Pegaspargase induced multiple organ failure with acute lymphoblastic leukemia: A case report

Abstract

BACKGROUND

The introduction of pegaspargase has greatly advanced the treatment of acute lymphoblastic leukemia (ALL). In the literature, only one case of pegaspargase-induced multiple organ failure has been reported, and the patient died due to multiple organ failure.

CASE SUMMARY

Herein, we present a rare case of a 40-year-old man with ALL who developed multiple organ failure after treatment with pegaspargase. The patient had two rare phenomena reflecting poor prognosis, including the discrepancy between clinical manifestations and liver function and persistently low alpha-fetoprotein (AFP) levels from subacute liver failure. However, the patient was successfully treated using a multidisciplinary team approach.

CONCLUSION

This is the first case report of successful treatment of pegaspargase-induced multiple organ failure. The findings emphasize the importance of a multidisciplinary team approach in treating pegaspargase-induced multiple organ failure.

Key Words: Pegaspargase; Multiple organ failure; Acute lymphoblastic leukemia; Liver failure; Case report

Core Tip: We reported a rare patient with acute lymphoblastic leukemia, who suffered from multiple organ failure following the first application of pegaspargase. To date, only one patient has been reported and the patient died due to multiple organ failure in the reviewed word literature. In the article, although the patient had two rare phenomena reflecting poor prognosis, the patient was the first case of successful treatment. Two rare phenomena including inconformity between clinical manifestation and liver function, and persistent low AFP concentrations from subacute liver failure patients will be discussed in this patient.

INTRODUCTION

With the introduction of pegaspargase, acute lymphoblastic leukemia (ALL) treatment has improved. However, pegaspargase may have adverse effects, including liver dysfunction, hepatic steatosis, hypersensitivity, pancreatitis, and thrombosis[1]. Unfortunately, effective treatments for pegaspargase-induced multiple organ failure are limited. To date, only one case of pegaspargase-induced multiple organ failure has been reported in the literature, and the patient died due to multiple organ failure[2]. Herein, we reported the first case of the successful treatment of multiple organ failure initially induced by pegaspargase, highlighting the importance of a multidisciplinary team approach.

CASE PRESENTATION

Chief complaints

A 40-year-old man with newly diagnosed ALL-L2 was admitted to our hospital. The patient received induction chemotherapy according to the ALL-consensus protocol. On November 6, phase I induction chemotherapy was completed with VDCLP (vindesine 4 mg d1, d8, d15, d22 + cyclophosphamide 1.5 d1, d15 + liposomal doxorubicin 40 mg d1, 20 mg d2 + mileson 60 mg d1-14, 40 mg d15-21, 20 mg d22-28 + pegaspargase 3750 IU d14). On December 4, cytarabine (50 mg) and methotrexate (10 mg) were administered.

Twenty-seven days after receiving pegaspargase, the patient developed abnormal liver function, which progressively worsened. The patient was treated with hepatoprotective drugs, including compound glycyrrhizin and transmetil. On December 6, the patient experienced acute cholecystitis and was treated with ceftriaxone and levofloxacin. On December 18, a small, red, maculopapular rash appeared on the front chest, indicating chickenpox. On December 19, the patient was diagnosed with subacute liver failure characterized by critical hyperbilirubinemia and prolonged prothrombin time (Table 1 and Supplementary Table 1) and was treated with an artificial liver support system.

Table 1 Time course of liver function and kidney function after treatment with pegasparaginase.

Date	TB, (μmol/L)	DB (μmol/L)	TP (g/L)	Alb (g/L)	ALT (U/L)	AST (U/L)	ALP (U/L)	γ-GT (U/L)	TBA (μmol/L)	eGFR (mL/min/1.73m2)
2020/10/31	8.4	1.8	71	42	117	73	83	56	/	/
2020/11/27	24.6	8.2	44	27	27	16	73	49	/	129
2020/12/4	31.7	17.4	52	29	121	89	187	235	/	124
2020/12/7	99.1	66.7	44	24	177	148	187	363	/	120
2020/12/10	212.2	133	44	25	235	225	499	669	/	125
2020/12/19	349.4	194.2	55	30	3018	8637	1425	876	/	131
2020/12/21	387.8	265.3	47	23	2115	5666	895	445	179.6	15
2021/1/2	476.5	306.7	41	23	51	144	177	235	79	57
2021/1/14	577.9	387.8	32	17	14	60	135	166	131.8	59
2021/1/16	593	360.7	54	34	23	65	158	181	83.7	72
2021/2/1	342.4	180.6	45	32	121	112	580	276	121.6	110
2021/2/8	317.7	218.3	53	38	162	150	363	210	102.3	110
2021/2/15	306	169	55	37	155	141	237	395	81.3	113
2021/3/1	196.9	109.1	47	32	111	108	276	424	64.9	115
2021/3/22	130.9	74.1	45	28	62	91	317	303	110.6	99
2021/4/1	116.4	66.2	47	29	61	86	354	271	157.5	102
2021/5/7	62.5	33.5	55	34	82	92	243	86	/	80
2021/6/24	45.3	21.8	61	34	50	30	194	73	/	/

γ-GT: γ-glutamyl transpeptidase; Alb: Albumin; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; DB: Direct bilirubin; eGFR: Glomerular filtration rate; TB: Total bilirubin; TBA: Total bile acid; TP: Total protein.

