- Email: [email protected]
Severe drug-induced hypertriglyceridemia treated with plasmapheresis in children with acute lymphoblastic leukemia
Transfusion and Apheresis Science xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
Severe drug-induced hypertriglyceridemia treated with plasmapheresis in children with acute lymphoblastic leukemia ⁎
Joanna Zawitkowskaa, , Monika Lejmanb, Agnieszka Zaucha-Prażmoa, Natasza Sekułac, Teresa Greczkowska-Chmielc,d, Katarzyna Drabkoa a
Department of Pediatric Hematology, Oncology and Transplantation, Medical University, Lublin, Poland Department of Pediatric Hematology, Oncology and Transplantation, University Children’s Hospital, Genetic Diagnostic Laboratory, Lublin, Poland c Department of Pediatric Hematology, Oncology and Transplantation, University Children’s Hospital, Lublin, Poland d Department of Blood Treatment, University Children’s Hospital, Lublin, Poland b
A R T I C LE I N FO
A B S T R A C T
Keywords: Hypertriglyceridemia Pancreatitis Children Acute lymphoblastic leukemia
Asparaginase (ASP) and steroids are a main part of treatment for ALL, in both front-line and relapse setting. It is known, that ASP can cause several toxicities such as hypersensitivity, pancreatitis, as well as severe lipid and coagulation disturbances. Administered steroids can result in diabetes, obesity, hyponatremia and also mild hyperlipemia, which can intensify side effects of asparaginase. When triglyceride elevation is greater than 1000 mg/dl, the risk of pancreatitis is significantly increased. We report two patients who were hospitalized in Department of Pediatric Hematology, Oncology and Transplantology, Medical University of Lublin in Poland and developed severe hypertriglyceridemia after receiving asparaginase and steroid therapy for acute lymphoblastic leukemia. These patients were treated using plasmapheresis. This procedure was performed with a venous catheter in the femoral vein and 5% albumin or fresh frozen plasma as the replacement fluid. We analysed the laboratory and clinical data of these children. Plasmapheresis was well tolerated in both cases and a decrease of hypertriglyceridemia was quickly observed. However, the girl developed pancreatitis. In our opinion, plasmapheresis appears to be safe and effective in reducing hypertriglyceridemia. We could recommend that this procedure should be performed early, as soon as the triglyceride level is above 1000 mg/dl, in order to prevent severe complications. Patients should continue chemotherapy without ASP. It is important to regularly monitor of the lipid profile, pancreatic enzymes and coagulation during ASP and steroids therapy.
1. Introduction Therapy protocols for acute lymphoblastic leukemia (ALL), both first and second line, are based on multi-agent chemotherapy regimens and corticosteroids. Asparaginase (ASP) and steroids are administered together during the induction and reinduction phases of the first line treatment protocol, and during each course of chemotherapy in the second line [1]. It is known that ASP can cause several toxicities, such as hypersensitivity, pancreatitis, as well as severe lipid and coagulation disturbances [2]. Steroid administration can result in diabetes, obesity, hyponatremia, and also mild hyperlipemia, which can intensify side effects of asparaginase. When triglyceride (TG) elevation is greater than 1000 mg/dl, the risk of pancreatitis is significantly increased [3]. Limited information is available on the epidemiology and management of hypertriglyceridemia (HTG; 150–499 mg/dl) and severe HTG
(SHTG; > 500 mg/dl) in children but literature data indicate that the cumulative risk of asparaginase‐associated pancreatitis (AAP) is 5.9% [4]. The treatment for asparaginase-induced hypertriglyceridemia, includes low-fat diets, fibrate therapy, heparinization, or plasmapheresis and the cessation of asparaginase [5]. We report two patients who developed SHTG after receiving asparaginase and steroid therapy for ALL and were treated using plasmapheresis. In both cases this procedure was performed with a doubleline venous catheter in the femoral vein (Arrow). SPECTRA OPTIA (cellular separator) was used to this procedure. The replacement fluid was the fresh frozen plasma or 5% albumin. Anticoagulant Citrate Dextrose Solution A was used during plasmapheresis. The length of the procedure was 59–135 min. The total volume of plasma has been replaced, and the number of processed total blood volume (TBV) was 1.33-1.35. We analysed the laboratory and clinical data of these
⁎ Corresponding author at: Department of Pediatric Hematology, Oncology and Transplantology, Medical University of Lublin, 6 Antoni Gębala Street, 20-093, Lublin, Poland. E-mail address: [email protected] (J. Zawitkowska).
https://doi.org/10.1016/j.transci.2019.08.025 Received 16 June 2019; Received in revised form 5 August 2019; Accepted 27 August 2019 1473-0502/ © 2019 Published by Elsevier Ltd.
