British Journal of Haematology 2000, 109, 571–575
`
`CCNU (lomustine), idarubicin and dexamethasone (CIDEX):
`an effective oral regimen for the treatment of refractory or
`relapsed myeloma
`
`R. Parameswaran, 1 Chrissy Giles, 2 M. Boots, 2 T. J. Littlewood, 2 M. J. Mills, 1 S. M. Kelsey 2 and
`Diana Samson 1 1The East London and Essex Haematology Research Group, The Royal London Hospital, London, and
`2The Riverside Haematology Group, Hammersmith Hospital, London
`
`Received 5 November 1999; accepted for publication 2 February 2000
`
`Summary. We report the results of a non-randomized pilot
`study of an oral regimen comprising CCNU (lomustine; 25
`or 50 mg/m2 on day 1), idarubicin (4-demethoxydaunoru-
`bicin) (10 mg/m2 on days 1–3) and dexamethasone (10 mg
`b.d. on days 1–4) in patients with relapsed or refractory
`myeloma. Treatment was given every 28 d for a maximum
`of six courses. Sixty patients were entered of whom 57 were
`evaluable. Overall response rate (partial or minor response)
`was 49% with 30% of patients achieving a partial response
`
`(50% tumour reduction). Response rates were higher in
`patients with untested relapse than in those with refractory
`disease (overall response rates 56% vs. 31%). The major
`toxicity was neutropenia and the regimen was otherwise well
`tolerated. The median survival from entry of all patients was
`15 months, with 30% of patients alive at 2 years. This regimen
`represents a useful addition to available treatment options.
`
`Keywords: myeloma, CCNU (lomustine), idarubicin.
`
`The optimum therapy for patients with relapsed or refractory
`myeloma disease is unclear. In patients progressing from first
`remission, treatment with the same regimen that produced the
`initial response will produce a second response in 50–60%
`cases (Belch et al, 1988; Buzaid & Durie, 1988). In patients
`with refractory disease or those progressing after second- or
`third-line therapy, a number of treatment regimens may be
`used, including dexamethasone alone (Alexanian et al, 1983,
`1986) or combined with infused doxorubicin and vincristine
`(the VAD regimen) (Barlogie et al, 1984). VAD has been
`considered to be the gold standard for relapsed and refractory
`disease, however in the only randomized study comparing
`VAD with a standard alkylator-based regimen in relapsed
`patients, VAD was not shown to be superior to VBMCP
`[vincristine, BCNU (carmustine), cyclophosphamide, mel-
`phalan, prednisolone] (Mineur et al, 1998). A non-rando-
`mized comparison of VAD with high-dose dexamethasone
`alone suggested that VAD is more effective in relapsed patients
`but that the response rate in refractory patients is similar
`(Alexanian et al, 1986). The advantages of the VAD regimen
`are therefore not entirely proven. In addition, it is unsuitable
`
`Correspondence, Dr D. Samson, Department of Haematology,
`Imperial College School of Medicine, Hammersmith Hospital,
`Ducane Road, London W12 0NN, UK. E-mail: d.samson@ic.ac.uk
`
`q 2000 Blackwell Science Ltd
`
`for most elderly patients because of the need for central access
`and the high dose of dexamethasone.
`Quality of life is extremely important in patients with relapsed
`and refractory myeloma in view of their limited life expectancy
`and an oral regimen would be preferable to intravenous
`therapy. Oral idarubicin (4-demethoxydaunorubicin), used
`as a single agent or in combination with prednisolone, has
`been shown to produce responses in 25–50% of relapsed
`patients (Chisesi et al, 1988; Alberts et al, 1990) and has
`also proved effective when combined with dexamethasone
`in newly diagnosed patients (Cook et al, 1996).
