A Comparison of Efficacy and Safety of Oral and IV, LRF CLL - Copy

A Comparison of the Efficacy and Safetyof Oral and Intravenous Fludarabine inChronic Lymphocytic Leukemia in theLRF CLL4 TrialClaire E. Dearden, MD1; Sue Richards, DPhil2; Monica Else, MSc1; Daniel Catovsky, DSc(Med)1; and Peter Hillmen, MD3

BACKGROUND: An oral formulation of fludarabine was introduced for use in chronic lymphocytic leukemia in 2001

following studies demonstrating the bioequivalence of a 40 mg/m2 oral dose with a 25 mg/m2 intravenous dose. We

assessed retrospectively the efficacy of these two routes of administration in the LRF CLL4 trial. METHODS: A total

of 777 patients were randomized from 1999-2004 to receive fludarabine, alone or with cyclophosphamide, or chlor-

ambucil. In 2001, a protocol amendment allowed the oral formulation. There were 117 assessable patients who

received fludarabine intravenously and 252 who received it orally. A total of 387 patients given chlorambucil acted as

a control group. RESULTS: Patients given oral fludarabine were less likely to receive the full dose (P ¼ .0004) and

experienced more, predominantly gastrointestinal, toxicity. Progression-free survival (PFS) and overall survival were

not affected by the route of administration (PFS hazard ratio, 1.10; 95% confidence interval, 0.87-1.40), but the overall

rate of response to treatment appeared to be lower with the oral formulation (P ¼ .003). However, patients recruited

since 2001 were older (P ¼ .03) and were more likely to have TP53 deletion, and response rates after 2001 were also

lower in the chlorambucil group. After excluding patients with TP53 deletion, no significant difference in outcome

was attributable to the route of administration. CONCLUSIONS: Although the LRF CLL4 data suggest no important

difference in the effectiveness of oral compared with intravenous fludarabine, randomized trials are needed to reliably

evaluate this comparison, particularly in combination with rituximab. Meanwhile, it is important to monitor compli-

ance and gastrointestinal side effects with the oral route and to switch to intravenous therapy if a reduced dose is

being received. Cancer 2011;117:2452–60. VC 2010 American Cancer Society.

KEYWORDS: chronic lymphocyctic leukemia, fludarabine, oral, intravenous, toxicity.

In 2001, an oral formulation of fludarabine was licensed for the treatment of chronic lymphocytic leukemia (CLL). Theoral formulation is now available in over 40 countries, and it was approved by the US Food and Drug Administration inDecember 2008. A phase 2 study suggested there was no difference in clinical efficacy between the oral and intravenous(iv) drug,1 and subsequent studies have confirmed this impression, whether used alone2,3 or in combination with oral cy-clophosphamide.4-6 Furthermore, the cost-effectiveness and convenience of oral over iv administration has provided adriver for the introduction of oral fludarabine in many countries. Not only is it 5% cheaper than the iv formulation, butthere are no associated clinic and nursing costs, reducing the overall cost per cycle of treatment to an estimated half of thatof the iv route. Elderly patients, in particular, can benefit from being treated at home and thereby participate more readilyin clinical trials. However, there has never been a comparison between oral versus iv fludarabine in a phase 3 trial, andquestions remain as to whether the efficacy and toxicity are the same.

A multicenter randomized clinical trial was undertaken in the United Kingdom (LRF CLL4) to compare the safetyand efficacy of chlorambucil to fludarabine, used either alone or with cyclophosphamide (FC), in previously untreated

DOI: 10.1002/cncr.25776, Received: July 19, 2010; Revised: October 6, 2010; Accepted: October 11, 2010, Published online December 14, 2010 in Wiley Online

Library (wileyonlinelibrary.com)

Corresponding author: Claire E. Dearden, MD, Department of Haematology, The Royal Marsden Hospital, Downs Road, Sutton, SM2 5PT, UK; Fax:

(011) 020-8642-6782; [email protected]

1Section of Haemato-Oncology, The Royal Marsden Hospital and The Institute of Cancer Research, Sutton, UK; 2Clinical Trial Service Unit, Oxford, UK; 3Leeds

Teaching Hospitals NHS Trust, Leeds, UK

We thank the National Cancer Research Institute Chronic Lymphocytic Leukaemia Working Group, and all doctors and patients involved, for their participation in

this study.

