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.

Mitoxantrone Improves the Outcome of Children with Central Nervous System (CNS) Involvement at First Relapse of Acute Lymphoblastic Leukemia (ALL)-Results of the International ALLR3 Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3303-3303
Author(s):  
Ashish Narayan Masurekar ◽  
Catriona Anne Parker ◽  
Satarupa Choudhuri ◽  
Carly Leighton ◽  
Jeremy Hancock ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Bone Marrow ◽  
Nervous System ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Cns Involvement ◽  
Cns Disease ◽  
Off Label ◽  
Cns Relapse ◽  
Time To Relapse

Abstract Abstract 3303 Introduction: Despite improvement in frontline therapy in childhood acute lymphoblastic leukemia (ALL), central nervous system (CNS) relapse remains a significant clinical problem. The ALLR3 trial (ISCRTN 45724312) was designed specifically to address this issue with the use of drugs known to penetrate the CNS. The trial incorporated a randomization between Mitoxantrone and Idarubicin during induction. Mitoxantrone showed an early benefit in all patients resulting in closure of the randomization in December 2007 (ASH Annual Meeting Abstracts, Nov 2009; 114:3390). Subsequently all patients now receive Mitoxantrone. Here we report on the outcome of patients with isolated CNS relapse (iCNSr) or combined CNS relapse (involvement of CNS and bone marrow, cCNSr). Methods: CNS involvement was defined as ≥5 WBC/μl with morphological evidence of blasts in the cerebrospinal fluid (CSF). Combined relapse (cCNSr) was defined as CNS disease with ≥ 5% blasts in the bone marrow. Time to relapse was classified as, Very Early: within 18 months of first diagnosis; Early: after 18 months of first diagnosis but within 6 months of stopping therapy and Late: more than 6 months after stopping therapy. All patients received 3 blocks of chemotherapy. Subsequently, allogenic stem cell transplant (allo-SCT) was offered to all very early relapses (iCNSr & cCNSr), early iCNSr (irrespective of immunophenotype), all T-cell cCNSr (irrespective of time to relapse) and early or late pre-B cCNSr that had a minimal residual disease level of ≥ 104 at the end of induction. All other patients were offered chemotherapy and cranial radiotherapy. Results: Of a total of 330 relapsed patients, 102 (31%) had CNS involvement. Of these 63 (62%) had iCNSr and 39 (38%) had cCNSr. The incidence of CNS disease was higher in males (M:F, CNS relapses 2.5:1 vs all relapses 1.5:1). CNS relapses had a higher proportion of T-cell disease (pre B:T CNS relapses 3.6:1 vs all relapses 7.8:1]. The number of patients presenting in very early, early and late phases were 19 (19%), 55 (54%) and 28 (27%) respectively. All late iCNSr patients were males. Almost all late relapses (iCNSr and cCNSr) (27/28) were of a pre B phenotype. At the end of induction phase, 91/102 (89%) achieved complete remission (CR) and 82/102 (80%) remained in CR after 3 blocks of chemotherapy. The estimated 3-year overall survival (OS) and progression free survival (PFS) for all patients with CNS disease was 45.5% (95%CI 32.9, 58.0) & 43.4% (95%CI 32.0, 54.7) respectively. There were no significant differences in survival with respect to site of the disease (combined vs isolated), gender or immunophenotype (pre B vs T). As shown in Table 1, CNS relapse patients who received Mitoxantrone had a significantly improved outcome when compared to those who received Idarubicin. This was most evident in those who had i) iCNSr, ii) pre-B phenotype and iii) allo-SCT, when analyzed on an intention to treat basis. This represents a considerable improvement in outcome compared to the results obtained in these sub-groups of patients in the previous UK ALLR2 study (Roy A et.al. Br. J. Haem. 2005;130:67-75). Conclusion: Mitoxantrone is highly effective in children with relapsed pre B ALL who have CNS involvement. As there were no other differences between patients treated on Mitoxantrone or Idarubicin, effective systemic therapy is as important as CNS directed therapy, if not more, in treating patients with CNS relapse. Disclosures: Off Label Use: Most drugs used in this protocol are off label as the majority of drugs used in childhood ALL are not liscensed for use in children.

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.

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.

