Paroxysmal Atrial Fibrillation After High-Dose Melphalan in Five

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Bone Marrow Transplantation, (1998) 21, 1049–1053  1998 Stockton Press All rights reserved 0268–3369/98 $12.00 http://www.stockton-press.co.uk/bmt Paroxysmal atrial ﬁbrillation after high-dose melphalan in ﬁve patients autotransplanted with blood progenitor cells

A Olivieri1, L Corvatta1, M Montanari1, M Brunori1, M Ofﬁdani1, GF Ferretti2, M Centanni2 and P Leoni1 ` 1Clinica di Ematologia and 2Servizio di Cardiologia Universita di Ancona, Italy

Summary: because it could be a limiting factor in the use of HDM in patients with heart diseases. Among the drugs used in conditioning regimens for We describe five cases with well-documented acute stem cell transplantation, high-dose melphalan (HDM) reversible cardiotoxicity out of 76 patients conditioned plays an important role for both its strong myelo- with HDM. ablative effect and for its favourable dose–response ratio. Here we report five cases of high frequency atrial fibrillation (AF) developing after HDM. Duration of the Patients and methods arrhythmia was always very short, beginning at variable intervals after the administration of HDM, in the We transplanted 76 patients with regimens including HDM absence of other factors potentially able to trigger AF. at doses ranging from 120 to 200 mg/m2. In all patients sinus rhythm was restored within 72 h Nine patients (11.8%) received melphalan 200 mg/m2 and the follow-up did not show any cardiac damage. To alone, 63 patients (82.7%) a regimen including busulphan, the best of our knowledge, this side-effect has never thiotepa, mitoxantrone, etoposide, carmustine, cytosine ara- been reported to occur after HDM. binoside and HDM (140–180 mg/m2). For the remaining Keywords: paroxysmal atrial fibrillation; high-dose four patients (5.5%) conditioning regimens included the melphalan; peripheral blood stem cell transplantation association of melphalan 140 mg/m2 and TBI (1200 cGy in six fractions, at a dose rate of 5 cGy/min over three days) (Table 1). In all patients HDM was administered intravenously on Among the drugs used in conditioning regimens for peri- day −2 (48 h before PBPC reinfusion) using a central pheral blood progenitor cell transplantation (PBPCT), high- venous catheter (CVC), 15 min immediately after reconsti- dose melphalan (HDM) given intravenously plays an tution with buffer solution containing 60% w/v propylene important role for both its myeloablative efficacy and for glycol with sodium citrate and ethanol. In all cases mel- 1 its very favourable dose–response curve. Melphalan is an phalan (vials of 50 mg each) was kindly provided by alkylating agent with a wide spectrum of activity against Glaxo-Welcome (Verona, Italy) free of charge. The CVC 2–5 many hematological malignancies and solid tumors. This position was checked by chest X-ray. Fifteen minutes 2 agent, when given at doses ranging from 50 to 100 mg/m , before HDM administration all paients received ondanse- has proved to be very effective but also extremely myelo- tron 8 mg i.v. toxic in multiple myeloma treated without stem cell res- None of the patients receiving HDM received large fluid 6–9 cue. Thereafter, the use of stem cells rescue has allowed volumes (Ͼ3000 ml/24 h) or furosemide in order to force an increase in the dose of melphalan used in combination diuresis. 10 chemotherapy regimens for lymphoma (eg BEAM) and Three patients received bone marrow alone harvested 11–13 alone, or even associated with TBI for multiple under general anesthesia and 73 patients received PBPC 14,15 myeloma. mobilized with G-CSF after priming with cyclophospham- 2 When used at doses ranging from 140 to 200 mg/m mel- ide 7 g/m2 (42 patients),18 DHAP regimen (21 patients),19 phalan is well tolerated, with a dose-limiting toxicity etoposide 2 g/m2 (six patients)20 or VACOP-B regimen 16 mainly characterized by mucositis. This property, associa- (four patients). ted with its very short in vivo half-life makes the use of Concomitant routine prophylactic medication included melphalan preferable to high-dose cyclophosphamide in ciprofloxacin (500 mg orally twice daily), fluconazole myeloablative regimens, which is an alkylating agent asso- (200 mg orally once daily) and acycloguanosine 10 mg/kg 17 ciated with cardiotoxicity. Indeed, to date, no reports have i.v. in two divided doses daily starting from day −1. Pheno- been published concerning cardiotoxic events relating to barbital 100 mg orally once daily was administered as the use of HDM, although this should be investigated prophylaxis against seizures in only those patients receiving busulphan or TBI. ` Correspondence: Dr A Olivieri, Clinica di Ematologia Universita di All patients were scheduled for transplantation according Ancona Ospedale Regionale Torrette, 60020 Ancona, Italy to the following general criteria: good performance status Received 12 September 1997; accepted 17 December 1997 (0 or 1 ECOG), absence of severe aberrations liver (total Paroxystic atrial fibrillation after high-dose melphalan A Olivieri et al 1050 Table 1 Characteristics of 76 patients transplanted with regimens including HDM

