_ Abstracts 2-CdA-1
____________________________________________________________________
Clinical Cancer Research Vol. 6, 1328-1332, April 2000
© 2000 American Association for Cancer Research
Sequential Treatment of a Resistant Chronic Lymphocytic
Leukemia Patient with Bryostatin 1 Followed by 2Chlorodeoxyadenosine: Case Report1
Ishtiaq Ahmad, Ayad M. Al-Katib, Frances W. J. Beck and Ramzi M. Mohammad2
Department of Medicine, Division of Hematology and Oncology, Karmanos Cancer Institute, Wayne State
University School of Medicine, Detroit, Michigan 48201
Bryostatin 1 (Bryo-1) has been shown to differentiate chronic lymphocytic leukemia (CLL) cells
to the hairy cell leukemia phenotype.
The purine analogue 2-chlorodeoxyadenosine (2-CdA) exhibits enhanced activity in patients
with hairy cell leukemia compared to those with CLL.
Here we present a case report of a patient diagnosed with resistant CLL and treated sequentially
with Bryo-1 followed by 2-CdA for three cycles.
Molecular and biochemical parameters relative to the sequential treatment with these agents in
vivo were comparable to those found in the WSU-CLL cell line in vitro (R. M. Mohammad et al.,
Clin. Cancer Res., 4: 445–453, 1998; R. M. Mohammad et al., Biol. Chem., 379: 1253–1261,
1998).
There was a significant reduction of lymphocyte count from 37.1 x 103/µl before the treatment to
3.4 x 103/µl after treatment, and partial remission was achieved 2 months after the treatment.
The percentage of morphologically differentiated lymphocytes was increased from 3% before
treatment to 92% with the first cycle of Bryo-1.
Similarly, expression of CD22, a marker of differentiation, increased from 38% to 97% and was
maintained at a high level for the duration of the treatment.
Analysis of the molecular markers of apoptosis in isolated peripheral blood lymphocytes revealed
an increase in the Bax:Bcl-2 ratio after treatment with Bryo-1 in cycles 2 and 3, with associated
poly(ADP-ribose) polymerase cleavage after Bryo-1 and 2-CdA treatment.
The deoxycytidine kinase:cytosolic 5'-nucleotidase activity ratio increased modestly after Bryo-1
treatment, indicating increased sensitivity of the peripheral blood lymphocytes to 2-CdA.
In summary, we found that sequential treatment with Bryo-1 and 2-CdA caused a significant
reduction in peripheral blood lymphocytes (CLL cells) with simultaneous induction of
differentiation and the initiation of the Bax:Bcl-2 apoptotic pathway.
1
Annals of Oncology, Vol 9, Issue 7 721-726, Copyright © 1998 by European Society for Medical Oncology
Reduced dose of subcutaneous cladribine induces identical
response rates but decreased toxicity in pretreated chronic
lymphocytic leukaemia. Swiss Group for Clinical Cancer
Research (SAKK)
D. C. Betticher, D. Ratschiller, S. F. Hsu Schmitz, A. von Rohr, U. Hess, G. Zulian, M.
Wernli, A. Tichelli, A. Tobler, M. F. Fey and T. Cerny
Institute of Medical Oncology, Inselspital, Bern, Switzerland. daniel.betticher@insel.ch
PURPOSE:
To study the efficacy and the safety of cladribine (2-chlorodeoxyadenosine, 2-CDA)
administered as 24-hour infusions or as subcutaneous bolus injections at two different doses to
patients with relapsing or refractory chronic lymphocytic leukaemia (CLL).
PATIENTS AND METHODS:
In this non randomised 2-cohort study, 20 patients with pretreated CLL received cladribine at a
dose of 0.7 mg/kg/cycle as continuous i.v. infusions over seven days (group 1) and 35 patients
were treated at a reduced dose of 0.5 mg/kg/cycle given as s.c. bolus injections for five days
(group 2). After two cycles of four week duration, response was assessed. In the case of
progressive disease, therapy was discontinued, otherwise a maximum of four additional cycles
were administered until best response.
RESULTS:
A total of 130 cycles were administered (group 1: 41, group 2: 89). Patient characteristics in both
groups were comparable. The median dose intensities were 0.172 mg/kg per week and 0.123
mg/kg per week for groups 1 and 2, respectively (P < or = 0.0001). The overall response rate for
all 55 patients was 38% (95% confidence interval (95% CI): 25%-52%), with 5% CR and 33%
PR. Response was similar in both patient groups (35% in group 1, 40% in group 2). No
association between cladribine dose intensity and response rate was found, and there was no
difference between patients relapsing after or refractory to previous therapies (11 of 24 vs. 10 of
31). Median remission duration was six months in both groups. Toxicity, in particular infections
(all WHO grades, 34% in group 1 versus 7% in group 2) and myelosuppression (grade 1-4
neutropenia, 72% versus 41% of cladribine cycles) were statistically significantly more frequent
in group 1.
CONCLUSION:
Cladribine is active in heavily pretreated patients with chronic lymphocytic leukaemias. Dose
reduction by 29% led to similar response and remission duration, but to a significant decrease of
myelotoxicity and risk of infection. Cladribine administered as s.c. bolus injections at 0.5 mg/kg
per cycle is safe and this dose level should not be exceeded in this patient population.
2
Journal of Clinical Oncology, Vol 16, 850-858, Copyright © 1998 by American Society of Clinical Oncology
Fewer infections, but maintained antitumor activity with
lower-dose versus standard-dose cladribine in pretreated
low-grade non-Hodgkin's lymphoma
DC Betticher, A von Rohr, D Ratschiller, SF Schmitz, T Egger, T Sonderegger, R
Herrmann, T Kroner, GB Zulian, F Cavalli, MF Fey and T Cerny
Institute of Medical Oncology, University of Bern, Inselspital, Switzerland. daniel.betticher@insel.ch
PURPOSE:
To study the efficacy and the safety of cladribine (2- chlorodeoxyadenosine [2-CDA])
administered at two different dosages.
PATIENTS AND METHODS:
In this two-cohort study, patients with low-grade refractory/relapsing non-Hodgkin's lymphoma
(NHL) received 2-CDA at a dose of 0.7 mg/kg per cycle as a continuous intravenous (i.v.)
infusion (group 1, n = 44) or at a reduced dose of 0.5 mg/kg per cycle as a subcutaneous (s.c.)
bolus injection (group 2, n = 60). Three 2-CDA cycles at > or = 4-week intervals were planned,
then treatment could be pursued until six cycles.
RESULTS:
A total of 300 cycles were administered (group 1, 114 cycles; group 2, 186). Patient
characteristics in both groups were comparable. The median dose- intensities were 0.17
mg/kg/wk and 0.13 mg/kg/wk for groups 1 and 2, respectively (P < or = .0001). The overall
response rate for all 104 patients was 54% (95% confidence interval [CI], 45% to 66%; 15%
complete response [CR] and 39% partial response [PR]). Response was similar in both patient
groups (57% in group 1 and 53% in group 2; P = .72), and no association between 2-CDA doseintensity and response rate was found (P = .35). Median remission duration was 7 and 12 months
in groups 1 and 2, respectively (P = .21). Toxicity, in particular opportunistic infections (> or =
grade 2, 30% in group 1 v 7% in group 2; P = .003) and myelosuppression (> or = grade 3
neutropenia, 33% v 8% of 2-CDA cycles, P < .0001), were more frequent in group 1. Multiple
logistic regression analysis showed that the infection risk (grade > or = 2) was decreased by 81%
with 2-CDA dose reduction in group 2 after adjusting for number of pretreatment regimens and
time since diagnosis (P = .01).
CONCLUSION:
When administered as a s.c. bolus injection, 2- CDA at 0.5 mg/kg per cycle is safe and this dose
level should not be exceeded in this patient population.
3
Blood, Volume 62, Issue 4, pp. 737-743, 10/01/1983
Copyright © 1983 by The American Society of Hematology
Specific toxicity of 2-chlorodeoxyadenosine toward resting
and proliferating human lymphocytes
DA Carson, DB Wasson, R Taetle and A Yu
2-Chlorodeoxyadenosine (CdA), an adenosine-deaminase-resistant purine deoxynucleoside, is
markedly toxic toward human T-lymphoblastoid cell lines in vitro and is an effective agent
against L1210 leukemia in vivo.
