Fludarabine:An Update of its Pharmacology and Use in the Treatment of Haematological Malignancies
Julie C. Adkins,David H. Peters and Anthony Markham
Adis International Limited, Auckland,New Zealand
Various sections of the manuscript reviewed by:
M.K.Angelopoulou,First Department of Internal Medicine,National and Kapodistrian University of Athens School of Medicine,Laikon General Hospital,Athens,Greece;A.B.Astrow,Department of Medicine,Saint Vincent’s Hospital and Medical Center,New York,New York,USA;V.Avramis,Department of Medicine, Saint Vincent’s Hospital and Medical Center, New York, New York, USA; D. Catovsky, Academic Haematology and Cytogenetics,The Royal Marsden Hospital NHS Trust, London, England; B. Cheson, National Cancer Institute,Clinical Investigations Branch, Bethesda, Maryland, USA;S. Gillis, Department of Hematology,Hadassah Medical Center,Jerusalem,Israel;G. Juliusson, Department of Hematology, University Hospital,Linköping,Sweden;S.A.Johnson, Department of Haematology, Taunton and Somerset Hospital,Taunton,Somerset, England; M.Leporrier,Service d’Hématologie Clinique,Centre Hospitalier Universitaire, Caen,France; F.M. Muggia, Kaplan Cancer Center,New York University Medical Center,New York,New York, USA; J.F. Seymour,Ludwig Institute for Cancer Research,Royal Melbourne Hospital, Parkville,Victoria,Australia.
Contents
Summary 1006
1. Overview of Pharmacodynamic Properties 1009
1.1 Mechanismn of Action 1009
1.2 In Vitro Studies. 1009
1.2.1 Synergy between Fludarabine and Other Chemotherapeutic Agents 1010 1.3 In Vivo Studies….
2. Overview of Pharmacokinetic Properties 1012
3. Therapeutic Efficacy.
10133.1 Chronic Lymphocytic Leukaemia
10133.1.1 Fludarabine Monotherapy
10153.1.2 Fludarabine Combination Therapy 1017
3.1.3 Prolymphocytic Leukaemia 1018
3.1.4 T Cell CLL.. 10183.2 Acute Leukaemias 1018
3.3 Non-Hodgkin’s Lymphoma 1019
3.3.1 Fludarabine Monotherapy 1019
3.3.2 Fludarabine-Based Combination Therapy 1022
3.4 Cutaneous T Cell Lymphomas 1023
3.5 Lymphoplasmacytoid Lymphoma and Waldenstrom’s Macroglobulinaemia 1024
3.6 Other Haematological Malignancies 1024
3.7 Application in Peripheral Blood Stem Cell and Bone Marrow Transplantation 1025 4. Tolerability…
10254.1 Myelosuppression and Infection 1025
4.2 Neurotoxicity 1026
4.3 Autoimmune Complications 1026 
4.4 Other Events. 1027
4.5 Comparative Tolerability 1027
5.Dosage and Administration. 1027
6.Place of Fludarabine in the Management of Haematological Malignancies 1028
Summary
Synopsis
Pharmacodynamic
Properties

Fludarabine is an antineoplastic agent which has been studied in patients with a variety of lymphoproliferative malignancies.
Clinical evidence from comparative studies in chronic lymphocytic leukaemia (CLL)suggests that fludarabine is at least as effective as CAP (cyclophos-phamide,doxorubicin and prednisone) or CHOP (cyclophosphamide,vincris-tine,doxorubicin and prednisone) in previously treated or chemotherapy-naive patients and significantly more effective than chlorambucil in terms of response rate and duration and survival in chemotherapy-naive patients. Promising results have also been reported with fludarabine-based combination therapy in the treat-ment of patients with CLL. In addition, sequential therapy with fludarabine and cytarabine has demonstrated good efficacy in the treatment of acute leukaemias, as has fludarabine monotherapy and combination therapy in low grade non-Hodgkin’s lymphoma.
A favourable cytoreductive response has been reported in patients with lymphoplasmacytoid lymphoma and in a smaller number of patients with cuta-neous T cell lymphomas, CLL of T cell origin or prolymphocytic leukaemia. Recent data also support the use of fludarabine, either as a component of a nonmyeloablative conditioning regimen or in the attainment of minimal residual disease,in patients undergoing peripheral blood stem cell or bone marrow trans-plantation.
The tolerability profile of fludarabine is similar to that ofCAP,with the most common adverse events being granulocytopenia,thrombocytopenia,anaemia and infection. Alopecia and nausea/vomiting appear to be less frequent with fludarabine therapy than with CAP although the development of immune cyto-penias is more frequent with fludarabine.Severe neurotoxicity has been reported with fludarabine but this is mostly confined to the use of high doses.
Clinical experience therefore indicates that fludarabine is an effective and generally well-tolerated antineoplastic agent for the second-line treatment of advanced CLL. Recent data from comparative studies also support the earlier use of fludarabine in the treatment of chemotherapy-naive patients with CLL. Furthermore,results of available studies are increasingly highlighting an impor-tant future role for fludarabine in the treatment of acute leukaemias and low grade NHL and possibly other lymphoproliferative disorders, particularly when used as a component of combination chemotherapy.
Postulated mechanisms for the antitumour activity of fludarabine include termi-nation of DNA and RNA synthesis by incorporation of theactive metabolite F-ara-A(9-β-D-arabino-furanosyl-2-fluoroadenine) triphosphate (F-ara-ATP) into elongating nucleic acid chains, inhibition of DNA and RNA polymerases, DNA primase,DNA ligase and ribonucleotide reductase and potentiation of de-oxycytidine kinase activity. Both in vitro and in vivo studies have highlighted apoptosis as an additional important mode of fludarabine-induced cell death.
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Fludarabine:An Update
Pharmacokinetic
Properties
Therapeutic Efficacy

1007
However,the relative importance of inhibition of DNA and RNA synthesis in the induction of the apoptotic process by fludarabine has not been fully elucidated.
In vitro,fludarabine demonstrated concentration-and time-dependent cyto-toxicity against human leukaemia cell lines. Fludarabine has been shown to po-tentiate the activity of a number of antitumour agents in vitro including cytarabine,cisplatin, mitoxantrone and gallium nitrate. Fludarabine has in vivo antitumour activity against a wide range of murine tumour models and has been shown to induce radiosensitisation in the Meth-a fibrosarcoma,SA-NH sarcoma and MCA-K and MCA-4 murine mammary carcinoma models. The mechanism of fludarabine-induced radiosensitisation appears to involve the elimination of cells in S-phase by apoptosis and synchronisation of the remaining cells to a more radiosensitive cell cycle phase.Fludarabine also reduced the number of lympho-cytes able to proliferate and trigger rejection in mice after total body irradiation, suggesting a possible future immunosuppressant role for fludarabine in bone marrow transplantation conditioning.
Within 5 minutes of intravenous administration, the prodrug fludarabine under-goes complete dephosphorylation to F-ara-A. The plasma pharmacokinetics of F-ara-A appear to be linear with no accumulation following repeated daily ad-ministration. In adults, volume of distribution at steady state and plasma clearance were up to=10-fold greater than the corresponding values in children, and wide interstudy differences in the area under the plasma concentration-time curve were reported at each fludarabine dosage level studied.
A predominantly biphasic decline in plasma F-ara-A concentrations has been reported with distribution and terminal elimination half-lives of 0.9 to 1.7 hours and 6.9 to 33.5 hours,respectively.However,a triphasic decline in plasma F-ara-A concentrations which included an initial distribution phase of 5 to 9 minutes has also been reported.
Peak intracellular levels of the active metabolite of fludarabine,F-ara-ATP, have been reported within 3 to 4 hours after termination of fludarabine infusion.
Renal mechanisms play an important role in the elimination of fludarabine with a reported correlation between increased serum creatinine and blood urea nitrogen levels and decreased F-ara-A elimination.In addition,fludarabine-associated neutropenia appears to be more severe in patients with a creatinine clearance <50 ml/min(<3 L/h).
In the treatment of advanced chronic lymphocytic leukaemia(CLL),response to fludarabine monotherapy has been shown to be strongly correlated to stage of disease,extent of previous chemotherapeutic treatment and response to prior chemotherapy.
Following treatment with single-agent fludarabine(20 to 30 mg/㎡/day for 5 days repeated every 3 to 5 weeks) in noncomparative studies, objective response rates of 12 to 94% have been reported in previously treated patients and up to 78% in chemotherapy-naive patients.Notably,the recent results of a large multi-centre comparative study have shown fludarabine (25 mg/㎡/day for 5 days re-peated every 4 weeks) to be significantly more effective than chlorambucil(40 mg/m-/day on day 1 every 4 weeks) in themanagement of previously untreated patients with CLL in terms of objective response rate (70 vs 43%),response duration (33 vs 17 months) and progression-free survival (27 vs 17 months).
Comparative studies have also shown fludarabine (25 mg/m/day for 5 days) to be at least as effective as standard therapy with CAP or CHOP in terms of
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Tolerability
Dosage and
Administration