2452 Cancer June 1, 2011

Original Article

patients with CLL requiring therapy. During the courseof the trial, oral fludarabine became available, and a proto-col amendment allowed its use at a bioequivalent dose.7

Although the comparison of oral versus iv fludarabine wasnot planned as a prospective analysis, the availability ofthe oral form provided an opportunity to compare the ef-ficacy and safety of the 2 routes of administration. Theprotocol for patients randomized to receive chlorambucilremained unchanged, and these patients therefore formeda control group against which to test whether any changesin clinical outcomes after the introduction of oral fludara-bine were attributable to the oral formulation or were theresult of other changes that took place over time. We pres-ent here the results of this retrospective analysis.

MATERIALS AND METHODSOver a 66-month period from February 1999 to October2004, 387 patients in the LRF CLL4 trial were random-ized to receive chlorambucil, 194 received fludarabinealone, and 196 received fludarabine with cyclophospha-mide. The diagnosis of CLL was confirmed via centralreview of morphology and immunophenotype with 5markers: CD5, CD23, CD79b, FMC7, and surfaceimmunoglobulins with antibodies against light chains.

Other variables recorded at trial entry (either in allor in the majority of patients) and included in analyseswere: stage of disease, age, gender, b2 microglobulin level,lactate dehydrogenase level, and absolute lymphocytecount. A range of other prognostic markers was analyzedcentrally for the majority of trial patients: immunoglobu-lin heavy chain variable gene (IGHV) mutation status,CD38, ZAP-70 expression, and cytogenetics via fluores-cence in situ hybridization (FISH). Five FISH probeswere used: for trisomy 12 and deletions at 6q21, 11q23,13q14, and 17p13 (the TP53 locus).

Case report forms were kept simple to maximizerecruitment and answer the primary study question.Questions concerning the treatment given were: datestarted, number of courses, administration route, whetherthe full dose was given and date completed. Informationwas not collected concerning the details of any dose reduc-tions, nor whether these were protocol-mandated (ie, dueto persistent neutropenia or thrombocytopenia or reducedkidney function) or the result of individual physician orpatient decisions. The definition of full dose was as perprotocol. No guidance was given on howmuch of a reduc-tion from this should be classified as not full dose, but wasaccording to the individual physician’s judgement.

Chlorambucil was administered orally, 10 mg/m2/dfor 7 days, every 28 days, for up to 12 cycles. Fludarabinewas administered initially iv, 25 mg/m2/d for 5 days, orfor 3 days together with cyclophosphamide 250 mg/m2/dfor 3 days. When the protocol amendment allowed oralfludarabine, after February 2001, patients receiving oralfludarabine monotherapy were given fludarabine at a dos-age of 40 mg/m2/d for 5 days, and those receiving oral FCwere prescribed fludarabine at a dosage of 24 mg/m2/d to-gether with cyclophosphamide at a dosage of 150 mg/m2/d for 5 days. The change from 3 to 5 days for the oralcombination was undertaken to improve gastrointestinaltolerance and patient compliance. Whether administerediv or orally, fludarabine and FC were given every 28 daysfor up to 6 cycles.

All patients provided written informed consent. Thetrial was approved by a United Kingdom multicenterresearch ethics committee and followed UK MedicalResearch Council guidelines for good clinical practice.The study was registered as an International StandardRandomized Controlled Trial (ISRCTN58585610). Pri-mary results were published in 2007.8

Table 1. Number of Patients Receiving Intravenous and Oral Fludarabine

Fludarabine(n5194)

Fludarabine 1Cyclophosphamide(n5196)

Total(N5390)

Intravenous1999-2000 33 33 66

2001-2004 25 26 51

Oral 123 129 252

Unknown whether

intravenous/oral

7 5 12

Allocated but

not given

6* 3y 9

* Among these patients, 3 received chlorambucil, 1 received fludarabine þ cyclophosphamide, 1 died before

treatment, and 1 failed to return to the clinic.

yAmong these patients, 2 received chlorambucil and 1 died before treatment.