Please cite this article as: Joanna Zawitkowska, et al., Transfusion and Apheresis Science, https://doi.org/10.1016/j.transci.2019.08.025
Transfusion and Apheresis Science xxx (xxxx) xxx–xxx
J. Zawitkowska, et al.
children. The patients were hospitalized in Department of Pediatric Hematology, Oncology and Transplantology, Medical University of Lublin in Poland.
(February 2018). Currently, she is alive and well.
2. Case one
A 10-year old boy was admitted to our hospital because of suspected relapse of leukemia. His condition was good. There were no co-morbidities, such as obesity, diabetes and a familiar history of dyslipidemia. The child diagnosed with preB common positive ALL was treated between the years 2014 – 2016. During first line chemotherapy hypertriglyceridemia (964/μl) occurred once but a use a low molecular weight heparin was effective at that time. Therapy of relapse (site of disease: bone marrow and testis) started in January, 2017. He was started on treatment according to IntReALLSR 2010 [7]. The patient was classified to standard risk group. The second course of chemotherapy, which included PEG-ASP and steroids, was complicated by SHTG. Laboratory parameters in a time-dependent manner are presented in Table 1. Despite therapy of subcutaneously -low-molecular heparin, insulin, an infusion of 10% glucose and a low-fat diet, the triglyceride concentrations quickly increased. That's why we decided to early perform plasmapheresis. The procedure was continued for three days. High plasma triglyceride concentrations (8000 mg/dl) and hyponatremia (131 mmol/l) were observed for three days. The child’s condition was good. CT showed enlargement of the pancreas without focal changes. Plasmapheresis was performed with excellent effect in reducing hypertriglyceridemia (Fig. 1b). Picture 1 shows the apheresis product. The replacement fluid was 5% albumin. The procedure lasted 125–135 min and TBV processed was 1.35. Complications were not observed during the plasmapheresis. The patient did not develop pancreatitis. Following this episode, asparaginase was not applied in the next course of chemotherapy. Due to several complications (SHTG, fungal pneumonia), the patient was qualified for matched related donor bone marrow transplantation, which was performed in August, 2017. Currently, the patientis alive and well.
3. Case two
A 5-year old girl was admitted to our hospital because of a fever for 7 days, pain in the lower limbs and a fainting episode. Medical history included paralysis of the left shoulder plexus during delivery. There were no co-morbidities, such as obesity, diabetes and a familiar history of dyslipidemia. The child was diagnosed with preB common positive ALL and started treatment in March 2016, according to ALL IC-BFM 2009 [6]. She was classified to intermediate risk group. From day 12 of the induction phase pegylated (PEG) formulation of ASP was used due to hypersensitivity reaction to Escherichia coli-derived asparaginase. During that phase of therapy (from day 22), the level of triglycerides still increased. Hyponatremia (122 mmol/l) was also observed. Initially, when the level of TG was above 500 mg/dl, insulinotherapy was introduced in the form of 10% glucose infusion, a low-fat diet and low molecular weight heparin subcutaneously, but without effect. Therefore, plasmapheresis was applied when triglyceridemia reached 9300 mg/dl on the 33rd day of ALL therapy. The replacement fluid was fresh frozen plasma. The procedure lasted 59–77 min and TBV processed was 1.33. Plasmapheresis was well tolerated. We continued the procedure for three days. Decrease of hypertriglyceridemia was quickly observed (Fig. 1a). However, the child’s condition quickly deteriorated and pancreatic enzymes became elevated. Laboratory parameters in a time-dependent manner are presented in Table 1. Computer tomography (CT) showed an enlarged pancreas with disseminated pancreatic necrosis and a vast hypodense fluid area near the pancreas reaching to the smaller pelvis (Picture 2). She developed a seizure episode and multi-organ failure and she was transferred to the intensive care unit (ICU). Supportive care in ICU included parenteral nutrition, subcutaneously low-molecular heparin, metronidazole, metoclopramide, co-trimoxazole, liposomal amphotericin B, ornithini aspartas, acidum ursodeoxycholicum, meropenem, vancomycin, and then ciprofloxacin, gentamycin, rifaximin. Surgical therapy with drainage of abdominal cavity was performed. The patient remained in the ICU for 24 days before being returned to our department. Despite intensive treatment, the child constantly presented numerous clinical problems and therefore, we decided to stop the chemotherapy completely on the 33th day of the induction phase of therapy. The patient required several surgical procedures, such as cholecystectomy and another drainage to recover from abdominal complications. After improvement of the general condition, the child was followed on an outpatient basis. Bone marrow relapse occurred in September 2017. The girl received chemotherapy according to IntReALL HR 2010 without PEG-ASP but with steroids [7]. We did not observe SHTG. After achieving remission stem cell transplantation from a matched related donor was performed