`Both doxorubicin and BCNU (carmustine) have well-
`established activity in the treatment of myeloma. We
`therefore proposed to investigate the efficacy of a combina-
`tion of
`the similar oral drugs idarubicin and CCNU
`(lomustine) with the addition of dexamethasone in a dose
`which would be suitable for older patients. In October 1993,
`we began a pilot study evaluating this CIDEX regimen in
`patients with relapsed and refractory myeloma. The study
`was closed in August 1997 after 60 patients had been
`entered and we now report the final results.
`
`METHODS
`
`Study design. This was a non-randomized pilot study open
`
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`572 R. Parameswaran et al
`
`to patients with relapsed or refractory myeloma who had
`not received idarubicin or CCNU before enrolment in the
`study. The study was approved by the Local Ethical
`Committees of participating hospitals.
`The chosen dose of oral idarubicin was a total of 30 mg/
`m2 to be given over 3 d, i.e. approximately 10 mg/m2/d.
`Idarubicin 10 mg/m2/d for 3 d has been safely used in
`combination with other drugs such as cytarabine and
`etoposide in acute myeloid leukaemia (AML) (Jackson et al,
`1997) and chlorambucil in lymphoma (unpublished obser-
`vations). The initial aim was to use a dose of 50 mg/m2
`CCNU in combination with 30 mg/m2 idarubicin (and
`dexamethasone)
`in a 4-weekly schedule for up to six
`courses. CCNU 50 mg/m2 was used successfully in combi-
`nation with melphalan, cyclophosphamide and predniso-
`lone in a 4-weekly schedule in the third MRC Myelomatosis
`trial with no significant myelotoxicity (Medical Research
`Council’s Working Party on Leukaemia in Adults, 1980).
`However, as idarubicin had not previously been used in
`combination with CCNU, an initial evaluation of myelotoxi-
`city was made using a lower CCNU dose of 25 mg/m2. At
`the time the study was commenced, CCNU capsules were
`available in two strengths, 10 mg and 40 mg, allowing
`accurate dosage on the basis of surface area, but the 10-mg
`capsules were subsequently withdrawn from the UK market.
`When it was found that the higher dose of CCNU was
`associated with an unacceptable incidence of
`severe
`neutropenia (see below), it was therefore not possible to
`evaluate an intermediate CCNU dose. The remaining
`patients received a standard dose of 40 mg, which equates
`to a dose of 25 mg/m2 for a patient of 1·7 m2.
`Patients were required to have a neutrophil count
`. 1·0 (cid:2) 109/l and a platelet count of . 50 (cid:2) 109/l at
`entry. An upper limit of 200 mmol/l was set for serum
`creatinine because idarubicinol and active metabolites of
`CCNU are excreted by the kidney.
`Patient characteristics. No data were returned on three
`patients. The characteristics of the remaining 57 patients
`are shown in Table I. Of the 49 patients with relapsed
`disease, 17 were in second or subsequent relapse and eight
`had refractory relapse, i.e. were progressing on treatment
`given at relapse. Eight patients had primary refractory
`disease. Twenty-seven patients
`(45%) had previously
`received doxorubicin, of whom four were known to be
`refractory to a doxorubicin-containing regimen. Twelve
`patients had received prior BCNU. Although an upper
`limit for serum creatinine of 200 mmol/l had been set, five
`patients had creatinine levels between 200 and 350 mmol/l
`whereas three had levels over 500 mmol/l. One of these
`three patients was already on long-term dialysis at the time
`of disease progression whereas two of the three patients
`developed renal
`failure in association with progressive
`disease.
`Treatment regimens. CIDEX was given in a 4-weekly cycle for
`a maximum of six courses. CCNU was given as a single dose on
`the first day, idarubicin 30 mg/m2 total dose divided over 3 d
`and dexamethasone 10 mg twice daily for 4 d. The dose of
`CCNU was 25 mg/m2 in the first eight patients, 50 mg/m2 in
`the next 25 patients (group B) and 40 mg as a single dose in the
`
`Table I. Patient characteristics.