response rate in patients with previously treated or untreated advanced CLL.A significant increase in remission duration and a tendency towards longer overall survival with fludarabine compared with CAP was also reported in chemother-apy-naive patients.Promising results have been reported following the use of fludarabine in combination with other chemotherapeutic agents such as doxoru-bicin, cyclophosphamide, epirubicin and mitoxantrone in the treatment of che-motherapy-naive and previously treated patients with CLL.
Complete remission rates of 36 to 64% in acute myelogenous leukaemia and/or been reported with sequential fludarabine and cytarabine therapy (with or without granulocyte colony-stimulating factor).Likewise,complete response rates of 4 to 37% were achieved with fludarabine monotherapy (18 to 30 mg/㎡/day for 5 days repeated every 3 to 5 weeks) and up to 89% with fludarabine-based combi-nation chemotherapy in patients with low grade NHL.
Fludarabine has also shown activity in the treatment of the cutaneous T cell lymphomas,mycosis fungoides and Sézary syndrome,lymphoplasmacytoid lym-phoma including Waldenström's macroglobulinaemia,CLL of T cell origin and prolymphocytic leukaemia.However, further evaluation in larger patient popu-lations is necessary.
Recently the use of fludarabine-based combination chemotherapy has demon-strated promising utility as a nonmyeloablative conditioning regimen in al-logeneic bone marrow or peripheral blood stem cell transplantation for patients with haematological malignancies.
In a study comparing fludarabine with CAPin patients with advanced-stage CLL, the most frequent adverse events(WHO grade III/IV) reported with fludarabine were granulocytopenia (19% of cycles), thrombocytopenia (14%) and anaemia (7%).Fludarabine produced less nausea/vomiting and alopecia than the standard CAP regimen but was associated with an increased incidence of autoimmune phenomena (including autoimmune haemolytic anaemia and thrombocytopenia). Compared with CAP,fludarabine did not increase the incidence of infectious events(which has been associated with a depletion of CD4+cells);the results of other studies suggest that an increase in infectious episodes with fludarabine therapy is predominantly attributable to the concomitant administration of corti-costeroids.
Severe neurotoxicity following fludarabine therapy is clearly dose-related and is minimal with the use of standard dosages of the drug.Isolated cases of tumour lysis syndrome,interstitial pneumonitis and haemolytic uraemic syndrome fol-lowing treatment with fludarabine have also been reported.
For the treatment of CLL,the recommended dose of fludarabine is 25mg/㎡, administered as a 30-minute intravenous infusion or as an intravenous bolus injection daily for 5 days and repeated at 28-day intervals. Dosages of 20 to 30 mg/m/day for up to 5 consecutive days repeated every 3 to 5 weeks in combina-tion with cytarabine in the treatment of acute leukaemia and as single-agent or combination therapy in NHL have also been used successfully.
Fludarabine dosage reductions based on creatinine clearance values is recom-mended in patients with known or suspected renal impairment; the drug is con-traindicated in those with a creatinine clearance <30 ml/min (1.8 L/h).
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Fludarabine is a synthetic adenine nucleoside analogue(fig. 1)which is currently indicated for the second-line treatment of chronic lymphocytic leukaemia(CLL).The pharmacology and thera-peutic activity of this agent in patients with CLLor other haematological malignancies were first re-viewed in Drugs by Ross et al.I'This review pres-ents an overview of information presented in the previous review supplemented with more recently published data.
1. Overview of
Pharmacodynamic Properties
1.1 Mechanism of Action
The mechanism of action of fludarabine is con-sidered to be partly attributable to incorporation of the active metabolite F-ara-A (9-β-D-arabino-furanosyl-2-fluoroadenine) triphosphate (F-ara-ATP) into elongating nucleic acid chains,which results in the termination of DNA or RNA synthe-sis.l1,21 Additional intracellular actions postulated to contribute to the antineoplastic activity of fludarabine include inhibition of several intracel-lular enzymes including DNA and RNA polymer-ases and DNA primase,13-81 DNA ligasel3,91 and ribonucleotide reductase,131 and potentiation of de-oxycytidine kinase activity.110
Programmed cell death (apoptosis) is an impor-tant mode of cell death following the exposure of leukaemic cells to fludarabine.Several in vitro stud-ies demonstrated that fludarabine is able to trigger apoptosis in human leukaemia cell lines.l11-14| Fur-thermore,fludarabine-induced apoptosis was also reported in vivo in murine mammary (MCa-4)and ovarian (OCa-I) adenocarcinomas.l151 A correla-tion between in vitro apoptosis and clinical re-sponse to chemotherapy was reported in a prelim-inary study.1161
The exact mechanism whereby the apoptotic response to fludarabine occurs is not fully eluci-dated at present.The incorporation of fludarabine into DNA was reported to be a critical process in the stimulation of the apoptotic process in human T-lymphoblastoid CEM cells.ll7| Fludarabine-
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Fig.1.Structural formula of fludarabine.
mediated inhibition of nucleotide excision repair in quiescent human lymphocytes was also associated with an increased incidence of apoptosis.l18| How-ever,the results of another study suggested that inhibition of RNA rather than DNA synthesis may be an important factor in this respect.1191
Correlation between a high rate of spontaneous apoptosis and in vitro sensitivity to fludarabine in cells isolated from patients with CLL of B cell ori-gin(B-CLL),has been reported.1201 Furthermore, several studies demonstrated a correlation between mutations in the p53 gene,which is thought to be involved in the regulation of apoptosis,and resis-tance to chemotherapeutic agents, including fludarabine, in CLL.121-231
The results of a recent in vivo study suggest that fludarabine spares natural killer cells and may stimulate natural killer cell activity in some pa-tients with CLL.1241
More efficient intracellular transport and in-creased phosphorylation of F-ara-A have been pos-tulated as potential mechanisms for the toxicity of fludarabine in leukaemic lymphocytes as opposed to healthy tissue.125,26|
1.2 In Vitro Studies
The in vitro activity of fludarabine against hu-man leukaemia cell lines has been demonstrated in several studies which typically showed concentra-tion-and time-dependent cytotoxicity.127,281 In freshly isolated B-CLL cells,the mean cytotoxicity
Drugs 1997 Jun:53(6) 

of fludarabine was reported to be 45%,which was similar to that of cladribine (55%) and higher than that of pentostatin (20%).[12] An ICso value (con-centration of drug required to reduce the surviving cell fraction by 50%) of 4.83 mg/L was reported after incubation of peripheral blood cells from pa-tients with B-CLL with fludarabine 0.05 to 50 mg/L for 48 hours.1291 Subsequent treatment of 9 of these patients with fludarabine 25 mg/㎡2/day for 5 days resulted in an ICso value of 4.75 mg/L among responding patents and 5.5 mg/L for nonrespon-ders. In another study, the ICso value for fludarab-ine in B-CLL cells was 2.19 to >36.52 mg/L and was significantly lower for chlorambucil-sensitive than for chlorambucil-resistant cells(p<0.01).1231
The in vitro antitumour activity of fludarabine has been compared with that of cladribine and chlorambucil in CLL cells.1301 On a molar basis,the ranked median cytotoxic activities were in the or-der chlorambucil>cladribine>fludarabine.Cells from approximately 90% of patients had a similar relative order of sensitivity to fludarabine and cladribine.
Through inhibition of the primer RNA com-ponent of Okazaki fragments (small units of new-ly synthesised DNA comprising approximately 1000 nucleotides), fludarabine has been shown to block the development of CAD gene amplifica-tion and subsequent PALA(N-phosphonoacetyl-L-aspartic acid) resistance induced by cytarabine or aphidicolin in human CCRF-CEM leukaemia cells.[31]
1.2.1 Synergy between Fludarabine and Other Chemotherapeutic Agents
Several in vitro studies have investigated possi-ble synergy between fludarabine and other chemo-therapeutic agents including cytarabine,cisplatin, mitoxantrone and gallium nitrate. The results of these studies are summarised in table I.
Fludarabine demonstrated useful synergistic ac-tivity in vitro when leukaemic cells were incubated with fludarabine before exposure to cytarabine. The degree of cytotoxicity of cytarabine is directly proportional to the amount of drug incorporated into DNA,which in turn is largely dependent upon
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the intracellular concentration of the active triphos-phate metabolite (Ara-CTP). Prior administration of fludarabine produced an increase in cellular up-take of cytarabine and an increase in the accumu-lation of Ara-CTP.[10,32-351 Furthermore,the ability to accumulate Ara-CTP was increased by 11-to 13-fold in lymphoblasts isolated from 2 patients during treatment with fludarabine compared with lymphoblasts isolated from the same patients be-fore treatment with fludarabine.[46]
An important synergistic antitumour effect has also been reported with the combination of cis-platin and fludarabine in human colon cancer cell linesl421 and in primary cultures of human mela-noma and ovarian cancer (table I).[431 Inhibition by fludarabine of the cellular repair of cisplatin-induced DNA damage has been postulated as a pos-sible mechanism for this synergism. The synergy seen with the combination of fludarabine and cytarabine or cisplatin has been applied in the man-agement of patients withvarious haematological malignancies(section 3).
1.3 In Vivo Studies
The in vivo antitumour activity of fludarabine has been demonstrated in a variety of murine tu-mour models including L1210 leukaemia,P388 leukaemia,human LX-1 lung tumour and CD8F1 mammary carcinoma cell lines.147-49]
Fludarabine has been shown to increase the sen-sitivity of tumour cells to radiation in vivo, which suggests that it may have a future role as a radiosensitising agent.1501 It enhanced radiation-induced delay in regrowth and local tumour cure in several mouse tumour models,including the Meth-a fibrosarcoma, SA-NH sarcoma and MCA-K and MCA-4 mammary carcinoma models.151-531 This effect was both dose-and schedule-dependent and occurred after both single-and fractionated-radiation schedules.151,521 Furthermore, a combina-tion of fludarabine and indomethacin improved the therapeutic ratio of radiotherapy in a murine sar-coma model.1541 Fludarabine also slightly potenti-ated radiation-induced spinal cord toxicity in rats without significantly altering the fractionation sen-
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Fludarabine: An Update

1011
Table I. In vitro studies evaluating the cytotoxic effects of F-ara-A(9-β-D-arabino-furanosyl-2-fluoroadenine) in combination with other chemotherapeutic agents
Reference Drug combination Cell culture Comment
Gandhi & Plunkettl10] F-ara-A+Ara-C K562 CML cell lines Rate of Ara-CTP accumulation ↑ by F-ara-ATP
(concentration-dependent) vs Ara-C alonea
Gandhi et al,[32] F-ara-A+Ara-C Human CLL cells Intracellular accumulation of Ara-CTP↑2.2-fold vs
Ara-C alonea
Seymour et al,[33] F-ara-A+Ara-C K562 CML cell lines Intracellular levels of Ara-CTP↑2.2-2.8-fold after
incubation with F-ara-A(30 mol/L) and then Ara-C
(0.3-10 mol/L)b vs Ara-C aloneab
Santini et al.34] F-ara-A+Ara-C HL60 AML cell lines Significant ↑in intracellular Ara-C uptake vs cells
not pretreated with F-ara-A(p<0.01)a
Rayappa et al.[35] F-ara-A+Ara-C OCI/AML-2 and ↑ cytotoxicity of Ara-C (dose-and
OCI/AML-3 AML cell lines schedule-dependent) via ↑Ara-CTP accumulation
vs Ara-C alone
Tosi et al.(36) F-ara-A+Ara-C+G-CSF Human AML cells Additive cytotoxic effect of F-ara-A+Ara-C
significantly ↑by G-CSF (p=0.05)
Lichtenthaler et al.[37] GM-CSF+F-ara-A+Ara-C Human AML cells and Synergistic effect of F-ara-A(at all concentrations
HL60,K562,KG1 AML tested) and Ara-C on HL60 and K562 but not KG1
cell lines cells.Heterogeneous effect with GM-CSF plus
F-ara-A
Avramis et al.38] F-ara-A+Ara-C+PCX CEM/O and CEM/7A 2-fold ↑ synergism when PCX added after F-ara-A
leukaemia cell lines + Ara-C compared with F-ara-A+Ara-C alone.
2.8-fold antagonism compared with F-ara-A+
Ara-C in CEM/O cells following reversal of drug
sequence(PCX+Ara-C+F-ara-A)
Knauf et al.[39] F-ara-A+MIT Human CLL cells Additive cytotoxicity
Di Raimondo et al.401
Lundberg & Chitambar(41) F-ara-A+GN HL60 AML cell lines Additive cytotoxicity
Yang et al.[42] F-ara-A+CIS LoVo and CP2.0 human Synergistic effect considered attributable to
colon carcinoma cell lines inhibition of cellular repair of cisplatin-induced DNA
damage
Zaffaroni et al.43] F-ara-A+CIS Primary cultures of Synergistic effect in 5 of 10 melanomas and 4 of
human melanoma and 10 ovarian cancers. Additive effect reported in
ovarian cancer remaining 11 tumours
Di Raimondo et al.[44] F-ara-A+IFN-α or IFN-β Human CLL cells IFN↑F-ara-A cytotoxicity in CLL cells from early
stage disease and ↓ F-ara-A cytotoxicity in cells
from more advanced disease
Morabito et al.[45] F-ara-A+Ara-C+IFN-a or
IL-2 Human CLL cells IL-2 protected CLL cells and IFNa exerted either a
protective or synergistic effect on CLL cells
a Cytotoxic effect of Ara-C is dependent upon intracellular levels of Ara-CTP.
b Plasma Ara-C levels are<10 mol/L with clinically utilised continuous infusion schedules.Results of this study suggest that potentiation of Ara-CTP accumulation is possible with F-ara-A following continuous infusion Ara-C therapy.
c Approximately 50% of cells were resistant to Ara-C alone and in combination with F-ara-A.
Abbreviations and symbols: AML=acute myeloid leukaemia; Ara-C=cytarabine;Ara-CTP= cytarabine triphosphate; CIS= cisplatin: CLL=chronic lymphocytic leukaemia;CML=chronic myeloid leukaemia;F-ara-ATP=9-β-D-arabino-furanosyl-2-fluoroadenine triphosphate; G-CSF=granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; GN=gallium nitrate; IFNα=interferon-a;IFNβ=interferon-β; IL-2=interleukin-2; MIT=mitoxantrone; PCX=paclitaxel;↑=increased;↓=decreased.
sitivity.1551 The results of a further studysuggest that the radiosensitising effect of fludarabine in-volves the elimination of cells in S-phase by apoptosis and the synchronisation of remaining
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cells to a more radiosensitive cell-cycle phase.1561 Generally,the radiosensitising effect of fludarab-ine appears to be more pronounced in tumour than in normal tissue although an increase in response
Drugs 1997 Jun:53(6) 