4. Discussion Therapeutic plasmapheresis is a medical procedure which is based on removal of autoantibodies, immune complexes, antigens, proteins, enzymes and clotting factors, or cytokines (together with the plasma) from the blood. Indications for plasmapheresis treatment include different disorders with hematological, neurological, nephrological and toxicological indications. The most commonly reported complications of this procedure are: hypotension, hypokalemia, hypocalcemia, muscle cramps, a metallic taste in the mouth, allergic reactions, bacterial infections, and severe suppression of the immune system [8]. Children suffering from ALL treated with asparaginase and corticosteroids are prone to severe lipid disorders, but according to presently published studies, this complication is often undiagnosed. Severe hypertriglyceridemia is a rare but clinically significant side effect of PEGASP and steroids. Additionally, some factors such as obesity or diabetes may and older age (> 10 years) increase the risk of developing HTG
Fig. 1. a, b. Serum triglyceride levels before, during and after plasmapheresis in the first (a) and second (b) case. 2
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Table 1 Laboratory parameters in a time-dependent manner in the first and second case. Parameters
Case 1 - ALL IC 2009 protocol*
Days WBC (μl) TG (mg/dl) amylase (U/l) lipase (U/l) AT (%) fibrinogen (g/l) d-dimers (ng/ml)
1 7540 90 36 24 91 4.46 2072
8 1120 293 38 29 nd nd nd
15 600 115 35 25 58 0.68 5271
22 1130 293 45 33 84 0.72 561
24 1800 530 55 43 75 0.82 570
Case 2 - SCA1 course** 29 2720 734 57 24 51 0.35 489
30 nd 1000 nd nd 80 0.8 480
31 nd 1724 nd nd nd nd nd
32 nd 9000 nd nd nd nd nd
33 2160 9300 63 47 49 1.87 214
34 11140 2500 63 29 47 1.1 277
35 12330 1571 67 132 49 1.23 297
36 1580 803 1002 1294 56 1.75 1131
1 5170 136 60 38 101 2.61 518
8 3610 150 53 nd nd nd nd
15 nd 520 43 48 76 1.52 nd
16 3500 707 nd nd 53 2.93 319
17 nd 878 nd nd nd nd nd
18 3360 8000 43 44 22 0.45 221
19 3150 1480 51 43 42 0.44 194
20 2080 702 52 36 36 0.72 293
WBC-white blood cells; TG-triglycerides; AT-antithrombin; nd- not dome. * Prednison 60 mg/m2/day (28 days); Vinristine 1.5 mg/m2/day (day 8,15, 22, 29); Daunorubicin 30 mg/m2/day (day 8,15,22,29); L-Asparaginase 5000 U/m2/ day (day 12,15,18, 21,24,26,29, 33), in this case due to hypersensitivity – PEG-Asparaginase 1000 U/m2/day (used day 13, 24). ** Dexamethasone 6 mg/m2/day (14 days); Vinristine 1.5 mg/m2/day (day 1,8,15, 22); Idarubicin 6 mg/m2/day (day 1, 8,15,22); PEG-Asparaginase 1000 U/ m2/day (day 1, 11).
[2,5]. The studies on mechanisms of ASP-induced HTG suggest the excess endogenous very-low-density lipoprotein (VLDL) and decreased lipoprotein lipase activity (LPL). Moreover, ASP can cause a metabolic disturbance of lipoproteins. Similarly, steroids increase VLDL production in the liver, but also LPL activity. However, ASP used with steroids will overcome the compensatory effect of steroid-induced LPL activity [5]. Our patients had their TG levels frequently monitored during PEGASP therapy. We observed quickly increasing triglyceride concentrations in both cases. In the girl, the first procedure was performed after ten days of HTG, and in the second patient, we decided to introduce plasmapheresis earlier in the course of HTG. Plasmapheresis was performed in both children; however, only the girl demonstrated severe pancreatitis. The procedures were well-tolerated in both cases. The literature presents case reports of ALL children and adults treated with steroids and asparaginase for whom plasmapheresis was performed and effective. No severe adverse effects of this procedure were reported [9]. We summarized cases of adult and pediatric patients with SHTG undergoing chemotherapy for ALL in Table 2 [1,3,5,10]. In our opinion, plasmapheresis appears to be safe and effective in reducing hypertriglyceridemia. We could recommend that this procedure should be performed early, as soon as the triglyceride level is above 1000 mg/dl, in order to prevent severe complications. Patients should continue chemotherapy without ASP. It is important to regularly monitor of the lipid profile, pancreatic enzymes and coagulation during ASP and steroids therapy.
Picture 2. CT scan of the abdominal cavity of the first scan.
Authorship contributions JZ, KD were responsible for the study design. JZ, ML, KD, AZP, TGC, NS collected and analysed the clinical data. JZ, KD supervised the paper. All authors read and approved the final manuscript.
Funding sources This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
ICMJE statement All authors meet the ICMJE authorship criteria.
