Central nervous system relapse in a patient with acute promyelocytic leukaemia: does the risk stratification matter?

Arsenic trioxide and mannitol for the treatment of acute promyelocytic leukemia relapse in the central nervous system Approximately 3% to 5% of patients with acute promyelocytic leukemia (APL) will have an extramedullary relapse in their lifetimes, most commonly in the central nervous system (CNS).1 CNS relapse can be isolated or associated with a bone marrow (BM) relapse. The most appropriate clinical management remains controversial. 2 The major obstacle to all treatments is the need for the therapeutic drugs to penetrate the blood-brain barrier (BBB). Although arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are among the frontline medications for APL intramarrow treatment, these water-soluble medicines have limited ability to cross the BBB and cannot reach therapeutically effective levels in the cerbrospinal fluid (CSF). With regular oral doses, the ATO level in CSF has been reported to reach only 17.7% of the corresponding levels in plasma. 3 Previously, we investigated the potential efficacy of combination therapy with mannitol and ATO using a rabbit model, and we showed that the approach caused a transient increase in the BBB permeability for ATO, thereby increasing the ATO concentration in CSF. 4 Our experiments using human cortical neurons revealed a differential tolerance of APL blasts to different concentrations of ATO. 5,6 We also identified a safe range of ATO concentrations in the human CNS. 7,8The results from these collective studies allowed an ATO concentration in CSF that was both safe and therapeutic to be achieved. Here, we describe our efforts to extend the application of our method to additional patients. This study was registered at www.isrctn.org (#ISRCTN94954912). The study protocol was reviewed and approved by the Harbin Medical University Medical Ethics Committee, and signed informed consent was obtained from all patients or their legal guardians. Seventeen CNS APL patients diagnosed between 2000 and 2010 were included in this study (10 males and 7 females, between 6 and 50 years old). Expression of the PML/RARa gene [or t(15;17)(q22;q21) transcripts] was detected in all patient CSF. For all patients, the induction treatment was started immediately on diagnosis. The daily protocol was as follows: a bolus infusion of 125 mL of 20% mannitol mixed in 100 mL normal saline (NS) (for children #15 years old: 50 mL mannitol and 50 mL NS) was administered intravenously at a flow rate of 12 ;20 mL/min (;8-11 minutes total), followed by a slow intravenous infusion of 125 mL of 20% mannitol plus 7.0 mg/m 2 /day ATO (for children #15 years: 50 mL mannitol and 0.16 mg/kg/day ATO) in 500 mL NS at a flow rate of 1.0 mL/min (;9-10.5 hours total). Patients were instructed to rest in bed during the entire procedure. Urine flow was measured to ensure maintenance of a rate of at least 30 to 50 mL/h. Daily infusions were continued until the patient's CSF was found to be free of APL blasts/ promyelocytes. The level of elemental arsenic metabolites was measured in each patient's CSF and blood s...

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“…1 The rates of second primary malignancies (SPMs) in childhood ALL are significantly higher than in the general population.…”

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confidence: 99%

Arsenic trioxide and mannitol for the treatment of acute promyelocytic leukemia relapse in the central nervous system

Wang

Cao

et al. 2014

Blood

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“…This could be related to the poor‐prognosis biology of CD56+ APL blasts, the only poor‐risk factor in this case. Although CNS relapse has been described in high and intermediate relapse risk cases (based on TLC and platelet count) to our knowledge this is the first case report of isolated CNS relapse in an otherwise low‐risk patient who was CD56 positive.…”

Section: Discussionmentioning

confidence: 76%

“Tear drops” in the cerebrospinal fluid: Correct by scatter, but pathognomonic by site

