling time, diffuse marrow infiltration pattern—entered the study in which

they were treated upfront according to the following protocol: Flu 25 mg/m2+Cy 250 mg/m2/3 days each month until morphological remission, then an attempt to mobilize PBPC by Cy 3 g/m2+G-CSF

and if successful (ie >2 × 106 CD34+cells/kg harvested), the patients proceeded directly to ASCT after conditioning with Cy (50 mg/kg for four consecutive days, i.e. 200 mg/kg total

dose). From 1998, 46 patients completed the protocol. Of these, 22 of them underwent ASCT. In 24 patients, the mobilization failed and they were treated with Flu–Cy only. In the group of

patients who completed the whole protocol, we unexpectedly experienced clustering of two cases of EBV-BLPD. Patient 1 was a 57-year-old male diagnosed as having CLL stage I Rai in November

1996. In August 1998, disease progression was noted and because of the rapid doubling time the patient entered the Flu–Cy–ASCT protocol. Cytogenetic analyses revealed normal karyotype; EBV

was seropositive. A nodular PR was attained after four cycles of Flu–Cy and 3 months later, he was successfully mobilized with the yield of 11.52 × 106 CD34+ cells/kg. High-dose Cy followed

by PBSC infusion started 1 month after harvest. Haematological recovery was fast and uneventful and on restaging the attainment of complete remission according to NCI criteria10 was

established. Furthermore, negative FACS and IgH rearrangement studies were consistent with immunophenotypic and molecular CR. At 5 months after ASCT, he developed progressive generalized

adenomegaly and splenomegaly accompanied with fever. One cycle of CHOP chemotherapy was urgently applied because of presumed CLL relapse. However, the patient deteriorated rapidly and died

on day +170. The bone marrow (BM) as well as FACS analysis showed no signs of CLL. Lymph node biopsies allowed a histological diagnosis of post-transplant lymphoproliferative disorder of

polymorphic type. Immunohistochemistry studies demonstrated B-cell phenotype, monoclonality and positive stain for EBV-LMP1 (latent membrane protein; 1:25 monoclonal mouse antibody, clones

CS 1-4, Dako, Glostrup, Denmark). The diagnosis of EBV-BPLD was further supported by positive PCR (DNA from PB, BM, lymph node) using different sets of primers for Epstein–Barr encoded RNA

(EBER) and Epstein–Barr nuclear antigen (EBNA).11,12 At autopsy, there was no evidence of CLL and all histological findings from enlarged lymph nodes were in agreement with the diagnosis of

polymorphic type of EBV-LPD. Patient 2 was a male aged 49 years with Rai stage II CLL with a normal karyotype. Serological tests for EBV were positive. The patient was treated from March

1999 according to the protocol, and after four cycles of Flu–Cy he entered nodular PR, and 2 months after the last chemotherapy, he was successfully mobilized (2.73 × 106 CD 34+ cells/kg).

High-dose chemotherapy with stem cell reinfusion was given immediately with an uneventful post-transplant period. The restaging 1 month after transplantation showed partial nodular

remission, with no sign of disease in lymph nodes, spleen, and liver. At 2 months after ASCT, mediastinal and cervical adenomegaly developed abruptly. BM was negative on cytology and

residual CLL nodules corresponded histologically with continuing nodular PR. Immunophenotypic analyses corroborated the presence of residual disease only. Surprisingly, lymph node biopsy

showed a B-lineage LPD of monomorphic, diffuse large cell-type. An immunohistochemistry stain for EBV-LPD was inconclusive, but EBER and EBNA were again detected by PCR as in the previous

case. The adenomegaly rapidly progressed to respiratory insufficiency requiring ventilatory support and the patient died on day +75 after ASCT, before the results of the tests were

available. Autopsy was not performed. Serological tests for EBV in both the patients were not repeated after ASCT. This is a preview of subscription content, access via your institution

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  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Haematology and Oncology Charles University Hospital, Plzeň Pilsen, Czech Republic P Jindra,

 V Koza, V Vozobulová, K Černá, M Karas, D Lysák & M Švojgrová * Sikl's Department of Pathology, Charles University Hospital, Plzeň Pilsen, Czech Republic L Boudová Authors * P

Jindra View author publications You can also search for this author inPubMed Google Scholar * V Koza View author publications You can also search for this author inPubMed Google Scholar * L

Boudová View author publications You can also search for this author inPubMed Google Scholar * V Vozobulová View author publications You can also search for this author inPubMed Google

Scholar * K Černá View author publications You can also search for this author inPubMed Google Scholar * M Karas View author publications You can also search for this author inPubMed Google

Scholar * D Lysák View author publications You can also search for this author inPubMed Google Scholar * M Švojgrová View author publications You can also search for this author inPubMed 

Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Jindra, P., Koza, V., Boudová, L. _et al._ Epstein–Barr virus-associated B-cell

lymphoproliferative disorder in CLL patients after treatment with fludarabine and cyclophosphamide followed by high-dose chemotherapy with autologous stem cell transplantation. _Bone Marrow

Transplant_ 31, 951–952 (2003). https://doi.org/10.1038/sj.bmt.1704026 Download citation * Received: 27 September 2002 * Accepted: 22 October 2002 * Published: 15 May 2003 * Issue Date: 01

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