Picture 1. The apheresis product of the second child. 3
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Table 2 Cases of adult and pediatric patients with asparaginase-induced SHTG treated for ALL. Patients (age)
Sex
Year of therapy
ASP formulation
TG Peak [mg/dl]
Treatment
Pancreatitis
Author
5 10 6 10 10 21 32 34
F M F F M M M M
2016 2017 2015 2011 2008 2008 2014 2008
PEG-ASP PEG-ASP L-ASP L-ASP L-ASP L-ASP PEG-ASP L-ASP
9300 8000 1250 9250 4000 9226 4420 5620
Low-fat diet, heparin, insulin, plasmapheresis Low-fat diet, heparin, insulin, plasmapheresis Low-fat diet, hyperhydration, plasmapheresis Plasmapheresis Plasmapheresis Low-fat diet, plasmapheresis, fibrates Low-fat diet, heparin Plasmapheresis
Yes No Yes No Yes No No Yes
Patient 1 Patient 2 Morand et al. Solano-Paez et al. Ridola et al. Nakagawa et al. Galindo et al. Kfoury-Baz et al.
TG-triglycerides; L-ASP-asparaginase; PEG-ASP- pegylated asparaginase.
Declaration of Competing Interest
in the NOPHO ALL2008 protocol. Br J Haematol 2014;165(April 1):126–33. https:// doi.org/10.1111/bjh.12733. PubMed PMID: 24428625. [5] Galindo RJ, Yoon J, Devoe C, Myers AK. PEG-asparaginase induced severe hypertriglyceridemia. Arch Endocrinol Metab 2016;60(April 2):173–7. https://doi.org/10. 1590/2359-3997000000068. PubMed PMID: 26331232. [6] Zawitkowska J, Lejman M, Zaucha-Prazmo A, Drabko K, Plonowski M, Bulsa J, et al. Clinical characteristics and analysis of treatment result in children with Ph-positive acute lymphoblastic leukaemia in Poland between 2005 and 2017. Eur J Haematol 2018;101(October 4):542–8. https://doi.org/10.1111/ejh.13142. PubMed PMID: 30007093. [7] Karawajew L, Dworzak M, Ratei R, Rhein P, Gaipa G, Buldini B, et al. Minimal residual disease analysis by eight-color flow cytometry in relapsed childhood acute lymphoblastic leukemia. Haematologica 2015;100(July 7):935–44. https://doi.org/ 10.3324/haematol.2014.116707. PubMed PMID: 26001791; PubMed Central PMCID: PMCPMC4486228. [8] Misanovic V, Pokrajac D, Zubcevic S, Hadzimuratovic A, Rahmanovic S, Dizdar S, et al. Plasmapheresis in pediatric intensive care unit. Med Arch 2016;70(October 5):332–5. https://doi.org/10.5455/medarh.2016.70.332-335. PubMed PMID: 27994290; PubMed Central PMCID: PMCPMC5136426. [9] Gavva C, Sarode R, Agrawal D, Burner J. Therapeutic plasma exchange for hypertriglyceridemia induced pancreatitis: a rapid and practical approach. Transfus Apher Sci 2016;54(February 1):99–102. https://doi.org/10.1016/j.transci.2016.02.001. PubMed PMID: 26947356. [10] Morand A, Barlogis V, Rouby F, Reynaud R, Marrec C, Michel G. Hypertriglyceridemia, discorvered on a pseudohyponatremia, induced by L-asparaginase in the treatment of B acute lymphoblastic leukemia in child. Therapie 2015:16. https://doi.org/10.2515/therapie/2015051. Oct PubMed PMID: 26475748.
