Keywords Philadelphia-chromosome-positive acute lymphoblastic leukemia - acute pancreatitis
- ventricular thrombus - gastric perforation - L-asparaginase
Introduction
L-asparaginase has become an integral part in the management of childhood acute lymphoblastic
leukemia (ALL) and failure to receive its intended course has been associated with
poor outcome.[1 ]
[2 ] However, L-asparaginase is also associated with a number of unique toxicities, some
of which can have life threatening consequences.[3 ] Here we present a patient with Philadelphia-Chromosome-positive Acute Lymphoblastic
Leukemia (Ph+ ALL) who experienced two rare complications during induction therapy: gastric perforation
and a left ventricular thrombus which led to his demise.
Case Report
An 8-year-old male presented with on and off fever, bruising over shin and chest and
easy fatigability for 2 weeks. A complete blood count showed a total leukocyte count
(TLC) of 153 × 109 /L with a differential count of 60% lymphocytes, 3% neutrophils, 0.1% eosinophils,
and 27% blasts in the peripheral blood. A bone marrow examination was done, flow cytometric
analysis along with FISH study which was positive for t(9;22), confirmed the diagnosis
of B-lineage Ph+ ALL. A real-time quantitative polymerase chain reaction (RT-PCR) was suggestive of
p190 BCR/ABL fusion transcript. Cerebrospinal fluid analysis was uninvolved for disease.
He was treated as per the modified COG AALL1131 protocol. Induction chemotherapy consisted
of prednisolone (60 mg/m2 /day; 1–28 days), vincristine (1.5 mg/m2 /d; days 1, 8, 15, and 22), native Escherichia coli L-asparaginase (10,000 U/m2 /d; days 1,4, 7, 10, 13, 16, 19, and 22) daunorubicin (30 mg/m2 /d; days 1 and 15), intrathecal methotrexate (12 mg; days 1, 8, and 30) along with
daily imatinib (340 mg/m2 /once daily) from day 10. Chemotherapy was administered through peripheral intravenous
lines on an outpatient basis. Treatment was uneventful up to day 29 of induction when
he presented with abdominal pain and fever. On examination, heart rate was 86/min,
blood pressure was 100/70 mm Hg and respiration was 22/min. Abdomen was mildly distended,
diffusely tender, and bowel sounds were present. He was started on intravenous fluids,
intravenous antibiotics (cefoperazone-sulbactam and amikacin), and analgesics for
abdominal pain. The complete blood count showed a hemoglobin of 5 g/dL, platelet of
49 × 109 /L, and TLC of 0.42 × 109 /L with an absolute neutrophil count of 0.1 × 109 /L. Blood tests showed an elevated lipase (1,164 U/L), elevated D-dimer (3,700 ng/mL),
with a normal serum sodium (137 mEq/L) and potassium (4.2 mEql/L) and no organism
was isolated from blood culture. In view of the above symptoms in a neutropenic child,
computerized tomography (CT) scan of the abdomen with contrast was performed on the
day of admission which revealed a bulky pancreas with fat stranding consistent with
acute pancreatitis, as well as perforation of the greater curvature of the stomach
resulting in pneumoperitoneum ([Fig. 1a ] and [b ]). An incidental finding on CT scan was a well-defined hypodense mass in the left
ventricle (LV) of the heart which an ultrasound study showed lacked vascularity; two-dimensional
echocardiography confirmed a mass of 3.01 × 1.49 cm arising from the interventricular
septum with a normal ejection fraction of 60% ([Fig. 1a ] and [c ]). Imaging findings and elevated D-dimer both strongly suggested a diagnosis of intraventricular
thrombus. The child was shifted to the intensive care unit (ICU) where he was continued
on analgesics and intravenous antibiotics and kept nil by mouth. He underwent an emergency
laparotomy for his abdominal emergency. Intraoperatively, there was a single perforation
on the posterior wall of the stomach, and two impending perforations on the proximal
jejunal wall, all of which were closed in two layers, using 4-0 polydioxanone suture
([Fig. 1d ] and [e ]). The surgical procedure was uneventful. Postoperatively, the child continued to
be neutropenic (absolute neutrophil count: of 0.1 × 109 /L) with a platelet count of 40 × 109 /L. He was continued on intravenous antibiotics and was started on the low-molecular
weight heparin (LMWH) enoxaparin at 1 mg/kg/dose twice a day for the large cardiac
thrombus. Given his postoperative state and neutropenia, it was decided to defer any
major cardiac surgery. The day after surgery the child was extubated from the ventilator
and started on clear liquids, his pancreatic enzymes had returned to normal. On the
subsequent day (postoperative day 2) he developed a sudden cardiac arrest and could
not be revived. Permission for autopsy was not obtained.
Fig. 1 (A ) CT abdomen showing left ventricular thrombus (arrow head ) and pneumoperitoneum (*) (B ) with gastric perforation (arrow ). (C ) 2D-echocardiography confirming the presence of left ventricular thrombus (outlined circle ). (D ) Intraoperative findings showing perforation of greater curvature of stomach (arrow head ) (E ) impending perforation of jejunum (double arrow ).