The present studies have examined the toxicity, and in some cases, metabolism, of CdA in
(1) multiple established human cell lines of varying phenotype,
(2) leukemia and lymphoma cells taken directly from patients,
(3) normal bone marrow cells, and
(4) normal peripheral blood lymphocytes.
Nanomolar concentrations of CdA blocked the proliferation of lymphoblastoid cell lines with a
high ratio of deoxycytidine kinase to deoxynucleotidase.
The drug had virtually no effect on the growth of cell lines derived from solid tissues.
The CdA inhibited the spontaneous uptake of tritiated thymidine by many T and non-T, non-B
acute lymphoblastic leukemia cell specimens at concentrations less than or equal to 5 nM.
The same concentrations did not impair either thymidine uptake or granulocyte-monocyte colony
formation by normal bone marrow cells.
In common with deoxyadenosine, but unlike several other agents affecting purine and purine
metabolism, CdA was lethal to resting normal T lymphocytes and to slowly dividing malignant
T cells.
In both resting and proliferating lymphocytes, the CdA was phosphorylated by deoxycytidine
kinase and entered a rapidly turning over nucleotide pool.
Dividing lymphocytes also incorporated abundant CdA into DNA.
The selective toxicity of CdA toward both dividing and resting lymphocytes may render the drug
useful as an immunosuppressive or antileukemic agent.
4
Journal of Clinical Oncology, Vol 13, 2431-2448, Copyright © 1995 by American Society of Clinical Oncology
Infectious and immunosuppressive complications of purine
analog therapy
BD Cheson
Division of Cancer Treatment, National Cancer Institute, Bethesda, MD 20892-7436, USA.
PURPOSE:
The purine analogs fludarabine, cladribine, and pentostatin are active agents in the treatment of
indolent lymphoid malignancies. This report reviews the pattern, severity, and consequences of
the immunosuppression and myelotoxicity associated with these agents.
METHODS:
The literature was searched using MedLine and Cancerline, as well as the bibliographies of
published reports through the winter of 1994 and 1995.
RESULTS:
Each of these drugs induces profound lymphocytopenia. A marked decrease in CD4 cells may
persist for several years, while other mononuclear-cell populations recover more rapidly. The
spectrum of infections encountered in these patients appears to be altered to include a wide range
of opportunistic organisms. Factors that increase the risk of these infections include concurrent
corticosteroids, extensive prior therapy, particularly with another purine analog, and poor
response to purine analog treatment.
CONCLUSION:
Because of the frequency of life-threatening infections with unusual pathogens that may occur in
patients treated with purine analogs, aggressive and early diagnostic evaluation and appropriate
use of myeloid growth factors may be necessary to ensure appropriate antimicrobial therapy.
5
Journal of Clinical Oncology, Vol 12, 2216-2228, Copyright © 1994 by American Society of Clinical Oncology
Neurotoxicity of purine analogs: a review
BD Cheson, DA Vena, FM Foss and JM Sorensen
Division of Cancer Treatment, National Cancer Institute, Bethesda, MD 20892.
PURPOSE:
The purine analogs, fludarabine, cladribine, and pentostatin, are active against a broad spectrum
of indolent lymphoid malignancies. They also have similar toxicities, including
myelosuppression, immunosuppression, and sporadic neurotoxicity. This review compares the
spectrum of neurotoxicity of each of these agents. Now that these drugs are commercially
available and are being widely used, physicians should be aware of potentially serious side
effects that may be encountered.
METHODS:
The literature was searched using MedLine and Cancerline, as well as the bibliographies of
published reports through the fall of 1993. In addition, case records from National Cancer
Institute (NCI) Group C protocols were reviewed for fludarabine in chronic lymphocytic
leukemia (CLL), and cladribine and pentostatin in hairy cell leukemia (HCL), as well as adverse
drug reactions reported to the NCI from January 1980 through September 1993.
RESULTS:
At higher than recommended doses, life-threatening and fatal neurotoxicity were encountered
with all three drugs. At the recommended doses, each agent induced neurotoxicity in
approximately 15% of patients, mostly mild and reversible. However, severe neurologic
complications were reported; these were occasionally delayed, sometimes fatal, but often at least
partially reversible.
CONCLUSION:
The doses of these three agents should not be increased above the recommended levels.
Development of moderate or worse neurotoxicity should result in discontinuation of that drug.
6
Journal of Clinical Oncology, Vol 16, 3007-3015, Copyright © 1998 by American Society of Clinical Oncology
Treatment of hairy cell leukemia with 2chlorodeoxyadenosine via the Group C protocol mechanism
of the National Cancer Institute: a report of 979 patients
BD Cheson, JM Sorensen, DA Vena, MJ Montello, JA Barrett, E Damasio, M Tallman, L
Annino, J Connors, B Coiffier and F Lauria
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. chesonb@ctep.nih.gov
PURPOSE:
To provide cladribine (CdA) to physicians for the treatment of patients with previously treated
or untreated hairy cell leukemia (HCL), and to determine the response rate, response duration,
survival, and toxicity with this agent.
PATIENTS AND METHODS:
This Group C phase II study was open to all eligible patients whose primary physician obtained
written permission from the National Cancer Institute (NCI) to register patients onto this
protocol. Of 979 patients registered, 861 were assessable for response and 895 for toxicity.
RESULTS:
The complete remission (CR) rate was 50% and the partial remission (PR) rate was 37%. At a
median follow-up of 52 months, 12% of patients were reported to have progressed and 62 (7%)
have died of disease.
CONCLUSION:
This large experience confirms the excellent response rates and remission duration of CdA in
patients with HCL. Nevertheless, the response rates in this setting, which approximates general
clinical practice, were lower than in other series. In general, CdA was well tolerated, but the
potential increased risk for secondary malignancies requires additional follow-up evaluation.
CdA can now be considered as one of the best agents for the treatment of HCL.
7
Journal of Clinical Oncology, Vol 20, Issue 20 (October), 2002: 4217-4224
© 2002 American Society for Clinical Oncology
Interim Comparison of a Continuous Infusion Versus a
Short Daily Infusion of Cytarabine Given in Combination
With Cladribine for Pediatric Acute Myeloid Leukemia
By Kristine R. Crews, Varsha Gandhi, Deo Kumar Srivastava, Bassem I. Razzouk, Xin
Tong, Fred G. Behm, William Plunkett, Susana C. Raimondi, Ching-Hon Pui, Jeffrey E.
Rubnitz, Clinton F. Stewart, Raul C. Ribeiro
From the Departments of Pharmaceutical Sciences, Biostatistics, Hematology-Oncology, and Pathology, St Jude
Children’s Research Hospital, Memphis, TN, and Departments of Experimental Therapeutics and Leukemia,
University of Texas M.D. Anderson Cancer Center, Houston, TX.
Address reprint requests to Kristine R. Crews, Department of Pharmaceutical Sciences, St Jude Children’s Research
Hospital, 332 N Lauderdale, Memphis, TN 38105-2794; email: mailto:kristine.crews@stjude.org
PURPOSE:
To identify the optimal schedule for infusion of cytarabine (ara-C) given with cladribine (2CdA) to pediatric patients with acute myeloid leukemia (AML), and to compare the effects of the
two schedules on the pharmacokinetics of ara-C triphosphate (ara-CTP) in leukemic cells.
PATIENTS AND METHODS:
Forty-nine pediatric patients with newly diagnosed primary AML received a 5-day course of araC 500 mg/m2/d and 2-CdA 9 mg/m2/d. They were randomly assigned to receive ara-C as either a
2-hour daily infusion (arm A) or a continuous infusion (arm B). Cellular pharmacokinetics were
studied on days 1 and 2. All patients then received two courses of remission induction
chemotherapy with daunorubicin, ara-C, and etoposide (DAV).
RESULTS:
Thirty-two percent of patients (seven of 22) in arm A and 63% (17 of 27) in arm B entered
complete remission (P = .045) after ara-C and 2-CdA therapy. Coadministration of 2-CdA
increased the intracellular concentration of ara-CTP in 20 of 36 patients, although we found no
statistically significant difference between the treatment arms in this effect (P = .63). The
incidence of toxicity did not differ significantly between the two treatment arms (P = .53). After
two courses of DAV, the rate of complete remission was 91% in arm A and 96% in arm B
(P = .58).