Oral vs Intravenous Fludarabine in LRF CLL4/Dearden et al

Cancer June 1, 2011 2453

Statistical Methods

The response recorded was the best achieved at any timedue to first-line treatment. Overall survival was calculatedfrom randomization to death from any cause. Progres-sion-free survival (PFS) was time from randomization torelapse needing further treatment, or to other progressiondate if reported, or death from any cause. (Relapse need-ing further treatment was defined as any of the following:lymphocyte doubling time<12 months; downward trendin hemoglobin level and/or platelet count;�50% increasein size of liver, spleen, or lymph nodes; appearance oflymphadenopathy, hepatomegaly, or spenomegaly if notalready present; or B-symptoms not attributable to othercauses.) For nonresponders and those with progressivedisease, the date of progression was when nonresponse orprogressive disease was recorded.

All main analyses were intention to treat; all patientswere analyzed according to the initial treatment given andthe initial route of administration. Comparisons betweencategorical variables were made using the chi-squared test;comparisons between quantitative variables were madeusing the Wilcoxon rank sum test. Cochran-Mantel-Haenszel statistics were used to examine associationsbetween toxicities and route of administration or treat-ment, allowing for the other variable. Logistic regressionmodels were used to determine whether response wasassociated with iv versus oral fludarabine independently

of other factors. Multivariate Cox regression analysis wasused to determine which factors were independently asso-ciated with PFS and survival. All P values were 2-sided.

RESULTS

Patients

The route of administration of fludarabine was known in369 cases. Of these, 32% received it intravenously (half ofwhom were treated before the oral option became avail-able in 2001, the other half of whom were treated subse-quently) and 68% received it orally (Table 1). In 2001,70% of patients given fludarabine received the oral for-mulation, increasing to 84% in 2002, 88% in 2003, and89% in 2004 (P for trend¼ .001).

In the trial as a whole, the 641 patients randomizedin 2001-2004 were older (median age, 65 years; range,35-86 years) than the 136 patients randomized in 1999-2000 (median age, 63 years; range, 42-84 years) and, inthose tested, more likely to be in the poor risk category(>10% TP53-deleted cells),9 but there were no differen-ces in the men:women ratio or disease stage at entry(Table 2). Patients who received fludarabine orally wereno different in gender or disease stage from those whoreceived it intravenously, but they were older, and all 18patients with TP53 deletion who were allocated to fludar-abine or FC received it orally (Table 2). The proportion

Table 2. Demographic Characteristics of LRF CLL4 Patients by Trial Entry Date, Drug, and Intravenous Versus Oral Fludarabine

All Trial Patients Fludarabine (Alone orwith Cyclophosphamide)*

Chlorambucil

1999-2000(n5136)

2001-2004(n5641)

P Intravenous(n5117)

Oral(n5252)

P 1999-2000(n566)

2001-2004(n5321)

P

Age, y .04y .01y NS

<60 56 (41) 199 (31) 48 (41) 74 (29) 27 (41) 100 (31)

60-69 45 (33) 243 (38) 40 (34) 96 (38) 22 (33) 122 (38)

‡70 35 (26) 199 (31) 29 (25) 82 (33) 17 (26) 99 (31)

Gender NS NS NS

Men 105 (77) 468 (73) 87 (74) 185 (73) 15 (23) 86 (27)

Women 31 (23) 173 (27) 30 (26) 67 (27) 51 (77) 235 (73)

Binet stage NS NS NS

A progressive 30 (22) 161 (25) 28 (24) 61 (24) 12 (18) 84 (26)

B 64 (47) 288 (45) 59 (50) 113 (45) 32 (48) 140 (44)

C 42 (31) 192 (30) 30 (26) 78 (31) 22 (33) 97 (30)

Tested for TP53 deletion 108 463 77 198 52 228

TP53-deleted 2 (2) 31 (7) .05 0 (0) 18 (9) .006 2 (4) 13 (6) NS

All data are presented as n (%).

NS indicates not significant.

* Excludes 21 patients whose route of administration was unknown or who did not receive the treatment allocated.

yWilcoxon rank sum test.

Original Article


of patients who received the full dose was similar overtime in the chlorambucil group, but for those on fludara-bine or FC, it was greater overall among those randomizedin 1999-2000 (Table 3). However, it was similar overtime in the iv group, and this difference was due to itbeing less likely that the full dose was received if the drugwas given orally. The older the patient, the more likelythey were to receive a reduced dose, whether given iv ororally (Table 4). Reasons for the reduced dose were notrecorded. There was no significant difference in the num-ber of cycles of treatment given by route of administration(data not shown).

