Thirty-six patients with ANLL received carmustine at a dose of 800 mg/m2, and cytosine arabinoside 900 mg/m2 over 3 days by continuous infusion, etoposide at ...
Bone Marrow Transplantation, (1999) 23, 533–537 1999 Stockton Press All rights reserved 0268–3369/99 $12.00 http://www.stockton-press.co.uk/bmt
Adverse events occurring during bone marrow or peripheral blood progenitor cell infusion: analysis of 126 cases EP Alessandrino1, P Bernasconi1, D Caldera1, A Colombo1, M Bonfichi1, L Malcovati1, C Klersy2, G Martinelli1, M Maiocchi1, G Pagnucco1, M Varettoni1, C Perotti3 and C Bernasconi1 1
Centro Trapianti di Midollo Osseo, Istituto di Ematologia, 2Biometry-Scientific Direction, 3Servizio di Immunoematologia e Trasfusione, IRCCS Policlinico S Matteo, Pavia, Italy
Summary: Bone marrow (BM) and/or peripheral blood progenitor cells (PBPC) given after high-dose chemo-radiotherapy are commonly cryopreserved. Re-infusion of the thawed product can cause cardiovascular and other complications. We compared two groups of adult patients receiving autologous BM or PBPC transplant to assess the incidence of adverse events occurring during infusion. Fifty-one patients received BM, and 75 PBPC. The two groups were comparable in respect of age, total volume infused, quantity of dimethylsulfoxide (DMSO) and number of polymorphonuclear neutrophils. Patients receiving PBPC had a higher number of nucleated cells per kg of body weight; those in the BM group received a significantly greater quantity of red cells. Non-cardiovascular complications occurred in 19% and 8% of patients rescued by BM and PBPC respectively. The incidence of hypertension was 21% in the BM and 36% in the PBPC group. Asymptomatic hypotension was more frequent in PBPC patients (P ⬍ 0.001). Bradyarrhythmia was noticed in two of 75 PBPC patients and in 14 of 51 BM patients (P ⬍ 0.001). In the former group one patient had heart block; he died of renal failure 10 days later. Bradycardia and hemoglobinuria were more common in patients receiving BM where a higher concentration of red cells was present (P ⬍ 0.001). Since bradyarrhythmias may be a life-threatening complication we advise continuous careful monitoring during infusion of thawed BM. The strong correlation between bradycardia and red blood cell contamination suggests the use of purified products with a very low red cell content. Keywords: cryopreservation; bone marrow transplantation; bradycardia; DMSO; peripheral blood progenitor cell transplantation
High-dose chemo-radiotherapy followed by autologous cryopreserved bone marrow (BM) or peripheral blood progenitor cell infusion (PBPC) is increasingly used in patients with hematological malignancies or solid tumors. These Correspondence: Dr EP Alessandrino, Centro Trapianti di Midollo Osseo, Istituto di Ematologia, IRCCS Policlinico S Matteo, 27100 Pavia, Italy Received 24 April 1998; accepted 22 October 1998
modalities require cryopreservation and storage of BM or PBPC graft using dimethylsulfoxide (DMSO) as a cryoprotectant; patients receive several days of chemotherapy or chemo-radiotherapy, followed by the infusion of the thawed graft containing DMSO and products of cell lysis.1–5 The incidence of lethal complications related to autologous transplant resulting from the intensive cytotoxic preparative regimen and bone marrow aplasia is usually low; some authors, however, report that cryopreserved marrow infusion may induce complications ranging from nausea, vomiting, abdominal pain, hypotension to life-threatening renal failure or cardiac arrhythmias.6–12 The use of DMSO has been implicated in the pathogenesis of cardiovascular and other changes observed during infusion; other authors suggest that damaged cells and lysis products may play a role.7,8 In recent years autologous cryopreserved PBPC have been more frequently utilized than BM as rescue after highdose chemotherapy;13 few authors have noticed complications during cryopreserved PBPC infusion.5,7 We hypothesize that the different cellular compositions may induce diverse incidences of complications within each group. In this study we compare two groups of patients undergoing either cryopreserved autologous BM transplantation or autologous PBPC transplantation to assess the incidence of adverse events occurring during infusion. Methods One hundred and twenty-six consecutive patients undergoing either autologous BM or PBPC transplantation entered the study. Fifty-one had an autologous cryopreserved bone marrow graft (auto-BM); 75 were rescued by autologous cryopreserved PBPC (auto-PBPC). The main characteristics of both groups are reported in Table 1. Eight patients in the auto-BM group were transplanted after diagnosis of Hodgkin’s disease (HD) and three after diagnosis of non-Hodgkin’s lymphoma (NHL), 35 had acute non-lymphocytic leukemia (ANLL), two had acute lymphoblastic leukemia (ALL), three had chronic granulocytic leukemia in chronic phase (CGL-CP). In the autoPBPC group, 17 of 75 patients had HD, 31 NHL, 23 multiple myeloma (MM), three CGL-CP, and one ANLL in early relapse. The age ranges were from 15 to 60 years (median 35) in the auto-BM group, and from 13 to 60 years (median 39) in the auto-PBPC group.