CONCLUSION:
Intracellular accumulation of ara-CTP is increased when 2-CdA is given with ara-C, but no
schedule-dependent differences in this effect were seen. The combination of 2-CdA and ara-C
seems to be effective therapy for pediatric AML.
8
Journal of Clinical Oncology, Vol 18, Issue 1 (January), 2000: 214
© 2000 American Society for Clinical Oncology
Waldenström’s Macroglobulinemia: Clinical Features,
Complications, and Management
By Meletios A. Dimopoulos, Panayiotis Panayiotidis, Lia A. Moulopoulos, Petros Sfikakis,
Marinos Dalakas
From the Departments of Clinical Therapeutics, Internal Medicine, Radiology, and Neurology, University of Athens
School of Medicine, Athens, Greece.
Address reprint requests to Meletios A. Dimopoulos, MD, 227 Kifissias-Ave, Kifissia, Athens 14561, Greece; email
mailto:mdipom@cc uoa.gr.
ABSTRACT
PURPOSE:
To review the clinical features, complications, and treatment of Waldenström’s
macroglobulinemia, a low-grade lymphoproliferative disorder that produces monoclonal
immunoglobulin (Ig) M.
METHODS:
A review of published reports was facilitated by the use of a MEDLINE computer search and by
manual search of the Index Medicus.
RESULTS:
The clinical manifestations associated with Waldenström’s macroglobulinemia can be classified
according to those related to direct tumor infiltration, to the amount and specific properties of
circulating IgM, and to the deposition of IgM in various tissues. Asymptomatic patients should
be followed without treatment. For symptomatic patients, standard treatment consists primarily of
oral chlorambucil; nucleoside analogs, such as fludarabine and cladribine, are effective in one
third of previously treated patients and in up to 80% of previously untreated patients. Preliminary
evidence suggests that anti-CD20 monoclonal antibody may be active in about 30% of
previously treated patients and that high-dose therapy with autologous stem-cell rescue is
effective in most patients, including some with resistance to nucleoside analogs.
CONCLUSION:
Waldenström’s macroglobulinemia has a wide clinical spectrum that practicing physicians need
to recognize early to reach the correct diagnosis. When therapy is indicated, oral chlorambucil is
the standard primary treatment, but cladribine or fludarabine can be used when a rapid
cytoreduction is desirable. Prospective randomized trials are required to elucidate the impact of
nucleoside analogs on patients’ survival. A nucleoside analog is the treatment of choice for
patients who have been previously treated with an alkylating agent.
9
Neurology 2000;55:1714-1718
© 2000 American Academy of Neurology
Articles
Whole brain volume changes in patients with progressive
MS treated with cladribine
M. Filippi, MD, M. Rovaris, MD, G. Iannucci, MD, S. Mennea, M. P. Sormani, PhD and G.
Comi, MD
From the Neuroimaging Research Unit (Drs. Filippi, Rovaris, Iannucci, and Sormani, and S. Mennea) and Clinical
Trials Unit (Dr. Comi), Department of Neuroscience, Scientific Institute Ospedale San Raffaele, University of
Milan, Italy.
Address correspondence and reprint requests to Dr. Massimo Filippi, Neuroimaging Research Unit, Department of
Neuroscience, Scientific Institute Ospedale San Raffaele, Via Olgettina, 60, 20132 Milan, Italy; e-mail:
m.filippi@hsr.it
Article abstract
OBJECTIVE:
To compare changes in whole brain volume measured using MRI scans in patients with
progressive MS enrolled in a double-blind, placebo-controlled trial assessing the efficacy of two
doses of cladribine (0.7 and 2.1 mg/kg) and to assess the correlations between change in whole
brain volume and change in other conventional MRI measures.
BACKGROUND:
Measuring brain parenchymal volumes is an objective and reliable surrogate for the destructive
pathologic process in MS. The dynamics and the mechanisms of tissue loss in progressive MS
are unclear.
METHODS:
Whole brain volumes were measured using postcontrast T1-weighted scans with 3 mm slice
thickness from 159 patients with progressive MS (70% secondary progressive and 30% primary
progressive) enrolled in a double-blind, placebo-controlled trial of 12-month duration.
RESULTS:
Whole brain volumes were similar in the placebo and cladribine-treated patients on the baseline
scans. A significant decrease of brain volume over time was observed both in the entire
population of patients (p = 0.001) and in the placebo patients in isolation (p = 0.04). No
significant treatment effect of either dose of cladribine on brain volume changes over time was
found. In the 54 patients who received placebo, the change in brain volume was not significantly
correlated with other MRI measures at baseline (enhancing lesion number and volume and T2hyperintense and T1-hypointense lesion volumes) or at follow-up (cumulative number of
enhancing lesions and absolute and percentage changes of enhancing T2- and T1-hypointense
lesion volumes).
CONCLUSIONS:
This study shows in a large cohort of patients that brain parenchymal loss occurs, even over a
short period of time, in progressive MS and that cladribine is not able to alter this process
significantly. It also suggests that MRI-visible inflammation and new lesion formation has a
marginal role in the development of brain atrophy in patients with progressive MS.
10
Journal of Clinical Oncology, Vol 21, Issue 5 (March), 2003: 891-896
© 2003 American Society for Clinical Oncology
Extended Follow-Up of Patients With Hairy Cell Leukemia
After Treatment With Cladribine
Grant R. Goodman, Carol Burian, James A. Koziol, Alan Saven
From the Division of Hematology/Oncology and Ida M. and Cecil H. Green Cancer Center of Scripps Clinic/Scripps
Cancer Center, and Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla,
CA.
Address reprint requests to Alan Saven, MD, Division of Hematology and Oncology, Scripps Clinic, 10666 N Torrey
Pines Rd, La Jolla, CA 92037; saven.alan@scrippshealth.org.
Purpose:
Hairy cell leukemia (HCL) is an uncommon, indolent, chronic B-cell lymphoproliferative
disorder involving the marrow and spleen. Therapy for HCL includes splenectomy, interferon
alfa-2a and alfa-2b, pentostatin, and cladribine. The purpose of this article was to report the
extended follow-up of HCL patients treated with cladribine.
Patients and Methods:
Two hundred nine patients with HCL who were treated with cladribine had at least 7 years of
follow-up. A course of cladribine constituted a 7-day continuous intravenous infusion at a dose
of 0.1 mg/kg/d.
Results:
Of the 207 assessable patients who had at least 7 years of follow-up, 196 (95%) achieved a
complete response (CR) and 11 (5%) achieved a partial response (PR) after a single course of
cladribine (overall response rate, 100%). The median first-response duration for all responders
was 98 months. Seventy-six patients (37%) experienced relapse after their first course of
cladribine. The median time to first relapse for all responders was 42 months. Time to treatment
failure of CRs compared with PRs was statistically significant (P < .0005). The overall survival
rate was 97% recorded at 108 months. Forty-seven patients developed 58 second malignancies.
The observed-to-expected ratio for second malignancies was 2.03 (95% confidence interval, 1.49
to 2.71).
Conclusion:
These results confirm previous observations that single courses of cladribine administered to
patients with HCL induce high response rates, the majority of which are CRs. Most patients
enjoy long-lasting complete remissions, and those patients who experience relapse can be
successfully re-treated with cladribine.
Supported in part by research funding and a free supply of cladribine from Ortho Biotech,
Raritan, NJ.
Presented in part at the Thirty-Seventh Annual Meeting of the American Society of Clinical
Oncology, San Francisco, CA, May 12–15, 2001.
11
Journal of Clinical Oncology, Vol 20, Issue 18 (September), 2002: 3872-3877
© 2002 American Society for Clinical Oncology
Treatment of Extranodal Marginal Zone B-Cell Lymphoma
of Mucosa-Associated Lymphoid Tissue Type With
Cladribine: A Phase II Study
By Gerald Jäger, Peter Neumeister, Ruth Brezinschek, Thomas Hinterleitner, Wolfgang
Fiebiger, Melitta Penz, Hans J. Neumann, Brigitte Mlineritsch, Maria DeSantis, Franz
Quehenberger, Andreas Chott, Christine Beham-Schmid, Gerald Höfler, Werner
Linkesch, Markus Raderer
From the Division of Hematology, Division of Gastroenterology, Institute of Medical Informatics, Statistics and
Documentation and Institute of Pathology, Karl-Franzens University of Graz, Graz; Departments of Internal
Medicine I, Division of Oncology and Division of Clinical Pathology, University of Vienna, and 3.Med Division,
Kaiser Franz Josef-Spital, Vienna; and Internal Medicine S. Veit, Department of Hematology and Oncology,
General Hospital Salzburg, Salzburg, Austria.