Discussion
Philadelphia chromosome (Ph+ ) ALL comprises only 3%–5% of childhood ALL, the outcomes of which have been dismal
until the addition of tyrosine kinase inhibitor, imatinib.[4 ]
[5 ] While imatinib has been linked to pneumatosis intestinalis in a child with acute
leukemia, most clinical trials for childhood Ph+ ALL have not reported this as a significant toxicity.[4 ]
[5 ]
[6 ] Of interest was L-asparaginase, linked to pancreatitis in 6.7%–18% of children being
treated for ALL.[7 ] The clinical course of drug-induced pancreatitis can vary from mild to severe and
in our patient serum lipase returned to normal within 72 hours and CT abdomen showed
no evidence of pseudocyst or necrosis, excluding severe pancreatitis as a cause of
gastrointestinal perforation.[8 ] Gastrointestinal tract perforation is reportedly seen in less than 1% of patients
on induction therapy for ALL.[9 ] L-asparaginase-related jejunal perforation has been described in a patient with
ALL, with the etiology related to the prothrombotic state induced by reducing levels
of natural anticoagulants such as protein C, protein S, Antithrombin III, and plasminogen.[10 ]
[11 ] Also, imatinib has very rarely been reported to cause bowel perforation, but given
the rarity and length of exposure it is unlikely to be the causative factor in our
patient.[12 ]
[13 ]
[14 ]
Thrombotic complications are seen in 2%–7% of patients with ALL receiving asparaginase.
The driving mechanism for thrombosis is related to the depletion of L-asparaginase-dependent
hemostatic protein synthesis. Thrombotic events most often occur during induction
and corticosteroids may contribute by increasing synthesis of procoagulants as well
as by inducing vascular changes.[15 ] Majority of patients develop venous thrombosis, but arterial thrombosis has also
been reported.[16 ] Thrombosis secondary to L-asparaginase is usually managed with LMWH. L-asparaginase
may need temporary discontinuation in the presence of clinically significant thrombotic
events, however, re-exposure is considered to be safe and feasible and is usually
done under the cover of anticoagulation therapy.[3 ] Intracardiac thrombus amongst patients receiving L-asparaginase usually involves
the right atrium in 2%–14% of children with ALL and is usually related to the presence
of catheter tip in right atrium while the LV has not been described as a site for
a thrombus.[17 ]
[18 ] LV thrombosis has been described in patients with hypereosinophilic syndrome, as
well as in a child with acquired protein C deficiency.[19 ]
[20 ] Amongst adults, LV thrombus commonly occurs following myocardial infarction but
has also occasionally been described amongst patients with cancer.[21 ]
[22 ]
[23 ] LV thrombus poses a risk of embolism resulting in ischemic stroke and peripheral
embolism, because of which immediate anticoagulation therapy is recommended. In adults
the preferred anticoagulation is usually oral warfarin along with low dose aspirin
for 3 to 6 months.[23 ] Surgery is recommended if the general condition of the patient is preserved. Since
our patient was a child who had undergone a major gastric surgery, he was commenced
on subcutaneous LMWH and since he was severely neutropenic it was decided to defer
any cardiac surgery until the time of count recovery.
Our patient did not have any past history of thrombotic episodes or family history
of thrombophilia, but the co-occurrence of these unusual complications made us strongly
suspect a underlying prothrombotic condition exacerbated by L-asparaginase therapy.[10 ] The prevalence of genetic prothrombotic abnormalities amongst children with ALL
varies around the world, and we do not pre-emptively screen for thrombophilia given
that such testing is expensive, and not easily available. The Dutch Children's Oncology
Group has debated the benefit of more aggressive screening and LMWH prophylaxis during
induction for those found to have thrombophilia.[24 ] The role of genetic predisposition for pancreatitis is less clear but recent genome-wide
association studies have found different candidate single-nucleotide polymorphisms
associated with pancreatitis in patients with ALL.[25 ] We could not rule out a pre-existing cardiac thrombus as a baseline 2D-echo was
unavailable. Also, thrombotic events and gastric perforation during ALL therapy are
often considered to be multifactorial rather than secondary to a single drug. But,
the occurrence of several unique toxicities which are often shown to be associated
with L-asparaginase, all occurring simultaneously in a patient would be the highlight
of this case report.
Conclusion
Though L-asparaginase is an essential drug for the management of childhood ALL, it
does possess a unique toxicity profile. Unfortunately, our patient simultaneously
experienced several toxicities, including pancreatitis, LV thrombus, and gastrointestinal
perforation leading to his demise. Lack of familiarity of the toxicity profile of
this drug can make L-asparaginase a difficult drug to use. Being vigilant for these
unusual toxicities especially during induction chemotherapy is essential for optimal
patient care.
