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Blood, 15 March 2002, Vol. 99, No. 6, pp. 2245-2247
BRIEF REPORT
Campath-1H and fludarabine in combination are highly active in
refractory chronic lymphocytic leukemia
Ben Kennedy,
Andy Rawstron,
Chris Carter,
Mary Ryan,
Kevin Speed,
Guy Lucas, and
Peter Hillmen
From the Haematological Malignancy Diagnostic Service,
University of Leeds, United Kingdom; Department of Hematology,
Huddersfield Royal Infirmary, Yorkshire, United Kingdom; Department of
Hematology, Altnagelvin Area Hospital, Londonderry, Derry City,
Northern Ireland, United Kingdom; Department of Hematology, Princess of
Wales Hospital, Grimsby, United Kingdom; University Department of
Hematology, Manchester Royal Infirmary, United Kingdom.
 |
Abstract |
Campath-1H (alemtuzumab) is the most effective
monoclonal antibody in single-agent use in B-cell chronic lymphocytic
leukemia (CLL) with reported response rates of 33% to 70%.
Combination therapy is now the conventional treatment for most
hematologic malignancies. Monoclonal antibody treatments may sensitize
tumor cells to subsequent chemotherapy. We report the combination of Campath-1H with fludarabine in patients with CLL refractory to each
agent used singly. Six patients who had received a median of 8 courses
of fludarabine (range, 4-10 courses) and 16 weeks of Campath-1H (range,
8-32 weeks) were treated. Five patients responded, including one who
had a complete response by National Cancer Institute criteria. The
responses observed were better in each patient than responses after
each agent used singly. Complete morphologic bone marrow responses were
seen in 3 patients, including eradication of disease measured by
sensitive flow cytometry in 2. Campath-1H combined with fludarabine is
a highly promising novel therapy for refractory CLL.
(Blood. 2002;99:2245-2247)
© 2002 by The American Society of Hematology.
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Introduction |
Patients with chronic lymphocytic leukemia
(CLL) resistant to purine analogues have a median survival of 10 months.1 Campath-1H (alemtuzumab) can lead to
durable responses in up to 59%2-4 of refractory cases.
Patients who are resistant to chemotherapy and fail to respond to
Campath-1H therapy have an overall survival of 9 months (B.K., personal
observation, 2000), and currently no effective therapy for these
patients is available. Evidence suggests that monoclonal antibodies may
sensitize malignant cells to chemotherapy.5,6 We therefore
treated 6 patients, all men, previously refractory both to fludarabine
and to Campath-1H, with a novel combination of intravenous Campath-1H
and fludarabine.
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Study design |
All patients had progressive B-cell CLL with heavy marrow
involvement and significant lymph node disease. Patients were enrolled in a prospective multicenter clinical trial to receive single-agent Campath-1H for disease refractory to purine analogues. Approval was
obtained from the Institutional Review Board for these studies. Informed consent was provided according to the Declaration of Helsinki.
Patients who tolerated single-agent Campath-1H but who failed to attain
a satisfactory response subsequently consented to receive Campath-1H
and fludarabine in combination. Patients were excluded if there was
active infection or in the presence of profound cytopenia (neutrophils
< 1.0 × 109/L or platelets
< 50 × 109/L). Treatment was continued to maximum
response, with a minimum planned duration of 8 weeks (2 cycles). All
received cotrimoxazole and acyclovir prophylaxis, and were
prospectively monitored for cytomegalovirus (CMV) reactivation.
Patients were assessed for response (National Cancer Institute
criteria9) by marrow and whole body computerized tomography
(CT) 2 months after completing therapy. Sensitive 4-color flow
cytometry for residual disease (MRD flow),7,8 which
detects fewer than 0.05% lymphocytes with a clonal B-CLL phenotype in
a polyclonal background,8 was performed on marrow samples
before treatment, every 4 weeks during treatment, and 2 months
after treatment. Patients who were already receiving Campath-1H
at the time of the addition of fludarabine continued at a dose level of
30 mg intravenously 3 times a week. Patients who were recommencing
Campath-1H as part of combined therapy received an escalating dose,
starting at 3 mg. Fludarabine 25 mg/m2 was infused
intravenously for 3 days every 28 days.
| |
Results and discussion |
Unique Patient Number 1 (UPN1) presented at the age of 48 in 1987. In 1997, he received 4 courses of fludarabine followed by combination
chemotherapy (cyclophosphamide, hydroxydaunomycin, Oncovin, prednisone
[CHOP]), but had persistent lymphadenopathy and diffusely infiltrated
marrow. In 1998, he achieved a complete remission after 12 weeks of
Campath-1H. His disease progressed in February 2000 and he was
retreated with 12 weeks of intravenous Campath-1H but failed to
respond, and then continued with Campath-1H together with 2 cycles of
simultaneous fludarabine (Table 1). He
achieved a partial remission, had peripheral blood stem cells (PBSCs)
harvested, and underwent an autologous peripheral blood stem cell
transplantation (PBSCT) following cyclophosphamide and total body
irradiation (Cyclo/TBI). Eight months after autograft he has no
detectable disease.
UPN2 presented at the age of 50 in 1992. He did not achieve a response
to 10 courses of fludarabine in 1996, and thus received 12 weeks of
Campath-1H. He proceeded to a BCNV, Etoposide, ARA-C, Melphalan
(BEAM) autograft in May 1997. Sixteen months later his disease
progressed, but failed to respond to a further 20 weeks of
Campath-1H. He had bulky lymphadenopathy and heavy marrow infiltration. His disease did not respond to Campath-1H and fludarabine in
combination (2 cycles). He remains alive 12 months after combined therapy.