Address reprint requests to Gerald Jäger, MD, Department of Internal Medicine, Division of Hematology, KarlFranzens-University, Auenbruggerplatz 38, 8036 Graz, Austria; email: mailto:gerald.jaeger@kfunigraz.ac.at
PURPOSE:
As chemotherapy has not been extensively studied in patients with lymphoma of the mucosaassociated lymphoid tissue (MALT), we initiated a prospective study to evaluate the activity of
the nucleoside analog cladribine (2-chlorodeoxyadenosine [2-CdA]) in this disease.
PATIENTS AND METHODS:
Patients with histologically verified MALT-type lymphoma were enrolled. 2-CdA was
administered at a dose of 0.12 mg/kg body weight on 5 consecutive days, as a 2-hour infusion.
Cycles were repeated every 4 weeks for a maximum of six cycles.
RESULTS:
Nineteen patients with gastric and seven patients with extragastric MALT lymphoma were
enrolled. All patients were chemotherapy-naive, and two had been locally irradiated before
systemic relapse of the lymphoma. A total of 102 cycles was administered to our patients
(median number of cycles per patient, four). All 25 assessable patients responded to treatment:
21 patients (84%) achieved complete remission (CR) and four patients achieved partial
remission. All patients (100%) with gastric presentation, but only three patients (43%) with
extragastric presentation, achieved CR. Toxicities were moderate and mainly hematologic and
required dose reduction and/or premature discontinuation of therapy in only three cases. Two
patients died from vascular events, one shortly after the first cycle because of myocardial
infarction and the other from stroke 3 months after the second course. Three patients relapsed
after 13, 18, and 22 months and one patient showed progressive disease after 15 months. At
present, 24 patients are alive at a median follow-up time of 32 months.
CONCLUSION:
Our data demonstrate that 2-CdA is highly effective in inducing CR in 84% of patients with
MALT-type lymphoma.
12
Annals of Oncology, Vol 7, Issue 4 373-379, Copyright © 1996 by European Society for Medical Oncology
Long-term survival following cladribine (2chlorodeoxyadenosine) therapy in previously treated
patients with chronic lymphocytic leukemia
G. Juliusson and J. Liliemark
Department of Medicine, Huddinge Hospital, Sweden.
PURPOSE:
To assess long-term survival following cladribine salvage treatment for previously treated
patients with chronic lymphocytic leukemia.
PATIENTS AND METHODS:
Fifty-two patients aged 39-84 years with previously treated CLL received cladribine 0.12
mg/kg/day in 2-hour infusions for 5 days in monthly courses. Two-thirds were refractory to
previous therapy, and 8 had prior fludarabine.
RESULTS:
Sixteen (31%) patients achieved complete response (CR) and 14 (27%) partial remission (PR)
according to consensus criteria. Response correlated with clinical stage, number of previous
treatment regimes, blood lymphocyte count, and lymphocyte halflife following the first
cladribine course. Toxicity included pneumonia (n = 9), herpes zoster (n = 7), and septicemia (n
= 2). Four patients in CR underwent high-dose chemotherapy with autologous blood stem cell
support, and 2 remain in CR 48 and 60 months from start of cladribine, and 2 had relapse at 42
and 48 months, respectively. Median progression-free survival (Kaplan-Meier analysis) for CR
patients was 23 months from start of cladribine treatment, and for PR patients 16 months. The
projected overall survival was 80% at 3 years for CR patients, and the median survival 28
months for PR patients and 4 months for non-responding patients.
CONCLUSIONS:
Our previous finding of durable CRs from cladribine in advanced CLL is thus confirmed in a
larger patient material, and follow-up indicate that long-term survival may be achieved.
13
Annals of Oncology, Vol 6, Issue 4 371-375, Copyright © 1995 by European Society for Medical Oncology
Neutropenic fever following cladribine therapy for
symptomatic hairy-cell leukemia: predictive factors and
effects of granulocyte-macrophage colony-stimulating factor
G. Juliusson, R. Lenkei, G. Tjonnfjord, D. Heldal and J. Liliemark
Department of Medicine, Huddinge Hospital, Sweden.
BACKGROUND:
Neutropenic fever is the commonest complication of cladribine therapy for hairy-cell leukemia
(HCL), leading to a 3% mortality rate. Our aim was to identify predictive factors and evaluate the
effects of concomitant granulocyte-macrophage colony-stimulating factor (GM-CSF).
PATIENTS AND METHODS:
We studied 102 patients with active HCL given cladribine for 7 days. Pretreatment parameters
predicting neutropenic fever were analysed. Twelve patients at high risk for febrile complications
also received 400 micrograms GM-CSF per day on days 1 through 21.
RESULTS:
Pretreatment anemia, hypocholesterolemia, bone marrow differential with a high percentage of
hairy cells and a low percentage of myelopoietic cells, low albumin, and high C-reactive protein
predicted neutropenic fever. The addition of GM-CSF did not improve the kinetics of recovery
for neutrophils, hemoglobin or platelets, as compared to matched control patients. However, GMCSF significantly reduced cladribine-induced lymphopenia, but not the incidence of neutropenic
fever.
CONCLUSION:
Factors predicting febrile neutropenia were identified. GM-CSF protected from cladribine
lymphotoxicity but did not improve neutropenia or febrile episodes.
14
Cancer Research, Vol 54, Issue 5 1235-1239, Copyright © 1994 by American Association for Cancer Research
Pharmacokinetics of cladribine (2-chlorodeoxyadenosine) in
children with acute leukemia
CM Kearns, RL Blakley, VM Santana and WR Crom
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
Cladribine is a synthetic purine nucleoside with demonstrated activity in hairy cell leukemia and
acute myeloid leukemia.
We have studied the pharmacokinetics of this drug in 25 pediatric patients with acute leukemia
treated with cladribine as a single agent, 8.9 mg/m2/24 h, for 5 days by continuous i.v. infusion.
Twelve patients were in relapse, and acute myeloid leukemia was newly diagnosed in 13
patients.
Plasma, urine, and cerebrospinal fluid cladribine concentrations were determined by a
radioimmunoassay with a limit of detection of 1 nM.
An open two-compartment model was fit to the plasma concentration data.
The mean (SD) clearance was 39.4 (12.4) liters/h/m2 and ranged from 14.4-55.4 liters/h/m2.
When clearance was normalized to body weight (liters/h/kg) it was negatively correlated with
age, with older patients having slower clearances per unit of body weight.
However, when clearance was normalized to body surface area, no significant correlation with
age was observed.
The mean (SD) steady-state plasma concentration (predicted 120-h concentration) was 37.7
(17.3) nM and ranged from 23.2-84.5 nM.
The terminal phase half-life in 22 patients ranged from 14.3-25.8 h, with a mean (SD) of 19.7
(3.4) h.
The volume of distribution at steady state was highly variable, with a mean (SD) of 356.6 (225.2)
liters/m2.
None of these parameters was significantly different between patients in relapse and patients
with newly diagnosed disease.
Renal clearance was determined in 7 patients and ranged from 34.6-643.6 ml/min/m2, with a
mean (SD) of 317.9 (208.7) ml/min/m2. Renal clearance as a percentage of total systemic
clearance ranged from 11.0-85.1%, with a mean of 51.0%.
In 11 patients, the mean (SD) cerebrospinal fluid concentration was 6.1 (3.97) nM, a mean of
18.2% of the steady-state plasma concentration.
The CSF:plasma concentration ratio was significantly higher on day 5 (22.7% in 7 patients) than
on day 4 (7.6% in 3 patients; P = 0.03).
Additional studies are needed to further define the metabolic fate of cladribine.
In this paper we provide the first comprehensive description of the pharmacokinetics of this drug
in children and provide data which suggest that cladribine may be useful in the treatment of
patients with meningeal leukemia or malignancies of the central nervous system.
15
Neurology, Vol 51, Issue 1 228-233, Copyright © 1998 by American Academy of Neurology
Assessing information in T2-weighted MRI scans from
secondary progressive MS patients
JA Koziol, S Wagner and HP Adams
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
BACKGROUND:
Magnetic resonance imaging is used routinely for diagnosing MS and for objective assessment of
the extent of disease as a marker of treatment efficacy in MS clinical trials. Nevertheless, in
many clinical studies only weak correlations have been reported between MRI findings and
clinical outcome measures.