Toxicity

Toxicity by treatment group has been reported previ-ously.8 Briefly, neutropenia, nausea and vomiting, alope-cia, and any World Health Organization grade 3 or 4toxicity were significantly more frequent with FC thanwith either chlorambucil or fludarabine alone (all P <

.0001), as were diarrhea (P¼ .01) and ‘‘other toxicity’’ (P¼ .004). Hemolytic anemia was less frequent with FC (P¼ .01).10 These differences remained significant afteradjustment for the oral or iv route for fludarabine, apartfrom grade 3 or 4 diarrhea, which was no longer signifi-cantly different between fludarabine and FC. Hemolytic

anemia was more common with the oral than the iv flu-darabine formulation, as were diarrhea and ‘‘other toxic-ity,’’ but no other differences in toxicity between theroutes of administration were seen (Table 5). It is notknown how many patients experiencing toxicity with theoral form were switched to the iv route, but the numberwas estimated to be low and was unlikely to have influ-enced these results.

Allowing for age, treatment, and treatment route,doses were significantly more likely to be reduced inpatients experiencing febrile episodes (P¼ .01), thrombo-cytopenia (P ¼ .007) and ‘‘other toxicity’’ (P ¼ .02), andmay have been reduced in some cases of neutropenia oranemia. Doses were not apparently reduced as a result ofany of the other categories of recorded toxicities. In ananalysis of dose by route, with age, treatment, and anemiaor ‘‘other toxicity’’ included in the model, the route stillaffected the dose significantly (P¼ .006).

Response to Treatment

As previously reported, the overall response rate and‘‘good’’ response rate (complete response plus nodularpartial response) were significantly better with FC thanwith either chlorambucil or fludarabine alone (P <

.0001).8 Responses appeared less good with the oral

Table 3. Number of Patients Receiving Full Dose Chemotherapy by Treatment, Route of Administration, and Trial Entry Date

Treatment Route ofAdministration

Trial EntryDate

No. of PatientsAssessable

No. of PatientsReceiving Full Dose (%)

P

Chlorambucil 1999-2000 64 54 (84)NS

2001-2004 315 261 (83)

F All 1999-2000 32 30 (94).06

2001-2004 153 122 (80)

IV 1999-2000 32 30 (94)NS

2001-2004 25 25 (100)

IV All years 57 55 (96).0004

Oral 2001-2004 122 91 (75)

FC All 1999-2000 33 29 (88)NS

2001-2004 158 127 (80)

IV 1999-2000 33 29 (88)NS

2001-2004 26 23 (88)

IV All years 59 52 (88)NS

Oral 2001-2004 127 99 (78)

F and FC All 1999-2000 65 59 (91).03

2001-2004 311 249 (80)

IV All years 116 107 (92).0003

Oral 2001-2004 249 190 (76)

Patients who were not given their allocated treatment (chlorambucil, n ¼ 3; fludarabine, n ¼ 6; fludarabine with cyclophosphamide, n ¼ 3) or for whom dose

information was missing (chlorambucil, n ¼ 5; fludarabine, n ¼ 3; fludarabine with cyclophosphamide, n ¼ 2) were excluded.

NS indicates not significant; F, fludarabine; FC, fludarabine with cyclophosphamide; IV, intravenous.



formulation of fludarabine than with iv, including in thosewho received the full dose; however, the differences wereless marked when the TP53-deleted cases were excluded(Table 6). Response rates were lower in patients receiving areduced dose compared with patients receiving the fulldose, irrespective of the route of administration (Table 6).In addition, a (nonsignificant) decline in response rates wasseen during the course of the trial in all age groups, includ-ing in the chlorambucil group (Table 7).