Central Nervous System Involvement in Adult Acute Lymphoblastic Leukemia (ALL) at Diagnosis and/or at First Relapse: Results from the GET-LALA Group.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4326-4326
Author(s):  
Oumedaly Reman ◽  
Arnaud Pigneux ◽  
Francoise Huguet ◽  
Norbert Vey ◽  
Andre Delannoy ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Lymphoblastic Leukemia ◽  
Central Nervous System Involvement ◽  
Unrelated Donor ◽  
Cns Involvement ◽  
Cns Disease ◽  
Cns Relapse ◽  
First Relapse ◽  
B Lineage

Abstract Outcome of adult ALL with central nervous system (CNS) involvement is not clearly defined. We studied 104 patients presenting with CNS involvement at diagnosis among 1493 patients (7%) included into the LALA-87 or LALA-94 trials, and 109 patients (9% of first remitters) presenting CNS disease at the time of first relapse among the 709 relapsing patients (15%) included initially in these trials. Treatment of patients presenting CNS involvement at diagnosis consisted in initial chemotherapy completed by 18 double or triple intrathecal injections associated with 15 to 20 Gy cranial irradiation, followed when possible by intensification by allogeneic or autologous stem cell transplantation (SCT). At diagnosis, 43 patients (41%) presenting with CNS involvement had T-lineage ALL, 53 (51%) had B-lineage ALL (of whom 9 were diagnosed as Philadelphia (Ph) chromosome positive ALL), 8 had undifferentiated ALL or unknown immunophenotype. Eighty-seven of 104 (84%) patients with CNS involvement at diagnosis achieved complete remission (CR). Fifty-three patients underwent SCT (25 allogeneic SCT from matched related or unrelated donor, 28 autologous SCT). Overall survival at 7 years was 34% in those with CNS involvement at diagnosis versus 29% (p = NS) for those without. DFS at 7 years was 35% versus 28% (p = NS). There were no significant differences between patients with CNS involvement and those without CNS involvement regarding T lineage ALL, B lineage ALL (including or not Ph ALL). There were also no significant differences regarding patients who underwent transplantation as consolidation intensification, while in patients receiving only chemotherapy patients without initial CNS involvement had a better outcome (p = 0.01). Among the 709 patients with primary relapse, 66 patients (61%) presented a CNS relapse combined with bone marrow relapse, whereas 17 relapses (15%) and 26 relapses (24%) were CNS relapses combined with another extramedullary relapse or isolated CNS relapses respectively. Median time to relapse was 6.7 months (range, 1–62) in patients with CNS relapse versus 11.2 months (1.7–111) in relapsing patients without CNS involvement. Eleven patients (10%) with CNS relapse had CNS involvement at diagnosis, while 98 patients were diagnosed with CNS disease only at the time of first relapse. Overall, 38 out of 109 patients with CNS relapse (35%) achieved CR. The median OS was 6.3 months. Outcome was similar in terms of CR proportion and OS in relapsing patients without CNS involvement. The 2-year OS rates did not show any difference among patients with CNS relapse who had CNS involvement at diagnosis and those with CNS disease only diagnosed at the time of first relapse.Overall, CNS leukemia in adult ALL is uncommon at diagnosis. Patients have a similar outcome than those who did not present with CNS involvement. However, patients benefit from intensification therapy by autologous or allogeneic SCT. CNS leukemia at first relapse are also uncommon but probably underestimated. Outcome is particularly poor as this of all adult ALL in first relapse.

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.

Clinical Significance of Occult Central Nervous System Disease in Adult ACUTE Lymphoblastic Leukemia. a Multicenter,Report from the Campus ALL/Gimema Network

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 658-658 ◽  
Author(s):  
Maria Ilaria Del Principe ◽  
Elisa Buzzati ◽  
Fabio Forghieri ◽  
Federica Lessi ◽  
Silvia Imbergamo ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Lymphoblastic Leukemia ◽  
Advisory Board ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Cns Disease ◽  
Wbc Count

