Download Prolonged neutropenia following anti CD20 therapy in a patient with

Annals of Oncology 12: 1493-1494. 2001.
Letters to the editor
Prolonged neutropenia following
anti CD20 therapy in a patient with
relapsed follicular non-Hodgkin's
lymphoma and corrected with IVIG
Mabthera or rituxan, a chimeric monoclonal antibody (mAb)
directed against the B-cell receptor, the CD20 antigen, is
rapidly emerging as a first or second line therapy for management of low-grade lymphomas (NHL) [1-3]. It acts by depleting both malignant and normal pre-B and mature lymphocytes
by a variety of mechanisms, such as complement-dependent
cytotoxicity, antibody-dependent cell-mediated cytotoxicity
and induction of apoptosis, after binding to the CD20 antigen
expressed on their surfaces. It is a reasonably safe agent and
long-term complications have been reported to be rare. However, these are early days and we are bound to come across
some relatively rare but significant complications of this agent.
The incidence of neutropenia and thrombocytopenia has been
reported to be very low and have been transitory.
We have recently treated a patient with follicular lymphoma
who relapsed after multiple chemotherapy regimens. The patient continued to have persistent neutropenia even six months
after antiCD20 therapy. G.F., a 54-year-old male was diagnosed to have follicular, small and large cells type NHL, stage
IVB with marrow involvement in 1995. Following six cycles of
the standard CHOP chemotherapy the response was reported
to be complete. Subsequently, he was given six cycles of
fludarabine in a dose of 25 mg/sq.m/d x 5 when a relapse was
noted. The disease showed partial response. He returned to us
for unremitting fever in March 1999. CBC showed Hb - 8.29
g/dl,WBC-2.54x 10 9 /l,ANC-1.29x 109/l, platelet-47.6 x
109/l. He had evidence of intra-abdominal NHL with splenomegaly and retroperitoneal lymphadenopathy. Consent for
marrow examination could not be obtained. He was put on
oral chlorambucil and prednisolone. This combination immediately produced results with remission of fever and improvement in blood counts. After three cycles of oral chlorambucil
and prednisolone, followed by CEPP regimen of cyclophosphamide, etoposide, procarbazine and prednisolone x 3 cycles.
Due to progression of the disease by the time he completed
CEPP x 3, he was informed about the role of mabthera in
relapsed low-grade NHLs. He gave consent to use the drug. He
received Mabthera in a dose of 375 mg/sq.m/week x 4 (dose
rounded off to 700 mg for each dose) during the month of
February 2000.
The following events were noted subsequent to administration of mabthera. In the second week of April he came febrile.
A complete blood count showed severe neutropenia of 0.235
x 109/l, with hemoglobin of 11.9 g/dl and platelet counts of
208 x 109/l. A bone marrow aspirate showed hypocelluar
marrow with about 40% mature lymphocytes. There was no
evidence of myelodysplasia. A trephine biopsy of the bone
marrow would have been more informative, but the patient
did not consent. Ultrasound examination of the abdomen
showed only subcentimeter lymph nodes in the retroperitoneum, suggesting favorable response to mabthera. He required
multiple admissions for treatment of his oro-pharyngeal and
esophageal ulcers and febrile episodes. He received multiple
antimicrobials, parenteral nutrition, blood components and
hematopoietic growth factors GM-CSF and G-CSF. Growth
factors have been able to improve the neutrophil counts only
temporarily. We diagnosed his case to be chronic neutropenia
with clinical manifestations of oral ulcers and epidermolysis.
Serum immunoglobulin levels showed marked lowering of
immunoglobulins: IgG - 280 mg/dl (normal value 700-1500
mg), IgA - 68 mg/dl (90-450 mg) and IgM - 84 mg/dl (60-250
mg). This apparently resulted from severe suppression of B
lymphocytes. He was treated with intravenous immunoglobulins (IVIG), 30 G every week for three weeks. Four weeks post
IVIG, the CBC had normalized and the oral and skin ulcers
completely healed. Figure I shows the details of treatment and
hematologic pictures from the time of administration of rituxan
to date. The serum Ig levels also returned to normal. The
disease and hematology continue to be normal to date.