Because the comparison of oral and iv administrationwas not randomized, an adjustment for possible confound-ing factors is necessary. A multivariate analysis of response

was therefore conducted for several variables, including age,randomized treatment, disease stage, gender, and route ofadministration. Because no patients in the iv-treated grouphad TP53 deletion, and this group is known to respondextremely poorly ,9,11 they were excluded from the analysis.In the remaining 331 patients receiving fludarabine or FCas allocated and whose administration route was known,treatment was the only significant variable (P < .0001),with better response rates for FC (odds ratio [OR], 2.43;95% confidence interval [CI] , 1.58-3.73). The OR for ivtreatment was 1.48 (95% CI, 0.94-2.33; P¼ .09). Restric-tion to the group that received the full dose did not

Table 4. Number of Patients Receiving Full Dose by Drug, Route of Administration, and Age

Drug and Route ofAdministration

Age, y No. ofPatientsAssessable

No. of PatientsReceiving FullDose (%)

P forTrend

Intravenous fludarabine <60 48 47 (98)

.0560-69 40 36 (90)

�70 28 24 (86)

Oral fludarabine <60 73 62 (85)

.00960-69 94 73 (78)

�70 82 55 (67)

Chlorambucil <60 123 103 (84)

.360-69 142 123 (87)

�70 114 89 (78)

Patients who were not given their allocated treatment or for whom dose information was missing were excluded.

The interaction between age and route of administration was not significant.

Table 5. Percentage of Fludarabine-Treated Patients Experiencing Toxicity by IntravenousVersus Oral Treatment Route

Toxicity* No. of PatientsAssessable†

% with Toxicity P (Adjusted‡)

Intravenous Oral

Neutropenia 366 47 50 NS

Thrombocytopenia 365 13 15 NS

Hemolytic anemia 364 3 10 .03 (.06)

Febrile episodes§ 356 28 35 NS

Nausea and vomiting 358 11 9 NS

Nausea and vomiting (all grades) 358 42 43 NS

Alopecia 327 2 0.5 NS

Mucositis 353 1 0.4 NS

Diarrhea 347 3 3 NS

Diarrhea (all grades) 347 15 28 .01 (.01)

Other toxicity|| 298 3 10 .05 (.07)

Other toxicity (all grades) 298 23 41 .002 (.005)

NS indicates not significant.

*World Health Organization grades 3 and 4 only, unless specified otherwise.

y Includes only patients randomized to fludarabine or fludarabine plus cyclophosphamide who received the allo-

cated treatment by known route (n¼369) and where individual toxicity question was completed.

zAllowing for age and treatment.

§One or more episodes.||Where the grade was not specified, grade 1 or 2 toxicity was assumed. Cases of ‘‘other toxicity’’ (n¼106)

included skin rash (25 cases), infection (22 cases), cardiovascular event (10 cases), fatigue (6 cases), and consti-

pation (5 cases).

Original Article


materially alter this finding (OR, 1.42; 95% CI, 0.86-2.35). Other risk factors (11q deletion, elevated b2 micro-globulin level, and unmutated IGHV genes and/orIGHV3-21 usage) were available for only 152 of thepatients in this group, and in this subset the OR for iv treat-ment was 1.20 (95%CI, 0.61-2.36).

PFS and Overall Survival

At a median follow-up of 8 years for the iv group and 6years for the oral group, there was no significant differencebetween groups in either PFS or overall survival, eitheroverall (P¼ 1.00, 0.25, respectively), or within the fludara-bine and FC treatments (Figure 1). In multivariate analysesin the trial as a whole, prognostic factors found to be signifi-cant were unmutated IGHV genes and/or IGHV3-21usage, 11q deletion, elevated b2 microglobulin level andtreatment allocation, for predicting shorter PFS, and olderage, elevated b2 microglobulin level, unmutated IGHVgenes and/or IGHV3-21 usage and treatment allocation,for predicting shorter overall survival.9 In Cox regressionanalyses, excluding TP53-deleted cases, the hazard ratios(HR) for oral versus iv administration were 1.02 (95% CI,0.80-1.31) for PFS and 1.07 (95%CI, 0.78-1.48) for over-

all survival, in a model including only treatment and route.In subsets with complete data, the HRs were modifiedfrom 0.85 (95% CI, 0.59-1.21) to 0.91 (95% CI, 0.63-1.31) for PFS and from 0.81 (95% CI, 0.52-1.27) to 0.82