to radiation following treatment with fludarabine has been reported in some normal tissue,for exam-ple,mucosal tissue.1531
The results of an in vivo study in mice demon-strated fludarabine to be a suitable immunosup-pressive substitute for cyclophosphamide during bone marrow (BM) transplant conditioning after total body irradiation (TBI). The absolute number of residual lymphocytes able to proliferate and trig-ger rejection was similar with TBI plus fludarabine and TBI plus cyclophosphamide and considerably lower than with TBI alone.1571 This approach has also been investigated in clinical practice(see sec-tion 3.7).
Fludarabine has also demonstrated important immunosuppressive activity following organ transplantation; in cynomolgus monkeys,fludara-bine (50 mg/㎡/day administered intravenously) prolonged skin allograft survival from 8 to 16 days compared to controls. In addition, graft survival was prolonged after secondary allotransplantation into presensitised animals, previously treated with fludarabine,compared with those not previously treated with the drug (8 vs 5 days).1581
2.Overview of Pharmacokinetic Properties
The clinical pharmacokinetics of fludarabine have been reviewed previously.11.59 Thus,only an overview of the most pertinent pharmacokinetic properties of the drug is provided here.
The prodrug fludarabine undergoes extensive and rapid dephosphorylation to F-ara-A after intra-venous administration.160-631 Because the parent drug is detectable for less than 5 minutes in the plasma, the plasma metabolite F-ara-A has been the main focus of pharmacokinetic investigations. These studies have been conducted in patients with CLL receiving the following fludarabine adminis-tration schedules: rapid intravenous bolus admin-istration,1621 short intravenous infusion over 30 minutesl60,61,63,641 and continuous intravenous in-fusion for 5 consecutive days.1461 A summary of the mean values of the pharmacokinetic parameters de-termined in these studies is provided in table II.

The pharmacokinetics of F-ara-A appear to be linear with no accumulation after repeated daily administration.I46,61| Most studies have described a biphasic decline in plasma F-ara-A concentra-tion|46,60,61,631 with a distribution half-life of 0.9 to 1.7 hours and a terminal elimination half-life of 6.9 to 33.5 hours.However,2 studies,one evaluating a rapid bolus injection1621 and the other a standard short infusion regimen,1641 reported a triphasic de-cline in plasma F-ara-A concentrations which in-cluded an initial short distribution phase of 5 to 9 minutes.Wide variations in the area under the plasma concentration-time curve (AUC)were also noted within studies at each dosage level.
The volume of distribution and plasma clear-ance of fludarabine were found to be considerably lower in children (10.8 L/㎡2 and 0.7 L/h/m2,re-spectively)|461 than in adultsl61,62.641 (table II),pos-sibly because of differences in pharmacokinetic handling.The relatively high volumes of distribu-tion reported in adults (44.2 to 96.2 L/㎡2) suggest extensive tissue binding.
Table II. Summary of the pharmacokinetic properties of the fludarabine metabolit F-ara-A(9-β-D-arabino-furanosyl-2-fluoro-adenine) after administration of fludarabine by rapid intravenous bolus(62) or short intravenous infusion (over 30 min)160,61,63.64) to adults with chronic lymphocytic leukaemia
Parameter Mean value
Cmax 0.3-1.0mg/La
tmax <5 min
Vss 44.2-96.2L/㎡
AUC[0-24h] 7.8->24 mol/L·h
t1/2ub 0.9-1.7h
t1/2β 6.9-33.5h
24h urinary excretion 27-60
(% of administered dose)
CL 4.1-9.1L/h/m2c
CL
a Cmax=2.5 mol/L in 1 study.164]
b Initial rapid distribution phase of 5-9 min was reported in 2 studies,[62,64]
c In 1 study CL=15.0 L/h possibly derived from a single dose,1641 Abbreviations: AUC= area under the plasma concentration-time curve;Cmax=peak plasma concentration; CL=plasma clearance; tmax=time to Cmax;t1/2u=initial phase plasma elimination half-life; t1/2β= terminal phase plasma elimination half-life; Vss=apparent volume of distribution at steady-state.  
Fludarabine: An Update
F-ara-Aundergoes intracellular phosphoryla-tion to the active metabolite F-ara-ATP.Although subject to wide interpatient variability,peak intra-cellular levels of F-ara-ATP occur within 3 to 4 hours after termination of fludarabine infu-sion.160,63,651 Monophasic elimination kinetics have been reported for F-ara-ATP with a median half-life of 23 hours,1651
In patients with CLL, no significant correlation was reported between clinical response and peak F-ara-ATP concentration or accumulation of F-ara-ATP in leukaemic lymphocytes isolated during fludarabine therapy.1651 However,leukaemic cells demonstrated a greater ability to accumulate and retain F-ara-ATP than non-malignant bone marrow cells.1631
Fludarabine is predominantly eliminated from the body in the urine.Astatistically significant cor-relation between creatinine clearance and total body clearance of F-ara-A has been identified.1621 Individuals with renal impairment were shown to have a significantly lower total body clearance of F-ara-A and a lower volume of distribution than those with normal renal function.1621 An increase in blood urea nitrogen levels has also been corre-lated with a decrease in total body clearance of F-ara-A.162I Furthermore,fludarabine-associated neutropenia appears to be more severe in patients with a creatinine clearance <50 ml/min (<3 L/h).1611
In a preliminary evaluation of an oral solution of fludarabine,F-ara-A was detectable in plasma as early as 2 minutes after administration.Oral bio-availability was approximately 70% and a peak plasma concentration of 0.9 μmol/L was reached in 1.5 hours.1661
3.Therapeutic Efficacy
The therapeutic efficacy of fludarabine has been most extensively evaluated in patients with CLL. Numerous noncomparative studies have been con-ducted,mostly involving patients with refractory CLL who had previously received chemotherapy. More recently,results from several important com-parative studies in both previously treated and chemotherapy-naive patients have become avail-
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1013
able. In addition, data are available regarding the use of fludarabine in the treatment of a variety of other haematological malignancies including acute leukaemia, low grade non-Hodgkin's lymphoma (NHL), cutaneous T cell lymphoma and lympho-plasmacytoid lymphoma.
3.1 Chronic Lymphocytic Leukaemia
CLL arises from a clonal expansion of immune-incompetent lymphocytes usually of B cell lin-eage.The prognosis of patients with CLL is highly variable: some patients survive for many years without treatment whereas others develop rapidly progressive disease.1671 Although clinical stage as designated by the Binetl681 or Rail691 classification systems is the most important predictor of survival in patients with CLL,1671 several other prognostic parameters are also considered to correlate with disease progression and survival; these include lymphocyte count,lymphocyte doublingtime,pat-tern of bone marrow infiltration,cytogenetics and immunophenotype.167,70,711
Chemotherapy is generally reserved for patients with intermediate(Binet stage B;Rai stage I or II) or advanced (Binet stage C; Rai stage III or IV) clinical disease.Patients with quiescent/smoulder-ing CLL,defined as Rai stage O or Binet stage A together with a nondiffuse pattern of bone marrow involvement,serum haemoglobin concentration ≥13 g/dl,blood lymphocyte count <30x10° cells/L and a lymphocyte doubling time greater than 12 months, and other newly diagnosed pa-tients with Rai stage O or Binet stage A disease should be followed without treatment and receive therapy only when there is clear evidence of dis-ease progression.167,72-74I Notably,there appears to be no significant difference in overall survival be-tween early and deferred treatment with te stand-ard first-line agent chlorambucil in the treatment of patients with Binet stage A CLL.175-771
Patients with intermediate stage disease may also be followed without treatment until signs of disease progression are evident, although in prac-tice Binet stage B patients are usually treated.1671 The majority of patients with Rai stage III or IV
Drugs 1997 Jun: 53 (6) 
Table Ill.Noncomparative studies of intravenous fludarabine in patients with previously treated chronic lymphocytic leukaemia (CLL)
Reference CLL subtype
(no.of pts) No. of pts
evaluable Fludarabine
regimen Clinic
CR PR SD Median
duration of Median survival time
(mo)
for (mg/㎡/dayx5 response
response days qxwk) (mo)
Angelopoulou et B cell(20) 20 25 q4 33 25 15 NR NR
al,182]
De Rossi et al.183] B cell(22) 22 25 q5a 5 36 NR NR NR
Fenchel et al.[84] B cell(59)b 56 25q5 5 68 NR NR Overall survival
T cell(2) probability 42% at 12
and 18mo
Gillis et al,185] B cell(10) 10 25q4 10 30 NR PR 9.7 NR
Gjedde et al.[86] B cell(30) 22 25q4 5 27 32 8 Responders:24
Nonresponders:9
Grever et al.[87] NR(32) 32 20q4 3 9 NR CR>12 NR
PR>5-8
Hensel et al,88] B cell (46)a 46 25q4 4 30 NR 12 NR
Herrero et al.[89] B cell(6) 6 30q4 0 50° NR NR NR
Hiddeman et al.,90] B cell(20) 20 25q4 25 30 NR NR NR
Hocepied et al.(91) NR(17) 17 25q4 23 41 6 4.9 11.9
Johnson et al.[92] NR(126) 126 25q4 5 21 18 NR NR
Kemena et a1.1931 B cell(47) 46 30mg/㎡x 15 9 NR NR Responders:≥26
1 day q1 Nonresponders:8
Knauf et al,139] B cell (9) 9 25q4 11 44 22 NR NR
Montillo et al.94) B cell(16) 13 25q4 31 38 NR NR >6->17
Montserrat et al.95] B cell(75) 68 20-30mg/㎡2x 4 24 NR NR Nonresponders:11
3-5 days q4
O’Brien et al,[96] NR(169) 169 30q4 37 15 NR 22 18
O’Brien et al,197] B cell(27)’ 37 25q4 11 329 NR PR 16 PR 23
CLL/PL(5) Nonresponders:6
B cell PLL (3)
T cell PLL(2)
Puccio et al.[198] B cell(49) 42 20mg/㎡+30h 0 52 12 8 6-11
T cell (2)
Robertson et al,99] B cell(80) 80 30mg/㎡x 25 21 NR NR 28(projected value)
3 days q4
Sorensen et al,100] NR(724) 703 25q4 3 29 NR 13.1 12.6
Whelan et al,[101]
Wijermans et al.102] NR
B cell(17)* 11
17 25 q3-4
25q4 0
12 27
82 NR
6 NR
NR NR
NR
a All patients received oral prednisone 30 or 40 mg/㎡/day for 5 days every 4wk simultaneously with fludarabine.
b Up to 8 patients were chemotherapy-naive.
c Study also included patients with non-Hodgkin’s lymphoma who were included in the assessment of duration of response.
d Includes 1 patient with Waldenström’s macroglobulinaemia.
e Included 1 nodular remission.
f One patient may have been chemotherapy-naive.
g Responses were not reported in patients with T cell PLL.
h Fludarabine was administered as a 20 mg/㎡ intravenous bolus followed by a 30 mg/㎡2/day continuous infusion for 48h.
Includes 12 nodular CRs.
j 89% of patients were considered to have high risk disease according to the Rai classification.
k Includes 4 patients with Waldenstrom’s macroglobulinaemia or NHL-type immunocytoma.
Includes 6 chemotherapy-naive patients.
Abbreviations:CLL/PL=CLL with increased prolymphocytes;CR=complete response;NR=not reported;PLL=prolymphocytic leukaemia; PR= partial response;qxwk=every x weeks; SD=stable disease;pts=patients;”mean value.
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Drugs 1997 Jun:53(6) 