`
`Total
`Age (years)
`Sex
`Status
`Untested relapse 1
`Untested relapse $ 2
`Refractory relapse
`Primary refractory
`Prior therapy
`One regimen*
`Two regimens*
`Three regimens*
`Previous ABMT/PBSCT
`Interferon
`Serum creatinine . 200 mmol/l
`
`57
`Median 66 (range 39–89)
`Male 38/female 19
`
`24
`17
`8
`8
`
`29
`21
`7
`8
`14
`8
`
`*Conventional chemotherapy regimen(s).
`ABMT, autologous bone marrow transplant.
`PBSCT, peripheral blood stem cell transplant.
`
`final 24 patients. Patients who received CCNU 25 mg/m2 or
`40 mg were combined for analysis (group A).
`Monitoring of response. Serum paraprotein concentration
`and/or urinary light-chain excretion were measured at the
`beginning of each cycle of treatment and every 4–8 weeks
`afterwards. Bone marrow examination was performed only
`if clinically indicated or required to document response in
`non-secretory disease or to confirm complete response (CR)
`and radiographs were carried out only if clinically indicated.
`The definitions used for response or progression were those
`of Blade et al (1998). We have considered patients meeting
`the criteria for CR, partial response (PR) or minor response
`(MR) to have had a response to treatment.
`Statistical methods. Mortality from disease or treatment-
`related causes before the third course of CIDEX was defined
`as early death. Response duration and survival were
`analysed using graphpad prism software according to the
`product limit method of Kaplan–Meier. Progression-free
`survival was analysed in responders only and patients were
`censored if and when they withdrew because of toxicity, if
`they received a stem cell transplant, if they died of unrelated
`causes or if they were lost to follow-up. Overall survival was
`analysed in all patients regardless of any subsequent
`treatment and patients were only censored if they died of
`unrelated causes or were lost to follow-up.
`
`RESULTS
`
`Frequency of response (see Table II)
`There were eight early deaths and five patients were
`withdrawn before completing three courses. Of the remain-
`ing 44 patients, 28 responded (17 PR, 11 MR), giving an
`overall response rate of 49% and a response rate in
`evaluable patients of 64%. Patients with untested relapse
`had a significantly higher response rate than patients with
`refractory disease. Of
`the four patients known to be
`refractory to anthracycline, one responded, one showed no
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`Table II. Response to treatment.
`
`CCNU, Idarubicin and Dexamethasone for Relapsed Myeloma 573
`
`All patients
`
`By disease status
`
`By CCNU dose
`
`Untested relapse
`
`Refractory disease
`
`Group A
`
`Group B
`
`Total
`Early death
`Withdrawal
`Evaluable
`
`PR
`MR
`NC
`Progression
`
`Response (percentage all patients)
`Response (percentage evaluable patients)
`PR (percentage all patients)
`PR (percentage evaluable patients)
`
`57
`8
`5
`44
`
`17
`11
`6
`10
`
`49
`64
`30
`39
`
`41
`5
`5
`31
`
`14
`9
`2
`6
`
`56
`74*
`34
`45
`
`16
`3
`0
`13
`
`3
`2
`4
`4
`
`31
`38*
`19
`23
`
`32
`5
`2
`25
`
`10
`7
`2
`6
`
`53
`68
`31
`40
`
`25
`3
`3
`19
`
`7
`4
`4
`4
`
`44
`58
`28
`37
`
`*P (cid:136) 0·025.
`PR, partial response; MR, minor response; NC, no change.
`
`change and two progressed. There was no significant
`difference in response rates between groups A and B.
`
`Toxicity
`The major toxicity was neutropenia (Table III). Day 15
`blood counts were returned in 42 patients who received 159
`treatment courses. Grade 3 or 4 neutropenia occurred in
`25% of courses and was more frequent at the higher CCNU
`dose (33% of courses vs. 20%). Grade 3 or 4 thrombocy-
`topenia occurred in only 7% of courses even at the higher
`CCNU dosage. The frequency of grade 3 or 4 neutropenia
`remained high throughout treatment in group B but only
`one patient in group A had grade 4 neutropenia after the
`second course. This suggests that haematological toxicity
`lessened as the patient responded to treatment and marrow
`function improved.
