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Blood, 1 December 2000, Vol. 96, No. 12, pp. 4000-4001
CORRESPONDENCE
To the editor:
Hyperleukocytosis during induction therapy with arsenic
trioxide for relapsed acute promyelocytic leukemia associated with
central nervous system infarction
Arsenic trioxide is a new and investigational agent for the
treatment of relapsed or refractory acute promyelocytic leukemia (APL).
Leukocytosis has been commonly noted with its use; however, this side
effect usually resolves spontaneously and is generally not treated. To
date, no deaths have been reported from the complications of
leukocytosis associated with the use of arsenic trioxide. We report on
a patient who died from the complications of a cerebral vascular event
secondary to hyperleukocytosis and probable cerebral leukostasis, which
occurred while the patient was receiving arsenic trioxide for
relapsed APL. A 27-year-old female was diagnosed with APL in May 1998. She was
initially treated with all-trans-retinoic acid (ATRA),
followed by consolidation chemotherapy with idarubicin, high-dose
cytarabine, and ATRA. She presented to our clinic 6 months after
completion of ATRA consolidation treatment with a white blood cell
(WBC) count of 21.2 × 103/µL (50% promyelocytes and
myeloblasts) and a platelet count of 19 × 103/µL.
There was no disseminated intravascular coagulation (DIC), as evidenced
by a normal fibrinogen level (248 ng/dL) and a normal activated partial
thromboplastin time (PTT) (24.1 seconds). A bone marrow biopsy and
aspirate confirmed the diagnosis of relapsed APL, and fluorescence in
situ hybridization (FISH) analysis was positive for t(15;17). After the
patient signed informed consent, treatment with daily intravenous
arsenic trioxide 0.15 mg/kg was started. Arsenic trioxide was obtained
from the National Cancer Institute under a compassionate
individual patient special exception protocol. The patient's WBC count
at the initiation of treatment with arsenic trioxide was 8.2 ×
103/µL, and her platelet count was
41 × 103/µL. After 2 doses of arsenic trioxide, the
WBC count had increased to 15.1 × 103/µL. After 3 doses, the patient was febrile at 38.2°C, and her WBC count had
increased to 20.9 × 103/µL, but she was otherwise
asymptomatic. Corticosteroid therapy was initiated at this time. The patient's WBC count continued to rise, and on the seventh
day of treatment she was asymptomatic, with a WBC of
101 × 103/µL and a platelet count of
61 × 103/µL. Following the eighth dose, the WBC count
increased to 212.6 × 103/µL (89% myeloblasts) with a
platelet count of 30 × 103/µL, and the arsenic
trioxide was discontinued. Evidence of DIC included
schistocytes on the blood smear, prothrombin time (PT) of 16.1 seconds, PTT of 23 seconds, decreasing fibrinogen (101 mg/dL), and
increasing fibrinogen degradation products (FDP 8 mcg/dL). Later
that day, the patient was found confused with slurred speech and
right-sided weakness. A CT scan of the head was consistent with
an early left middle cerebral artery (MCA) territorial infarct with no evidence of hemorrhage, mass effect, or midline shift. The
patient was transferred to an intensive care unit and received high
doses of decadron and platelet transfusions. Twelve hours later the
patient had a generalized seizure. Another CT scan of the head showed
an acute left MCA territorial infarct with diffuse cerebral edema and
signs indicative of central herniation. The patient's WBC count was
now 292.2 × 103/µL, and chemotherapy with idarubicin
and cytarabine was started. The patient continued to deteriorate and
expired on the fifteenth hospital day. The family declined an autopsy. We report here for the first time death associated with
hyperleukocytosis secondary to treatment with arsenic trioxide for relapsed APL. Leukocytosis is a well-documented effect of treatment with arsenic trioxide. Most patients experience a gradual increase in
the WBC, which peaks between 2 and 3 weeks after starting treatment with arsenic trioxide. Soignet et al1 reported on 12 patients treated with arsenic trioxide for relapsed APL. Six patients
(50%) experienced a leukocytosis with WBC counts ranging from 20.8 to 144.2 × 103/µL. None of the patients received therapy
for the leukocytosis, and all continued on treatment. The leukocytosis
resolved in all patients without treatment or complications. More
recently, Niu et al2 presented toxicity and
follow-up data on 47 patients with relapsed APL treated with
arsenic trioxide. Leukocytosis was observed in 55% of patients
treated, with WBC counts ranging from 11.9 × 103/µL to
167 × 103/µL. The WBC counts in 42% of these patients
returned to normal after chemotherapy, and 54% of them normalized
spontaneously. One patient with leukocytosis died from cerebral
hemorrhage with a low platelet count and low fibrinogen. Interestingly,
Niu et al alluded to leukocytosis as possibly being causative in the treatment failure and death of one patient treated with arsenic trioxide with newly diagnosed APL, but no details were given. Camacho
et al3 presented data on 26 patients with relapsed or
refractory APL treated with arsenic trioxide. They observed a 58%
incidence of leukocytosis with no associated deaths. Leukocytosis with
a WBC count as high as 260 × 103/µL resolved in all
cases without administration of cytotoxic therapy or discontinuation of
the arsenic trioxide (R. P. Warrell, personal communication, 1999). Current protocols and clinical practice do not advocate cessation
of arsenic trioxide in the setting of hyperleukocytosis. Recent reports
indicate that leukocytosis during treatment with arsenic trioxide has
an incidence of 50% to 60%, with the majority of cases resolving
spontaneously. The treatment of ATRA-associated leukocytosis with
chemotherapy is controversial and potentially harmful, and the role of
chemotherapy in arsenic trioxide-associated hyperleukocytosis is
unknown.4 Our case highlights that arsenic trioxide-associated hyperleukocytosis may be associated with central nervous system sequelae and can be fatal. This case is unusual due to
the rapid rise in leukocytosis, which continued during the duration of
the patient's treatment. The WBC count at which a cerebral event
occurred was lower than the peak level of other reported cases in which
there were no sequelae or discontinuation of drug. In conclusion, this
case illustrates the need for a cautionary approach to the management
of hyperleukocytosis associated with the administration of arsenic trioxide.
Todd F. Roberts, Kellie Sprague, David Schenkein, and Kenneth B. Miller
Division of Hematology/Oncology Department of Medicine
Tufts-New England Medical Center Boston, MA
Valerie Relias
Department of Pharmacy Tufts-New England Medical Center
Boston, MA
References
1.
Soignet SL, Maslak P, Wang Z-G, et al.
Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide.
N Engl J Med.
1998;339:1341-1348[Abstract/Free Full Text].
2.
Niu C, Yan H, Yu T, et al.
Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients.
Blood.
1999;94:3315-3325[Abstract/Free Full Text].
3.
Camacho LH, Soignet SL, Heller G, Chanel S, Ho R, Warrell RP.
Leukocytosis and the "Retinoic acid syndrome" during induction treatment of acute promyelocytic leukemia with arsenic trioxide [abstract].
Blood.
1999;94:595a.
4.
Vahdat L, Maslak P, Miller WH, et al.
Early mortality and the retinoic acid syndrome in acute promyelocytic leukemia: impact of leukocytosis, low-dose chemotherapy, PMN/RAR- isoform, and CD13 expression in patients treated with all-trans retinoic acid.
Blood.
1994;84:3843-3849[Abstract/Free Full Text].
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