et al. 2014

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Extramedullary relapse in acute promyelocytic leukemia (APL) is rare, but occurs most commonly in central nervous system (CNS), generally in high-risk cases (total leucocyte count 10,000/mL, atypical morphology or disseminated intravascular coagulation at presentation), and concomitant with bone marrow (BM) relapse. Here, we describe a case of APL who except for CD56 positivity was low risk but had a CNS relapse without concomitant BM involvement. Diagnosis of isolated CNS relapse was based on char- Acute promyelocytic leukemia (APL) is a unique type of acute myeloid leukemia characterized by distinct cytomorphological features, molecular rearrangement [t(15;17) involving the promyelocytic leukemia (PML) and retinoic acid receptor alpha (RARa) genes] and a very good response to all-trans retinoic acid (ATRA) (1).Extramedullary relapse occurs in 3-5% of cases, generally in the central nervous system (CNS) (2,3). This is almost always associated with bone marrow (BM) relapse and carries a poor prognosis. Its associated highrisk factors are imprecisely defined and include total leucocyte count (TLC) 10,000/mL, platelet count 40,000/mL, atypical morphology, presence of FLT3-ITD mutation, presence of bcr3 PML-RARa breakpoint fusion oncogene, and disseminated intravascular coagulation (DIC) at presentation (2,4-6).Here, we describe a case of APL who had an isolated CNS relapse during remission and apart from positivity for CD56 had only low relapse risk factors. The case was of interest also because the characteristic CD45/side scatter (SS) immunophenotypic pattern of APL on flow cytometric analysis of the cerebrospinal fluid (CSF) was retained, and helped confirm the diagnosis rapidly. CASE REPORTAn 18-year-old male presented at our center with high-grade fever, nausea, and delirium for 1 month. Baseline laboratory investigations showed TLC of 8,500/mL with 48% abnormal promyelocytes with normal haemoglobin and platelet counts. On flow cytometry, abnormal promyelocytes formed a single major cluster with a wide range of SS producing a characteristic tear-drop pattern on CD45 versus SS and were positive for cytoplasmic MPO, CD117, CD13, CD33, CD9, CD64, and CD15. CD56 showed dim positivity. These cells were negative for CD34, CD2, CD11b, CD18, CD14, CD38, CD4, and HLA-DR. Reverse transcription polymerase chain reaction (RT-PCR) was positive for PML-RARa. On cytomorphological examination, CSF was acellular, flow

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“…However, with the increasing number of patients exhibiting disease-free-survival, some patients with late relapse have been observed in clinical practice [18], particularly those with CNS relapse; the majority of these patients have FLT3-ITD gene mutations or other high-risk factors, including cerebral hemorrhage, hyperleukocytosis syndrome in the induction period, a high expression of adhesion molecules (CD56) induced by ATRA treatment, and the bcr3 subtype of the PML/Rara fusion gene [19][20][21]. However, compared with the number of patients with APL exhibiting CR and long-term survival, the number of patients experiencing relapse is almost negligible.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, previous studies have reported that arsenic can penetrate the blood-brain-barrier on its own [25,26], although at a very low concentration [20]; the ratio of CSF/ plasma arsenic concentration has been shown to be 10-20%, with substantial diferences observed among individuals [27]. Some researchers have reported high concentrations of arsenic and diferentiation-syndrome-like phenomena in the CSF of patients, particularly in those with a history of irradiation treatment [28,29].…”

Section: Discussionmentioning

confidence: 99%

Treatment of a Patient with Acute Promyelocytic Leukemia with Multiple Isolated Relapses in the Central Nervous System: A Case Report and Mini-Review of the Literature

Sun,

Chen,

Wang

et al. 2024

Case Reports in Hematology

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The efficacy of therapeutics for acute promyelocytic leukemia (APL) has exhibited an increase in recent years. Only a few patients experience relapse, including extramedullary relapse, and in patients with extramedullary relapse, the central nervous system (CNS) is the most common site. To date, there is no expert consensus or clinical guidelines available for CNS relapse, at least to the best of our knowledge. The optimal therapeutic strategy and management options for these patients remain unclear. The present study reports the treatment of a patient with APL with multiple isolated relapses in the CNS. In addition, through a mini-review of the literature, the present study provides a summary of various reports of this disease and discusses possible treatment options for these patients.

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Central nervous system relapse in a patient with acute promyelocytic leukaemia: does the risk stratification matter?

Cited by 4 publications

References 17 publications

Arsenic trioxide and mannitol for the treatment of acute promyelocytic leukemia relapse in the central nervous system

Arsenic trioxide and mannitol for the treatment of acute promyelocytic leukemia relapse in the central nervous system

“Tear drops” in the cerebrospinal fluid: Correct by scatter, but pathognomonic by site

Treatment of a Patient with Acute Promyelocytic Leukemia with Multiple Isolated Relapses in the Central Nervous System: A Case Report and Mini-Review of the Literature

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