scholarly journals Pharmacogenetics of the Central Nervous System—Toxicity and Relapse Affecting the CNS in Pediatric Acute Lymphoblastic Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2333
Author(s):  
Judit C. Sági ◽  
András Gézsi ◽  
Bálint Egyed ◽  
Zsuzsanna Jakab ◽  
Noémi Benedek ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Acute Lymphoblastic Leukemia ◽  
Gene Polymorphisms ◽  
Lymphoblastic Leukemia ◽  
Toxic Encephalopathy ◽  
Inverse Association ◽  
Central Nervous System Toxicity ◽  
Cns Relapse ◽  
The Central Nervous System

Despite improving cure rates in childhood acute lymphoblastic leukemia (ALL), therapeutic side effects and relapse are ongoing challenges. These can also affect the central nervous system (CNS). Our aim was to identify germline gene polymorphisms that influence the risk of CNS events. Sixty single nucleotide polymorphisms (SNPs) in 20 genes were genotyped in a Hungarian non-matched ALL cohort of 36 cases with chemotherapy related acute toxic encephalopathy (ATE) and 544 controls. Five significant SNPs were further analyzed in an extended Austrian-Czech-NOPHO cohort (n = 107 cases, n = 211 controls) but none of the associations could be validated. Overall populations including all nations’ matched cohorts for ATE (n = 426) with seizure subgroup (n = 133) and posterior reversible encephalopathy syndrome (PRES, n = 251) were analyzed, as well. We found that patients with ABCB1 rs1045642, rs1128503 or rs2032582 TT genotypes were more prone to have seizures but those with rs1045642 TT developed PRES less frequently. The same SNPs were also examined in relation to ALL relapse on a case-control matched cohort of 320 patients from all groups. Those with rs1128503 CC or rs2032582 GG genotypes showed higher incidence of CNS relapse. Our results suggest that blood-brain-barrier drug transporter gene-polymorphisms might have an inverse association with seizures and CNS relapse.

Case report of neurotoxicity with blinatumomab and concurrent intrathecal chemotherapy in second relapse of acute lymphoblastic leukemia with central nervous system disease

2018 ◽  
Vol 25 (8) ◽  
pp. 2027-2030 ◽  
Author(s):  
Jason Chen ◽  
Dat Ngo ◽  
Joseph Rosenthal
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Case Report ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Central Nervous System Involvement ◽  
Altered Mental Status ◽  
Intrathecal Chemotherapy ◽  
Speech Impairment ◽  
Central Nervous System Toxicity

A 26-year-old male with a history of pre-B cell acute lymphoblastic leukemia and seizures presented with second relapse of acute lymphoblastic leukemia and central nervous system involvement, 19 years after the initial diagnosis. Over the next two months, the patient received six doses of triple intrathecal chemotherapy (cytarabine, methotrexate, and hydrocortisone), three concurrently with continuous blinatumomab in the second month. Approximately 12 days after blinatumomab initiation, he developed central nervous system toxicity manifesting as speech impairment, altered mental status, incontinence, and diffuse weakness. Blinatumomab was discontinued, and he was started on dexamethasone. Within the next couple of months, his neurologic status recovered, and he was able to perform all of his baseline activities without limitation. Unfortunately, the patient eventually expired after further relapse approximately one year later. To our knowledge, this is the first published case report of severe neurotoxicity in a patient who was given blinatumomab concurrently with intrathecal chemotherapy.

Acute reversible toxic encephalopathy during capecitabine and oxaliplatin treatment

2017 ◽  
Vol 25 (2) ◽  
pp. 497-501 ◽  
Author(s):  
João Godinho ◽  
Mafalda Casa-Nova ◽  
Teresa Mesquita ◽  
Maria João Baptista ◽  
Francisco Araújo ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Clinical Findings ◽  
Neurological Dysfunction ◽  
Toxic Encephalopathy ◽  
Central Nervous System Toxicity ◽  
Cerebellar Dysfunction ◽  
Oxaliplatin Treatment ◽  
Tumor Involvement ◽  
The Central Nervous System

Introduction Capecitabine is a fluoropyrimidine commonly used in the treatment of colorectal cancer which may cause central nervous system toxicity, namely cerebellar dysfunction. Case report We describe a 77-year-old man undergoing adjuvant treatment of colon cancer with capecitabine and oxaliplatin who presented with acute cerebellar ataxia and encephalopathy that progressed to coma. Diagnosis of toxic encephalopathy was made after the exclusion of alternative causes of neurological dysfunction and complete resolution of clinical findings with permanent discontinuation of chemotherapy. Discussion When patients with cancer develop symptoms and signs of central nervous dysfunction, metabolic and infectious causes plus tumor involvement of central nervous system must be sought. However, chemotherapy may also cause toxicity to the central nervous system. Capecitabine is no exception, although cerebellar dysfunction is rarely reported. Conclusion Although rare, capecitabine-induced encephalopathy may be severe and physicians should be aware of this possible side effect.