disease require treatment at presentation although monitoring without therapy until there is evidence of progressive or symptomatic disease is often fea-sible for many patients.1721 Although patients with progressive and/or advanced CLL may initially re-spond to chlorambucil,all will ultimately relapse and many will go on to receive second-line or sal-vage chemotherapy with combination regimens, for example,CAP(cyclophosphamide,doxorubi-cin and prednisone),COP (cyclophosphamide, vincristine and prednisone) or CHOP (COP plus doxorubicin). Good response rates have been re-ported with these regimens; however,most pa-tients with CLL eventually die of progressive dis-ease.[67,74]
Fludarabine has been evaluated as monotherapy or as a component of combination or sequential therapy with other chemotherapeutic agents. In a small number of studies, patients treated with fludarabine also received concomitant oral cortico-steroid therapy.Published clinical trials evaluating the efficacy of fludarabine in patients with CLL are mostly noncomparative,although recently 3 large randomised studies comparing fludarabine with conventional chemotherapy in this setting have been completed. The assessment of response in both noncomparative and comparative studies was based predominantly on the National Cancer Insti-tute(NCI) Working Group criteria,1781 which de-fine a complete remission as disappearance of all palpable disease,neutrophil count ≥1500 cells/μl, platelet count >100 000 cells/μl,haemoglobin level >11 g/dl and a bone marrow relative lympho-cyte count of <30%.A partial remission is defined as a ≥50% reduction of measurable disease mani-festations and a >50% improvement of all abnor-mal blood counts.
Most studies recruited patients with previously-treated,mostly refractory CLL. Because the NCI Working Group definition of complete response in CLL includes a reduction in the bone marrow in-filtration to <30% lymphocytes,a complete re-sponse may be associated with a degree of residual clonal disease which eventually leads to clinical relapse.For this reason,flow cytometry and DNA
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analysis have become important methods for de-tecting minimal residual disease following the treatment of patients with CLL.Using these meth-ods,no minimal residual disease was evident in a small number of patients who had achieved a com-plete remission after treatment with fludarab-ine.179-81]However,larger long term studies are required to determine whether the absence of min-imal residual disease translates into longer overall survival.
3.1.1 Fludarabine Monotherapy
Noncomparative Studies
Objective response rates (complete plus partial response) of 12 to 94% together with a median du-ration of response of 4.9 to 22 months and a median survival of up to ≥26 months have been reported in patients with previously treated CLL receiving fludarabine therapy (table III).
Most patents were resistant to at least 1 other chemotherapeutic regimen and responded to treat-ment with an intravenous fludarabine dosage regi-men of 20 to 30 mg/㎡2/day for 5 consecutive days repeated every 3 to 5 weeks. In addition,objective response rates of up to 78%,[103,104] together with a median survival time of up to 67 months,[104] have been reported in previously untreated patients with CLL who received standard fludarabine ther-apy with or without oral prednisone.
Important correlations have been reported be-tween response to treatment with fludarabine and stage of disease and extent of response to previous therapy in patients with CLL.[95.96,1051 In one study, treatment of 169 previously treated patients (median 3 prior chemotherapy regimens) and 95 chemotherapy-naive patients with fludarabine 30 mg/㎡2/day plus oral prednisone 30 mg/㎡/day for 5 consecutive days repeated every 4 weeks pro-duced objective response rates of 52 and 79%,re-spectively,(p<0.001).1961 Notably, objective re-sponse rates were significantly higher for patients with Rai stage O to II versus III to IV disease(79 vs 42%; p<0.001) and for previously treated pa-tients with previously sensitive (n =31)compared with refractory (n=138)disease (68 vs 49%;p< 0.001).In addition,time to disease progression and
Drugs 1997 Jun: 53(6) 

survival time were also shorter for previously treated patients (22 and 18 months, respectively) than for chemotherapy-naive patients.
Similarly,in a long term follow-up (minimum 3 years) of 78 patients with previously treated CLL who received fludarabine,survival time was longer among patients with CLL not refractory to prior treatment than in patients with previously refrac-tory disease (29 vs 9 months). In addition,fewer responses were reported in patients who had re-ceived >3 previous regimens than for those who had received only 1 regimen (44 vs 82%).11051 In another study,treatment with fludarabine(20 to 30 mg/㎡2/day for 3 to 5 days repeated every 4 weeks) produced a significantly higher objective response rate in patients with relapsed CLL than in patients with previously resistant disease (62 vs 21%; p= 0.005).1951 Furthermore,patients who received >3 cycles of fludarabine had a higher objective re-sponse rate than those who received ≤3 cycles(36 vs 15%).
Comparative Studies
Comparisons of various fludarabine dosage re-gimens have been performed. Administration of a weekly low-dose fludarabine regimen(30 mg/㎡/ day administered on I day each week) to 47 pa-tients with previously treated CLL produced partial and complete response rates of 9 and 15%,respec-tively.1931 A subsequent prospective study reported a higher objective response rate (46%) in patients with previously treated CLL treated with fludarab-ine 30 mg/㎡/day for 3 days every 4 weeks.1991 However,this was lower than the objective re-sponse rate (52%)reported with a weekly 5-day fludarabine schedule in a similar patient group.1961 Comparable objective response rates were reported in a nonrandomised study comparing 2 doses of fludarabine 25 or 30 mg/㎡/day administered for 5 consecutive days every 4 weeks (53vs 59%).1106|
Recently,several important studies have been conducted comparing fludarabine with conven-tional chemotherapeutic agents used in the treat-ment of CLL.
In a large European randomised multicentre trial,fludarabine(25 mg/m2/day for 5 consecutive
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Previously untreated FA patients
Previously untreated CAP patients
Previously treated FA patients
Previously treated CAP patients
Time in study(mo)
Fig.2. Survival rates with fludarabine (FA) versus CAP. Com-parison of survival rates for chemotherapy-naive (n = 100)and previously treated (n =96) patints with chronic lymphocytic leukaemia treated with FA(25 mg/㎡2/day on days 1 to 5) or CAP (cyclophosphamide 750 mg/㎡/day and doxorubicin 50 mg/㎡2/day on day 1 and prednisone 40 mg/㎡/day on days 1 to 5) every 28 days for 6 courses in a randomised European study.1107) The median survival times for previously treated pa-tients were 728 and 731 days for the fludarabine and CAP treat-ment groups, respectively. The median survival time for chemotherapy-naive patients had not been reached for fludarabine-treated patients and was 1580 days for the CAP treatment group (p =0.087).
days) was compared with a standard combination regimen (CAP) in 100 untreated and 96 previously treated patients with advanced B-CLL.11071 Objec-tive response rates were higher with fludarabine in both previously treated(48 vs 27%;p=0.036)and untreated (71 vs 60%;p =0.26)patients.In the previously treated patient group,survival rates and response durations did not differ significantly; however, in the previously untreated group fludarabine produced a significantly longer median remission duration than CAP (>208 [median not yet reached] vs 208 days;p<0.001)and tended to be associated with longer overall survival times (fig.2).
In another study using the same dosage regimen, fludarabine appeared to be more effective than the standard regimens of CAP or CHOP in 338 pre-viously untreated patients with stage B CLL.11081 Clinical and haematological partial remission was
Drugs 1997 Jun: 53(6) 

reported in 19,32 and 49%, respectively,of CAP-, CHOP-and fludarabine-treated patients. Further-more,confirmation of complete response by bone marrow biopsy revealed a complete response rate of 36% for fludarabine versus 10% for both CHOP and CAP. No significant differences in response rates were reported for an additional 155 patients with stage C CLL included in the study.
The efficacy of fludarabine (25 mg/㎡/day for 5 days every 4 weeks) was also compared with that of oral chlorambucil (40 mg/㎡2 on day 1 every 4 weeks) for up to 12 months in previously untreated patients with active CLL.11091 In a multicentre randomised study, complete and partial response rates of 27 and 43%, respectively,were reported for 166 evaluable patients receiving fludarabine; corresponding response rates for the 173 patients receiving chlorambucil were 3 and 40%,respec-tively(p=0.0001).Similarly,median response du-ration (33 vs 17 months; p = 0.0002) and median progression-free survival times (27 vs 17 months; p<0.0001)were significantly longer for fludarab-ine-treated patients.
Interim results of a randomised study which compared the efficacy of fludarabine (25 mg/m/ day for 4 days every 3 weeks) with high-dose con-tinuous oral chlorambucil (10 mg/㎡/day) for 18 weeks in evaluable patients with untreated CLL(n =40)have been reported recently.l110 After a me-dian follow-up of II months,overall complete and partial response rates were 45 and 32.5%, respec-tively.Results of the effects of each treatment on response rate and survival times are awaited.
3.1.2 Fludarabine Combination Therapy
Fludarabine has been used in combination with other chemotherapeutic agents including doxoru-bicin,cyclophosphamide,epirubicin and mitoxan-trone in the treatment of CLL,with promising re-sults.
Treatment of 29 patients with B-CLL with fludarabine (25 to 30 mg/㎡/day for 3 to 4 days) plus doxorubicin (50 mg/㎡/day for I day) on a monthly basis produced an objective response rate of 55%.!''!|This was despite prior treatment of 24 patients with fludarabine and included a response

in 2 patients who did not respond when initially treated with the drug. In another study, treatment of 57 patients with CLL with fludarabine (30 mg/㎡2/day for 3 days) plus cyclophosphamide (300 to 500 mg/㎡/day for 3 days) produced re-sponse rates(type of response not reported)of 93% for chemotherapy-naive patients(n=14)and 83% for patients who had previously received alkylator therapy(n=6). A high response rate (90%)was also reported for 21 patients previously responsive to fludarabine and this contrasted with a response rate of 31% for patients refractory to prior flu-darabine with or without alkylator therapy (n=16). Four patients with CLL variants did not respond to treatment with fludarabine plus cyclophos-phamide.
Preliminary evaluation of a combination regi-men comprising fludarabine(25 mg/㎡/day on day 1) plus epirubicin (25 mg/㎡/day on days 4 and 5)repeated every 4 weeks showed this regimen to be an effective treatment option when used as first-line therapy or for the treatment of first relapse in patients with CLL (objective response rate 81% and median remission duration ≥17 months).!112| Similarly,treatment ofCLL patients with fludarab-ine (30 mg/㎡/day for 3 days)plus mitoxantrone (10 mg/㎡/day on day 1)produced complete and nodular complete (absence of residual lymphoid nodules in the bone marrow) response rates,re-spectively, of 20 and 46% for chemotherapy-naive patients (n = 35), 7 and 20% for patients previously treated with alkylator therapy (n = 15)and 11 and 7% for patients who had previously responded to fludarabine therapy(n=26).No complete re-sponses were reported for those previously refrac-tory to fludarabine therapy(n=12).11131
Combination therapy with fludarabine plus chlorambucil did not produce a significant im-provement in response rate compared with fluda-rabine alone in patients with CLL and was also associated with an unacceptably high level of haematological toxicity.l114-116 Similarly,no sig-nificant improvement in response rate or survival was reported with the addition of oral cortico-steroids to fludarabine therapy in patients with 