On December 20, the patient experienced septic shock characterized by high fever (axillary temperature 39.2 °C), hypotension (blood pressure 80/40 mmHg), increased heart rate (124 beats/min), and elevated inflammation indicators (Supplementary Table 2). The patient was treated with imipenem/cilastatin and levofloxacin for bacterial infections, and caspofungin for fungal infection, noradrenaline for maintaining blood pressure, and immunoglobulin for anti-inflammatory treatment. On December 21, the patient experienced anuria, and renal function tests revealed renal failure (Table 1). Thus, the patient was managed with hemodialysis. On December 23, the patient developed a large hematoma at the root of the left thigh after arterial blood was drawn, and routine blood tests showed a significant decrease in hemoglobin (50 g/L). Hemostasis was achieved by compression and red blood cell transfusion.

A multidisciplinary team comprising infectious disease, nephrology, vascular surgery, blood transfusion, and hematology specialists were involved in patient management. The patient continued to have a high fever, and vancomycin was administered for anti-infection on December 27. Despite using the artificial liver support system, the total bilirubin level gradually increased, γ-glutamyl transpeptidase (γ-GT) and alkaline phosphatase (ALP) levels decreased, and coagulation function improved. Hyperbaric oxygen therapy and methylprednisolone (40 mg, qd, ivgtt) were administered, and the artificial liver support system was continued. Methylprednisolone was gradually reduced and was changed to oral methyldehydrocortisone. Subsequently, γ-GT and ALP levels increased, and cholestyramine was administered. Figure 1 shows the time course of laboratory parameters associated with multiple organ failure.

Figure 1 Time course of laboratory parameters associated with multiple organ failure after pegaspargase treatment. A: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT); B: Total bilirubin (μmol/L); C: Alkaline phosphatase (ALP) (U/L), γ-Glutamyl transpeptidase (γ-GT) (U/L), and total bile acid (TBA) (μmol/L); D: Glomerular filtration rate (eGFR) (mL/min/1.72 m²); E: Hemoglobin (Hb) (g/L); F: Procalcitonin (PCT) (ng/mL) and C-reactive protein (CRP) (mg/L); G: Prothrombin (PT) time (s) and activated partial thromboplastin time (APTT) (s); H: International normalized ratio (INR); I: Alpha-fetoprotein (AFP) (IU/mL)over time after pegaspargase treatment.

On January 15, 2021, the patient experienced symptoms such as cough and expectoration. Chest CT showed scattered oozing in both lungs (Supplementary Figure 1), sputum culture revealed Stenotrophomonas maltophilia infection, and levofloxacin was administered. The patient’s condition was stable, and he was discharged on April 1, 2021.

Oral hepatoprotective drugs, including transmetil and ursodeoxycholic acid, were continued after discharge. The patient fully recovered from the severe complications of pegaspargase. Bone marrow biopsy showed complete remission on May 7, 2021. On May 11, 2021, lumbar puncture and intrathecal chemotherapy (cytarabine 50 mg + methotrexate 10 mg + dexamethasone 5 mg) were administered. On June 9, 2021, cytarabine 50 mg, methamine pterin 10 mg, dexamethasone 5 mg, vindesine 4 mg d1, and milesone 60 mg d1-d7 were administered. Later, the patient’s condition was stable.

History of present illness

A 40-year-old man was diagnosed as ALL-L2 on Oct 2020. The patient received induction chemotherapy according to the ALL-consensus protocol. On November 6,2020, phase I induction chemotherapy was completed with VDCLP (vindesine 4 mg d1, d8, d15, d22 + cyclophosphamide 1.5 d1, d15 + liposomal doxorubicin 40 mg d1, 20 mg d2 + mileson 60 mg d1-14, 40 mg d15-21, 20 mg d22-28 + pegaspargase 3750 IU d14). On December 4, 2020, cytarabine (50 mg) and methotrexate (10 mg) were administered.

History of past illness

The patient had a history of hypertension for 6 years, with a maximum of 180/110 mmHg. The patient had been taking valsartan amlodipine once a day and carvedilol once a day orally for a long time, and the blood pressure can be well controlled.

Personal and family history

There is no history of genetic diseases or tumors in the family

Physical examination

The patient was admitted with ALL without any obvious positive signs. Subsequently, with the use of chemotherapy drugs, he developed symptoms such as papules, chickenpox, yellow staining of the skin and sclera, wet rales on lung auscultation, edema, etc.