None. Acknowledgement No acknowledgements. References [1] Ridola V, Buonuomo PS, Maurizi P, Putzulu R, Annunziata ML, Pietrini D, et al. Severe acute hypertriglyceridemia during acute lymphoblastic leukemia induction successfully treated with plasmapheresis. Pediatr Blood Cancer 2008;50(February 2):378–80. https://doi.org/10.1002/pbc.20986. PubMed PMID: 16883590. [2] Persson L, Harila-Saari A, Hed Myrberg I, Heyman M, Nilsson A, Ranta S. Hypertriglyceridemia during asparaginase treatment in children with acute lymphoblastic leukemia correlates with antithrombin activity in adolescents. Pediatr Blood Cancer 2017;64(October 10). doi: 10.1002/pbc.26559. PubMed PMID: 28440015. [3] Solano-Paez P, Villegas JA, Colomer I, Gutierrez MD, Fernandez-Teijeiro A. LAsparaginase and steroids-associated hypertriglyceridemia successfully treated with plasmapheresis in a child with acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2011;33(April 3):e122–4. https://doi.org/10.1097/MPH.0b013e3181faf7a1. PubMed PMID: 21399528. [4] Raja RA, Schmiegelow K, Albertsen BK, Prunsild K, Zeller B, Vaitkeviciene G, et al. Asparaginase-associated pancreatitis in children with acute lymphoblastic leukaemia
4
Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
Severe drug-induced hypertriglyceridemia treated with plasmapheresis in children with acute lymphoblastic leukemia ⁎
Joanna Zawitkowskaa, , Monika Lejmanb, Agnieszka Zaucha-Prażmoa, Natasza Sekułac, Teresa Greczkowska-Chmielc,d, Katarzyna Drabkoa a
Department of Pediatric Hematology, Oncology and Transplantation, Medical University, Lublin, Poland Department of Pediatric Hematology, Oncology and Transplantation, University Children’s Hospital, Genetic Diagnostic Laboratory, Lublin, Poland c Department of Pediatric Hematology, Oncology and Transplantation, University Children’s Hospital, Lublin, Poland d Department of Blood Treatment, University Children’s Hospital, Lublin, Poland b
A R T I C LE I N FO
A B S T R A C T
Keywords: Hypertriglyceridemia Pancreatitis Children Acute lymphoblastic leukemia
Asparaginase (ASP) and steroids are a main part of treatment for ALL, in both front-line and relapse setting. It is known, that ASP can cause several toxicities such as hypersensitivity, pancreatitis, as well as severe lipid and coagulation disturbances. Administered steroids can result in diabetes, obesity, hyponatremia and also mild hyperlipemia, which can intensify side effects of asparaginase. When triglyceride elevation is greater than 1000 mg/dl, the risk of pancreatitis is significantly increased. We report two patients who were hospitalized in Department of Pediatric Hematology, Oncology and Transplantology, Medical University of Lublin in Poland and developed severe hypertriglyceridemia after receiving asparaginase and steroid therapy for acute lymphoblastic leukemia. These patients were treated using plasmapheresis. This procedure was performed with a venous catheter in the femoral vein and 5% albumin or fresh frozen plasma as the replacement fluid. We analysed the laboratory and clinical data of these children. Plasmapheresis was well tolerated in both cases and a decrease of hypertriglyceridemia was quickly observed. However, the girl developed pancreatitis. In our opinion, plasmapheresis appears to be safe and effective in reducing hypertriglyceridemia. We could recommend that this procedure should be performed early, as soon as the triglyceride level is above 1000 mg/dl, in order to prevent severe complications. Patients should continue chemotherapy without ASP. It is important to regularly monitor of the lipid profile, pancreatic enzymes and coagulation during ASP and steroids therapy.
1. Introduction Therapy protocols for acute lymphoblastic leukemia (ALL), both first and second line, are based on multi-agent chemotherapy regimens and corticosteroids. Asparaginase (ASP) and steroids are administered together during the induction and reinduction phases of the first line treatment protocol, and during each course of chemotherapy in the second line [1]. It is known that ASP can cause several toxicities, such as hypersensitivity, pancreatitis, as well as severe lipid and coagulation disturbances [2]. Steroid administration can result in diabetes, obesity, hyponatremia, and also mild hyperlipemia, which can intensify side effects of asparaginase. When triglyceride (TG) elevation is greater than 1000 mg/dl, the risk of pancreatitis is significantly increased [3]. Limited information is available on the epidemiology and management of hypertriglyceridemia (HTG; 150–499 mg/dl) and severe HTG
(SHTG; > 500 mg/dl) in children but literature data indicate that the cumulative risk of asparaginase‐associated pancreatitis (AAP) is 5.9% [4]. The treatment for asparaginase-induced hypertriglyceridemia, includes low-fat diets, fibrate therapy, heparinization, or plasmapheresis and the cessation of asparaginase [5]. We report two patients who developed SHTG after receiving asparaginase and steroid therapy for ALL and were treated using plasmapheresis. In both cases this procedure was performed with a doubleline venous catheter in the femoral vein (Arrow). SPECTRA OPTIA (cellular separator) was used to this procedure. The replacement fluid was the fresh frozen plasma or 5% albumin. Anticoagulant Citrate Dextrose Solution A was used during plasmapheresis. The length of the procedure was 59–135 min. The total volume of plasma has been replaced, and the number of processed total blood volume (TBV) was 1.33-1.35. We analysed the laboratory and clinical data of these
⁎ Corresponding author at: Department of Pediatric Hematology, Oncology and Transplantology, Medical University of Lublin, 6 Antoni Gębala Street, 20-093, Lublin, Poland. E-mail address: [email protected] (J. Zawitkowska).
https://doi.org/10.1016/j.transci.2019.08.025 Received 16 June 2019; Received in revised form 5 August 2019; Accepted 27 August 2019 1473-0502/ © 2019 Published by Elsevier Ltd.
Please cite this article as: Joanna Zawitkowska, et al., Transfusion and Apheresis Science, https://doi.org/10.1016/j.transci.2019.08.025
Transfusion and Apheresis Science xxx (xxxx) xxx–xxx
J. Zawitkowska, et al.
children. The patients were hospitalized in Department of Pediatric Hematology, Oncology and Transplantology, Medical University of Lublin in Poland.