Conditioning regimen No. patients % Patients Melphalan dose (mg/m2)

BEAM 35 46 140 Thiotepa + melphalan 19 25 180 Melphalan 9 11.8 200 Busulphan + melphalan 6 7.8 120 TBI + melphalan 4 5.5 140 Mitoxantrone + melphalan 3 3.9 180 Total patients 76 100

bilirubin Ͼ2 mg/dl) or renal function (creatinine Table 2 Characteristics of patients transplanted with regimens includ- Ͻ1.4 mg/dl); moreover, in all patients respiratory and car- ing or not including HDM diac function was carefully checked by physical examin- HDM No HDM P ation, chest X-ray, electrocardiogram, O2 saturation and = = venous Ph, electrolyte balance and, when indicated, echo- (n 82) (n 36) cardiography, respiratory function evaluation and T3, T4, Median age 46.5 46.5 0.2899 TSH measurement. Sex The PBPC infusion was performed after premedication Male 38 22 with clorfenamine (10 mg i.v. in 10 min), after thawing the 0.1394 bags in a waterbath at 37°C, using a blood ﬁlter and a sili- Female 44 14 Priming with cyclophosphamide cone CVC (Hohn of BARD, Salt Lake City, UT, USA); Yes 47 13 a median of 160 ml/patient (range 60–240) was reinfused 0.0339 containing 10% of DMSO (16 ml/patient; range 6–24). No 35 23 PBPCs were cryopreserved by adding an equal volume of cryoprotective solution containing DMSO 20% and human albumin 8% and using a controlled rate modiﬁed Planer variable intervals (26–297 h) from the administration of R201 freezing device. HDM and no relationship was found between AF and con-

All five patients who developed AF underwent a follow- comitant medications used. In all patients O2 saturation up after transplantation including the folowing tests: exer- myocardial enzymes, electrolytes, venous Ph, T3, T4 and cise test, dynamic ECG (Holter), Doppler and mono-two- TSH serum levels were all normal. Chest X-ray was normal dimensional echocardiography. and neither fever nor bacteremia were documented before All linear measurements were performed with a monodi- or during AF. In all patients except one, the AF quickly mensional technique, according to the recommendations of responded to propanfenone i.v. and sinus rhythm was re- American Society of Echocardiography.21 The data ana- established within 72 h. lyzed included left atrium telesystolic diameter, left ven- The main characteristics of the five patients developing tricular internal diameter in diastole (LVIDd), left ventricu- AF after HDM are shown in Table 3. lar internal diameter in systole (LVIDs), interventricular septal thickness (IVSTd) and posterior wall thickness Case 1 (UPN 56) (PWTd). The above parameters were used to calculate the ejection fraction and the left ventricular mass (LVMi) as A 62-year-old man with multiple myeloma received HDM previously described.22 The Doppler examination of trans- 360 mg on day −2 and 26 h later he developed high- valve fluxes was accomplished by apical projection in order frequency AF. During the AF he underwent echocardiogra- to exclude pending valvular regurgitation. phy, thyroid function and functional respiratory tests; all investigations were negative. He received propanfenone as a 2 mg/kg bolus followed by 1 mg/min continuous i.v. Case reports infusion over 2 h. He then received the same drug orally: 300 mg every 8 h; normal sinus rhythm was achieved 70 h Among the 76 patients transplanted with HDM, we after the onset of the arrhythmia. observed the onset of high frequency atrial fibrillation (AF) Six months later, the patient underwent a second autolog- never associated with haemodynamic disturbance or ous PBPCT with melphalan 120 mg/m2 plus busulphan ischaemic heart disease in five cases. In a control group of 12 mg/m2, continuing the prophylaxis with oral propan- 36 patients autotransplanted with conditioning regimens not fenone and no cardiac toxicity was observed. including HDM we observed no arrhythmias. These two groups of patients, observed during the same period, were Case 2 (UPN 58) matched for age, sex and number of pretransplant chemotherapy courses (Table 2). A 64-year-old man with NHL received conditioning regi- The duration of arrhythmia was very short, beginning at men including TBI plus HDM 220 mg. During TBI Paroxystic atrial fibrillation after high-dose melphalan A Olivieri et al 1051 Table 3 Patients developing atrial fibrillation after HDM

UPN Sex Age (years) Diagnosis Previous chemotherapy Conditioning regimen Melphalan total dose (courses) (mg)

56 M 62 MM VID (4); Melphalan 360 Cyclophosphamide 7 g/m2 (200 mg/m2) 58 M 64 NHL CEOP (10) TBI + melphalan 220 DHAP (2) (140 mg/m2) 76 F 63 MM VID (4); Melphalan 325 Cyclophosphamide 7 g/m2 (200 mg/m2) 101 M 54 MM VAD (3); Cyclophosphamide 7 g/m2; Melphalan 340 Etoposide 2 g/m2 (200 mg/m2) 107 M 47 NHL VACOP-B (12 weeks); Thiotepa + melphalan 300 DHAP (2) (180 mg/m2)

VAD = vincristine, doxorubicin, dexamethasone; VID = vincristine, idarubicin, dexamethasone; CEOP = cyclophosphamide, etoposide, vincristine, prednisone; DHAP = cisplatin, cytosine arabinoside, dexamethasone; VACOP-B = etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin.

(1200 cGy divided into six fractions days −5to−3), he was with thiotepa 1000 mg on day −4 and HDM 300 mg on day − monitored twice a day by ECG, venous pH and O2 satu- 2. He developed atrial fibrillation 44 h after the adminis- ration. On day −2 he received melphalan (220 mg), and on tration of melphalan and sinus rhythm was spontaneously day 0 thawed PBPC. Seventy-one hours after the adminis- re-established 4 h afterwards. This patient died 3 months tration of HDM he developed high-frequency AF (rate after transplantation for progressive disease, but without 150 b.p.m.) and he was immediately treated with propan- any signs of cardiac involvement or underlying structural fenone as previously described. After 4 h he achieved cardiac damage. normal sinus rhythm. In all five patients chest X-ray performed before the cardiac arrhythmia developed was negative and T3, T4 and Case 3 (UPN 76) TSH serum levels were normal. During the follow-up after transplantation echocardiography was performed in all A 63-year-old woman with multiple myeloma developed patients except one (case number 5) and it showed a normal high-frequency AF 73 h after conditioning regimen con- ejection fraction, normal morphology of the mitral valve sisting of HDM 325 mg administered on day −2. Chest X- and no enlargement of the atria or ventricles. No obvious ray was normal and echocardiography was not performed alterations of echogenicity or cardiac volume (restrictive during AF. The patient was treated with propanfenone pattern) suggestive of amyloid infiltration were detected. 2 mg/kg as a bolus followed by 1 mg/kg over 2 h. The Lastly, none of the patients we examined showed noticeable arrhythmia lasted for 5 h without signs or symptoms of alterations in cardiac flow; exercise tests were also negative hemodynamic disturbance; however prophylactic therapy for coronary artery disease in all four patients and the with oral propanfenone was given. This patient had a pre- dynamic ECG (Holter) showed no evidence of significant vious history of atrial flutter which had appeared during dysrhythmia or ischaemia. priming with high-dose cyclophosphamide (7 g/m2). After 4 months, a second autologous PBPCT was performed and 9 months afterwards, the patient was disease-free, Discussion without signs or symptoms of cardiopathy. In all five patients who developed AF, this arrhythmia arose in absence of a detectable structural heart disease; indeed Case 4 (UPN 101) before the onset of AF no patients had shown signs or A 54-year-old man with multiple myeloma received mel- symptoms of cardiopathy and only patient number 3 had phalan 340 mg i.v. on day −2 before the infusion of PBPC. previously developed paroxysmal atrial flutter after the On day +12 after the administration of the alkylating agent administration of cyclophosphamide 7 g/m2. he developed atrial fibrillation and treatment with propan- All five patients underwent further examination soon fenone as previously described was started. This therapy after the AF and four of them also 1 year after transplan- did not affect normal sinus rhythm and amiodarone 5 mg/kg tation; even in this case, we found no alterations in cardiac i.v. bolus was administered with normalization of the ECG kinetics or in cardiac morphology assessed by echocardio- after 44 h. graphy; in particular, we found no evidence of myocardial The patient is alive, 9 months after transplantation, in amyloid. The exercise test and the dynamic ECG (Holter) partial remission without signs or symptoms of cardiopathy. showed no evidence of asymptomatic ischaemic heart disease. Finally, before starting the conditioning regimen with HDM, none of the five patients had any predisposing fac- Case 5 (UPN 107) tors for AF such as hyperthyroidism, constrictive pericar- A 47-year-old man with NHL developed the arrhythmia on ditis, a mediastinal mass, acute or chronic respiratory the day of reinfusion of PBPC (day 0) after conditioning disease. Paroxystic atrial fibrillation after high-dose melphalan A Olivieri