`Steroid-induced psychosis occurred in two patients,
`myopathy in another and another patient died from a
`bleeding duodenal ulcer. One patient developed palpitations
`during the first course of
`treatment. There was no
`abnormality on examination and an electrocardiograph
`and echocardiogram were normal. No other cardiotoxicity
`was reported. Nausea, vomiting and diarrhoea were reported
`in eight patients, WHO grade 1–2 in four of the patients and
`grade 3 in the other four patients. Alopecia was generally
`mild to moderate, with grade 3 alopecia reported in only
`three patients and no patient reported with grade 4 alopecia.
`
`Toxicity in patients with renal impairment
`Of the five patients with serum creatinine in the range 200–
`350 mmol/l, one declined further treatment after the first
`course, one stopped treatment after course 4 because of
`disease progression and the remaining three patients
`received six courses of treatment. No instance of neutrope-
`nia or thrombocytopenia . grade 0 was observed in these
`patients and no non-haematological toxicity was reported.
`
`failure in
`the two patients who developed renal
`Of
`association with progressive disease, one patient died at
`day 7 as a result of pneumonia. The second patient
`responded to therapy with normalization of serum creatin-
`ine after three courses of treatment and then proceeded to
`high-dose therapy. There was no haematological or non-
`haematological toxicity during the CIDEX therapy. The final
`patient, who was already on long-term dialysis, received
`three courses of treatment with no haematological or non-
`haematological toxicity. Four weeks later he developed a
`bleeding duodenal ulcer, from which he died; the platelet
`count was normal at this time.
`
`Withdrawals and treatment modifications
`There were five withdrawals, because of toxicity in two
`patients, because of poor performance status in another
`two patients and one patient declined further treatment.
`Two patients required dose reduction of dexamethasone
`because of psychosis and the CCNU dose was reduced
`from 50 mg/m2 to 40 mg in one patient because of
`grade 4 neutropenia. Four patients stopped treatment before
`completion of six courses,
`two because there was no
`
`Table III. Neutropenia and thrombocytopenia during 159 courses
`of treatment evaluable for haematological toxicity.
`
`WHO grade
`
`Neutropenia (%)
`
`Thrombocytopenia (%)
`
`0
`1
`2
`3
`4
`
`43
`15
`17
`11
`14
`
`66
`19
`8
`6
`1
`
`Figures are percentage of total courses associated with each toxicity
`grading.
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`574 R. Parameswaran et al
`
`response (i.e. they had stable disease) and two because of
`neutropenia.
`
`Remission duration and survival
`Of the 28 responders, one underwent a haemopoietic cell
`transplant and was censored from analysis of progression-
`free survival (PFS) at the relevant time point. Four patients
`died in remission, one from fungal infection after course 5,
`one from bleeding duodenal ulcer after course 3 and two
`from unrelated causes. The remaining 23 patients have all
`progressed. The median PFS is 13 months, with 30% of the
`responding patients alive and progression free at 2 years
`(Fig 1). Three patients had a response lasting over 3 years.
`Overall survival
`is shown in Fig 2. The median overall
`survival was 15 months, with 30% of patients alive at
`2 years. Median survival
`in responding patients was
`24 months, with 30% alive at 3 years.
`
`DISCUSSION
`
`This regimen is clearly effective in inducing response or
`stabilization of disease in patients with relapsed and
`refractory myeloma. The overall response rate of 50%
`including 30% PR is encouraging given that half of the
`patients were beyond first relapse or had refractory disease.
`Because the published data on the treatment of relapsed and
`refractory myeloma comprises predominantly small series
`with heterogeneous patients, as does the present study, it is
`not possible to determine whether this new regimen is better
`than other regimens for relapsed and refractory disease.