PURPOSE:
The purpose of this study is to compare clinical outcome measures (neurologic scales) with MRI
findings (evaluation of T2-weighted MRI scans using a semiautomated quantitative technique
and with an independent assessment by a neurologist) in the context of a randomized clinical trial
evaluating the efficacy of cladribine for treatment in secondary progressive MS.
METHODS:
Baseline, 6-month, and 12-month scans from 41 secondary progressive MS patients were
examined and ranked in terms of lesion burden from the quantitative assessment and
independently in terms of severity by neurologic evaluation. Comparison is made to monthly
Expanded Disability Status Scale (EDSS) and Scripps Neurologic Rating Scale (SNRS)
determinations in these patients with a nonparametric statistical procedure.
RESULTS:
Average rank correlations between any of the MRI assessment procedures and either clinical
outcome measure were less than 0.15 in absolute magnitude. The average rank correlation
between the two MRI assessment procedures was 0.10. There is only a weak degree of
association between the MRI assessment procedures and the clinical parameters, although the
study has statistical power in excess of 0.90 to find even a moderate level of association between
them.
CONCLUSIONS:
Disease-related activity in T2-weighted scans of secondary progressive MS patients is a
multidimensional construct, and is not summarized adequately solely by quantification of overall
lesion burden or by assessment of severity. Neither method of summarizing information from T2weighted scans is strongly related to measures of the clinical course of disease as assessed by the
EDSS or SNRS.
16
Cancer Research, Vol 51, Issue 20 5570-5572, Copyright © 1991 by American Association for Cancer Research
On the pharmacokinetics of 2-chloro-2'-deoxyadenosine in
humans
J Liliemark and G Juliusson
Department of Clinical Pharmacology, Karolinska Hospital, Stockholm, Sweden.
The antitumoral effect of 2-chloro-2'-deoxyadenosine (CdA) in the treatment of
lymphoproliferative diseases in general and of hairy cell leukemia in particular has recently been
demonstrated.
Detailed information on the pharmacokinetics of CdA, however, is lacking.
The pharmacokinetics of CdA after 2- and 24-h infusions of 0.14 mg/kg was described in 12
patients with lymphoproliferative diseases using a newly developed high-performance liquid
chromatography method.
The plasma concentration data from individual patients were fitted to a two-compartment model
with alpha- and beta-half-lives of 35 +/- 12 (mean +/- SD) min and 6.7 +/- 2.5 h, respectively.
The volume of distribution was 9.2 +/- 5.4 liters/kg.
The steady-state concentration of CdA during the 24-h infusion was 22.5 +/- 11.1 nM.
The areas under the time versus concentration curves were 552 +/- 258 and 588 +/- 185 nM x h,
respectively, for the 24- and 2-h infusions.
The interindividual variability of the determinants of the plasma pharmacokinetics of CdA was
small (the coefficients of variation were between 0.22 and 0.58).
At 6.3 +/- 1.5 h after the start of the 2-h infusion, the concentration of CdA was the same as the
steady-state concentration during the 24-h infusion.
When the mean plasma concentrations of the 12 patients were fitted to a 3-compartment model,
the half-lives of the alpha-, beta-, and tau-phases were 8 min, 1 h 6 min, and 6.3 h, respectively.
The long terminal half-life of CdA after 2-h infusion supports the use of intermittent infusions.
17
Volume 341:55 July 1, 1999 Number 1
Epstein–Barr Virus–Associated Lymphoma after Treatment
of Macroglobulinemia with Cladribine
To the Editor: Purine analogues, including cladribine (2-chlorodeoxyadenosine), are
increasingly used in the treatment of Waldenström's macroglobulinemia and other hematologic
cancers.1 Cladribine can cause profound immunosuppression, lymphopenia, and increased
susceptibility to opportunistic infections.2 We report on a patient with Waldenström's
macroglobulinemia in whom an Epstein–Barr virus (EBV)–associated diffuse large-cell
lymphoma developed after treatment with cladribine.
A 69-year-old woman received the diagnosis of Waldenström's macroglobulinemia with IgM
kappa in 1991. Because of the progression of the disease, treatment with standard doses of
cladribine was initiated in June 1994 and repeated in August 1994. The patient had a remarkable
response, with alleviation of her symptoms and more than 90 percent reduction of the serum
paraprotein level. Five months after the completion of treatment with cladribine, pain developed
in the right hip, and a right acetabular lytic lesion was found.
Laboratory tests showed lymphopenia, normal serum viscosity, and a stable IgM level.
Additional studies revealed a mass in the liver. Biopsies from both the right acetabulum and the
liver revealed morphologically identical lymphocytic infiltrates that were consistent with the
presence of diffuse large-cell lymphoma. The liver-biopsy specimen was positive on staining for
CD20, IgA kappa, and EBV latent membrane protein 1 (Figure 1). The patient subsequently died,
and an autopsy revealed diffuse large-cell lymphoma that was positive for EBV latent membrane
protein 1 in both liver and kidney specimens. An antemortem serologic test was positive for EBV
(data not shown).
Figure 1. Liver-Biopsy
Specimen Showing Dense
Infiltration with Large-Cell
Lymphoma (Immunoperoxidase
Stain, x100).
The malignant cells are positive
for Epstein–Barr virus latent
membrane protein 1.
18
The demonstration of IgA kappa light chain and the positive staining for EBV latent membrane
protein 1 in the lymphoma sample strongly suggest the development of a new, aggressive B-cell
diffuse large-cell lymphoma rather than Richter's transformation, which is rare in Waldenström's
macroglobulinemia.3 Although the role of prior EBV infection in the development of diffuse
large-cell lymphoma remains to be investigated, this case justifies the cautious use of cladribine
in patients who are seropositive for EBV.
Ruben Niesvizky, M.D.
Andrew X. Zhu, M.D., Ph.D.
Diane Louie, M.D.
Joseph Michaeli, M.D.
Memorial Sloan-Kettering Cancer Center
New York, NY 10021
References
1.
Dimopoulos MA, Kantarjian H, Weber D, et al. Primary therapy of Waldenstrom's
macroglobulinemia with 2-chlorodeoxyadenosine. J Clin Oncol 1994;12:2694-2698.[Abstract]
2.
Cheson BD. Infectious and immunosuppressive complications of purine analog therapy. J
Clin Oncol 1995;13:2431-2448.[Abstract]
3.
Harousseau JL, Flandrin G, Tricot G, Brouet JC, Seligmann M, Bernard J. Malignant
lymphoma supervening in chronic lymphocytic leukemia and related disorders: Richter's
syndrome: a study of 25 cases. Cancer 1981;48:1302-1308.[Medline]
19
Blood First Edition Paper
prepublished online March 27, 2003; DOI 10.1182/blood-2003-01-0014
Phase II study of rituximab in the treatment of cladribinefailed patients with hairy cell leukemia
Jorge Nieva, Kelly Bethel, and Alan Saven*
Division of Hematology and Oncology, Scripps Clinic, La Jolla, CA, USA
Department of Pathology, Scripps Clinic, La Jolla, CA, USA
*
Corresponding author; email: saven.alan@scrippshealth.org.
Hairy cell leukemia (HCL) is an indolent B-cell neoplasm, strongly expressing CD20. Despite
initial very high response rates following cladribine, many patients (pts.) ultimately relapse.
Twenty-four HCL pts.(21 male, 3 female), with a median age of 53.5 years, having relapsed after
prior treatment with cladribine, were treated with rituximab at 375mg/m2 intravenously weekly
x 4.
Three pts. (13%) achieved complete remissions and 3 pts. (13%) partial responses. Thus, six of
24 (25%) pts. achieved a response following rituximab.
At a median follow-up of 14.6 months, 2 responders have relapsed; median time to relapse not
yet reached.
The only grade III or IV toxicities demonstrated were culture-negative febrile neutropenia,
transient and reversible disseminated intravascular coagulation related to rituximab
administration, and a diverticular abscess, each in single patients.
Of 18 non-responders, 9 pts. subsequently received other treatments; 5 pts. were retreated with
cladribine, 3 underwent splenectomy and 1 received pentostatin.
