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
- Select a language for the TTS:
- UK English Female
- UK English Male
- US English Female
- US English Male
- Australian Female
- Australian Male
- Language selected: (auto detect) - EN
Play all audios:
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.
Anyone you share the following link with will be able to read this content: