ABSTRACT
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/µL, 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 characteristic tear-drop pattern for CD45/side scatter plot on flow cytometry, a full compatible immunophenotype and cytomorphology in the cerebrospinal fluid. The case illustrates the value of the latter and the importance of including CD56 in risk assessment of APL.
Subject(s)
Biomarkers, Tumor/immunology , Central Nervous System/immunology , Disseminated Intravascular Coagulation/diagnosis , Granulocyte Precursor Cells/immunology , Leukemia, Promyelocytic, Acute/diagnosis , Leukocyte Common Antigens/immunology , Adolescent , Bone Marrow/immunology , Bone Marrow/pathology , Central Nervous System/pathology , Disseminated Intravascular Coagulation/cerebrospinal fluid , Disseminated Intravascular Coagulation/immunology , Disseminated Intravascular Coagulation/pathology , Fatal Outcome , Flow Cytometry , Granulocyte Precursor Cells/pathology , Humans , Immunophenotyping , Leukemia, Promyelocytic, Acute/cerebrospinal fluid , Leukemia, Promyelocytic, Acute/immunology , Leukemia, Promyelocytic, Acute/pathology , Male , RecurrenceSubject(s)
Arsenicals/administration & dosage , Central Nervous System Neoplasms/drug therapy , Leukemia, Promyelocytic, Acute/drug therapy , Mannitol/administration & dosage , Oxides/administration & dosage , Adolescent , Adult , Arsenic Trioxide , Arsenicals/cerebrospinal fluid , Blood-Brain Barrier/drug effects , Central Nervous System Neoplasms/cerebrospinal fluid , Child , Female , Humans , Induction Chemotherapy , Leukemia, Promyelocytic, Acute/cerebrospinal fluid , Male , Middle Aged , Oxides/cerebrospinal fluid , Recurrence , Remission Induction , Young AdultABSTRACT
Extramedullary relapse is an uncommon complication of acute promyelocytic leukaemia (APL). The most common site of extramedullary relapse is the central nervous system (CNS), and the majority of CNS relapses occur in patients with high-risk disease in which white blood cell count at presentation is greater than 10×10(3)/µL. The best management of such patients is still controversial. We describe a 47-year-old man with APL who developed two CNS relapses which were diagnosed through the presence of t(15;17)(q22;q21) on PCR of the cerebrospinal fluid (CSF), despite presenting initially with intermediate-risk disease. We conclude that the intermediate risk group is very heterogeneous and these patients sometimes may behave like high-risk patients. Also, clinicians should take into account symptoms that can be related to CNS relapse in patients with APL and consider lumbar puncture even if radiological imaging does not reveal anything.
Subject(s)
Central Nervous System Neoplasms/pathology , Leukemia, Promyelocytic, Acute/pathology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Central Nervous System Neoplasms/cerebrospinal fluid , Central Nervous System Neoplasms/drug therapy , Central Nervous System Neoplasms/genetics , Chromosomes, Human, Pair 15 , Chromosomes, Human, Pair 17 , Fatal Outcome , Humans , Leukemia, Promyelocytic, Acute/cerebrospinal fluid , Leukemia, Promyelocytic, Acute/drug therapy , Leukemia, Promyelocytic, Acute/genetics , Magnetic Resonance Imaging , Male , Middle Aged , Polymerase Chain Reaction , Recurrence , Risk Factors , Translocation, GeneticABSTRACT
Cerebrospinal fluid-acute leukemia (CSF-acute leukemia) is a frequent and serious complication in patients with acute leukemia. One of the major problems of this complication is the diagnosis process itself. CSF cytology is currently considered the gold standard for establishing the diagnosis, a technique which presents various processing limitations, seriously impacting the predictive values. In the last 11 years, studies of CSF flow cytometry analysis done in patients with acute leukemia have demonstrated superiority in comparison with CSF cytology. Although comparative studies between these two techniques have been reported since 2001, no new consensus or formal changes to the gold standard have been established for the CSF acute leukemia diagnosis. The evidence suggests that positive flow cytometry cases, considered as indeterminate cases, will behave like disease in the central nervous system (CNS). Nevertheless, we think there are some variables and considerations that must be first evaluated under research protocols before CNS relapse can be established with only one positive flow cytometry analysis in the setting of indeterminate CSF samples. This paper proposes a diagnostic algorithm and complementary strategies.
