To the Editor:

We write to report the development of peripheral T-cell lymphoma following therapy for B-cell lymphoma with the monoclonal antibody anti-CD20 (Rituximab) in the trial recently published inBlood.1 The patient was a 59-year-old man of Anglo-Asian extraction who presented in 1992 with generalized lymphadenopathy and constitutional B symptoms. Excision biopsy yielded a diagnosis of high-grade B-cell lymphoma, polymorphic centroblastic type (Kiel), diffuse large B-cell lymphoma (ILSG), the immune phenotype being CD20+, CD79α+, Ig A+, Epstein-Barr virus (EBV), CD3, CD2. Clinical remission, with persistent mediastinal abnormality, was achieved with cyclical combination chemotherapy. The first recurrence (August 1993) was treated with further induction chemotherapy, consolidated with high-dose therapy with peripheral blood progenitor cell rescue. The second (November 1996) was treated with Rituximab as described,1 to partial remission consolidated with irradiation, both recurrences having been shown on excision biopsy to have the same histological and immunological appearance. Fifteen months after treatment with Rituximab, the patient developed rapidly enlarging cervical lymphadenopathy with radiological evidence of progression at other sites. Excision biopsy specimen showed an entirely different pathological picture of diffuse high-grade peripheral T-cell lymphoma of pleomorphic medium cell type (Kiel), peripheral T-cell lymphoma, not otherwise specified [ILSG]. There was a loosely packed infiltrate of small- to medium-sized moderately pleomorphic lymphoid blast cells. The immune phenotype was CD2+, CD3+, TCRβ+, CD4+ CD20, CD79α, CD8, and TDT. Cytotoxic granule–associated protein was absent as detected by TIA1. Thus, the change in type of lymphoma was unequivocal. Palliative chemotherapy was initiated, but only transiently effective, with further progression and death occurring within 3 months. In summary, the patient had B-cell lymphoma, repeatedly responsive to cytotoxic therapy and then anti–B-cell antibody therapy, but died following the development of T-cell lymphoma.

Repeat biopsy in patients with recurrent or progressive large cell lymphoma is not routinely undertaken; hence, the frequency of phenotype change is unknown. However, it is extremely uncommon in follicular lymphoma at St Bartholomew’s Hospital2 where a rigorous rebiopsy policy is followed.

In a different setting, an association between T-cell imunosuppression and the development of B-cell non-Hodgkin’s lymphoma has been described under circumstances of idiopathic or iatrogenic suppression and is usually related to EBV.3,4The association between B-cell immunosuppression and lymphoma has been found only amongst B-cell immunodeficiency and has been of T-lymphoblastic type.

The case reported does not fit these patterns, but draws further attention to the possibility, raised previously,5 that the appearance of T-cell lymphoma may in some way be related to anti–B-cell antibody therapy. Rituximab is a monoclonal human-mouse chimeric antibody. It binds CD20 with high affinity, killing CD20+ cells in vitro by both complement-mediated lysis and antibody-dependent cell-mediated cytotoxicity with effective in vivo depletion of peripheral blood and lymph node cells.6 It has been stressed that “antibody negative” lymphomas may develop after therapy with highly efficient antibodies,5 although this in itself certainly does not implicate Rituximab in the event described above, or negate its potential value. However, it does reinforce the importance of close observation of patients receiving novel, and particularly biological therapy, so that the potential significance of unusual and unexpected complications may be determined.

REFERENCES

REFERENCES
1
Coiffier
B
Haioun
N
Ketterer
A
Engert
A
Tilly
H
Ma
D
Johnson
P
Lister
A
Feuring-Buske
M
Radford
JA
Capdeville
R
Diehl
V
Reyes
F
Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory agressive lymphoma: A Multicenter Phase II Study.
Blood
92
1998
1927
2
Cotter
FE
Hall
PA
Young
BD
Lister
TA
Simultaneous presentation of T and B-cell malignant lymphoma with bcl-2 gene involvement.
Blood
73
1989
1387
3
Shapiro
RS
McClain
K
Frizzera
G
Gajl-Peczalska
KJ
Kersey
JH
Blazar
BR
Arthur
DC
Patton
DF
Greenberg
JS
Burke
B
Epstein-Barr virus associated B cell lymphoproliferative disorders following bone marrow transplantation.
Blood
71
1998
1234
4
Micallef
INM
Chhanabhai
M
Gascoyne
RD
Shepherd
JD
Fung
HC
Nantel
SH
Toze
CL
Klingemann
H-G
Sutherland
HJ
Hogge
DE
Nevill
TJ
Le
A
Barnett
MJ
Lymphoproliferative disorders following allogeneic bone marrow transplantation: The Vancouver Experience.
Bone Marrow Transplant
22
1998
981
5
Tetreault
S
Abler
SL
Robbins
B
Saven
A
Peripheral T cell lymphoma after anti-CD20 antibody therapy.
J Clin Oncol
16
1998
1635
(letter)
6
Reff
ME
Carner
K
Chambers
KS
Chinn
PC
Leonard
JE
Raab
R
Newman
RA
Hanna
N
Anderson
DR
Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20.
Blood
83
1994
435