Outcome of the Rotterdam-84 CNS-ALL Chemotherapy Protocol without Radiotherapy for Isolated Central Nervous System Relapsed Acute Lymphoblastic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1955-1955
Author(s):  
Auke Beishuizen ◽  
Femke K. Aarsen ◽  
Jeanette E.W.M. van Dongen ◽  
Isabelle C. Streng ◽  
Rob Pieters ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Lymphoblastic Leukemia ◽  
Total Duration ◽  
Treatment Protocol ◽  
Severe Toxicity ◽  
Visual Spatial ◽  
Cns Relapse

Abstract Introduction Current protocols use radiotherapy (craniospinal irradiation) as the treatment of choice to cure isolated central nervous system (CNS) acute lymphoblastic leukemia (ALL) relapses. The severe toxicity of this treatment encouraged us to develop a new CNS-ALL protocol without radiotherapy. Patients and methods From Jan 1987 till Aug 2004, 13 children were diagnosed in our centre with an isolated CNS relapse after initial treatment according to standard DCOG-ALL protocols. Treatment of CNS relapse consisted of induction by weekly intrathecal Methotrexate (MTX). At remission, an Ommaya reservoir was implanted and CNS-directed intraventricular sandwich therapy, consisting of MTX day 1; ARA-C day 2 and MTX day 3 (dosage according to age) was given every four weeks for one year. At the same time systemic treatment, based on the ALL-6 protocol (JCO1996;14:911–8), was started in which at week 23, 44 and 65 intensification courses of 6 weeks duration with Teniposide, HD-ARA-C and HD-MTX were inserted. The total duration of treatment is 95 weeks. Six of 13 patients could be assessed for behavior, intelligence, memory, visual-spatial and visual-motor skills before and after treatment using the CBCL and WISC-RN tests among others. Results All 13 patients, 3 girls and 10 boys aged 2.3 till 14.8 years (9 precursor B-ALL and 4 T-ALL), had an early isolated CNS relapse after a median first remission duration of 16 months (range 2–30 months). Nine of them were high risk according to BFM relapse criteria (male, age < 6 years, T-ALL phenotype, relapse < 18 months from diagnosis). At present, eight patients are alive in 2nd complete remission (CR) with a median follow up of 82 months (range 7–189 months). Five patients relapsed, all high risk, of which three died. One died after a secondary AML, one after a bone marrow (BM) relapse in 2nd CR due to fungal sepsis and one after a combined BM and CNS relapse due to streptococcal meningitis/encephalitis during neutropenia. The fourth patient had a second CNS relapse after 42 months in second remission. He is still in 3rd CR for 86 months after an autologous BM infusion. The fifth patient had recently an isolated BM relapse after 11 months in 2nd CR and started systemic reinduction therapy. The 5 years EFS of this study is 57% ± 15% and the 5 years OS 73% ± 14%. Before start of chemotherapy no significant differences in psychological testing were found in comparison with the normal population. After stop chemotherapy significant lower scores were obtained on the domains of perceptual organization and behavior similar to those found in other patients treated for cancer. Furthermore, our treatment protocol has no significant effect on neurocognitive functioning in comparison with craniospinal radiotherapy. Conclusion Sandwich intraventricular therapy together with systemic anti-leukemia therapy without radiotherapy seems to be an effective treatment with minimal neurocognitive disfunctioning for isolated CNS-ALL relapse. Further investigations in a larger group of patients are essential with special emphasis on comparing late effects of this therapy with radiotherapy.

Chemokines in Leukemic Infiltration of the Central Nervous System in Childhood Acute Lymphoblastic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1627-1627
Author(s):  
Manuel Ramirez ◽  
Ana M Gomez ◽  
Carolina Martinez ◽  
Alvaro Lassaletta ◽  
Jose L Fuster ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Flow Cytometry ◽  
Nervous System ◽  
Acute Lymphoblastic Leukemia ◽  
Chemokine Receptors ◽  
Lymphoblastic Leukemia ◽  
Cns Disease ◽  
Leukemic Infiltration ◽  
Cns Relapse ◽  
Chemokine Ligands