CLL,183,96] An increased incidence of infectious episodes has also been documented with this regi-men(section 4.1).
Sequential therapy with fludarabine and cyta-rabine has been most extensively investigated in the treatment of acute leukaemias(section 3.2).In the treatment of advanced CLL refractory to fludarabine,this regimen with or without cisplatin had minimal efficacy.[117,118] However,promising results were reported with sequential cytarabine or cyclophosphamide therapy followed by cisplatin and fludarabine therapy in the treatment of Rich-ter's syndrome, a form of CLL with diffuse histio-cytic lymphoma. Among 11 evaluable patients,2 complete and 3 partial responses were reported to-gether with an overall median survival of 17 months.[119]
3.1.3 Prolymphocytic Leukaemia
Prolymphocytic leukaemia (PLL) is a rare form of CLL characterised by high blood prolymphocyte counts.It may occur de novo or as a terminal trans-formation of CLL and is usually resistant to con-ventional chemotherapy.
Two partial responses were reported among 8 patients with B cell PLL or increased pro-lymphocyte counts treated with fludarabine (25 mg/㎡2/day for 5 days repeated every 4 weeks).197] In a larger study, treatment of 16 patients with B cell PLL or the prolymphocytoid variant of CLL with fludarabine (30 mg/㎡/day for 5 days re-peated every 4 weeks) resulted in 3 partial and 3 complete responses; I patient was receiving con-comitant prednisone therapy.The duration of re-sponse varied from >5 to>23 months for the 6 re-sponding patients.[120] Several other reports have documented a favourable response to fludarabine in individual patients with PLL.(121-1251 However, long term follow-up is required to further evaluate the efficacy of fludarabine in this indication.
3.1.4T Cell CLL
CLL of T cell origin (T-CLL) is a rare form of CLL that can be subdivided into CD8+/CD3+large granular lymphocytosis (LGL) or a more aggres-sive form of the disease-T-prolymphocytic leu-kaemia(T-PLL) [CD4+/CD3+].[126] A recent case

report described a complete response after treat-ment with 4 cycles of fludarabine in a patient with CD8+/CD3+LGL.However,in the same report a second patient with CD4+/CD3+T-PLL who had relapsed while receiving chlorambucil plus cladri-bine therapy was unresponsive to subsequent flu-darabine monotherapy.11261 Other studies which have included patients with T-PLL197.1201 or T-CLL1981 have failed to demonstrate a response with fludarabine.
3.2 Acute Leukaemias
Acute leukaemia is usually a rapidly progres-sive form of leukaemia involving clonal expansion of stem cells. Acute myelogenous leukaemia (AML) is more common than acute lymphoblastic leukaemia(ALL) and develops more frequently in patients aged >50 yearsl1271 Acute leukaemias,par-ticularly AML,may develop secondary to the treat-ment of another malignancy such as Hodgkin’s dis-ease.l1281 Commonly used chemotherapy regimens for remission/induction therapy include cytarabine plus an anthracycline such as daunorubicin or doxorubicin for AML and vincristine, prednisone
Early studies using fludarabine in the treatment of acute leukaemias used high-dose monotherapy (150 or 125 mg/㎡/day,respectively,for 5 or 7 consecutive days). Although complete responses were reported,further evaluation of this approach was prevented by the frequent development of se-vere CNS toxicity.1129]
More recently,however, the efficacy of a com-bination regimen of cytarabine (which is currently the most active single agent in AML) plus lower dose fludarabine therapy has been investigated. The rationale for this combination was based on the finding that fludarabine is able to modulate the metabolism of cytarabine in vitro,thereby increas-ing the accumulation of Ara-CTP (section 1.2.1).110,33-351 Furthermore,administration of flu-darabine 30 mg/㎡2 4 hours prior to an infusion of cytarabine 1 g/m2 for 2 hours potentiated the metabolism of cytarabine in patients with AML.In circulating AML cells,the AUC and the rate of ac- 

cumulation of Ara-CTP were significantly in-creased by the prior infusion of fludarabine(by 1.8-fold,p=0.004,and 2-fold,p=0.001,respec-tively) compared with baseline values reported for cytarabine.l1301 Fludarabine 15 mg/㎡2 twice daily has been shown to maximally modulate cytarabine metabolism following cytarabine administration every 12 hours.[131]
Although not currently considered to be stand-ard therapy, several trials have investigated the clinical efficacy of sequential administration of fludarabine and cytarabine [with or without gran-ulocyte colony-stimulating factor (G-CSF) and other anticancer agents] in the treatment of patients with acute leukaemias and myelodysplastic syn-drome (MDS) [table IV]. MDS is a clonal haema-topoietic stem cell disorder,encompassing a hetero-geneous group of normocytic anaemias which frequently precede the onset of overt leukaemia. The majority of clinical studies used fludarabine 30 mg/㎡2/day administered on days 1 to 5 or 2 to 6 plus cytarabine 1 to 3 g/㎡/day administered over 2 to 6 hours on days 1 to 5 or 6. To maximise synergy,fludarabine was generally administered 4 hours before the infusion of cytarabine.In these studies a complete response was typically defined as morphologically normal bone marrow with<5% blast cells together with normal peripheral and dif-ferential counts and normal physical findings.Par-tial response was based on similar criteria except for the presence of 5 to 30% of bone marrow blast cells.
Complete response rates of 36 to 60% were re-ported with fludarabine plus cytarabine therapy in the treatment of patients with relapsed or refractory AML or MDS.I133,134,1401 Median duration of com-plete response was 39 weeks in one study.l1331 In a retrospective comparison,this regimen produced a significantly (p <0.05)higher objective response rate(70%)than high-dose or low-dose cytarabine monotherapy (39 and 33%,respectively)in pa-tients with an initial remission duration of >I year. However,no significant difference in response rate was evident in patients with initial remissions of <1 year.[133] Sequential administration by contin-
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uous infusion of fludarabine followed by cytarab-ine in children with AML or ALL also produced promising results in a phase I evaluation.[144]
Coadministration of G-CSF to patients receiv-ing fludarabine plus cytarabine was reported to produce a 40% increase in the rate of accumulation of F-ara-ATP in AML cells;however,G-CSF did not increase ara-CTP accumulation.11451 In an ef-fort to reduce neutropenia and decrease the rate of infection,G-CSF has been added to fludarabine plus cytarabine therapy (FLAG regimen) in clini-cal practice. Studies evaluating FLAG in patients with AML or MDS reported complete response rates of 58 to 64%(table IV).(132,134,138,139|together with an overall median survival time of up to 24 months in 1 study.(1391 FLAG has also beencom-bined with idarubicin as salvage therapy in patients with poor prognosis AML.1135-1371 Complete re-sponse rates of 50 to 70% were reported with a median duration of response of up to 34 months.
Estey et al.[146 reported a significantly shorter duration of neutropenia (p<0.0001) and a higher complete response rate (63 vs 53%) with FLAG but no significant improvement in survival compared with fludarabine plus cytarabine therapy in pa-tients with newly diagnosed AML or MDS.Re-sponses to FLAG therapy (± novantrone or idarubicin) in chronic myelogenous leukaemia (CML) have also been noted in a small clinical study (n=4)[147] and in 2 case reports.l148,1491
Fludarabine plus cytarabine with or without G-CSF has also been evaluated in patients with re-lapsed or refractory ALL;complete response rates of 30 to 80% were reported together with a median survival of up to 36 months.[141-143]
3.3 Non-Hodgkin's Lymphoma
3.3.1 Fludarabine Monotherapy
NHL encompasses a heterogeneous group of malignancies of the lymphoid system,the majority of which are of B cell origin. Several different his-tological classification systems have been sug-gested for NHL,two of which are the International Working Formulation used predominantly in the USA and the Kiel system used in Europe.[1501 Un-
Drugs 1997 Jun: 53 (6) 
Table IV. Studies evaluating the efficacy of sequential fludarabine (FA)-based combination regimens in the treatment of acute leukaemias and myelodysplastic syndrome(MDS)
Reference Acute leukaemia Treatment regimen Clinical Median Overall
subtype(no.of response duration median
evaluable pts) (CR) of CR survival
[%] (wk) (wk)
Clavio et AML(51) FA 30 mg/㎡2 IV days 1-5+Ara-C 2 g/㎡2 IV days 1-5+G-CSF 59 2-26(range) NR
al.[132] 300 μg/day or FA 30 mg/㎡2 IV days 1-3+Ara-C 1 g/㎡2 IV days
1-3+MIT 10 mg/㎡ days 1-3+G-CSF 300 μg/day
Estey et AML rel/ref(59) FA 30 mg/㎡2 IV days 2-6+Ara-C 1-3 g/㎡2 IV days 1-6 36 39 NR
al.(133]
Estey et MDS(RAEB=6; FA 30 mg/㎡2 IV days 1-5 +Ara-C 2 g/㎡2 IV days 1-5 60 NR NR
al.[134] RAEB-t=19)
MDS(RAEB= FA 30 mg/㎡2 IV days 1-5+Ara-C 2 g/㎡2 IV days 1-5+ 64 NR NR
21;RAEB-t=24) G-CSF 400 μg/㎡
MDS (RAEB-t= IDA 12 mg/㎡2 IV days 1-3+Ara-C 1.5 g/㎡2 days 1-4 CI 80° NR NR
15)
Fleischhack AML rel (9) FA 30 mg/㎡2 IV days 1-4+Ara-C 2 g/㎡2 IV days 1-4 IDA 12 70 8.9(mean) NR
et al.[135] MDS(1) mg/㎡2 IV days 2-4+G-CSF 400μg/㎡/day
Parker et AML/MDS (14)d FA 30 mg/㎡2 IV d1+IDA 10 mg/㎡2 IV d1 +Ara-C 2 g/㎡2 IV d1+ 50 NR NR
al.[136] G-CSF 400μg/㎡ CI
Steinmetz AML rel/ref(26) FA 25 mg/㎡2IV d1+IDA 8 mg/㎡2 IV d1,3,5+Ara-C 2 g/㎡2 IV 58 CR 15-34 NR
et al.[137] Secondary days 1-5+G-CSF 400μg/㎡ Cl
MDS/AML (27)
Taylor et AML rel/ref(6) FA 30 mg/㎡2 IV days 1-5+Ara-C 2 g/㎡2 IV days 1-5+ 64 3mo NR
al.[138] t-AML(4) G-CSF 5 μg/kg/day IV
MDS (2)°
Visani et AML ref(18) FA 30 mg/㎡2 IV days 1-5+Ara-C 2 g/㎡2 IV days 1-5+ 58 23.6 14-24
al,[139] Secondary AML G-CSF 5 mg/kg/day SC
(10)
Wiersma et AML(14)' FA 10.5+30.5mg/㎡2 IV+Ara-C 390+100 mg/㎡2 IV9 36 NR NR
al,[140]
Montillo et ALL rel (5) FA 30 mg/㎡2 IV days 2-6+Ara-C 2 g/㎡2 IV days 1-6+G-CSF 80 NR NR
al.[141)
Suki et ALL rel/ref (30) FA 30 mg/㎡ IV days 2-6+Ara-C 1 g/㎡2 IV days 1-6 30 22 12
al.[142]
Visani et ALL rel/ref(12) FA 30 mg/㎡2 IV days 1-5+Ara-C 2 g/㎡2 IV days 1-5+G-CSF 67 22.5 36al.[143]
a In 22 patients,the diagnosis of AML was preceded by MDS which lasted >6 mo; of the 29 de novo AML patients 8 were refractory to prior chemotherapy,9 were treated for early relapse and 12 had poor prognosis at diagnosis.
b CR was 80 and 30% for patients refractory to prior chemotherapy and patients treated for early relapse, respectively.
c IDA+Ara-C was administered to patients with a good prognosis whereas FA+Ara-C and FA+Ara-C+G-CSF were given first to patients with poor and then to those with better prognosis.
d Patients had RAEB (n=2), RAEB-t (n=2)or therapy-related AML/MDS((n=2).(n =2), relapsed MDS (n =3), relapsed or refractory AML (n =3) or AML transformed from a myeloproliferative disorder (n =2).
e Only 11 patients were evaluable for for clinical response.
fIncluded 10 patientswith relapsed or refractory disease, and 4 patients with poor prognosis AML.
g FA administered by intravenous bolus(10.5 mg/㎡)then by infusion 30.5 mg/㎡2/day for 2 days followed by Ara-C administered by intravenous bolus (390 mg/㎡2) followed by infusion (100 mg/㎡2) for 3 days.
Abbreviations:ALL=acute lymphoblastic leukaemia; AML=acute myeloid leukaemia;Ara-C=cytarabine; CI=continuous infusion; CR=complete response;G-CSF=granulocyte colony-stimulating factor; IDA=idarubicin;IV=intravenously;MIT=mitoxantrone;NR=not reported;pts=patients;RAEB=MDS subtype of refractory anaemia with excess blast cells;RAEB-t= MDS subtype of refractory anaemia with excess blast cells in transformation;rel=relapsed; ref=refractory;SC=subcutaneously;t-AML=MDS with progression to AML.
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Drugs 1997 Jun: 53 (6) 
Fludarabine:An Update
fortunately,the existence of different classification systems has hampered direct comparisons of clin-ical trials.The Revised European-American Lym-phoma (REAL) classification system,which is based on immunological,morphological and ge-netic criteria, has recently been proposed in an ef-fort to address this problem.11511
Using clinical criteria, the NHLs can be classi-fied into 2 major disease groups: low grade and high grade. These 2 categories differ according to several criteria including incidence,age distribu-tion,clinical course,response to chemotherapy and prognosis.lI50I High grade NHLs are usually re-sponsive to chemotherapy and are treated with curative intent,predominantly with combination chemotherapy.Low grade diseases generally fol-low an indolent course;treatment may be either