UPN3 presented at the age of 40 in 1992. He received 6 cycles of
fludarabine in 1995 followed by 6 cycles of CHOP. He had persisting
heavy marrow infiltration and massive lymphadenopathy. From November
1999 he received 16 weeks of Campath-1H during which time his
lymphadenopathy progressed. He then continued on 30 mg Campath-1H with
the addition of fludarabine for 4 cycles of therapy and attained a
complete remission. PBSCs were harvested and he underwent PBSCT with
Cyclo/TBI conditioning 2 months after combined therapy. He remains in
clinical complete remission 11 months after autograft.
UPN4 presented at the age of 38 in 1997. After 8 cycles of fludarabine
in December 1997, he had persistent cervical lymphadenopathy and a
peripheral lymphocytosis. In November 1998, after 6 courses of CHOP he
had persistent lymphadenopathy and became dependent on transfusions.
After failing to respond to 13 weeks of Campath-1H monotherapy he
continued Campath-1H with 2 cycles of combined fludarabine. He achieved
a partial remission (Table 1) but with cytopenia, which recovered after
treatment with methylprednisolone. Sixteen months after therapy his
disease is progressing with recurrent lymphadenopathy but he remains untreated.
UPN5 presented at the age of 67 in 1995. He received a single course of
fludarabine in June 1996, which led to prolonged neutropenia and an
aspergillus pneumonia. In June 1998, he began 8 weeks of Campath-1H.
Following this he had persistent 8-cm splenomegaly and 4-cm nodal
disease, and his marrow biopsy remained heavily infiltrated. In
September 1999, after 8 further cycles of fludarabine, he had
persistent disease (Table 1). Six weeks later he started 3 cycles of
combined Campath-1H and fludarabine, attaining a partial response.
Campath-1H was interrupted at week 8 because of pseudomonas bronchopneumonia, which occurred during neutropenia; Campath-1H was
recommenced after 5 days at the same dose of 30 mg. He remained well
for 15 months when he was admitted with recurrent bronchopneumonia and
died of overwhelming sepsis. Peripheral blood counts were normal. He
had a spleen palpable at 4 cm and low-volume lymphadenopathy.
UPN6 presented at the age of 44 in 1995. In 1998, his CLL failed to
respond to 6 cycles of fludarabine, which was combined with
cyclophosphamide for the final 3 courses. In December 1999, he received
3 cycles of CHOP without response. In May 2000, he completed 12 weeks
of intravenous Campath-1H. There was no improvement in his 1-cm
lymphadenopathy or in his bone marrow appearances. In September 2000, the marrow contained 53% clonal B cells. He then began 3 cycles of
combined Campath-1H and fludarabine attaining a partial remission
(Table 1). Eight months after therapy he remains well and untreated
with a peripheral lymphocytosis of 13.7 × 109/L.
Five of 6 patients with advanced stage B-CLL who failed to respond to
fludarabine or to Campath-1H when administered as single agents
responded significantly better (1 complete and 4 partial responses) to
both agents used in combination. Five patients are alive at a median
follow-up of 12 months (range of follow-up, 8-16 months).
Marrow trephine appearances normalized in 3 patients (UPN1, 3, and 5).
Two of these patients (UPN1 and 5) had no detectable disease by MRD
flow. Two other responders (UPN4 and 6) had hypocellular trephines with
0.8% and 0.35% clonal B cells detected. Complete resolution of
massive lymphadenopathy occurred in UPN3 (Figure 1). Toxicity during combined therapy was
acceptable with only one patient (UPN5) requiring hospital admission
with pseudomonas bronchopneumonia during neutropenia. No interruption
occurred in any other patient. Two neutropenic patients responded to
granulocyte colony-stimulating factor and no patients required platelet
transfusions. No CMV reactivation occurred. Two patients (UPN1 and 3)
have successfully undergone autologous PBSCT with stem cells collected
after combined therapy.
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| Figure 1.
Bone marrow trephine and CT scan appearances in patient UPN3 before and
after combined Campath-1H and fludarabine therapy.
Note heavy infiltrate (A) × 10 by small lymphocytes observed after 16 weeks of single-agent Campath-1H has completely cleared (B) × 20 with
normal erythropoiesis evident after combined Campath-1H and
fludarabine. Stained with hematoxylin-eosin. The CT scan (D) shows
almost complete radiologic resolution of his previously massive
lymphadenopathy (C).
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|
We have shown Campath-1H and fludarabine in combination can increase
the proportion of responses, including complete remissions, with
acceptable toxicity. It appears that the 2 agents act synergistically, allowing enhanced targeting by antibody to previously inaccessible lymph node disease. This pilot study will be extended to a phase 2 clinical trial. The combination of Campath-1H and fludarabine appears
to be effective and may represent a significant step forward in the
therapy of CLL.
| |
Footnotes |
Submitted April 23, 2001; accepted October 15, 2001.
Supported in part by the Yorkshire Cancer Research.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Ben Kennedy, Haematological Malignancy Diagnostic
Service, Institute of Pathology, Algernon Firth Bldg, University of
Leeds, Leeds LS2 9JT, West Yorkshire, United Kingdom; e-mail:
medbk{at}leeds.ac.uk.
| |
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Abstract
Introduction