Follow up data are available on 7 of these 9 patients; all 7 patients achieved improvements in
hematologic parameters.
Rituximab, administered at this dose and schedule, has only modest single agent activity in
cladribine-failed HCL patients when compared to other agents active in this disease.
20
Blood, Volume 78, Issue 10, pp. 2583-2587, 11/15/1991
Copyright © 1991 by The American Society of Hematology
Inhibitory effect of 2-chlorodeoxyadenosine on granulocytic,
erythroid, and T-lymphocytic colony growth
AL Petzer, R Bilgeri, U Zilian, M Haun, FH Geisen, I Pragnell, H Braunsteiner and G
Konwalinka
Department of Internal Medicine, University of Innsbruck, Austria.
Previous studies have shown that 2-chloro-2'-deoxyadenosine (CdA) is markedly toxic to normal
and malignant human lymphocytes in vitro and in vivo.
Recent clinical trials have shown that CdA is a very promising drug for the treatment of
lymphoid malignancies.
The present investigations were designed to test the effect of CdA on the in vitro clonal growth
of both myeloid progenitors and T-lymphocyte colony- forming cells (CFU-TL) obtained from
normal human bone marrow and peripheral blood.
Cells were exposed to CdA in doses up to 1280 nmol/L. To reduce indirect effects of CdA
mediated by accessory cells, monocyte- and T-lymphocyte-depleted bone marrow cells were
used for our investigations.
The results show a marked inhibition of myeloid progenitor and lymphocyte colony-forming
cells in a dose-dependent manner, correlating with maturation stage in that the immature
progenitor cells are more sensitive to this drug.
Furthermore, our studies suggest that a sequence of metabolic events previously described for
lymphocytes may be operative in myeloid progenitor cells because a minimal exposure time of
48 hours is required to obtain a marked inhibition. CdA toxicity was proposed to be linked with
phosphorylation by deoxycytidine-kinase (E.C. 2.7.1.74), the levels of which have been found to
be high in lymphocytes, but low in granulocytes.
However, the marked inhibition of myeloid progenitor cells shown in these studies suggests that
other factors such as modulation of the effect of CdA by the ambient levels of other
deoxynucleosides might influence the apparent sensitivity of myeloid cells.
21
Neurology 2000;54:1145-1155
© 2000 American Academy of Neurology
Articles
Cladribine and progressive MS
Clinical and MRI outcomes of a multicenter controlled trial
George P. A. Rice, MD, Massimo Filippi, MD, Giancarlo Comi, MD and for the Cladribine
Clinical Study Group* and for the Cladribine MRI Study Group,*
From the University Hospital (Dr. Rice), University of Western Ontario, London, Canada; and the Neuroimaging
Research Unit (Dr. Filippi) and Clinical Trials Unit (Dr. Comi), Department of Neuroscience, Scientific Institute
Ospedale San Raffaele, University of Milan, Italy.
Address correspondence and reprint requests to Dr. Rice, LHSC-UC, 339 Windermere Road, London, Ontario N6A
5A5, Canada; e-mail: grice@julian.uwo.ca
OBJECTIVE:
To evaluate the safety and efficacy of two doses of cladribine in patients with progressive MS.
BACKGROUND:
Treatment of progressive MS patients with cladribine in a previous single-center, placebocontrolled clinical trial was associated with disease stabilization.
METHODS:
In the current study, 159 patients with a median baseline Kurtzke’s Expanded Disability Status
Scale (EDSS) score of 6.0 were randomly assigned to receive placebo or cladribine 0.07
mg/kg/day for 5 consecutive days every 4 weeks for either two or six cycles (total dose, 0.7
mg/kg or 2.1 mg/kg, respectively), followed by placebo, for a total of eight cycles. Thirty percent
had primary progressive MS (PPMS) and 70% had secondary progressive MS (SPMS). EDSS
and Scripps Neurologic Rating Scale (SNRS) scores were assessed bimonthly and MRI was
performed every 6 months. The primary outcome measure was disability (mean change in
EDSS).
RESULTS:
Mean changes in disability did not differ among the groups at the end of the 12-month doubleblind phase. Both cladribine treatments were superior to placebo for the proportion of patients
having gadolinium-enhanced T1 lesions and for the mean volume and number of such lesions (p
0.003). Differences were statistically significant at the 6-month evaluation time, with 90%
reduction in volume and number of enhanced T1 lesions, which was maintained through final
evaluation. This effect segregated largely with the SPMS group. The T2 burden of disease
showed a modest improvement in cladribine-treated patients and worsened in placebo-treated
patients. Most adverse events were mild or moderate in severity and not treatment limiting.
CONCLUSION:
No significant treatment effects were found for cladribine in terms of changes in EDSS or SNRS
scores. Both doses of cladribine produced and sustained significant reductions in the presence,
number, and volume of gadolinium-enhanced T1 brain lesions on MRI, and cladribine 2.1 mg/kg
reduced the accumulation of T2 lesion load. Cladribine at doses up to 2.1 mg/kg was generally
safe and well tolerated.
Key words: Cladribine—MRI—Progressive MS—Suppression of disease activity.
22
Chest, Vol 112, 551-553, Copyright © 1997 by American College of Chest Physicians
Primary pulmonary hypertension in a patient with CD8/Tcell large granulocyte leukemia: amelioration by cladribine
therapy
LJ Rossoff, J Genovese, M Coleman and DR Dantzker
Department of Medicine, Long Island Jewish Medical Center, New Hyde Park, NY 11042, USA.
We report a case of primary pulmonary hypertension in an adult man with CD8/T-cell large
granulocyte leukemia. Successful treatment of his leukemia with cladribine resulted in dramatic
and sustained improvement of his pulmonary hypertension.
23
Annals of Oncology, Vol 10, Issue 1 115-117, Copyright © 1999 by European Society for Medical Oncology
Treatment of mantle-cell lymphomas with intermittent twohour infusion of cladribine as first-line therapy or in first
relapse
M. J. Rummel, K. U. Chow, E. Jager, D. K. Hossfeld, L. Bergmann, H. D. Peters, M. L.
Hansmann, A. Meyer, D. Hoelzer and P. S. Mitrou
Med. Klinik III, Johann Wolfgang Goethe-Universitatsklinik, Frankfurt/Main, Germany. rummel@em.unifrankfurt.de
PURPOSE:
Cladribine (2-chlorodeoxyadenosine, 2-CdA) has been reported to be effective in the treatment
of low-grade lymphomas. The objective of this multicenter study was to evaluate the activity of
cladribine in mantle-cell lymphomas as first-line therapy or in first relapse using an intermittent
two-hour infusion of cladribine.
PATIENTS AND METHODS:
A total of 47 courses, or an average of four courses per patient, were administered to 12 patients
(seven untreated, five relapsed) with 5 mg/m2 cladribine given as an intermittent two-hour
infusion over five consecutive days for a maximum of six cycles every four weeks.
RESULTS:
Cladribine showed activity in patients with mantle-cell lymphomas, achieving a response rate of
58% (95% confidence interval (95% CI): 28%-85%). Myelosuppression was the major toxicity
with 17% of grade 3 and 4 neutropenia. Thrombocytopenia was rare with only 2% of grade 3 and
4.
CONCLUSION:
These results demonstrate single-agent activity of cladribine in mantle-cell lymphomas using the
intermittent two-hour infusion dosage regimen. To further improve treatment results, cladribine
should be combined with other agents active in mantle-cell lymphomas.
24
Blood, 1 February 2003, Vol. 101, No. 3, pp. 943-945
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Efficacy of 2-chlorodeoxyadenosine in refractory factor VIII
inhibitors in persons without hemophilia
Sabah Sallah and Jim Y. Wan
From the Thrombosis and Hemostasis Program and Feist-Weiller Cancer Center, Louisiana State
University Health Sciences Center, Shreveport, LA; and the Department of Preventive Medicine,
University of Tennessee Health Sciences Center, Memphis.
The authors examined the efficacy of 2-chlorodeoxyadenosine (2-CdA) in the treatment of
refractory inhibitors to factor VIII in persons without hemophilia.
The drug was administered to 6 patients at a dose of 0.1 mg/kg as a 24-hour continuous infusion
for a total of 7 days each cycle.
An average of 3 immunosuppressive regimens per patient had been administered prior to
enrollment in this study.