Abstract Introduction. In a modern context of improved management of acute lymphoblastic leukemia (ALL), central nervous system (CNS) involvement at diagnosis remains an obstacle towards long-term cure. We have previously reported that flow cytometry (FCM) is better than conventional cytology (CC) in demonstrating the presence of leukemic cells in patients' (pts) cerebrospinal fluid (CSF), especially in samples with low cell counts. In the framework of the national Campus ALL program aimed at improving the management of adult ALL patients enrolled in the GIMEMA protocols, we retrospectively evaluated the incidence of occult CNS positivity and its impact on outcome in 221 adult pts with newly diagnosed ALL from 11 centers. Methods. Ninety-four patients (42%) were females and 127 (58%) males, with a median age of 44 years (range 17-80), a median white blood cell (WBC) count of 10.6x109/L (range 0.1-457). One hundred and seventy pts (77%) had B-lineage ALL. Cytogenetic/genetic data were available in 167 (75%) pts: 58 (35%) had a BCR/ABL rearrangement, 14 (8%) a complex karyotype and 11 (6%) a MLL rearrangement. Pts were treated according to the GIMEMA/NILG ALL protocols or with the Hyper-CVAD program. Ninety-eight pts underwent an allogeneic stem cell transplant (ASCT). Median follow up was 26.8 months (range 1-136.6). All CSF samples were evaluated both by CC and FCM. The presence of ≥10 clonally restricted or phenotypically abnormal events was regarded as a FCM positivity. Based on the results of CSF examination, three different categories were recognized: manifest CNS+ (CC+FCM+), occult CNS+ (CC-FCM+) and CNS- (CC-FCM-). Results. Overall, 16 (7%) pts had manifest CNS+, 39 (17%) occult CNS+ and 166 (75%) were CNS-Median age, WBC count, B/T lineage, cytogenetic/genetic features did not differ significantly between the three categories. A complete remission (CR) was achieved in 178 (80%) pts, 9 (4%) died early in induction and 104/178 (58%) experienced a relapse. The frequency of CR rate did not vary significantly across the three identified categories. In univariate analysis, the CNS status correlated significantly with the incidence of relapse (p=.004) and with censor (<.00002). The four-year overall survival (OS) for manifest CNS+, occult CNS+ and CNS- pts was 6%, 17% and 46%, respectively (p=.0007) (Figure). No difference in terms of OS was observed between manifestand occult CNS+ pts (p=.30). In multivariate analysis a baseline status of manifestor occult CNS+ (RR: 1.98, 95%CI 1.47-2.43, p=0.00001) and age>45 years (RR:1.45, 95% CI 1.47-2.43, p=0.04)were independently associated with a lower OS. Conclusions. Our large, multicenter CAMPUS ALL study showed that i) in ALL adult pts, FCM allows to detect occult CNS disease, even in conditions of low spinal fluid leukemic count; ii) the presence of occult CNS disease is associated with an unfavorable outcome. Further prospective studies on larger series are needed to confirm these data. Figure. Figure. Disclosures Del Principe: Gilead: Membership on an entity's Board of Directors or advisory committees. Fracchiolla:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Foà:NOVARTIS: Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; GILEAD: Speakers Bureau; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; INCYTE: Other: ADVISORY BOARD; ROCHE: Other: ADVISORY BOARD, Speakers Bureau.

scholarly journals Molecular Analysis of Central Nervous System Disease Spectrum in Childhood Acute Lymphoblastic Leukemia

2016 ◽  
Vol 10 ◽  
pp. CMO.S18180 ◽  
Author(s):  
Chindo Hicks ◽  
Jitsuda Sitthi-Amorn ◽  
Jessica Douglas ◽  
Ritika Ramani ◽  
Lucio Miele ◽  
...  
Keyword(s):  
Gene Expression ◽  
Central Nervous System ◽  
Nervous System ◽  
Acute Lymphoblastic Leukemia ◽  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Molecular Networks ◽  
Cns Disease

Treatment of the central nervous system (CNS) is an essential therapeutic component in childhood acute lymphoblastic leukemia (ALL). The goal of this study was to identify molecular signatures distinguishing patients with CNS disease from those without the disease in pediatric patients with ALL. We analyzed gene expression data from 207 pediatric patients with ALL. Patients without CNS were classified as CNS1, while those with mild and advanced CNS disease were classified as CNS2 and CNS3, respectively. We compared gene expression levels among the three disease classes. We identified gene signatures distinguishing the three disease classes. Pathway analysis revealed molecular networks and biological pathways dysregulated in response to CNS disease involvement. The identified pathways included the ILK, WNT, B-cell receptor, AMPK, ERK5, and JAK signaling pathways. The results demonstrate that transcription profiling could be used to stratify patients to guide therapeutic decision-making in pediatric ALL.

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