Complications during BM and PBPC infusion EP Alessandrino et al
534
Study design The study was a retrospective analysis of 126 consecutive patients treated at the BMT Unit – Istituto di Ematologia of Pavia from September 1992 to August 1997. Medical records were reviewed retrospectively to ascertain age, sex, diagnosis, doses of anthracycline and cyclophosphamide, history of radiation, ECG, characteristics and cellular composition of graft, adverse events occurring during or immediately after infusion. Conditioning regimen Thirty-six patients with ANLL received carmustine at a dose of 800 mg/m2, and cytosine arabinoside 900 mg/m2 over 3 days by continuous infusion, etoposide at the dose of 900 mg/m2 over 3 days (BAV). Fifty-nine patients with HD or NHL were prepared for transplant with carmustine 600 mg/m2, etoposide 1500 mg/m2 and cyclophosphamide 4000 mg/m2, all given intravenously over 4 days (CBV). Twenty-three patients with advanced MM had a modified BEM regimen14 including carmustine at a dose of 600 mg/m2, etoposide 1500 mg/m2, melphalan 200 mg/m2. Six patients with CGL-CP received busulphan and cyclophosphamide at the total dosage of 16 mg/kg and 120 mg/kg, respectively (BU-CY). Two patients with ALL had TBI and cyclophosphamide at standard dose (TBI-CY). Hemopoietic stem cell processing and infusion Autologous bone marrow grafts were harvested and processed as described elsewhere.3 Briefly, buffy coat cells were obtained by centrifugation of the graft with the Cobe cell washer (Cobe, Lakewood, CO, USA). The graft was then cooled to 4°C and resuspended with 10% DMSO for cryopreservation. It was frozen as 40–65 ml aliquots in liquid nitrogen and stored at −197°C. PBPCs were obtained by leukapheresis after mobilization with intermediate doses of cyclophosphamide (4 g/m2) and G-CSF given subcutaneously from the second day after the end of chemotherapy. Harvesting was performed on a Cobe leukapheresis machine. The minimum yield of PBPC per patient was 2 × 106 CD34/kg body weight. Each PBPC collection was processed to reduce the product volume and the amount of cryoprotectant required. Cryopreservation principles for PBPC were identical to those utilized for BM buffy coat. In both cases an automated programme which results in a slow cooling rate of −1°C per minute up to the final temperature of −160°C was utilized. At the time of infusion, bags were thawed in a 37°C water-bath and given to patients through a standard transfusion filter at a rate of 10 ml/min without any further manipulation. Before infusion, all patients received 20 mg of methylprednisolone intravenously. Only a minority of patients had diuretics to prevent fluid overload. Patient monitoring Electrocardiograms were available for all patients before and immediately after infusion. Fourteen out of 16 patients developing bradycardia had an ECG 1, 3 and 6 h after graft
infusion. Blood pressure, heart and respiratory rate were recorded every 5 min during infusion and every 30 min over 4 h thereafter. The total volume and the number of infused cells and symptoms occurring during the infusion were recorded by the nurses. Patients with more than four bags of cryopreserved product received the infusion over 2 or more days to avoid a fluid and DMSO overload. Hypotension was defined as systolic blood pressure of ⬍90 mmHg or as a reduction of 20% from the baseline value at the beginning of infusion. Hypertension was defined as a diastolic blood pressure of ⬎95 mmHg. Mild bradycardia was defined as a decrease in heart rate of 20% from the baseline; severe bradycardia was defined as reduction of heart rate ⬍50 beats per minute. Statistical evaluation Prevalence of symptoms between the two groups was tested by the Fisher exact test. The Mann–Whitney U test was used to compare medians; two-tailed probabilities of ⬍0.05 were considered significant. Results Table 1 shows the main characteristics of patients grouped according to stem cell source. Most patients had their transplant after a long history of chemotherapy or chemo-radiotherapy. The amount of anthracycline given previously was comparable in the two groups. Only patients who received PBPC were given an intermediate dose of cyclophosphamide as a hemopoietic progenitor cell mobilising agent, associated with G-CSF. Thirteen patients received radiotherapy Table 1
Main characteristics of patients
Parameters Number of cases Median age (range)
Auto-BM
Auto-PBPC
51 35 (15–60) years
75 39 (13–60) years
Sex Male 26 Female 25 Diagnosis Hodgkin’s disease 8 Non-Hodgkin’s lymphoma 3 Multiple myeloma — Chronic granulocytic leukemia 3 Acute non-lymphoid leukemia 35 Acute lymphoid leukemia 2 Priming therapy for stem cell collection — Cyclophosphamide (4 g/m2) with G-CSF Preparative regimen BEM — BAV 35 CBV 11 BU-CY 3 TBI-CY 2 Patients receiving anthracycline before 29/51 transplant Median dose: mg/kg (range) 365 (190– 1600) Mediastinal field radiotherapy 3
42 33 17 31 23 3 1 — 75 23 1 48 3 — 50/75 334 (100– 700) 13
Complications during BM and PBPC infusion EP Alessandrino et al
Table 2 Parameters
No. cases Volume (median and quartiles) DMSO (median and quartiles) Nucleated Cells (median and quartiles) Number of PMN (median and quartiles) Hct (median and quartiles) RBC (median and quartiles) Average duration of infusion (range) Infusion rate a
535
Characteristics and cellular composition of the infused products Auto-BM
Auto-PBPC
Mann–Whitney U test P value
51 380 (340–480) ml 0.60 (0.52–0.67) mg/kg 1 (1–2) ×108/kg 0.6 (0.54–0.75) ×108/kg 26.4 (24.6–28.6) 1.55 (1.31–1.92) ml/kg 40 (25–50) min 10 ml/min
75 400a (320–480) ml 0.59 (0.48–0.73) mg/kg 3 (2–5) ×108/kg 0.9 (0.6–1.02) ×108/kg 4.2 (3.2–5.1) 0.23 (0.19–0.34) ml/kg 45 (35–65) min 10 ml/min
0.593 0.636 ⬍0.001 NS 0.003 ⬍0.001 — —
32/75 patients received infusions over 2 consecutive days.
to the mediastinum. Only patients with HD, NHL, CGL or ALL had cyclophosphamide associated with other drugs as preparation for the transplant (67 cases).
Table 3 infusion
Symptoms and cardiovascular changes associated with
Parameters
Characteristics of the graft and clinical symptoms The median infused volume was 380 ml (range 120– 680 ml) in the auto-BM group. Comparable values were given to patients transplanted with PBPC. Thirty-two patients received a double infusion on 2 consecutive days. Data concerning the total number of cells per kg of body weight and DMSO are reported in Table 2. In both groups, infusion was rapid and a comparable amount of DMSO was given. The median number of PMN per kg of body weight was similar (0.9/kg in PBPC transplantation and 0.6/kg in the BM group) while the red cell volume per kg of body weight was significantly higher in the auto-BM group (P ⬍ 0.001) (Table 2). Heart rate decreased by at least 20% in 16 of 126 patients. In 12 of 51 patients rescued by BM, the heart rate values ranged from 32 to 50 beats per minute (median 42). Bradycardia recovered spontaneously within 1 h. Only two patients with severe bradycardia and a heart rate ⬍35 beats per minute required infusion of atropine 1 mg i.v. with prompt improvement. Chest discomfort was noticed in five patients with severe bradycardia. One patient had heart block; he died of infection and renal failure 10 days later without evidence of hemopoietic recovery; this patient who had never experienced heart block prior to graft infusion, received three bags of thawed BM. At the end of infusion he had abrupt dyspnea and chest discomfort with second-degree heart block followed by a brief period of ventricular fibrillation. Aggressive therapy resulted in prompt recovery of the pulse and blood pressure. Asymptomatic hypotension occurred in 18 patients. The incidence of this complication was prevalent in the autoPBPC group (P ⬍ 0.001). Hypertension was noticed in 27 cases receiving PBPC and in 11/51 cases treated with BM. Nine patients complained of nausea and vomiting; chest discomfort was noticed in five cases in the auto-BM group, and in only one in the auto-PBPC group. Because of the high concentration of red cells, all patients receiving cryopreserved BM had hemoglobinuria. This symptom was never reported in the auto-PBPC group (Table 3).
No. of patients Non-cardiovascular complications Nausea and vomiting Chills Flushing Abdominal pain Chest discomfort Headache Hemoglobinuria Cardiovascular complications Arrhythmia: Mild bradycardia Severe bradycardia Heart block Hypertension Hypotension
Auto-BMT
AutoPBPC
Fisher test P value
51
75
3
0.738
7 5 — 51
6 — — — 1 — —
14 2 11 1 11 2
2 2 — — 27 16
⬍0.001
0.113 0.001
Discussion Various complications during re-infusion of cryopreserved hemopoietic stem cells have been described. Stroncek et al6 reported that patients receiving cryopreserved bone marrow had significantly more nausea, vomiting, chills and fever than patients transfused with fresh allogeneic marrow; the incidence of the above-mentioned complications in patients receiving cryopreserved marrow was respectively 44.8, 23.9, 31.3 and 17.9%. In another report the incidence of non-cardiovascular clinical toxicity was 41% in patients treated with cryopreserved products and 6% in patients receiving allogeneic fresh marrow.9 In a prospective randomised study performed on high risk breast cancer patients receiving high-dose chemotherapy and cryopreserved BM buffy coat or CD34-selected autologous cryopreserved bone marrow support, none of the patients in the CD34-selected arm experienced adverse events during infusion, compared to 6% in the buffy coat arm.15 In our study aimed at comparing cryopreserved BM and cryopreserved PBPC, non-cardiovascular complications were noticed in 19 vs 8%, respectively. In 82 patients transfused with purged (73 cases) or
Complications during BM and PBPC infusion EP Alessandrino et al
536
unpurged (nine cases) cryopreserved bone marrow Davis et al8 reported second-degree heart block and asymptomatic bradycardia in 29% of cases; transient hypertension was reported in 91% of patients. In our study, the incidence of hypertension was 21% in the BM and 36% in the PBPC group; chest discomfort was noticed in 10% of patients receiving BM and in 1.3% of patients receiving PBPC. The incidence of bradyarrhythmia was significantly different in the two groups: it was seen in 2/75 PBPC patients and in 14/51 BM patients (P ⬍ 0.001). In the former group one patient had heart block; he died of renal failure and sepsis 10 days later. The pathogenesis of cardiovascular complications is not clear. Some authors focus on DMSO toxicity;9,12 however, there are several other possible causes of cardiac arrhythmias such as cell lysis products,7,8 hypothermia of infused product which may induce vagal responses, localized electrolyte abnormalities, acute volume expansion leading to reflex bradycardia.10 Experimental data show that DMSO can have an impact on mammalian myocardium: in the perfused rat heart, DMSO at concentrations of over 0.70 m produces increasing degrees of structural alteration and functional impairment of the myocardium.16 In our study, both BM and PBPC patients were infused with the same modalities and the DMSO amount was similar in both groups (Table 2) but cardiac complications developed only in patients receiving cryopreserved BM. We infer that other factors may determine the occurrence of such adverse events. Premedication with anti-histaminics to neutralize DMSO-induced histamine release,17 may itself provoke bradycardia. In this study, however, anti-histamine drugs were never used before BM or PBPC infusion. Toxic effects related to previous chemotherapy or conditioning regimens may contribute to cardiovascular complications.18 In our study, anthracycline quantity was comparable in both groups and only a minority of patients had had mediastinal radiotherapy. Cardiac toxicity from cyclophosphamide may induce pericarditis or myocardial necrosis.12,18–20 Styler et al12 reported an increased incidence of heart block in patients with prior exposure to cyclophosphamide. We, however, found no relationship between previous chemo-radiotherapy and incidence of cardiovascular complications. In a series of patients with lymphoma undergoing highdose chemotherapy and rescue with cryopreserved PBPCs, Kessinger et al7 observed a high incidence of renal failure. They recommend reducing red blood cell contamination in the PBPC product before cryopreservation, by the Ficoll– Hypaque technique. In our study, the amount of red blood cells in the final preparation of PBPCs was 0.23 ml/kg vs 1.55 ml/kg (median values) (Table 2). This parameter correlates with a higher incidence of cardiac complications; the red-cell massive lysis could provoke liberation of hemoglobin, electrolytes and cellular debris which may all have a role in the pathogenesis of bradycardia; it is, however, unlikely that cardiac complications observed during BM infusion could be induced only by the red cell content and/or its lysis products. Kessinger et al7 reported a high incidence of renal failure in patients receiving large amounts of cryopreserved red cells, while no cardiovascular complications were seen. Therefore, bradycardia occurring
during cryopreserved BM infusion could be multifactorial in pathogenesis. Bradycardia and hemoglobinuria were the commonest complications observed in patients receiving BM, while hypotension was more frequent in the PBPC group. Since bradyarrhythmias can be severe, as in one of our patients, we advise continuous careful monitoring during infusion of cryopreserved marrow. The close correlation between bradycardia and red blood cell contamination suggests the use of purified products with a very low red cell content. Acknowledgements We are grateful to Mrs Luisa Carenini and the nursing team of the BMT Unit of our Institution for the attention given to the patients.