Abstract Abstract 1627 Poster Board I-653 Background Leukemic blasts from B-cell acute lymphoblastic leukemia (B-ALL) and T-ALL circulate through the blood stream and may infiltrate different organs. Extramedullary organs may act as sanctuaries for lymphoblasts, preventing the exposure to adequate levels of chemotherapeutic drugs. Typical extramedullary relapses are seen in testes and in central nervous system (CNS). We aimed at determining whether chemokines may play a role in the infiltration of the CNS by leukemic blasts in childhood ALL. We studied the expression of chemokine receptors in ALL blasts in marrow, as well as the levels of chemokine ligands in the cerebrospinal fluid (CSF) of children with B- or T-ALL. If chemokines had a role in CNS leukemic infiltration, the following should be confirmed: leukemic blasts should express high levels of the chemokine receptor/s for which high levels of its corresponding ligand/s were detected at the CNS. Methods This prospective study was approved by the local ethical committees for clinical research. Samples from 80 children in 10 Spanish pediatric oncology units were obtained. We detected the presence of leukemic blasts in CFS by flow cytometry. We defined leukemic infiltration of CFS samples as the presence of cells with the same immunophenotype as the leukemia in the marrow aspirates. We detected the expression levels of 9 CCR and 6 CXCR molecules in ALL blasts by flow cytometry in marrow aspirates. Levels of chemokine ligands were quantitated by Cytometric Bead Array or by commercial ELISA kits in CSF samples. Results We found that chemokine receptors expression and levels of chemokine ligands varied depending upon the lineage (T versus B), the maturation state (pre-T versus T; pro-B versus pre-B versus common-B) and the risk-status (high versus non-high) of the leukemia. T-ALL patients with high levels of CNS leukemic infiltration expressed significantly higher levels of CXCL10 compared to the same parameters of T-ALL patients with low/absent levels of CNS disease (p=0,049). Common B-ALL patients with high levels of CNS leukemic infiltration expressed higher levels of CCL22 compared to that of common B-ALL patients with low/absent levels of CNS disease (p=0,059). Among the 4 patients with a CNS relapse, we detected higher levels of CXCR3 (p=0,0038) and of its ligand, CXCL10 (p=0,0169), compared to patients who did not relapse. Conclusions Our study suggests that the CXCR3/CXCL10 axis may be involved in the CNS relapse of high-risk ALL in children: high expression of CXCR3 on marrow blasts plus high levels of CXCL10 in the CNS was associated with leukemic CNS relapse. Disclosures No relevant conflicts of interest to declare.

Central Nervous System Disease in Acute Lymphoblastic Leukemia: Prophylaxis and Treatment

Hematology ◽  
2006 ◽  
Vol 2006 (1) ◽  
pp. 142-146 ◽  
Author(s):  
Ching-Hon Pui
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Treatment Options ◽  
Central Nervous System Disease ◽  
Cranial Irradiation ◽  
Childhood All ◽  
Excellent Outcome ◽  
Cns Relapse

Abstract Improved treatment for acute lymphoblastic leukemia (ALL) has virtually eliminated testicular relapse. However, the control of central nervous system (CNS) leukemia remains a therapeutic challenge in childhood ALL, partly because of the late complications arising from cranial irradiation. In most current pediatric protocols, cranial irradiation (12 to 18 Gy) is given to 5% to 25% of patients—those with T-cell ALL, overt CNS disease (CNS3 status) or high-risk cytogenetics. CNS control is a less urgent concern in adults with ALL, in whom systemic relapse remains the major problem. With current approaches, approximately 2% to 10% of patients can be expected to develop CNS relapse. Children with B-cell precursor ALL who have a late CNS relapse (after an initial remission of 18 months or more) and did not receive cranial irradiation have an excellent outcome after retrieval therapy, with a 5-year event-free survival (EFS) rate approaching that in newly diagnosed patients. Innovative treatment options are needed for children who develop CNS relapses after a short initial remission or after receiving cranial irradiation, and in any adults with CNS leukemia at diagnosis or relapse.

scholarly journals Concurrent hypopituitarism and leukemic retinopathy in a child with B-precursor acute lymphoblastic leukemia and isolated central nervous system relapse

2016 ◽  
Vol 23 (4) ◽  
pp. 431
Author(s):  
K.H. Wu ◽  
H.P. Wu ◽  
H.J. Lin ◽  
C.H. Wang ◽  
H.Y. Chen ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Acute Lymphoblastic Leukemia ◽  
Systemic Chemotherapy ◽  
Lymphoblastic Leukemia ◽  
Intrathecal Therapy ◽  
Central Nervous System Relapse ◽  
Cns Involvement ◽  
Lower Extremity Weakness ◽  
Cns Relapse

Hypopituitarism in leukemia is very rare. In addition, central nervous system (cns) relapse and leukemic retinopathy in childhood acute lymphoblastic leukemia (all) have declined with the use of modern systemic chemotherapy that includes cns prophylaxis. Here, we report the case of a 4-year-old girl who received chemotherapy and intrathecal therapy without cns radiation after a diagnosis of B-precursor all without cns involvement. Three months after chemotherapy completion, she presented with lower-extremity weakness and was diagnosed with an isolated cns relapse. Concurrent hypopituitarism and leukemic retinopathy were also found. After receiving craniospinal radiotherapy and systemic chemotherapy, her retinopathy and vision improved. She is now in complete remission, and she is still on chemotherapy according to the guideline from the Pediatric Oncology Group. Although rare, hypopituitarism and leukemic retinopathy should be taken into consideration in patients with cns involvement by leukemia.

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