The median inhibitor titer against human and porcine factor VIII before treatment with 2-CdA
was 31 Bethesda units (BUs) and 9 BU, respectively.
The median inhibitor titer against human and porcine factor VIII after treatment was 3.5 BU and
1.5 BU, respectively.
The median time to reach nadir inhibitor titer in this study was 137 days, whereas the median
time to reach a 50% increase in factor VIII was 117 days.
No major toxicity was observed in any patient in this study. Patients with acquired inhibitors to
factor VIII refractory to conventional immunosuppressive therapy may respond favorably to
2-CdA.
25
Journal of Clinical Oncology, Vol 15, 37-43, Copyright © 1997 by American Society of Clinical Oncology
Major activity of cladribine in patients with de novo B-cell
prolymphocytic leukemia
A Saven, T Lee, M Schlutz, A Jacobs, D Ellison, R Longmire and L Piro
Department of Pathology, Ida M. and Cecil H. Green Cancer Center, Scripps Clinic and Research Foundation, La
Jolla, CA 92037, USA.
PURPOSE:
De novo B-cell prolymphocytic leukemia (B-PLL) is a distinct clinicopathologic entity usually
characterized by marked lymphocytosis, massive splenomegaly, an aggressive course, and
refractoriness to therapy. Cladribine (2-chlorodeoxyadenosine [2-CdA]; Ortho Biotech, Raritan,
NJ) is a newer purine analog with potent activity against indolent lymphoproliferative disorders.
PATIENTS AND METHODS:
We treated eight patients with cladribine 0.1 mg/kg/d for 7 days by continuous infusion or 0.14
mg/kg/d over 2 hours for 5 days, every 28 to 35 days, for a median of three courses (range, two
to five). There were five men and three women, with a median age of 62 years and a median
pretreatment duration of 6 months; four patients were previously untreated.
RESULTS:
All eight patients were assessable: five achieved a complete response with a median response
duration of 14 months (range, 1+ to 55+), and three achieved a partial response with a median
duration of 3 months (range, 1 to 3). Of four patients who achieved a complete response and in
whom a peripheral-blood immunophenotypic analysis was performed, two had no circulating BPLL cells and one had no residual disease on Southern blot analysis. Myelosuppression and
infection were the major toxicities: three patients developed grade 3 or 4 myelosuppression, four
had bacterial infections, and two had herpes zoster infections.
CONCLUSION:
In this small study of patients with de novo B-PLL, cladribine was an active agent that induced a
high overall and complete response rate. These results require confirmation in larger numbers of
B-PLL patients.
26
Journal of Clinical Oncology, Vol 14, 978-983, Copyright © 1996 by American Society of Clinical Oncology
Pharmacokinetic study of oral and bolus intravenous 2chlorodeoxyadenosine in patients with malignancy
A Saven, WK Cheung, I Smith, M Moyer, T Johannsen, E Rose, R Gollard, M Kosty, WE
Miller and LD Piro
Division of Hematology and Oncology, Scripps Clinic and Research Foundation, La Jolla, CA, USA.
PURPOSE:
This study was designed to evaluate the absolute bioavailability (F value) of 2chlorodeoxyadenosine (cladribine; 2-CdA) after multiple oral administrations, and the
intersubject variability after oral and 2-hour intravenous (IV) administration schedules in patients
with malignancy.
PATIENTS AND METHODS:
Patients with advanced malignancies were eligible. There were two treatment cycles; during
cycle 1, patients received 2-CdA solution at 0.28 mg/kg/d orally under fasting conditions for 5
consecutive days concomitantly with omeprazole, and 4 weeks later during cycle 2 patients
received 2-CdA as a 2-hour IV infusion of 0.14 mg/kg/d for 5 consecutive days. Serial blood
samples for 2-CdA plasma levels were obtained after drug administrations on days 1 and 5
during each treatment cycle.
RESULTS:
Ten patients completed cycles 1 and 2. The F value of oral 2-CdA measured on days 1 and 5 was
37.2% and 36.7%, respectively. For both oral and IV multiple administrations, there was no
significant accumulation in maximum concentration (Cmax), and the intersubject variabilities
(coefficient of variation [CV], approximately 40%) in Cmax and area under the concentrationtime curve from 0 to 24 hours [AUC(0-24)] values were comparable for both routes on days 1
and 5. A three-compartment open model was applied to the plasma concentration data after oral
and IV administrations and resulted in good agreement between observed and simulated
concentration-time profiles. Neutropenia was the principal adverse event observed when 2-CdA
was administered orally and IV.
CONCLUSION:
The F value of 2-CdA after oral administration was approximately 37% and there were no
cumulative differences in bioavailability observed on multiple dosing of the drug. The absorption
and disposition characteristics of oral 2-CdA were linear and predictable with this dosing
regimen.
27
Journal of Clinical Oncology, Vol 13, 983-988, Copyright © 1995 by American Society of Clinical Oncology
Cladribine in the treatment of relapsed or refractory
chronic lymphocytic leukemia
MS Tallman, D Hakimian, C Zanzig, DK Hogan, A Rademaker, E Rose and D Variakojis
Department of Medicine, Robert H. Lurie Cancer Center of Northwestern University, Northwestern University
Medical School, Chicago, IL 60611, USA.
PURPOSE:
Cladribine (2-CdA), a purine analog resistant to adenosine deaminase, has significant activity in
a variety of lymphoproliferative diseases. This study was designed to determine the efficacy of 2CdA in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).
PATIENTS AND METHODS:
Twenty-six patients aged 40 to 88 years (median, 64) who either had relapsed after an initial
response or were refractory to conventional chemotherapy with at least an alkylating agent were
treated with 2-CdA 0.1 mg/kg/d by continuous intravenous infusion for either 5 or 7 days every
28 days for a maximum of six cycles.
RESULTS:
No complete remissions (CRs) occurred. Eight of 26 patients (31%) achieved a partial remission
(PR). The actuarial median time to progression (TTF) in responding patients is 16 months (range,
6 to 22). The actuarial median survival duration of the responding patients is 12 months (range, 8
to 28). Eight of 26 patients (31%) sustained early toxicity. Seven of these eight patients died
before the first reevaluation of infection (n = 3), pericardial tamponade (n = 1), Stevens-Johnson
syndrome (n = 1), and stroke (n = 2). No nausea, emesis, alopecia, or renal, hepatic, or cardiac
toxicity was observed.
CONCLUSION:
2-CdA has activity in patients with relapsed or refractory CLL. However, patients who have
received multiple prior regimens that included fludarabine are less likely to respond, and there
can be significant morbidity. Treatment of patients with less prior therapy earlier in the natural
history of the disease may lead to improved and more durable responses.
28
Annals of Oncology, Vol 11, Issue 2 231-233, Copyright © 2000 by European Society for Medical Oncology
Fludarabine and cladribine in relapsed/refractory low-grade
non-Hodgkin's lymphoma: a phase II randomized study
C. Tondini, M. Balzarotti, I. Rampinelli, P. Valagussa, M. Luoni, A. De Paoli, A. Santoro
and G. Bonadonna
Division of Medical Oncology, Istituto Nazionale Tumori, Milan, Italy. tondini@istitutotumori.mi.it
BACKGROUND:
It is unclear whether the purine analogs fludarabine (Flu) and cladribine (CdA) are non-resistant.
PATIENTS AND METHODS:
Sixty patients with relapsed or refractory low-grade NHL were randomly allocated to initial
treatment with either Flu 25 mg/m2, or CdA 0.14 mg/kg, each for five consecutive days every
four weeks. Upon treatment failure, eligible patients were crossed over to the other study drug.
RESULTS:
Overall response and CR were 68% and 48% with Flu, and 72% and 38% with CdA,
respectively. For responders, actuarial three-year progression-free survival was 58% with Flu and
52% with CdA. Treatment with both drugs was well tolerated, with toxic effects primarily
hematological. Two patients (8%) in the Flu group and 15 patients (47%, P = 0.001) in the CdA
group were taken off study because of persistent hematological toxicity. After cross over, none of
seven refractory patients responded, while eight of nine previously responsive patients achieved
second responses.
CONCLUSIONS:
Our study confirms that Flu and CdA have similar response rates and durations. However, further
studies are required to optimize the CdA schedule and dosage in order to ameliorate its toxic
profile while maintaining antitumor activity. The two drugs appear to be cross-resistant.