1021
initiated at diagnosis or deferred.11521 Although pa-tients can be maintained for several years on low-intensity chemotherapy regimens,low grade dis-ease appears to be refractory to cure, and death ultimately results from progression to a more ag-gressive subtype or from recurrent infection. Fol-licular B cell lymphoma represents approximately 80% of low grade cases.11531
Objective response rates of 30 to 71% have been reported in noncomparative studies evaluating fludarabine monotherapy in the treatment of NHL (table V). There was some interstudy variation in the criteria used for the definition of complete and partial response;however, frequently used defini-tions were disappearance of all manifestations (in-cluding clinical or radiological evidence and at-tainment of a normal bone marrow) for a complete
Table V.Noncomparative studies evaluating the efficacy of intravenous fludarabine in patients with non-Hodgkin’s lymphoma
Reference No.of evaluable pts Fludarabine Clinical response (% of pts) Duration of response
(no.of pts previously dosage regimen CR PR (mo)
treated) (mg/㎡/dayx5 days qx
Falkson et al.[154] 21(21) 25q4 33 29 4.6a
Fenchel et al.84] 14 (NR) 25q5 7 64 NR
Gillis et al.[85] 14(14) 25q4 21 50 NR
Hiddemann et al,(155] 38(38) 25 q4-5 13 18 NR
Hochster et al.!156] 60(60) 18 q4 15 15 NR
Leiby et al.[157] 25(NRb) 20mg/㎡+30° 4 28 CR>9; PR 2-20
Moskowitz et al.!158) 32 (NR) 25 qNR 6 44 12
O’Brien et al.97] 48(47 or 48) 25q4 10 40 PR 14;CR>14
Pigaditou et al.(159) 81°(45) 25 q3-4 15 34 NR
Pott et al,[160) 38(38) NR 13 18 NR
Redman et al.[161] 76(76) 20-30 q4 7 30 CR 8->27
Solal-Céligny et al.[162] 49(0) 25 q4 37 28 15.6
Whelan et al.[101] 34(34) 25 q3-4 18 209 NR
Whelan et al,[163]
Zinzani et al.(164) 25(25)
21(13) 25 q≥3
25 q4 14 68h
52 NR
NR
a Progression-free survival.
b Patients received a mean of 2.6 prior chemotherapy regimens.
c Fludarabine was administered as an intravenous loading dose followed by a continuous infusion for 48h.
d Patients received a median of 2 previous chemotherapy regimens.
e Of 81 evaluable patients, 16 were newly diagnosed, 20 had minimal residual disease and 45 had recurrence or treatment failure/progression.
f No responses were observed in 20 patients with intermediate or high grade lymphoma,diffuse small-cleaved cell lymphoma,diffuse large-cell lymphoma,lymphoblastic lymphoma or diffuse unclassified lymphoma.
g 2 of 11 patients with diffuse lymphoma responded(1 CR and 1 PR). Remaining patients had follicular lymphoma.
h Reported as overall response CR+PR.
Abbreviations:CR=complete response; NR=not reported; PR=partal response: pts=patients;qxwk=every x weeks.
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response and a ≥50% reduction in disease manifes-tations for a partial response. Most patients en-rolled in these studies had advanced low grade dis-ease and many were refractory to, or had relapsed on,prior chemotherapy. The majority of studies used a fludarabine dosage regimen of 20 to 30 mg/㎡2/day administered for 5 consecutive days and repeated every 3 to 5 weeks.
Solal-Céligny et al.1162] used fludarabine as first-line therapy to treat 49 evaluable patients with advanced follicular lymphoma and reported a pro-gression-free survival time of 15.6 months.Among previously treated patients, progression-free sur-vival of 4.6 months and overall survival of ≥28 months were reported in one study.l1541 The Ger-man Low Grade Lymphoma study group reported 7 out of 12 complete or partial responders,who had previously received extensive chemotherapy,to be in unmaintained remission for more than 12 months.[155]
Pigaditou et al.[159] analysed fludarabine-treated patients according to whether they were newly diagnosed, had minimal residual disease or had ei-ther recurrent or refractory lymphoma:objective

response rates for the 3 patient groups were 69,45 and 44%, respectively. In another study, patients were categorised into previously treated (with re-sistant and/or relapsed disease) and untreated pa-tient groups.[164] Prior chemotherapy was associ-ated with a lower objective response rate (75% in untreated patients, 66% in patients previously treated with 1 to 3 regimens and 50% in patients who had received >3 prior regimens).
When analysed separately,objective response rates with fludarabine therapy in patients with in-termediate or high grade lymphoma were consid-erably lower (0 to 14%) thanthose reported in low grade disease (52 to 55%).1156.161]
3.3.2 Fludarabine-Based Combination Therapy
A combination regimen comprising intravenous fludarabine,intravenous mitoxantrone and oral or intravenous dexamethasone 20 mg/㎡/day or intravenous prednisone 40 mg/day (day 1 to 5) re-peated every 3 to 4 weeks has been evaluated in 3 studies of patients with recurrent or refractory low grade NHL (table VI).1160,167,1691 Objective re-sponse rates of 41 to 94% were reported in these studies; median progression-free survival and
Table VI.Noncomparative studies evaluating the efficacy of fludarabine(FA)-based combination chemotherapy regimens in patients with low grade non-Hodgkin’s lymphoma
Reference Treatment regimen
[frequency(wk)] No.of evaluable pts
(no.of pts previously Clinical
CR PR
treated)
Chun et al.165] FA 20 mg/㎡2 IV days 1-5+IFN 3 or 6×106 units/㎡2 SC/IM 9(9) 0 89
3x wkly [NR]
Hochster et al.[166] FA 20 mg/㎡2 IV days 1-5+CYC 600-1000 mg/㎡2 IV d1[3-4] 27(0) 89 NR
McLaughlin et al.[167] FA 25 mg/㎡2 IV days 1-3+MIT 10 mg/㎡2 IV d1+DEX 20 mg 51(51) 47 47
IV/PO days 1-5[4]
Pott et al.[160] FA 25 mg/㎡2 IV days 1-3+MIT 10 mg/㎡2 IV d1+DEX 20 mg 34(NR2) 41b
days 1-5[4] 23(NR) 9 48
Tedeschi et al.168] FA 30 mg/㎡2 IV d1+IDA 8-10 mg/㎡2 IV d1+DEX 20 mg 12(12) 17 50
day 1[4]
Zinzani et al,[169] FA 25 mg/㎡2 IV days 1-3+MIT 10 mg/㎡2 IV day 1+ 18(18) 22 50
Zinzani et al.170] PRED 40 mg IV days 1-5 [3]
FA 25 mg/㎡2 IV days 1-3+IDA 12 mg/㎡2 IV day 1[3] 10(10) 20 50
a Patients received 2 cycles of study chemotherapy.
b Overall response CR+PR. CR+PR
c Patients received 4 cycles of study chemotherapy.
Abbreviations:CR= complete response;CYC= cyclophosphamide;DEX=dex IDA=ida
CYC=cycl
dexamethasone;IDA=idarubicin;IFN=interferon;
IM =intramuscularly;y;IV=inIV=intravenously; MIT=mitoxantrone;e;NR=not re ed;PO=orally;PR=pO=orally;PR=partial response; PRED = prednisone;
pts = patients; 3x wklyy=3 times weekly; SC =subcutaneously. ts;3x wkly=3 ti
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Drugs 1997 Jun:53(6) 

overall survival times of 14 and 34 months,respec-tively,were reported in one investigation.[167]
In an ongoing trial, a regimen of fludarabine, mitoxantrone and dexamethasone alternating with CHOP chemotherapy has been used to treat 46 pa-tients with bulky low grade lymphoma,including 41 patients with follicular lymphoma.[171] 29 pa-tients completed chemotherapy, 2 withdrew be-cause of the development of myelosuppression and 15 patients are continuing treatment.To date a complete response rate of 80% has been reported; furthermore,molecular complete remissions [de-noted by polymerase chain reaction (PCR) nega-tivity for bcl-2 translocations in bone marrow] were reported for 8 of 13 patients with follicular lymphoma.
First-line treatment of 27 patients with low grade NHL with fludarabine plus cyclophos-phamide therapy produced a complete response rate of 89%.[1661 However,3 cases of Herpes zoster infection and 4 cases of Pneumocystis carinii pneumonia were reported in this study. Objective response rates of 67 and 70% were reported in 2 studies evaluating a combination regimen com-prising fludarabine plus idarubicin (with or with-out dexamethasone) in the treatment of relapsed or refractory low grade NHL.(168,170]
In addition, the FluDAP regimen,which com-prises dexamethasone,cytarabine,fludarabine and cisplatin, used in conjunction with G-CSF has demonstrated promising efficacy in a recent pilot study;of 14 evaluable patients with recurrent or refractory aggressive NHL, 4 achieved a complete response and 9 a partial response.[1721
Promising preliminary results have also been reported from a study comparing the combination of fludarabine, mitoxantrone and dexamethasone (FND) with an I1-drug regimen(ATT) in patients with low grade lymphoma.(1731 For the 62 patients evaluable to date, complete response rates of 81 and 77% have been reported for the FND and ATT regimens,respectively.Evidence of molecular re-mission determined by PCR and denoted by bcl-2 gene rearrangement in peripheral blood and bone marrow of patients with follicular lymphoma was
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also similar following treatment with either regi-men for 6 months.
Fludarabine-based combination chemotherapy has also been evaluated in the management of pa-tients with intermediate or high grade NHL.A combination regimen of continuous infusion cis-platin (25 mg/㎡2/day for 4 days) with sequential fludarabine (30 mg/㎡/day on days 3 and 4) and cytarabine(500 mg/㎡/day on days 3 and 4) ther-apy repeated every 4 weeks was used to treat 18 patients with anthracycline-refractory intermedi-ate or high grade NHL.(174] G-CSF was also rou-tinely used.Among 16 evaluable patients,5 objec-tive responses were reported (2 complete and 3 partial responses). Median survival of the entire patient group was 13 weeks with a greater survival time reported among responding patients (p= 0.043). This study has now been expanded to an international multicentre phase II study. A review of therapies employed in the treatment of aggres-sive NHL is published elsewhere in this issue.12591
3.4 Cutaneous T Cell Lymphomas
Mycosis fungoides and the Sézary syndrome are low grade cutaneous T cell NHLs for which no cure is available.(1751 Promising results have been reported with fludarabine in the treatment of these malignancies.
An objective response rate of 19% was reported with fludarabine (18 to 25 mg/㎡/day for 5 days) in a study of 31 patients with mycosis fun-goides.[176] In another study in which 35 patients with advanced or refractory mycosis fungoides or the Sézary syndrome were treated with fludarabine (25 mg/㎡/day for 5 days) and interferon-α-2a(5 to 7.5×106 units/m2 3 times weekly),4 patients achieved a complete response and 14 had partial responses (objective response rate of 51%).The median duration of progression-free survival was 5.9 months.l177] A complete remission of 14 months’duration following treatment with flu-darabine has been reported in a patient with Sézary syndrome who experienced a lymphomatous trans-formation to large cell lymphoma.[1781
Drugs 1997 Jun:53(6) 