(February 2018). Currently, she is alive and well.
2. Case one
A 10-year old boy was admitted to our hospital because of suspected relapse of leukemia. His condition was good. There were no co-morbidities, such as obesity, diabetes and a familiar history of dyslipidemia. The child diagnosed with preB common positive ALL was treated between the years 2014 – 2016. During first line chemotherapy hypertriglyceridemia (964/μl) occurred once but a use a low molecular weight heparin was effective at that time. Therapy of relapse (site of disease: bone marrow and testis) started in January, 2017. He was started on treatment according to IntReALLSR 2010 [7]. The patient was classified to standard risk group. The second course of chemotherapy, which included PEG-ASP and steroids, was complicated by SHTG. Laboratory parameters in a time-dependent manner are presented in Table 1. Despite therapy of subcutaneously -low-molecular heparin, insulin, an infusion of 10% glucose and a low-fat diet, the triglyceride concentrations quickly increased. That's why we decided to early perform plasmapheresis. The procedure was continued for three days. High plasma triglyceride concentrations (8000 mg/dl) and hyponatremia (131 mmol/l) were observed for three days. The child’s condition was good. CT showed enlargement of the pancreas without focal changes. Plasmapheresis was performed with excellent effect in reducing hypertriglyceridemia (Fig. 1b). Picture 1 shows the apheresis product. The replacement fluid was 5% albumin. The procedure lasted 125–135 min and TBV processed was 1.35. Complications were not observed during the plasmapheresis. The patient did not develop pancreatitis. Following this episode, asparaginase was not applied in the next course of chemotherapy. Due to several complications (SHTG, fungal pneumonia), the patient was qualified for matched related donor bone marrow transplantation, which was performed in August, 2017. Currently, the patientis alive and well.
3. Case two
A 5-year old girl was admitted to our hospital because of a fever for 7 days, pain in the lower limbs and a fainting episode. Medical history included paralysis of the left shoulder plexus during delivery. There were no co-morbidities, such as obesity, diabetes and a familiar history of dyslipidemia. The child was diagnosed with preB common positive ALL and started treatment in March 2016, according to ALL IC-BFM 2009 [6]. She was classified to intermediate risk group. From day 12 of the induction phase pegylated (PEG) formulation of ASP was used due to hypersensitivity reaction to Escherichia coli-derived asparaginase. During that phase of therapy (from day 22), the level of triglycerides still increased. Hyponatremia (122 mmol/l) was also observed. Initially, when the level of TG was above 500 mg/dl, insulinotherapy was introduced in the form of 10% glucose infusion, a low-fat diet and low molecular weight heparin subcutaneously, but without effect. Therefore, plasmapheresis was applied when triglyceridemia reached 9300 mg/dl on the 33rd day of ALL therapy. The replacement fluid was fresh frozen plasma. The procedure lasted 59–77 min and TBV processed was 1.33. Plasmapheresis was well tolerated. We continued the procedure for three days. Decrease of hypertriglyceridemia was quickly observed (Fig. 1a). However, the child’s condition quickly deteriorated and pancreatic enzymes became elevated. Laboratory parameters in a time-dependent manner are presented in Table 1. Computer tomography (CT) showed an enlarged pancreas with disseminated pancreatic necrosis and a vast hypodense fluid area near the pancreas reaching to the smaller pelvis (Picture 2). She developed a seizure episode and multi-organ failure and she was transferred to the intensive care unit (ICU). Supportive care in ICU included parenteral nutrition, subcutaneously low-molecular heparin, metronidazole, metoclopramide, co-trimoxazole, liposomal amphotericin B, ornithini aspartas, acidum ursodeoxycholicum, meropenem, vancomycin, and then ciprofloxacin, gentamycin, rifaximin. Surgical therapy with drainage of abdominal cavity was performed. The patient remained in the ICU for 24 days before being returned to our department. Despite intensive treatment, the child constantly presented numerous clinical problems and therefore, we decided to stop the chemotherapy completely on the 33th day of the induction phase of therapy. The patient required several surgical procedures, such as cholecystectomy and another drainage to recover from abdominal complications. After improvement of the general condition, the child was followed on an outpatient basis. Bone marrow relapse occurred in September 2017. The girl received chemotherapy according to IntReALL HR 2010 without PEG-ASP but with steroids [7]. We did not observe SHTG. After achieving remission stem cell transplantation from a matched related donor was performed