`However, the overall survival appears at least as good as
`that reported by Alexanian et al (1986) for the VAD regimen
`in relapsed patients, in which median survival was only
`12 months. The regimen was well
`tolerated and the
`incidence of severe neutropenia at the lower CCNU dose
`was acceptable.
`The lack of evidence for increased toxicity in the patients
`with renal
`impairment
`is of
`interest as idarubicin is
`currently not recommended for use in these patients.
`Urinary excretion of the drug and its metabolites appears
`to be more important than biliary excretion (Pannuti et al,
`1986) and there is a significant correlation between
`
`Fig 1. Progression-free survival in responding patients (n (cid:136) 28).
`
`in all patients (n (cid:136) 57),
`Fig 2. Overall survival
`in responding
`patients (n (cid:136) 28) and in non-responders (n (cid:136) 29); P (cid:136) 0·05 for
`responders vs. all patients and P , 0·0001 for responder vs. non-
`responders.
`
`creatinine clearance and the clearance of idarubicin and
`idarubicinol (Cammagi et al, 1992). Previous studies of oral
`idarubicin in myeloma and other malignancies have there-
`fore excluded patients with serum creatinine levels above
`200 mmol/l. There are no published data on the use of
`CCNU in patients with renal impairment. In the present
`series, there was no evidence of increased toxicity in the five
`patients with creatinine levels between 200 and 350 mmol/l
`at entry. However, we do not have data on serial creatinine
`levels to indicate whether
`the same degree of renal
`impairment persisted throughout treatment. Only three
`patients with more severe renal failure were included in the
`study; renal failure rapidly improved in one patient, one
`patient died early and the third died after three courses of
`treatment. We cannot therefore draw any firm conclusions
`about the possibility of increased toxicity of either idarubicin
`or CCNU, particularly cumulative toxicity, in patients with
`persistently raised creatinine levels. However, in the light of
`our results, it appears that patients with creatinine levels up
`to 350 mmol/l might be safely treated with the CIDEX
`regimen without dose modification. Furthermore, as VAD is
`widely used in patients with renal failure and the oral Z-Dex
`(oral
`idarubicin and dexamethasone) regimen may be
`equally effective,
`further studies of oral
`idarubicin in
`patients with severe renal impairment are warranted.
`The metabolite of
`idarubicin,
`idarubicinol, has been
`shown to possess striking anti-tumour activity in doxor-
`ubicin-resistant cell lines, suggesting that it could be useful
`in circumventing multidrug resistance (Berman & McBride,
`1992). Of the four patients in this series who were known to
`be refractory to doxorubicin, one entered PR on treatment
`with CIDEX. Although it is not possible to conclude that this
`response was due to the idarubicin component of the
`regimen,
`it would be consistent with the activity of
`idarubicin in patients refractory to anthracycline.
`We conclude that CIDEX is an effective oral combination
`regimen for patients with relapsed or refractory myeloma
`and merits further evaluation in this setting. The Riverside
`Haematology Group, in association with the UK Myeloma
`Forum, is accordingly currently carrying out a randomized
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`CCNU, Idarubicin and Dexamethasone for Relapsed Myeloma 575
`
`controlled trial comparing CIDEX with melphalan and
`prednisolone in patients with myeloma at first or second
`relapse.
`
`ACKNOWLEDGMENTS
`
`We would like to acknowledge the following colleagues
`who also entered patients into the study: Dr C. Barton,
`Dr S. Basu, Dr E. Blundell, Dr S. M Fairhead, Dr P. Gravett,
`Dr G. Hughes, Dr E. Kanfer, Dr L. Jones, Dr J. Mercieca, Dr D.
`O’Shaughnessy, Dr C. Rist, Dr M. Semple, Dr C. Singer, Dr C.
`Tew and Dr E Watts.
`
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