Laboratory examinations

The laboratory examinations are shown in Table 1

Imaging examinations

The imaging examinations are shown in Supplementary Figure 1.

MULTIDISCIPLINARY EXPERT CONSULTATION

Multidisciplinary active treatment. Infection control from the infection department, hemodialysis from the nephrology department, hemostasis from vascular surgery department, ALL control from the hematology department, and adequate provision of red blood cells and plasma from the transfusion department.

FINAL DIAGNOSIS

Multiple organ failure; septic shock; severe anemia; ALL; primary hypertension (grade 3, very high risk).

TREATMENT

Anti infection, liver protection, hemodialysis, artificial liver support system, blood transfusion, nutritional support and other treatments.

OUTCOME AND FOLLOW-UP

Later, the patient’s condition was stable.

DISCUSSION

Pegaspargase enhances the therapeutic effect of ALL treatment. Liver dysfunction, pancreatitis, hypersensitivity, or thrombosis were the important adverse effects of pegaspargase[1,2]. Unfortunately, few successful treatments for pegaspargase-induced multiple organ failure have been reported.

A previous study showed that pegaspargase induces rapid development of cholestasis and hepatic steatosis[3]. The vitamin B complex and levocarnitine regimen have been reported to be an effective and safe therapy for pegaspargase-induced hepatotoxicity[4]. Pegaspargase-induced multiple organ failure is highly rare, and its mortality rate is high. Plasmapheresis improved the outcome of severe complications after pegaspargase treatment in three patients with ALL[5]. In the literature, only one case of pegaspargase-induced multiple organ failure has been reported, and the patient died due to multiple organ failure. The possible mechanisms explaining the findings observed in this patient are impaired liver mitochondrial function and alterations in very-low-density lipoprotein metabolism and secretion[2].

In our case, pegaspargase-induced subacute liver failure, varicella, and acute cholecystitis caused septic shock, which induced multiple organ failure, including liver and kidney failure, coagulation dysfunction, and immune system failure. The survival rate of patients with more than four organ failures is very low. However, our patient was successfully treated using a multidisciplinary team approach, and recovery of multiple organs was achieved.

Two interesting phenomena that reflect the poor prognosis should be discussed. First, the patient had kaolin-like stools, the total bilirubin gradually increased, and the levels of γ-GT, ALP, and total bile acid (TBA) declined. This may be due to vanishing bile duct syndrome (VBDS), which is associated with adverse drug reactions, infections, neoplasms, ischemia, allograft rejection, and autoimmune disease. The prognosis of VBDS depends on the capacity for biliary regeneration and the etiological trigger of biliary epithelial apoptosis[6]. The diagnosis of VBDS is confirmed when less than 50% of the bile ducts are seen on liver biopsy[7]. In our case, the most likely causes of VBDS were adverse drug reactions (vinblastine) and infections (varicella and acute cholecystitis). Capillary cholangitis is another possible cause. The patient had acute cholecystitis and was most likely to develop a secondary bacterial infection based on cholestasis, causing capillary cholangitis. Pegaspargase-induced liver damage may also cause capillary cholangitis. Unfortunately, liver puncture was not performed due to the patient’s poor condition and high jaundice level. The patient was then treated with methylprednisolone and ursodeoxycholic acid, which is a choleretic agent that has antioxidant activity, enhances glutathione levels, and inhibits liver cell apoptosis. The jaundice level decreased, the γ-GT, ALP, and TBA levels increased, and cholestyramine was administered. Liver function gradually recovered after comprehensive treatment.

Second, alpha-fetoprotein (AFP) is considered a marker of hepatocyte regeneration, and the capacity for hepatocyte regeneration is vital for the reversal of liver injury. However, the patient’s AFP level remained normal during the progression or recovery period of liver failure. A previous study showed that stratified AFP can accurately predict mortality in patients with liver failure[8]. Rising AFP levels are associated with transplant-free survival in non-acetaminophen acute liver failure[9]. In patients with acute-on-chronic liver failure, a value of log10^AFP ≥ 2.04 indicated a better prognosis with 62.5% sensitivity and 76.9% specificity, which could be a useful marker for predicting the outcomes of acute-on-chronic liver failure[10]. Usually, a persistently low AFP level is considered a regenerative failure in protracted cases, ultimately leading to death. Our patient who had persistently low AFP levels ultimately survived. One possible reason was that liver tissue repair occurred, followed by subsequent intensive care.

Liver failure is associated with persistently low AFP levels, VBDS, and capillary cholangitis. To the best of our knowledge, this is the first case report of successful treatment of multiple organ failure initially induced by pegaspargase. Unfortunately, liver puncture was not performed due to the patient’s poor condition.

CONCLUSION

This is the first case report of successful treatment of pegaspargase-induced multiple organ failure. The findings emphasize the importance of a multidisciplinary team approach in treating pegaspargase-induced multiple organ failure.

ACKNOWLEDGEMENTS

We would like to thank the patient that was involved in this study.