4. Discussion Therapeutic plasmapheresis is a medical procedure which is based on removal of autoantibodies, immune complexes, antigens, proteins, enzymes and clotting factors, or cytokines (together with the plasma) from the blood. Indications for plasmapheresis treatment include different disorders with hematological, neurological, nephrological and toxicological indications. The most commonly reported complications of this procedure are: hypotension, hypokalemia, hypocalcemia, muscle cramps, a metallic taste in the mouth, allergic reactions, bacterial infections, and severe suppression of the immune system [8]. Children suffering from ALL treated with asparaginase and corticosteroids are prone to severe lipid disorders, but according to presently published studies, this complication is often undiagnosed. Severe hypertriglyceridemia is a rare but clinically significant side effect of PEGASP and steroids. Additionally, some factors such as obesity or diabetes may and older age (> 10 years) increase the risk of developing HTG
Fig. 1. a, b. Serum triglyceride levels before, during and after plasmapheresis in the first (a) and second (b) case. 2
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Table 1 Laboratory parameters in a time-dependent manner in the first and second case. Parameters
Case 1 - ALL IC 2009 protocol*
Days WBC (μl) TG (mg/dl) amylase (U/l) lipase (U/l) AT (%) fibrinogen (g/l) d-dimers (ng/ml)
1 7540 90 36 24 91 4.46 2072
8 1120 293 38 29 nd nd nd
15 600 115 35 25 58 0.68 5271
22 1130 293 45 33 84 0.72 561
24 1800 530 55 43 75 0.82 570
Case 2 - SCA1 course** 29 2720 734 57 24 51 0.35 489
30 nd 1000 nd nd 80 0.8 480
31 nd 1724 nd nd nd nd nd
32 nd 9000 nd nd nd nd nd
33 2160 9300 63 47 49 1.87 214
34 11140 2500 63 29 47 1.1 277
35 12330 1571 67 132 49 1.23 297
36 1580 803 1002 1294 56 1.75 1131
1 5170 136 60 38 101 2.61 518
8 3610 150 53 nd nd nd nd
15 nd 520 43 48 76 1.52 nd
16 3500 707 nd nd 53 2.93 319
17 nd 878 nd nd nd nd nd
18 3360 8000 43 44 22 0.45 221
19 3150 1480 51 43 42 0.44 194
20 2080 702 52 36 36 0.72 293
WBC-white blood cells; TG-triglycerides; AT-antithrombin; nd- not dome. * Prednison 60 mg/m2/day (28 days); Vinristine 1.5 mg/m2/day (day 8,15, 22, 29); Daunorubicin 30 mg/m2/day (day 8,15,22,29); L-Asparaginase 5000 U/m2/ day (day 12,15,18, 21,24,26,29, 33), in this case due to hypersensitivity – PEG-Asparaginase 1000 U/m2/day (used day 13, 24). ** Dexamethasone 6 mg/m2/day (14 days); Vinristine 1.5 mg/m2/day (day 1,8,15, 22); Idarubicin 6 mg/m2/day (day 1, 8,15,22); PEG-Asparaginase 1000 U/ m2/day (day 1, 11).
[2,5]. The studies on mechanisms of ASP-induced HTG suggest the excess endogenous very-low-density lipoprotein (VLDL) and decreased lipoprotein lipase activity (LPL). Moreover, ASP can cause a metabolic disturbance of lipoproteins. Similarly, steroids increase VLDL production in the liver, but also LPL activity. However, ASP used with steroids will overcome the compensatory effect of steroid-induced LPL activity [5]. Our patients had their TG levels frequently monitored during PEGASP therapy. We observed quickly increasing triglyceride concentrations in both cases. In the girl, the first procedure was performed after ten days of HTG, and in the second patient, we decided to introduce plasmapheresis earlier in the course of HTG. Plasmapheresis was performed in both children; however, only the girl demonstrated severe pancreatitis. The procedures were well-tolerated in both cases. The literature presents case reports of ALL children and adults treated with steroids and asparaginase for whom plasmapheresis was performed and effective. No severe adverse effects of this procedure were reported [9]. We summarized cases of adult and pediatric patients with SHTG undergoing chemotherapy for ALL in Table 2 [1,3,5,10]. In our opinion, plasmapheresis appears to be safe and effective in reducing hypertriglyceridemia. We could recommend that this procedure should be performed early, as soon as the triglyceride level is above 1000 mg/dl, in order to prevent severe complications. Patients should continue chemotherapy without ASP. It is important to regularly monitor of the lipid profile, pancreatic enzymes and coagulation during ASP and steroids therapy.
Picture 2. CT scan of the abdominal cavity of the first scan.
Authorship contributions JZ, KD were responsible for the study design. JZ, ML, KD, AZP, TGC, NS collected and analysed the clinical data. JZ, KD supervised the paper. All authors read and approved the final manuscript.
Funding sources This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
ICMJE statement All authors meet the ICMJE authorship criteria.