Subject(s)
Central Nervous System Neoplasms/cerebrospinal fluid , Leukemia/cerebrospinal fluid , Acute Disease , Central Nervous System Neoplasms/diagnosis , Flow Cytometry , Humans , Leukemia/diagnosis , Leukemia, Myeloid, Acute/cerebrospinal fluid , Leukemia, Promyelocytic, Acute/cerebrospinal fluid , Magnetic Resonance Imaging , Neoplasm Proteins/cerebrospinal fluidABSTRACT
Central nervous system (CNS) involvement in acute promyelocytic leukemia (APL) is rare and tends to be seen mostly following treatment with all-trans retinoic acid (ATRA), due to prolonged patient survival and poor penetration of the drug in the CNS. At least 10% of extramedullary relapses in APL involve the CNS, and associated factors include an increased age, the BCR isoform, the development of differentiation syndrome, a high white cell count at presentation and hemorrhage into the CNS during induction therapy. We present the case of a patient with high-risk APL, CD56+, CD2+ in whom a CNS relapse was diagnosed through the presence of a PML/RARα rearrangement on PCR of the cerebrospinal fluid (CSF).
Subject(s)
Central Nervous System Neoplasms/diagnosis , Leukemia, Promyelocytic, Acute/diagnosis , Oncogene Proteins, Fusion/cerebrospinal fluid , Adult , Antineoplastic Agents/therapeutic use , CD56 Antigen/genetics , CD56 Antigen/metabolism , Central Nervous System Neoplasms/cerebrospinal fluid , Central Nervous System Neoplasms/drug therapy , Fatal Outcome , Humans , Leukemia, Promyelocytic, Acute/cerebrospinal fluid , Leukemia, Promyelocytic, Acute/drug therapy , Male , Neoplasm Recurrence, Local/cerebrospinal fluid , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Oncogene Proteins, Fusion/genetics , Polymerase Chain Reaction , Tretinoin , fms-Like Tyrosine Kinase 3/genetics , fms-Like Tyrosine Kinase 3/metabolismSubject(s)
Biomarkers, Tumor/analysis , Cell Nucleus Shape , Cell Nucleus/pathology , Leukemia, Promyelocytic, Acute/cerebrospinal fluid , Azure Stains , Cytodiagnosis/methods , Cytoplasmic Granules/pathology , Granulocyte Precursor Cells/pathology , Humans , Leukemia, Promyelocytic, Acute/diagnosis , Male , Middle Aged , Receptors, Retinoic Acid/analysis , Recurrence , Retinoic Acid Receptor alpha , Sialic Acid Binding Ig-like Lectin 3/analysisABSTRACT
Central nervous system (CNS) involvement in acute promyelocytic leukemia (APL) is rare, and the presence of CNS symptoms at the time of diagnosis of APL is even rarer. We report 2 cases of APL presenting with CNS involvement. A 43-yr-old woman presented with easy bruising and stuporous mentality. Her complete blood count (CBC) revealed leukocytosis with increased blasts. Bone marrow (BM) analysis was carried out, and the diagnosis of APL was confirmed. This was done by cytogenetic analysis and demonstration of PML-RARα rearrangement by reverse transcriptase PCR in the BM cells. A lumbar puncture was performed to investigate the cause of her stuporous mentality, and her cerebrospinal fluid (CSF) analysis revealed 97% leukemic promyelocytes. Despite systemic and CNS therapy, she died due to septic shock by infection and rapid disease progression only 3 days after her admission. Another patient, a 3-yr-old girl, presented with easy bruising and epistaxis, and her CBC showed pancytopenia with increased blasts. BM studies confirmed APL. Quantitative PCR for PML-RARα in the BM cells revealed a PML-RARα/ABL ratio of 0.33 and CSF analysis revealed 9.5% leukemic promyelocytes (2 of 21 cells). She received induction chemotherapy and intrathecal therapy and achieved complete remission (CR) in the BM and CNS. She has been maintained in the CR status for the past 31 months. Thus, patients with APL must be evaluated for CNS involvement if any neurological symptoms are present at the time of diagnosis.