3.5 Lymphoplasmacytoid Lymphoma and Waldenström's Macroglobulinaemia
Lymphoplasmacytoid lymphoma is a low grade B cell lymphoproliferative malignancy. Waldens-tröm's macroglobulinaemia is a subgroup of this condition and is characterised by the production of monoclonal immunoglobulin M (IgM) by well dif-ferentiated lymphoplasmacytic cells.11791
Studies recruiting patients with mainly ad-vanced and/or refractory lymphoplasmacytoid lymphoma,including Waldenström's macroglobu-linaemia,have reported partial response rates(gen-erally defined as a decrease of ≥50% in the mono-clonal IgM plasma concentration accompanied by a reduction in bone marrow infiltration and/or bone marrow involvement by >50%) of 32 to 80% fol-lowing the administration of fludarabine 20 to 30 mg/m2/day for 3 to 5 consecutive days every 4 to 5 weeks.184,180-184| Complete responses(defined as disappearance of abnormal protein by immuno-fixation and resolution of all other disease manifes-tations or by a circulating lymphocyte count of <4x 10° cells/L, granulocyte count >1.5x10° cells/L,thrombocyte count >100 x10°cells/L, haemoglobin >11 g/L,bone marrow infiltration <30% and serum IgM levels within normal range) were reported in 3 patients each recruited to 3 dif-ferent studies.184,180,182| No response was reported in 2 patients with Waldenström's macroglobulinae-mia in a study which recruited 85 patients with B and T cell malignancies.1971.
Long term follow-up of 7 patients with Waldens-tröm's macroglobulinaemia treated with fludarab-ine(25 mg/m2/day for 5 days every 4 weeks) re-vealed a response rate of 71%(type of response not specified).11851 Of the 4 of 6 previously treated pa-tients who responded, one had no evidence of dis-ease progression 5 years after treatment;the mean survival time for the others was 4.4 years.A patient who received further fludarabine treatment at dis-ease progression failed to respond.
Data from the largest study of fludarabine in the treatment of Waldenström's macroglobulinaemia conducted to date have been reported recently.1186| 74 patients with relapsed or resistant disease re-
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ceived a median of 6 courses of fludarabine therapy (dosage not stated). Of the 63 evaluable patients, 17 (27%)experienced a partial and 24 (38%) a good response(not defined).Seven of the respond-ing patients relapsed within a median time of 12 months and 5 of these 7 patients died.The overall median survival time of the treated patients was 654 days.
3.6 Other Haematological Malignancies
Promising results have also been reported with fludarabine in isolated cases of angioimmuno-blastic lymphadenopathy with dysproteinaemial187| and y-heavy-chain disease.1881 Successful treat-ment of I patient with refractory type II essential mixed cryoglobulinaemia and primary Sjögren's syndrome has been reported following fludarabine treatment.l189| However,in a series of 4 patients no clinical or laboratory improvement in essential mixed cryoglobulinaemia,refractory to previous treatment with interferon or alkylating agents,was observed after fludarabine therapy.l1901
Fludarabine induced remission in a patient with clinical symptoms of leukaemic meningitis attrib-utable to CLL meningeal involvement,which sug-gests that the drug may be useful in the prophylaxis and treatment of CNS involvement of lympho-proliferative diseases.11911
Fludarabine appears to have only minimal activ-ity in the treatment of plasma cell leukaemia,a highly aggressive form of multiple myeloma.l1921 No responses were reported in patients with multi-ple myeloma treated with fludarabine 12 to 15 mg/㎡2/day for 5 days every 3 weeksl1931 or a 15 mg/㎡2 loading dose followed by a continuous in-fusion of 20 to 37.5 mg/㎡/day for 48 hours.11941
Responses have been reported in a small num-ber of patients with hairy cell leukaemia resistant to other therapiesl195,196| or Hodgkin's lym-phoma.149,161l However,further trials involving larger patient numbers are required to fully evalu-ate the efficacy of fludarabine in the treatment of these conditions.
Drugs 1997 Jun:53(6) 

3.7 Application In Peripheral Blood Stem Cell and Bone Marrow Transplantation
Current procedures involved in allogeneic BM or peripheral blood stem cell (PBSC) transplanta-tion require the use of potentially toxic,myeloabla-tive conditioning regimens often comprising cyclophosphamide and TBI.Recently,a novel ap-proach has been adopted involving the use of non-myeloablative fludarabine-containing combina-tion regimens which are theoretically less toxic. Several small studies have shown such an approach to be sufficiently immunosuppressive to enable en-graftment in patients with acute or chronic leukae-mias or lymphoma.1197-2001
PBSC or BM transplantation preceded by myeloablative chemotherapy has been performed in a small number of patients with CLL who were pretreated with fludarabine therapy to achieve minimal residual disease.1201-2031 Three evaluable patients with stage B CLL and minimal residual disease after fludarabine therapy were alive and well 2 to 5 months after PBSC transplantation.12011 Of a further 2 patients who received intensification with high-dose chemotherapy and TBI followed by PBSC after a response to fludarabine,one was well 12 months after intensification,with normal haemoglobin levels and neutrophil counts but a persistent non-haemorrhagic thrombocytopenia. The other patient died of a viral lung infection 3 months after transplantation.12021
17 complete clinical remissions were reported in a cohort of 19 evaluable patients with poor prog-nosis B-CLL who received high-dose chemo-radiotherapy followed by autologous or allogenic BM transplantation; with the exception of 1 pa-tient, all patients had received a variety of induc-tion regimens,including fludarabine, to achieve minimal residual disease prior to BM transplanta-tion.12031 In another study, 10 of 15 patients with CLL were alive and in complete remission at a me-dian follow-up of 26 months after receiving al-logeneic stem cell transplantation; all 15 patients had received fludarabine prior to transplant.12041 Autologous transplantation of BM and/or PBSC has also been used with promising results in 18

patients with CLL, 10 of whom had received prior fludarabine therapy.12051
The use of a chemotherapy regimen comprising fludarabine,cytarabine and mitoxantrone has been shown to facilitate the collection of diploid-rich stem cells from patients with CML and has a pos-sible role in in vivo purging prior to autologous stem cell transplantation.12061
4.Tolerability
This section provides an overview of the toler-ability profle of fludarabine discussed in detail in the previous review in Drugsl'l and also includes an evaluation of more recently published data.
4.1 Myelosuppression and Infection
Myelosuppression is the major dose-limiting adverse effect associated with fludarabine ther-apy.l1.2071 In a large noncomparative study, NCI grade IV haematological toxicity (particularly anaemia and thrombocytopenia) was reported in 303 of 705 evaluable patients (43%) treated with fludarabine monotherapy.I1001 In another study,the administration of 479 fludarabine treatment cycles to 96 patients with CLL resulted in the develop-ment of granulocytopenia,thrombocytopenia and anaemia(WHO grade III/IV) during 19, 14 and 7% of treatment cycles, respectively.11071 In addition, anecdotalI reports cited in the literature refer to the development of pure red cell aplasial2081 and a case of fatal bone marrow necrosis in a patient with re-current low grade NHL treated with fludarab-ine.12091
The most frequent infectious complications as-sociated with fludarabine therapy are respiratory tract infections and unexplained fever.There have also been a number of reports of opportunistic in-fection including Cryptococcus neoformans men-ingitis,Pneumocystis carinii pneumonia and List-eria monocytogenes infection.196,210-218| However, many of these opportunistic infections developed predominantly in patients treated with fludarabine in combination with prednisone.
In I study, the use of corticosteroids in combi-nation with fludarabine in 31 patients with low 

grade lymphoid malignancies significantly in-creased the severity and incidence of infection compared with fludarabine monotherapy (35 vs 17%;p≤0.02).1218] However,compared with treat-ment with conventional chemotherapy (regimens not described) in the preceding 6 months,the in-cidence and severity of infections were greater during treatment with fludarabine monotherapy (p=0.01).
The results of several studies suggest that a sus-tained reduction in T lymphocyte count,particu-larly CD4+cells,may contribute to the increased incidence of infectious episodes associated with fludarabine therapy.l84,96,102]
In a large European study, the incidence of in-fectious episodes (grade I to IV) was similar in pa-tients with CLL treated with fludarabine (25 mg/㎡2/day for 5 days)or CAP(23 vs 19% of treat-ment cycles).11071 Furthermore, 25 patients with CLL treated with fludarabine plus G-CSF experi-enced a significantly(p=0.002) lower incidence of myelosuppression and pneumonia than 145 his-torical controls treated with fludarabine with or without prednisone.1219]
4.2 Neurotoxicity
Initial trials using high-dose fludarabine therapy (up to 125 mg/㎡2/day for 7 days) for the treatment of acute leukaemia were limited by the develop-ment of severe neurotoxicity leading to blindness, encephalopathy,coma and death.149,220-2221 Au-topsy findings revealed diffuse demyelination of the brain and spinal cord to be the underlying pa-thology.1221]
In a recent review of the literature and adverse drug reaction reports,neurotoxicity was reported to develop in 335 of 2136(16%)patients with a range of haematological malignancies, including CLL,treated with standard-dose fludarabine regi-mens.The majority of cases were mild and revers-ible and the incidence was similar to that reported for the other purine analogues, cladribine and pen-tostatin.12201 Furthermore, the majority of large studies have reported no or few severe neurologi-cal side effects with conventional dose fludara-
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bine therapy.184,95-97,1591 Investigators from a large European study reported the development of se-vere peripheral neuropathy (grade III/IV)after only 2 of a total of 479 fludarabine treatment cy-cles.[107]
Other cases of neurological adverse events re-ported after treatment with currently used low-dose fludarabine regimens (18 to 25 mg/㎡/day for 5 days) include both reversible neurotoxicity(in-cluding seizures, loss of consciousness,blurred vision and leg weakness)[156,223,224] and fatal neurotoxicity (including multifocal leucencepha-lopathy).1224,2251 Neurological adverse events were also reported in 8 of 219 patients with acute leu-kaemia or myelodysplasia treated with a combina-tion of fludarabine (30 mg/㎡/day for 5 days)plus cytarabine(1 to 3 g/㎡/day for 5 days).Five pa-tients developed peripheral neuropathy,1 devel-oped myelopathy and 2 patients with poor renal function developed fatal cerebral dysfunction.1226| However,the incidence of neurotoxicity in this study was considerably lower than that reported for cytarabine monotherapy.Possible potentiation of gentamicin-induced ototoxicity by fludarabine has been reported in 1 patient.1227)
4.3 Autoimmune Complications
The findings of earlier reports about a possible association between fludarabine treatment and the development of autoimmune haemolytic anaemia (AIHA)in patients with CLL were inconclusive, mainly because of the delayed development of the condition (up to 19 months after starting fludarab-ine therapy) or the inclusion of patients with a prior history of haemolytic anaemia.1228-2301
However,subsequent reports provide stronger evidence for a correlation between development of AIHA and fludarabine therapy. Myint et al.12311 re-ported the development of AIHA in 12 of 52 pa-tients with CLL treated with fludarabine.Of these patients only 3 had a previous history of haemo-lytic anaemia and 6 of 8 patients experienced an exacerbation of AIHA when retreated with flu-darabine after control of their haemolysis.Other investigators have reported the development of
Drugs 1997 Jun:53(6) 