Table 6. Response Rates by Oral Versus Intravenous Fludarabine

IV Oral Oral ExcludingTP53 Deletion

P

IV vsOral

IV vs Oral ExcludingTP53 Deletion

Fludarabine aloneTotal patients 56 116 108

Overall response 51 (91%) 87 (75%) 84 (78%) .01 .03

CR and NodPR 27 (48%) 48 (42%) 47 (44%) NS NS

Fludarabine plus cyclophosphamideTotal patients 57 118 110

Overall response 56 (98%) 108 (92%) 106 (96%) NS NS

CR and NodPR 39 (68%) 67 (57%) 66 (60%) NS NS

Full dose received*Total patients 104 180 167

Overall response 99 (95%) 153 (85%) 148 (89%) .009 NS

CR and NodPR 64 (62%) 96 (53%) 94 (56%) NS NS

Full dose not received*Total patients 8 52 49

Overall response 7 (87.5%) 41 (79%) 41 (84%) NS NS

CR and NodPR 2 (25%) 18 (35%) 18 (37%) NS NS

AllTotal patients 113 234 218

Overall response 107 (95%) 195 (83%) 190 (87%) .003 .03

CR and NodPR 66 (58%) 115 (49%) 113 (52%) NS NS

Only patients who received their allocated treatment and for whom response was assessable were included.

IV indicates intravenous; CR, complete response; NodPR, nodular partial response; NS, not significant.

*P values for all patients receiving versus not receiving the full dose were: overall response, P ¼ .07 (not significant); CR and NodPR, P ¼ .001.

Table 7. Response Rates by Treatment and Trial Entry Datea

Trial Entry Date P

1999-2000 2001-2004

Fludarabine aloneTotal patients 32 145

Overall response 29 (91%) 113 (78%) NS

CR and NodPR 15 (47%) 61 (42%) NS

Fludarabine plus cyclophosphamideTotal patients 33 147


CR and NodPR 23 (70%) 86 (58.5%) NS

ChlorambucilTotal patients 63 303


CR and NodPR 21 (33%) 77 (25%) NS

aOnly patients who received their allocated treatment and for whom

response was assessable were included.

NS indicates not significant; CR, complete response; NodPR, nodular par-

tial response.



(95% CI, 0.52-1.29) for overall survival via inclusion of allrelevant prognostic factors into the model.

DISCUSSIONOn first examination of the results, it seems clear that theoverall response rate is higher in the group of patientsreceiving iv versus oral fludarabine, alone or in combina-tion with cyclophosphamide. However, iv versus oral flu-darabine (with or without oral cyclophosphamide) wasnot a randomized comparison in the LRF CLL4 trial. It istherefore necessary to make adjustments for confoundingfactors when interpreting the results. Of note, a decline inresponse rates over the course of the trial affected thechlorambucil arm, for which no treatment change wasintroduced, as well as the fludarabine and FC arms.Therefore, other variables acting over time must haveaffected outcome for patients regardless of the treatment

they received. Two main factors are implicated: 1) therecruitment of older age patients, possibly as a result ofthe more readily administered oral treatment becomingavailable; 2) the increased numbers of patients with TP53deletion. The latter information was only available retro-spectively, and genetic risk was not controlled for in thetrial randomization. Unexpectedly, all the patients withTP53 deletion, which was associated with low responserates across all treatment arms,9 received oral rather thaniv fludarabine.

The trial results showed that, although older as wellas younger patients responded better to FC than to fludar-abine alone or chlorambucil, older age was associated withslightly poorer responses overall.8 The changes in agedemographics over the course of the trial therefore willhave had an impact on the results. It is more difficult tojudge any specific impact of older age on the efficacy oforal versus iv administration. Older patients were lesslikely than younger ones to receive the full dose, particu-larly if they received the oral formulation. Age-relatedphysiological changes may affect the pharmacology(absorption, distribution, metabolism, renal clearance),but there are no reliable data to confirm this. Further-more, the fact that older patients may be receiving moreconcomitant medications, and also may be less reliable inadministering the oral drugs, could have an impact.