Subject(s)
Leukemia, Promyelocytic, Acute/cerebrospinal fluid , Adult , Antineoplastic Agents/therapeutic use , Bone Marrow Cells/metabolism , Bone Marrow Cells/pathology , Central Nervous System/pathology , Child, Preschool , Contusions/etiology , Epistaxis/etiology , Female , Granulocyte Precursor Cells/pathology , Humans , Karyotyping , Leukemia, Promyelocytic, Acute/drug therapy , Leukemia, Promyelocytic, Acute/pathology , Oncogene Proteins, Fusion/analysis , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Spinal Puncture , Tomography, X-Ray Computed , Tretinoin/therapeutic useSubject(s)
Antineoplastic Agents/therapeutic use , Arsenicals/therapeutic use , Central Nervous System Neoplasms/drug therapy , Central Nervous System/pathology , Leukemia, Promyelocytic, Acute/drug therapy , Leukemic Infiltration/pathology , Meningeal Neoplasms/drug therapy , Oxides/therapeutic use , Adult , Arsenic Trioxide , Female , Humans , Leukemia, Promyelocytic, Acute/cerebrospinal fluid , Recurrence , Treatment OutcomeABSTRACT
Central nervous system (CNS) involvement in acute promyelocytic leukemia (APL) is rare, and the presence of CNS symptoms at the time of diagnosis of APL is even rarer. We report 2 cases of APL presenting with CNS involvement. A 43-yr-old woman presented with easy bruising and stuporous mentality. Her complete blood count (CBC) revealed leukocytosis with increased blasts. Bone marrow (BM) analysis was carried out, and the diagnosis of APL was confirmed. This was done by cytogenetic analysis and demonstration of PML-RARalpha rearrangement by reverse transcriptase PCR in the BM cells. A lumbar puncture was performed to investigate the cause of her stuporous mentality, and her cerebrospinal fluid (CSF) analysis revealed 97% leukemic promyelocytes. Despite systemic and CNS therapy, she died due to septic shock by infection and rapid disease progression only 3 days after her admission. Another patient, a 3-yr-old girl, presented with easy bruising and epistaxis, and her CBC showed pancytopenia with increased blasts. BM studies confirmed APL. Quantitative PCR for PML-RARalpha in the BM cells revealed a PML-RARalpha/ABL ratio of 0.33 and CSF analysis revealed 9.5% leukemic promyelocytes (2 of 21 cells). She received induction chemotherapy and intrathecal therapy and achieved complete remission (CR) in the BM and CNS. She has been maintained in the CR status for the past 31 months. Thus, patients with APL must be evaluated for CNS involvement if any neurological symptoms are present at the time of diagnosis.
Subject(s)
Adult , Child, Preschool , Female , Humans , Antineoplastic Agents/therapeutic use , Bone Marrow Cells/metabolism , Central Nervous System/pathology , Contusions/etiology , Epistaxis/etiology , Granulocyte Precursor Cells/pathology , Karyotyping , Leukemia, Promyelocytic, Acute/cerebrospinal fluid , Oncogene Proteins, Fusion/analysis , Reverse Transcriptase Polymerase Chain Reaction , Spinal Puncture , Tomography, X-Ray Computed , Tretinoin/therapeutic useABSTRACT
We assessed concentrations of arsenic trioxide (As(2)O(3)) and its metabolites in the plasma and cerebrospinal fluid in acute promyelocytic leukemia patients who achieved complete remission with intravenous As(2)O(3). Arsenic trioxide exists as high molecular mass proteins and low molecular mass proteins in the plasma, and metabolites seem to be able to penetrate blood-brain barrier. Methylarsonic acid (MA) in the cerebrospinal fluid is stably detected and its level was higher than that in plasma after As(2)O(3) treatment. Trivalent arsenic (AS(III)) and dimethylarsinic acid (DMA) became detectable after As(2)O(3) infusion, though the levels of arsenic metabolites in the cerebrospinal fluid was lower than plasma levels. Results suggest that a combinatory treatment of As(2)O(3) with other chemotherapeutics could be effective for APL patients with CNS involvement.
Subject(s)
Antineoplastic Agents/cerebrospinal fluid , Arsenicals/cerebrospinal fluid , Leukemia, Promyelocytic, Acute/cerebrospinal fluid , Oxides/cerebrospinal fluid , Adult , Antineoplastic Agents/blood , Antineoplastic Agents/therapeutic use , Arsenic Trioxide , Arsenicals/blood , Arsenicals/therapeutic use , Chromatography, High Pressure Liquid , Female , Humans , Leukemia, Promyelocytic, Acute/blood , Leukemia, Promyelocytic, Acute/drug therapy , Male , Middle Aged , Oxides/blood , Oxides/therapeutic useABSTRACT
The extent of and factors controlling arsenic penetration into the central nervous system (CNS) remain unclear. Elemental arsenic levels in 67 paired cerebrospinal fluid (CSF) and plasma samples from 9 patients with acute promyelocytic leukemia (APL) on oral arsenic trioxide (As2O3), obtained during intrathecal chemotherapy (treatment of CNS APL, n = 6; prophylaxis, n = 3) were measured. Median arsenic levels of CSF and plasma were 95.8 nmol/L (range, 3.5-318.9 nmol/L) and 498.9 nmol/L (range, 36.3-1892.8 nmol/L). As a group, CSF and plasma arsenic was linearly correlated (P < .001), with CSF at 17.7% the plasma level. The CSF/plasma arsenic ratio, which reflected the arsenic CSF penetration efficiency, varied significantly in individual patients (P < .001). Repeated intrathecal chemotherapy and presence of blasts in CSF did not affect the CSF/plasma arsenic ratio. Plasma arsenic was the only significant determinant of CSF arsenic levels. CSF arsenic was present at therapeutically meaningful levels, implying that As2O3 therapy might be beneficial in CNS APL.
Subject(s)
Antineoplastic Agents/therapeutic use , Arsenic/cerebrospinal fluid , Arsenicals/therapeutic use , Leukemia, Promyelocytic, Acute/cerebrospinal fluid , Leukemia, Promyelocytic, Acute/drug therapy , Oxides/therapeutic use , Administration, Oral , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Arsenic/blood , Arsenic Trioxide , Arsenicals/administration & dosage , Arsenicals/pharmacokinetics , Cytarabine/administration & dosage , Female , Humans , Injections, Spinal , Leukemia, Promyelocytic, Acute/blood , Male , Methotrexate/administration & dosage , Middle Aged , Oxides/administration & dosage , Oxides/pharmacokinetics , RecurrenceABSTRACT
In this report, we present images from a patient with acute promyelocytic leukemia who experienced several central nervous system relapses.
Subject(s)
Cell Nucleus/pathology , Central Nervous System Neoplasms/pathology , Leukemia, Promyelocytic, Acute/pathology , Adult , Antineoplastic Combined Chemotherapy Protocols , Central Nervous System Neoplasms/cerebrospinal fluid , Central Nervous System Neoplasms/drug therapy , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/secondary , Female , Humans , Idarubicin , Leukemia, Promyelocytic, Acute/cerebrospinal fluid , Leukemia, Promyelocytic, Acute/drug therapy , Leukemia, Promyelocytic, Acute/genetics , Oncogene Proteins, Fusion/cerebrospinal fluid , Oncogene Proteins, Fusion/genetics , RNA, Neoplasm/cerebrospinal fluid , RNA, Neoplasm/genetics , Recurrence , Remission Induction , TretinoinSubject(s)
Antineoplastic Agents/cerebrospinal fluid , Arsenicals/cerebrospinal fluid , Leukemia, Promyelocytic, Acute/drug therapy , Mannitol/metabolism , Meningeal Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapy , Oxides/cerebrospinal fluid , Adult , Antineoplastic Agents/therapeutic use , Apoptosis , Arsenic Trioxide , Arsenicals/therapeutic use , Female , Humans , Injections, Intravenous , Leukemia, Promyelocytic, Acute/cerebrospinal fluid , Leukemia, Promyelocytic, Acute/pathology , Magnetic Resonance Imaging , Meningeal Neoplasms/cerebrospinal fluid , Meningeal Neoplasms/pathology , Neoplasm Recurrence, Local/pathology , Oxides/therapeutic use , Remission InductionABSTRACT
We report on a 42-year-old patient whose relapse of acute promyelocytic leukaemia (APL) included meningeal infiltration. Since he had previously experienced ATRA syndrome, he received arsenic trioxide (ATO) plus intrathecal therapy with cytarabine, prednisone, and methotrexate. We measured the concentration of arsenic in his cerebrospinal fluid (CSF). Arsenic showed a peak CSF concentration of 0.008 mg/l (0.11 micromol/l) and a nadir of 0.002 mg/l (0.027 micromol/l), both representing about 14% of blood levels. ATO thus crosses the blood-CSF-barrier when administered intravenously, but the concentration in CSF is probably not sufficient for treatment of meningeal leukemia.
Subject(s)
Antineoplastic Agents/therapeutic use , Arsenic/cerebrospinal fluid , Arsenicals/therapeutic use , Leukemia, Promyelocytic, Acute/drug therapy , Oxides/therapeutic use , Adult , Antineoplastic Agents/pharmacokinetics , Arsenic Trioxide , Arsenicals/pharmacokinetics , Humans , Leukemia, Promyelocytic, Acute/cerebrospinal fluid , Leukemia, Promyelocytic, Acute/genetics , Male , Oxides/pharmacokineticsABSTRACT
Although new approaches have dramatically improved, the treatment of acute promyelocytic leukemia (APL) involvement of the central nervous system (CNS) confers a bad prognosis in the disease. Here, we report a patient who was diagnosed with relapsed APL preferentially involving the CNS. Treatment with arsenic trioxide led to impressive morphological changes in CNS cellularity consistent with the induction of a differentiation syndrome. Since arsenic trioxide could be identified in the CNS, we provide evidence that the drug can cross the blood-brain barrier and can be used for treatment of extramedullary APL.