References 1 Cheson BD, Lacerna L, Leyland-Jones B et al. Autologous bone marrow transplantation: current status and future directions. Ann Intern Med 1989; 110: 51–65. 2 Spitzer G. Autotransplantation in solid tumours. Blood Rev 1991; 5: 105–111. 3 Gorin NC. Collection manipulation and freezing of haemopoietic stem cells. Clin Haematol 1986; 15: 19–49. 4 Rowley SD. Hematopoietic stem cell cryopreservation: a review of current techniques. J Hematother 1992; 1: 223–250. 5 Kessinger A, Schmit-Pokorny K, Smith D, Armitage J. Cryopreservation and infusion of autologous peripheral blood stem cells. Bone Marrow Transplant 1990; 5 (Suppl. 1): 25–27. 6 Stroncek DF, Fautsch SK, Lasky LC et al. Adverse reactions in patients transfused with cryopreserved marrow. Transfusion 1991; 31: 521–526. 7 Kessinger A, Armitage JO, Smith DM et al. High-dose therapy and autologous peripheral blood stem cell transplantation for patients with lymphoma. Blood 1989; 74: 1260–1265. 8 Davis JM, Rowley SD, Braine HG et al. Clinical toxicity of cryopreserved bone marrow graft infusion. Blood 1990; 75: 781–786. 9 Lopez-Jimenez J, Cervero C, Munoz A et al. Cardiovascular toxicities related to the infusion of cryopreserved grafts: results of a controlled study. Bone Marrow Transplant 1994; 13: 789–793. 10 Keung Y-K, Lau S, Elkayam U et al. Cardiac arrhythmia after infusion of cryopreserved stem cells. Bone Marrow Transplant 1994; 14: 363–367. 11 Rapaport AP, Rowe JM, Packman CH, Ginsberg SJ. Cardiac arrest after autologous marrow infusion. Bone Marrow Transplant 1991; 7: 401–403. 12 Styler MJ, Topolsky DL, Crilley PA et al. Transient high grade heart block following autologous bone marrow infusion. Bone Marrow Transplant 1992; 10: 435–438. 13 Besinger W, Singer J, Appelbaum F et al. Autologous transplantation with peripheral blood mononuclear cells collected after administration of recombinant granulocyte stimulating factor. Blood 1993; 81: 3158–3163. 14 Ager S, Mahendra P, Richards EM et al. High dose carmustine, etoposide and melphalan (BEM) with autologous stem cell transplantation: a dose toxicity study. Bone Marrow Transplant 1996; 17: 335–340. 15 Shpall EJ, LeMaistre CF, Holland K et al. A prospective randomised trial of buffy coat versus CD34-selected autologous bone marrow support in high-risk breast cancer patients
Complications during BM and PBPC infusion EP Alessandrino et al
receiving high dose chemotherapy. Blood 1997; 90: 4313– 4320. 16 Shlafer M, Karow AM. Pharmacological effects of dimethylsulfoxide on the mammalian myocardium. Ann NY Acad Sci 1975; 243: 110–121. 17 Kligman AM. Topical pharmacology and toxicology of dimethyl sulfoxide – part 1. JAMA 1965; 193: 140–148. 18 Hertenstein B, Stefanic M, Schmeiser T et al. Cardiac toxicity of bone marrow transplantation: predictive value of cardio-
logic evaluation before transplant. J Clin Oncol 1994; 12: 998–1004. 19 Sculier JP, Coune A, Klastersky J. Transient heart block an unreported toxicity of high dose chemotherapy with cyclophosphamide and etoposide. Acta Clin Belg 1985; 40: 112–114. 20 Cazin B, Gorin NC, LaPorte JP et al. Cardiac complications after bone marrow transplantation. Cancer 1986; 57: 2061– 2069.
537