Patients of all ages were more likely to receive areduced dose if they were given oral rather than iv fludara-bine (24% vs 8%). Responses were poorer with the oral for-mulation even among patients receiving the full dose, butwere also poorer in patients who received a reduced dosecompared with patients receiving the full dose, irrespectiveof the route of administration. Clearly, some patientsreceived a reduced dose due to toxicity, but it is not knownwhich patients changed from oral to iv, and it is thereforenot possible to assess whether this change-over explains whysome patients with gastrointestinal toxicity were still able toreceive the full dose. The dosing schedule for oral adminis-tration is complex, involving a different number of tabletson different days to make up the full dose and usuallyinvolving other medications, such as anti-emetics, co-tri-moxazole, and fluconazole, each with an individual dosingschedule. For patients likely to find compliance difficult, itmay be helpful if they are either offered treatment by the ivroute or given aids to increase compliance, such as a chartshowing the schedule for all medications on a daily basis.

In multivariate analysis, route of administration wasnot significantly associated with response, either when themodel included randomized treatment, disease stage, age,

Figure 1. A comparison of intravenous and oral fludarabine isshown for (A) progression-free survival and (B) overall sur-vival. There were no significant differences between the oraland intravenous routes. Cases with TP53 deletion occurredonly in patients given the oral formulation and are notincluded.

Original Article


and gender or, in the subset with genetic risk factors meas-ured, when it included randomized treatment and otherrisk factors. Nor was the result any different when onlypatients who received the full dose were included. Thissuggests that the route of administration did not influencethe response rate after adjustment for known confoundingfactors.

Importantly, there was no significant difference ineither PFS or overall survival between the oral and iv flu-darabine treatment groups. There was some increased tox-icity with the oral formulation, including more reportedcases of diarrhea, which could have resulted in somepatients failing to receive optimal doses of treatment, and‘‘other toxicity,’’ including skin rashes, infections and car-diovascular events, which may also have resulted in dosereductions. This observation raises awareness of the needto switch patients from oral to iv therapy if they experi-ence gastrointestinal toxicity and, where possible, in casesof other toxicity.

The changes in results over time in the LRF CLL4trial raise a number of issues in relation to the conduct oftrials in general, especially those recruiting patients over aprotracted time period. There is a need to be aware thatthe generalizability of results is related both to the patientpopulation recruited and to management issues. Even inthe chlorambucil arm, there would have been differentresponse rates seen at an interim recruitment point com-pared with the end of the trial. This highlights the diffi-culty of extrapolating data from small nonrandomizedphase 2 trials and comparing results with historical stud-ies. In addition, it has raised our awareness of the inherentdifficulties in interpretation of the data after a trialamendment is made part-way through a study, even if noeffect on outcome is anticipated.

Although the treatments given in the LRF CLL4trial have now been superseded by the introduction ofchemo-immunotherapy combinations, the question ofthe efficacy of oral fludarabine compared with ivremains highly relevant. Fludarabine is still a majorcomponent of most regimens for the treatment of CLL(notably FC plus rituximab, which has been adminis-tered iv thus far12,13) and the ability to deliver the drugas an oral therapy offers practical and cost advantages.Overall, there was no evidence of any clinically relevantdifference in trial endpoints for patients treated on LRFCLL4 which could be attributed to the route of admin-istration of fludarabine. However, this was a retrospec-tive comparison, and large randomized trials are neededto reliably evaluate the efficacy of oral versus iv fludara-

bine, particularly in combination with rituximab andother chemo-immunotherapy agents. Meanwhile, it isimportant to recognize issues both of compliance andtolerability with the oral form, particularly gastrointesti-nal toxicity, which can lead to a reduced dose beingreceived, and to switch to iv therapy in such cases toensure that the optimal dose is given.

CONFLICT OF INTEREST DISCLOSURESThe LRF CLL4 trial was funded by a core grant from Leukae-mia Research UK. Laboratory studies were funded by an educa-tional grant from Schering Health Care (United Kingdom) andSchering AG (Germany). The Clinical Trial Service Unitreceived research support from the Medical Research Counciland Cancer Research UK. M.E. was supported by the ArbibFoundation. C.E.D. has acted as a consultant for Roche,BSPharma, and Genzyme Inc. D.C. has acted as a consultantfor and has received research funding from Roche, Glaxo-SmithKline, Parexel, and Schering AG. P.H. has acted as a con-sultant and received research support from Genzyme Inc, Roche,and GlaxoSmithKline.

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A Comparison of Efficacy and Safety of Oral and IV, LRF CLL - Copy