Subject(s)
Antineoplastic Agents/therapeutic use , Arsenicals/therapeutic use , Brain Neoplasms/drug therapy , Leukemia, Promyelocytic, Acute/drug therapy , Oxides/therapeutic use , Adult , Arsenic Trioxide , Brain Neoplasms/cerebrospinal fluid , Cell Differentiation , Cerebrospinal Fluid/cytology , Female , Humans , Leukemia, Promyelocytic, Acute/cerebrospinal fluid , Leukocytes/pathology , Remission Induction , Treatment OutcomeSubject(s)
Arsenic/cerebrospinal fluid , Arsenicals/therapeutic use , Leukemia, Promyelocytic, Acute/cerebrospinal fluid , Leukemia, Promyelocytic, Acute/drug therapy , Meningeal Neoplasms/secondary , Oxides/therapeutic use , Administration, Oral , Antineoplastic Agents/therapeutic use , Arsenic/blood , Arsenic Trioxide , Arsenicals/administration & dosage , Arsenicals/pharmacokinetics , Humans , Leukemia, Promyelocytic, Acute/blood , Male , Meningeal Neoplasms/blood , Meningeal Neoplasms/cerebrospinal fluid , Meningeal Neoplasms/drug therapy , Middle Aged , Oxides/administration & dosage , Oxides/pharmacokinetics , RecurrenceSubject(s)
Leukemia, Promyelocytic, Acute/cerebrospinal fluid , Leukemia, Promyelocytic, Acute/diagnostic imaging , Magnetic Resonance Imaging , Subarachnoid Hemorrhage/diagnosis , Tomography, X-Ray Computed , Diagnosis, Differential , Humans , Leukemia, Promyelocytic, Acute/pathology , Male , Middle Aged , Recurrence , Remission Induction , VentriculostomyABSTRACT
The involvement of central nervous system is rare in acute promyelocytic leukemia (APL). We report a APL patient of a 41 yr-old Korean male who presented with fever and petechia. Complete molecular remission was achieved with all-trans retinoic acid (ATRA), idarubicin, and cytarabine. Ten months later, he complained of a mild headache. The results of the physical examination and the complete blood counts were normal. The examination of cerebrospinal fluid showed the presence of promyelocyte. Bone marrow studies showed cytogenetic remission but with molecular relapse. He was treated with intrathecal and systemic chemotherapy.
Subject(s)
Leukemia, Promyelocytic, Acute/cerebrospinal fluid , Leukemia, Promyelocytic, Acute/diagnosis , Adult , Granulocyte Precursor Cells , Humans , Male , Meninges , RecurrenceABSTRACT
The involvement of central nervous system is rare in acute promyelocytic leukemia (APL). We report a APL patient of a 41 yr-old Korean male who presented with fever and petechia. Complete molecular remission was achieved with all-trans retinoic acid (ATRA), idarubicin, and cytarabine. Ten months later, he complained of a mild headache. The results of the physical examination and the complete blood counts were normal. The examination of cerebrospinal fluid showed the presence of promyelocyte. Bone marrow studies showed cytogenetic remission but with molecular relapse. He was treated with intrathecal and systemic chemotherapy.
Subject(s)
Adult , Humans , Male , Granulocyte Precursor Cells , Leukemia, Promyelocytic, Acute/cerebrospinal fluid , Meninges , RecurrenceABSTRACT
Extramedullary relapse occurs infrequently in acute promyelocytic leukaemia (APL) but has been increasingly reported after the advent of all-trans retinoic acid (ATRA) treatment, probably as a consequence of improved patient survival. We describe our single centre experience of six APL patients who had disease localization in the central nervous system (CNS). In three patients, clinical symptoms (headache and/or nausea) that presented during follow-up led to the performance of a lumbar puncture and detection of overt CNS infiltration. Two of these patients had simultaneous haematological relapse and one was in molecular remission when CNS leukaemia was documented. One patient with no local symptoms showed CNS infiltration at the time of molecular relapse. Following the introduction of routine lumbar puncture, carried out after front-line induction in all newly diagnosed patients with white blood cell count (WBC) greater than 10 x 109/l, two additional patients in molecular remission with no local symptoms were found to have initial APL localization in the CNS. Presenting features included in 6/6 patients an elevated WBC count (> 10 x 109/l) and a predominance of the PML/RAR bcr3 type (5/6 patients) and of microgranular morphology (5/6 patients). Our findings highlight the importance of carrying out lumbar puncture in APL patients presenting with high-risk features.