AIHA within 6 weeks of starting fludarabine therapy[232-2341 and worsening of haemolysis in patients with pre-existing AIHA.I2341 In a large European study of patients with CLL,5 fludarab-ine-treated patients developed autoimmune phe-nomena (including haemolytic anaemia, autoim-mune thrombocytopenia and pure red cell aplasia) compared with no patients in the CAP treatment group.[107] These findings warrant further investi-gation,as the relationship between fludarabine and the development of AIHA remains uncertain in view of the association of CLL with AIHA.12351
Other autoimmune complications reported fol-lowing fludarabine therapy include recurrence of autoimmune thrombocytopenia,12361 a case of fatal paraneoplastic pemphigusl2371 and a case of Stevens-Johnson syndrome.1821,Resolution of pure red blood cell aplasia possibly due to a reduction in the T cell population responsible for suppressing ery-throid colony-forming unit proliferation has also been reported anecdotally.12381
4.4 Other Events
Isolated cases of tumour lysis syndrome (TLS), including lysis pneumonopathy,associated with fludarabine treatment are cited in the litera-ture.184,239-244I In most cases,TLS was successfully treated and did not recur when subsequent flu-darabine treatment was preceded by prophylactic measures comprising hydration and allopuri-nol.1239,241,243,244] Eosinophilia, which resolved without medical intervention,has been reported in 2 patients with follicular lymphoma who were treated with fludarabine.1245]
Although acute renal failure associated with TLS in patients treated with fludarabine has been well documented,12441 acute renal failure in isola-tion has been reported less frequently.12461 A case of rapidly progressive glomerulonephritis with crescent formation was reported in a patient with CLL after treatment with fludarabine.I247]
A small number of case reports of transfusion-associated graft-versus-host disease in patients who had received fludarabine treatment have been cited in the literature.1248-2531 This has led to a rec-

ommendation by the British Committee for Stand-ards in Haematology that fludarabine-treated pa-tients should receive irradiated blood products if they require a transfusion.1254]
Other severe but infrequent adverse events ob-served in patients receiving fludarabine therapy have included interstitial pneumonitisl255-2571 and haemolytic uraemic syndrome with pulmonary toxicity.12581 Nausea/vomiting, diarrhoea and alo-pecia have also been reported, developing (all grades) during 5.5, 4.5 and 2.2% of treatment cy-cles,respectively.1107)
4.5 Comparative Tolerability
In a comparative trial involving 196 evaluable patients with CLL treated with fludarabine(25 mg/㎡/day for 5 days)or CAP every 4 weeks,the most frequent treatment-related adverse event was myelosuppression,particularly granulocytopenia, in both treatment groups (fig. 3).11071 Granulo-cytopenia(WHO grade III/IV) developed after 19 and 22% of fludarabine and CAP treatment cycles, respectively.However,the incidence(all grades) and severity of nausea/vomiting (5 vs 25%)and alopecia (2 vs 65%) were significantly lower(p< 0.001)in the fludarabine treatment group.
In a study comparing fludarabine (25 mg/m/ day for 5 days) and chlorambucil (40 mg/㎡/day on day 1) administered every 4 weeks to patients with CLL,both drugs were reported to be well tol-erated,although the incidence of grade III/IV leucopenia was higher with fludarabine (20 vs 7%; p=0.001).11091 However,in another study which compared fludarabine (25 mg/㎡/day for 4 days repeated every 3 weeks) with continuous high-dose chlorambucil(10 mg/㎡/day) in patients with CLL,grade III/IV haematological toxicity was less common with fludarabine(52 vs 74%).11101
5. Dosage and Administration
The recommended regimen for fludarabine in the treatment of CLL is a dosage of 25 mg/㎡ daily for 5 consecutive days repeated every 28 days. Fludarabine is administered as a 30-minute contin-uous intravenous infusion or as an intravenous bo- 

Cumulative adverse events
(% of treatment cycles)
Fig.3.Comparative tolerability of fludarabine and CAP. Toler-ability data (WHO grade I to IV),based on number of treatment cycles,from a randomised prospective multicentre trial compar-ing fludarabine(25 mg/㎡2/day for 5 days)with CAP (cyclophos-phamide 750 mg/㎡2/day and doxorubicin 50 mg/㎡2/day on day 1 and prednisone 40 mg/㎡/day on days 1 to 5) in the treatment of 196 patients with advanced chronic lymphocytic leukae-mia.(107)
lus injection in 0.9% sodium chloride. Although the optimal treatment duration has not been estab-lished, it is recommended that fludarabine is ad-ministered until a maximal response has been achieved, which usually requires the administra-tion of 6 treatment cycles.The drug should then be discontinued.However, in some clinical studies, patients who experienced a partial response or dis-ease stabilisation on fludarabine treatment contin-ued to receive the drug until the occurrence of dis-
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ease progression or attainment of maximal re-sponse.[85,98]
Fludarabine dosage reduction of up to 50% in conjunction with close haematological monitoring is recommended for patients with a creatinine clearance of 30 to 70 ml/min (1.8 to 4.2 L/h). Fludarabine is contraindicated in patients with a creatinine clearance <30 ml/min (1.8 L/h).Careful monitoring of elderly patients (>75 years) receiv-ing fludarabine therapy is also recommended.
There are currently no recommended dosage re-gimens for fludarabine in the treatment of other haematological malignancies.However,fludarab-ine dosages of 20 to 30 mg/㎡/day for up to 5 con-secutive days repeated every 3 to 5 weeks in com-bination with cytarabine in the treatment of acute leukaemia (section 3.2) and as single-agent or com-bination therapy for NHL (section 3.3) have re-sulted in good response rates.
6.Place of Fludarabine in the Management of Haematological Malignancies
Fludarabine is the first important advance in the treatment of CLL since the introduction of the current first-line agent, chlorambucil. The drug is currently indicated for the second-line treatment of CLL and has been extensively evaluated in this setting, mostly in noncomparative studies. Following fludarabine therapy,high rates of com-plete remission have been achieved in both pre-viously treated and untreated patients with ad-vanced CLL. Several factors have been shown to correlate strongly with response rate and survival following fludarabine therapy;these include the number of previous chemotherapy regimens,re-sponse to alkylating agents and Rai or Binet stage of disease.
Since the previous review of fludarabine in Drugs,I’l randomised comparative trials have pro-duced important results showing the efficacy of fludarabine to be similar to or greater than that of standard chemotherapeutic regimens in the treat-ment of CLL. Of particular note are the recently published results of a large multicentre randomised
Drugs 1997 Jun:53(6) 

study demonstrating a significant improvement in response rate,response duration and progression-free survival with fludarabine compared with chlorambucil in chemotherapy-naive patients.Flu-darabine has also demonstrated benefits over CAP and CHOP in terms of objective response rate,re-mission duration and survival, particularly in pre-viously untreated patients.These data support the earlier use of fludarabine in the treatment of CLL, i.e.in the treatment of chemotherapy-naive pa-tients.
In the treatment of CLL,fludarabine also has considerable potential for use in combination che-motherapy regimens.Several studies have shown promising results with fludarabine in combination with various chemotherapeutic agents including cyclophosphamide,doxorubicin,mitoxantrone and epirubicin in the treatment of CLL.
There is an increasing body of data to support the use of fludarabine-containing combination re-gimens in the treatment of patients with acute leu-kaemias,although such regimens are not currently considered to be standard therapy. High response rates with a lower incidence of severe neurotoxi-city than previously reported with high-dose fludarabine monotherapy have been reported with sequential fludarabine and cytarabine combination chemotherapy,most notably in patients with AML; response rates were significantly higher than those reported with intermediate-or high-dose cytarab-ine monotherapy. Good response rates were more likely to occur in previously treated patients who had experienced a previous long remission. The addition of G-CSF to sequential fludarabine and cytarabine therapy has also been shown to be ben-eficial in terms of response rate and amelioration of drug-induced neutropenia in patients with AML and MDS.However, trials comparing sequential fludarabine and cytarabine therapy (with or with-out G-CSF) with current standard chemotherapeu-tic regimens are required to more fully elucidate the role of fludarabine in the treatment of acute leukaemias.
Clinical trials have investigated the efficacy of fludarabine monotherapy in low grade NHL most
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extensively in relapsed and refractory patients. Follicular lymphoma appears to be particularly re-sponsive to fludarabine therapy. Notably,high re-sponse rates have been reported with fludarabine-based combination regimens which have included agents such as cyclophosphamide,mitoxantrone and dexamethasone.Promising results have also been demonstrated in a number of uncommon and variant forms of B cell neoplasms. These results suggest an important future role for fludarabine-based combination chemotherapy in this setting.
In addition to activity in acute and chronic leu-kaemias and low grade lymphoma, data from pre-liminary studies suggest that fludarabine may be effective in the treatment of Waldenström’s macroglobulinaemia,cutaneous T cell lymphomas (mycosis fungoides and Sézary syndrome),T-CLL and PLL.However, additional studies involving greater patient numbers are necessary to further reinforce our knowledge of the activity of fluda-rabine in the treatment of these lymphoprolifera-tive disorders.Experience with fludarabine in the treatment of hairy cell leukaemia is still limited.In view of the more extensive evaluation and high response rates reported with other purine ana-logues,namely pentostatin and cladribine,the fu-ture establishment of a major role for fludarabine in this setting is unlikely. Similarly,fludarabine ap-pears to have only minimal activity in the treatment of plasma cell leukaemia.
More recently,fludarabine has been utilised in PBSC or BM transplantation in patients with acute or chronic leukaemia or lymphoma either as a com-ponent of a nonmyeloablative conditioning regi-men or in the attainment of minimal residual dis-ease prior to transplantation.Overall,this novel approach has produced promising results and now requires further evaluation in larger patient num-bers.
Comparative analyses have shown fludarabine to have a tolerability profile similar to that of chlor-ambucil and to be associated with a lower inci-dence and severity of nausea/vomiting and alo-pecia than CAP. Initial concerns regarding an increased incidence of infectious events following
Drugs 1997 Jun:53(6) 

fludarabine therapy have not been realised in com-parative studies; this problem appears to be largely attributable to the concomitant administration of corticosteroid therapy.However,monitoring is rec-ommended.Furthermore, although a small risk,the potential for the induction or exacerbation of auto-immune cytopenias in patients receiving fludarab-ine also requires caution;further investigations are required to fully substantiate or negate this associ-ation. Although minimal,the development of de-layed neurotoxicity with standard-dose fludarabine therapy remains a potential risk.
In summary, available data indicate that flu-darabine is a highly effective treatment for CLL in patients who have relapsed on,or are refractory to, standard therapy. Emerging data from comparative clinical studies also suggest that fludarabine is an effective agent in chemotherapy-naive patients with CLL; thus, the drug is a potential alternative to existing standard first-line therapy.Clinical data also suggest an increasing role for fludarabine in this setting as a component of combination chemo-therapy regimens. In addition,fludarabine has shown promise in the treatment of other lympho-proliferative diseases including acute leukaemias and NHL and in PBSC and BM transplantation. Further studies are ongoing to more fully define the activity of the drug for these indications.The cost effectiveness of fludarabine therapy has not been addressed to date; however,the completion of two additional randomised studies should provide suf-ficient efficacy and toxicity data to devise a phar-macoeconomic model to compare fludarabine with standard therapy in this respect.
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Correspondence: Julie C. Adkins, Adis International Lim-ited,41 Centorian Drive,Private Bag 65901,Mairangi Bay, Auckland 10,New Zealand.
E-mail:[email protected]
Drugs 1997 Jun: 53 (6)