There is very little doubt that monoclonal antibody therapy
with antiCD20 molecule has found a niche in the treatment of
low-grade NHL. The agent can be safely administered in the
majority of patients without significant side effects. Development of severe neutropenia in this case was noted a few weeks
after antiCD20 therapy. Hence, it appears to be related to the
drug. Whether the agent itself or the pre-existent extensive
marrow involvement is responsible for prolonged neutropenia,
remains unknown. The etiology of cytopenia following mabthera treatment needs to determined. This could be an immune
phenomenon resulting from impact of the agent on hematopoietic stem cells or one of the committed lineages. One recent
case report implicated parvovirus B19 in development of pure
cell aplasia following treatment for NHL with chemotherapy
and concomitant rituximab [4]. The patient's hemoglobin level
improved following three doses of 30 g per week of intravenous
immunoglobulin (IVIG). As the authors did not report the
values of peripheral blood white cells and platelets, we presume these were within the normal limit. It has been reported
that depleted B-lymphocytes following mabthera treatment
may take a very long time to recover [5]. This renders the
patient immunocompromised. Our patient received a therapeutic trial of IVIG. This case has highlighted the possible
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Figure I. Hematological parameters following rituxan and IVIG.
I
1494
complications of prolonged neutropenia following antiCD20
monoclonal antibody therapy. This might be particularly applicable to the patients who have received extensive prior
chemotherapy and remain cytopenic at the time of initiation
of monoclonal antibody treatment.
T. K.. Saikia,* H. Menon & S. H. Advani
Department of Medical Oncology, Tata Memorial Hospital, Pare/, Mumbcii, India; * Author for correspondence
(e-mail: saikias{a) vsnl.com)
References
1. Mclaughlin P, Grillo-Lopez AJ. Link BK et al. Rituximub chimeric
anh-CD20 monoclonal antibody therapy for relapsed indolent
lymphoma Half of patients respond to a four-dose treatment
program J Clin Oncol 1998: 16. 2825-33.
2. Solal-Cehgny P. Brousse N, Eftikhan Pel al. Rituximab as first-line
treatment of Ibllicular lymphoma patients with a low tumor burden. Preliminary results of a phase II trial (Abstr). Ann Oncol
1999: 10 (Suppl 3): 130.
3. Hainsworlh JD, Burris III HA. Mornssey LH et al. Rituximab
monoclonal antibody as initial therapy for patients with low-grade
non-Hodgkin's lymphoma. Blood 2000; 95. 3052-6.
4. Sharma VR. Fleming DR and Slone SP. Pure red cell aplasia due to
parvovirus BI9 in a patient treated with rituximab. Blood 2000. 96:
1184-6.
5. Red" ME. Carncr K. Chambers KS et al. Depletion of B cells in vivo
by a chimeric mouse human monoclonal antibody to CD20. Blood
1994. 83: 435 45.
Use of gemcitabine (GEM) in
advanced myelodysplastic syndromes
Myelodysplastic syndromes (MDS) are an heterogeneous
group of diseases with an indolent course, but invariable
leukemic transformation and poor prognosis due to the resistance of leukemic cells to chemotherapy [I]. Supportive care is
the mainstay of therapy in elderly patients, with allogeneic
bone-marrow transplantation being the treatment of choice,
when available, in the youngest [2].
The aim of our study is to verify the safe use of a new
nucleoside analogue with anti-leukemic activity, gemcitabine
(GEM), in advanced MDS or secondary acute leukemias
(sAL) [3, 4] Ten patients, mean age 71 years (median 71. range
65 to 79) (2 RAEB-t, 1 CMMoL. 7 sAL) were treated following
oral informed consent, with GEM 1000 mg/day weekly for a
mean of seven doses (median 8, range 2 to 14) in a day-hospital
regimen. Antibacterial prophylaxis with cyprofloxacine and
transfusional support were given when Hb <8.0 g/dl and
platelets <20 x 10y/l. An objective response to the treatment
was considered to be a stable increase in peripheral blood cell
count and/or a reduction in bone marrow immature cells. The
control group was represented by 20 historical patients (mean
age 70.5 (median 70.5, range 52 to 85) (9 RAEB. 7 RAEB-t.