Picture 1. The apheresis product of the second child. 3
Transfusion and Apheresis Science xxx (xxxx) xxx–xxx
J. Zawitkowska, et al.
Table 2 Cases of adult and pediatric patients with asparaginase-induced SHTG treated for ALL. Patients (age)
Sex
Year of therapy
ASP formulation
TG Peak [mg/dl]
Treatment
Pancreatitis
Author
5 10 6 10 10 21 32 34
F M F F M M M M
2016 2017 2015 2011 2008 2008 2014 2008
PEG-ASP PEG-ASP L-ASP L-ASP L-ASP L-ASP PEG-ASP L-ASP
9300 8000 1250 9250 4000 9226 4420 5620
Low-fat diet, heparin, insulin, plasmapheresis Low-fat diet, heparin, insulin, plasmapheresis Low-fat diet, hyperhydration, plasmapheresis Plasmapheresis Plasmapheresis Low-fat diet, plasmapheresis, fibrates Low-fat diet, heparin Plasmapheresis
Yes No Yes No Yes No No Yes
Patient 1 Patient 2 Morand et al. Solano-Paez et al. Ridola et al. Nakagawa et al. Galindo et al. Kfoury-Baz et al.
TG-triglycerides; L-ASP-asparaginase; PEG-ASP- pegylated asparaginase.
Declaration of Competing Interest
in the NOPHO ALL2008 protocol. Br J Haematol 2014;165(April 1):126–33. https:// doi.org/10.1111/bjh.12733. PubMed PMID: 24428625. [5] Galindo RJ, Yoon J, Devoe C, Myers AK. PEG-asparaginase induced severe hypertriglyceridemia. Arch Endocrinol Metab 2016;60(April 2):173–7. https://doi.org/10. 1590/2359-3997000000068. PubMed PMID: 26331232. [6] Zawitkowska J, Lejman M, Zaucha-Prazmo A, Drabko K, Plonowski M, Bulsa J, et al. Clinical characteristics and analysis of treatment result in children with Ph-positive acute lymphoblastic leukaemia in Poland between 2005 and 2017. Eur J Haematol 2018;101(October 4):542–8. https://doi.org/10.1111/ejh.13142. PubMed PMID: 30007093. [7] Karawajew L, Dworzak M, Ratei R, Rhein P, Gaipa G, Buldini B, et al. Minimal residual disease analysis by eight-color flow cytometry in relapsed childhood acute lymphoblastic leukemia. Haematologica 2015;100(July 7):935–44. https://doi.org/ 10.3324/haematol.2014.116707. PubMed PMID: 26001791; PubMed Central PMCID: PMCPMC4486228. [8] Misanovic V, Pokrajac D, Zubcevic S, Hadzimuratovic A, Rahmanovic S, Dizdar S, et al. Plasmapheresis in pediatric intensive care unit. Med Arch 2016;70(October 5):332–5. https://doi.org/10.5455/medarh.2016.70.332-335. PubMed PMID: 27994290; PubMed Central PMCID: PMCPMC5136426. [9] Gavva C, Sarode R, Agrawal D, Burner J. Therapeutic plasma exchange for hypertriglyceridemia induced pancreatitis: a rapid and practical approach. Transfus Apher Sci 2016;54(February 1):99–102. https://doi.org/10.1016/j.transci.2016.02.001. PubMed PMID: 26947356. [10] Morand A, Barlogis V, Rouby F, Reynaud R, Marrec C, Michel G. Hypertriglyceridemia, discorvered on a pseudohyponatremia, induced by L-asparaginase in the treatment of B acute lymphoblastic leukemia in child. Therapie 2015:16. https://doi.org/10.2515/therapie/2015051. Oct PubMed PMID: 26475748.
None. Acknowledgement No acknowledgements. References [1] Ridola V, Buonuomo PS, Maurizi P, Putzulu R, Annunziata ML, Pietrini D, et al. Severe acute hypertriglyceridemia during acute lymphoblastic leukemia induction successfully treated with plasmapheresis. Pediatr Blood Cancer 2008;50(February 2):378–80. https://doi.org/10.1002/pbc.20986. PubMed PMID: 16883590. [2] Persson L, Harila-Saari A, Hed Myrberg I, Heyman M, Nilsson A, Ranta S. Hypertriglyceridemia during asparaginase treatment in children with acute lymphoblastic leukemia correlates with antithrombin activity in adolescents. Pediatr Blood Cancer 2017;64(October 10). doi: 10.1002/pbc.26559. PubMed PMID: 28440015. [3] Solano-Paez P, Villegas JA, Colomer I, Gutierrez MD, Fernandez-Teijeiro A. LAsparaginase and steroids-associated hypertriglyceridemia successfully treated with plasmapheresis in a child with acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2011;33(April 3):e122–4. https://doi.org/10.1097/MPH.0b013e3181faf7a1. PubMed PMID: 21399528. [4] Raja RA, Schmiegelow K, Albertsen BK, Prunsild K, Zeller B, Vaitkeviciene G, et al. Asparaginase-associated pancreatitis in children with acute lymphoblastic leukaemia
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