et al 1052 We were also unable to demonstrate any intercurrent phamide; the latter can be responsible for refractory and conditions potentially triggering AF: fever, septicemia, often fatal congestive heart failure. The pathologic findings electrolyte imbalance or significant haemodynamic are hemorrhagic endocarditis associated with hemorrhagic alterations. myocarditis.17 As regards iatrogenic factors potentially correlated with In conclusion, this is the first report concerning acute AF development, all patients had a CVC inserted 24 h conduction cardiotoxicity after conditioning regimens before the start of high-dose therapy and none underwent including HDM. In our experience HDM given intra- another surgical intervention; in all patients the chest X- venously is generally well tolerated up to a 200 mg/m2 ray showed that the CVC was in the superior vena cava. dose; the acute cardiotoxicity is a quite unexpected side- The infusion of cryopreserved PBPC has been reported effect. to be potentially associated with bradyarrhythmias and The frequency of this adverse event seems to be signifi- other cardiovascular changes but not with AF;23 only cant (6.6% overall); however, if we consider only patients patient number 5 developed AF 4 h before the PBPC receiving HDM alone the absolute frequency of AF in this reinfusion. group is 33%, and 22% excluding the patient who All drugs administered to the five patients during the 10 developed AF after 297 h. days before the onset of AF were studied both for interac- Perhaps this relatively high incidence of dysrhythmia can tions and for potential side-effects, by cross checking at be attributed to the relatively high mean age of our trans- least 15 items on Med-line (onco-disc and hemato-disc) and plant population even though this was not significantly dif- finally by consulting the PDR.24 As regards the drugs ferent in a comparable group of patients not receiving administered, only ciprofloxacin was found to be associated HDM. It is also of note that in the group transplanted with with sinus tachycardia or atrial flutter (with a frequency of HDM there was a higher frequency of patients with mul- less than 1%); also, we cannot completely exclude that in tiple myeloma who had been previously treated with CTX one patient (case number 2) TBI may have contributed to 7 g/m2; thus, it cannot be completely excluded that the pre- the AF and that high-dose thiotepa in another patient (case vious administration of CTX facilitated the AF in patients number 5) could have similarly induced an additive cardio- number 1, 3 and 4. toxic effect. AF has never been associated with documented acute or In the remaining three patients HDT was only with HDM chronic structural heart damage; moreover, long-term fol- and AF started at variable intervals (26, 73 and 297 h, low-up of the evaluable patients shows no evidence of respectively) after the administration of this drug. These organic heart damage. variable intervals could be explained by the extreme intra- Studies are necessary to look into the possible relation- patient variability of melphalan pharmacokinetics para- ship between HDM and acute cardiotoxicity, but HDM meters that can be prospectively confirmed by determining administration should be carefully planned in patients with the AUC and t. ␣ and t. ␤ in every patient. Indeed, after a previous history of heart disease. i.v. administration, HDM shows a biphasic distribution with a very wide AUC (from 146 to 1515 mg/min/ml); it is rap- idly hydrolized to non-cytotoxic dihydroxy metabolites16 References but no information is available about the arrhythmogenic 1 Selby PJ, McElwain TJ, Nandi AC. Multiple myeloma treated potential of these compounds. Moreover, the plasma clear- with high-dose intravenous melphalan. Br J Haematol 1987; 2 ance of HDM ranges from 92 to 961 ml/min/ , while age 66: 55–61. apparently does not influence the HDM pharmacokinetics.25 2 Alexanian E, Bergsagel DE, Migliore PJ et al. Melphalan ther- Although one patient developed AF 297 h after HDM apy for plasma cell myeloma. Blood 1968; 31: 1–10. administration, it is only possible to hypothesize that the 3 Smith JP, Rutledge F. Advances in chemotherapy for gyneco- onset of this cardiotoxic event was related to this drug. logic cancer. Cancer 1975; 36: 669–674. However, there are many other examples of toxic events 4 Fisher B, Carbone P, Economou SG et al. L-phenylalanine occurring when plasma levels of the drug responsible are mustard (L-PAM) in the management of primary breast can- undetectable, because the biologic half-life is very different cer. A report of early findings. New Engl J Med 1975; 292: 117–122. from the plasma half-life. 5 Souhami R, Peters W. 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