4 sAL) treated with low-dose ara-C 15 mg, subcutaneously.
twice a day for a mean of eight cycles (median 4, range 1 to 8).
The differences between quantitative variables were estimated using the Mann-Whitney test. Observation time, defined as the time from entering the protocol to the death of the
patient was analyzed using the method of Kaplan and Meier.
In the GEM group, only one patient displayed a transient
reduction in bone marrow immature cells. Nine patients received RBC concentrates (a mean of 7 U; median 8, range 5 to
14) and three patients PLT random units (a mean of 4 U).
Infectious complications consisted of two bacterial pneumonitis. two sepsis, and one FUO and determined a mean of 2.5
days of hospitalization. Severe toxicity was observed in I
patient who discontinued GEM because of WHO grade 3
gastrointestinal toxicity. All patients died due to disease progression after a mean follow-up of 11 months (median 5, range
2 to 34).
In the control group, two patients died after one cycle of
therapy as a result of cerebral hemorrhage and fungal pneumonia, respectively. Transfusional support consisted of a mean
of 8 U of RBC (median 6.5, range I to 19) (P = 0.89) in all
patients and of 4.5 U of PLT (median 9, range 5 to 28) in eight
patients (P = 0.77). Eleven patients were hospitalized due to
infectious complications: two pneumonia, four sepsis and one
pulmonary TBC for a mean of 4.5 days (median 2, range 0 to
18) (P = 0.55). All patients had died at a mean follow-up of
eight months (median 7, range 1 to 28) (P = 0.92).
No statistically significant differences were observed in the
survival curves of the two groups of patients.
Whereas, response rate seems to be an important endpoint
for phase 2 studies of new agents to treat MDS. a relevant goal
should be to prolong patient survival while alleviating diseaserelated complications (chronic anemia, hemorrhage, infections) [5].
The safe use of GEM observed in our patients warrants
more studies to evaluate the role of GEM in MDS and/or
acute leukemias, perhaps in association with other anti-leukemic drugs (i.e. oral idarubicin) or differentiating agents. A
possible role in controlling erythropoiesis (as indicated by the
increase in highly fluorescent reticulocytes observed in four of
our patients) also makes the association of GEM therapy with
hemopoietic growth factors intriguing.
A. Di Mario,* L. Pagano, L. Mele, V. De Stefano &
G. Leone
Cattedra di Ematologia, Universitd Catto/ica del Sacro
Cuore, Rome, Italy; *Author for correspondence (e-mail:
a. dimario @ eudoramail. com)
References
1. Heaney ML. Golde DW Myelodysplasia. N Engl J Med 1999: 340:
1649-60.
2. Anderson JE. Appelbaum FR, Fisher LD et al. Allogeneic bone
marrow transplantation for 93 patients with myelodysplastic syndrome Blood 1993; 8. 677-81
3. Bergman AM, Pinedo HM. Jongsma APM et al. Decreased resistance to gemcitabine (2'. 2'-difluorodeoxycytidine) or cytosinc arabinoside-resistant myeloblastic murine and rat leukaemia cell lines:
Role of altered activity and substrate specificity of deoxycytidine
kinase. Biochem Pharmacol 1999: 57: 397-406.
4. Santini V. Bernabei PA. Zozzini A et al. Apoptotic and antiproliferative effects of gemcitabine and gemcitabine plus ara-C on blast
cell from patients with blast crisis chronic myeloprolifcrative disorders. Haematologica 1997; 82. 11-5
5. Cheson BD. Bennett JM, Kantarjian H et al. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 2000: 96. 3671-4.