29
Volume 330:1090 April 14, 1994 Number 15
Tumor Lysis Syndrome after Treatment of Chronic
Lymphocytic Leukemia with Cladribine
To the Editor: In the November 18 issue of the Journal, Dann et al.1 reported a case of tumor
lysis syndrome after treatment with 2-chlorodeoxyadenosine (cladribine) in a patient with
refractory chronic lymphocytic leukemia. We would like to report another case of tumor lysis
syndrome resulting from treatment with 2-chlorodeoxyadenosine.
A 59-year-old man presented to the Mayo Clinic for a second opinion concerning therapy for his
chronic myelogenous leukemia in chronic phase, which had been diagnosed approximately 18
months earlier. The patient could not tolerate hydroxyurea, had dose-limiting thrombocytopenia
when treated with busulfan, and did not want to try interferon alfa. He was therefore enrolled in a
phase 1 experimental protocol using 2-chlorodeoxyadenosine. He was not taking allopurinol
because of a history of a dermatologic reaction. Physical examination revealed a spleen palpable
10 cm below the left costal margin. The initial white-cell count was 138,200 per cubic
millimeter. The bone marrow-biopsy specimen contained 5 percent blasts, a finding consistent
with chronic myelogenous leukemia in chronic phase. Cytogenetic studies revealed the
Philadelphia chromosome. The initial electrolyte, creatinine, and uric acid concentrations were
normal. The protocol called for the patient to receive an infusion of 12 mg of 2chlorodeoxyadenosine per square meter of body-surface area over a period of two hours for five
days. On the morning after the second infusion, the patient had a temperature of 38.7 °C, was
nauseated, and generally felt unwell. The 2-chlorodeoxyadenosine was discontinued. A
laboratory evaluation revealed a serum potassium concentration of 5.5 mmol per liter, a serum
bicarbonate concentration of 19 mmol per liter, a uric acid concentration of 22.0 mg per deciliter,
and a creatinine concentration of 1.9 mg per deciliter; the white-cell count had decreased to
69,800 per cubic millimeter. The patient was treated with intravenous hydration, alkalinization of
the urine, and cautious reinstatement of allopurinol. Within 72 hours, all metabolic measures
normalized. The white-cell count reached a nadir of 2300 per cubic millimeter eight days after 2chlorodeoxyadenosine was initiated.
This case is a second example of tumor lysis syndrome resulting from 2-chlorodeoxyadenosine.
The use of this relatively new chemotherapeutic agent requires close monitoring of renal function
and serum uric acid concentrations and the prophylactic use of allopurinol.
Michael C. Trendle, M.D.
Ayalew Tefferi, M.D.
Mayo Clinic
Rochester, MN 55905
References
1.
Dann EJ, Gillis S, Polliack A, Okon E, Rund D, Rachmilewitz EA. Tumor lysis
syndrome following treatment with 2-chlorodeoxyadenosine for refractory chronic lymphocytic
leukemia. N Engl J Med 1993;329:1547-1548.[Full Text]
30
The authors reply:
To the Editor: A rapid decline in the white-cell count following treatment with 2chlorodeoxyadenosine in two patients with chronic myelogenous leukemia in blast crisis was
reported by Carson et al. 10 years ago,1 although full-blown tumor lysis syndrome was not
described in these patients. The patient described by Drs. Trendle and Tefferi seems to have been
given considerably higher doses of 2-chlorodeoxyadenosine, in terms of both peak levels and
total dose, than those given to the patients of Carson et al. (12 mg per square meter of bodysurface area per day over a 2-hour period vs. 0.1 to 0.15 mg per kilogram of body weight per day
over a 24-hour period). In previous phase 1 trials, doses of 2-chlorodeoxyadenosine exceeding
0.5 mg per kilogram per day were associated with nephrotoxicity2. It is possible that the acute
renal failure documented by Trendle and Tefferi in their patient may have resulted from
nephrotoxicity and not from tumor lysis syndrome itself.
Nonetheless, we fully concur that in patients being treated with this new drug, especially if
innovative dosing regimens are being used or if there is evidence of a large tumor burden, very
close monitoring of renal, biochemical, and hematologic variables is essential.
Eldad J. Dann, M.D.
Eliezer A. Rachmilewitz, M.D.
Deborah Rund, M.D.
Hadassah University Hospital
il-91120 Jerusalem, Israel
References
1.
Carson DA, Wasson DB, Beutler E. Antileukemic and immunosuppressive activity of 2chloro-2'-deoxyadenosine. Proc Natl Acad Sci U S A 1984;81:2232-2236.[Medline]
2.
Saven A, Piro LD. 2-Chlorodeoxyadenosine: a new nucleoside agent effective in the
treatment of lymphoid malignancies. Leuk Lymphoma 1993;10:Suppl:43-49.
This article has been cited by other articles:

Hansford, J. R, Mulligan, L. M (2000). Multiple endocrine neoplasia type 2 and RET:
from neoplasia to neurogenesis. J. Med. Genet. 37: 817-827 [Abstract] [Full Text]

Yeung, S.-C. J., Chiu, A. C., Vassilopoulou-Sellin, R., Gagel, R. F. (1998). The
Endocrine Effects of Nonhormonal Antineoplastic Therapy. Endocr Rev 19: 144-172 [Abstract]
[Full Text]
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Annals of Oncology 13:1641-1649, 2002
© 2002 European Society for Medical Oncology
Treatment of hairy cell leukemia with cladribine (2chlorodeoxyadenosine) by subcutaneous bolus injection: a
phase II study
A. von Rohr1,+, S.-F. H. Schmitz2, A. Tichelli3, U. Hess4, D. Piguet5, M. Wernli6, N.
Frickhofen7, G. Konwalinka8, G. Zulian9, M. Ghielmini10, B. Rufener2, C. Racine1, M. F.
Fey1, T. Cerny1, D. Betticher1 and A. Tobler11
1
Institute of Medical Oncology, Inselspital, Bern; 2 SIAK Coordinating Center, Bern; 3 Division of Hematology,
Kantonsspital, Basel; 4 Department of Internal Medicine, Kantonsspital, St Gallen; 5 Department of Internal
Medicine, Hôpital des Cadolles, Neuchâtel; 6 Department of Internal Medicine, Kantonsspital, Aarau, Switzerland; 7
Department of Internal Medicine, University Hospital, Ulm, Germany; 8 Department of Internal Medicine,
University Hospital, Innsbruck, Austria; 9 Department of Internal Medicine, University Hospital, Geneva; 10
Oncology Institute of Southern Switzerland, Bellinzona; 11 Central Hematology Laboratory, University Hospital,
Bern, Switzerland
Received 8 January 2002; revised 11 April 2002; accepted 24 April 2002
Background:
To assess the activity and toxicity of 2-chlorodeoxyadenosine (cladribine, CDA) given by
subcutaneous bolus injections to patients with hairy cell leukemia (HCL).
Patients and methods:
Sixty-two eligible patients with classic or prolymphocytic HCL (33 non-pretreated patients, 15
patients with relapse after previous treatment, and 14 patients with progressive disease during a
treatment other than CDA) were treated with CDA 0.14 mg/kg/day by subcutaneous bolus
injections for five consecutive days. Response status was repeatedly assessed according to the
Consensus Resolution criteria.
Results:
Complete and partial remissions were seen in 47 (76%) and 13 (21%) patients, respectively, for a
response rate of 97%. All responses were achieved with a single treatment course. Most
responses occurred early (i.e. within 10 weeks) after start of CDA therapy, but response quality
improved during weeks and even months after treatment completion. The median time to
treatment failure for all patients was 38 months. Leukopenia was the main toxicity. Granulocyte
nadir (median 0.2 x 109/l) was strongly associated with the incidence of infections (P = 0.0013).
Non-specific lymphopenia occurred early after CDA treatment, and normal lymphocytes
recovered slowly over several months. No significant associations were found between infections
and nadir count of lymphocytes or any lymphocyte subpopulation. No opportunistic infections
were observed.
Conclusions:
One course of CDA given by subcutaneous bolus injections is very effective in HCL. The
subcutaneous administration is more convenient for patients and care providers, and has a similar
toxicity profile to continuous intravenous infusion. The subcutaneous administration of CDA is a
substantial improvement and should be offered to every patient with HCL requiring treatment
with CDA.
Key words: 2-chlorodeoxyadenosine, cladribine, hairy cell leukemia
32