scholarly journals Importance of effective central nervous system therapy in isolated bone marrow relapse of childhood acute lymphoblastic leukemia. BFM (Berlin- Frankfurt-Munster) Relapse Study Group

Blood ◽  
1994 ◽  
Vol 83 (12) ◽  
pp. 3468-3472 ◽  
Author(s):  
C Buhrer ◽  
R Hartmann ◽  
R Fengler ◽  
S Schober ◽  
I Arlt ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Bone Marrow ◽  
Nervous System ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Multicenter Trial ◽  
Cranial Radiotherapy ◽  
The Difference ◽  
Multiagent Chemotherapy

Abstract Presymptomatic central nervous system (CNS) treatment in children with a late isolated first bone marrow (BM) relapse of acute lymphoblastic leukemia (ALL) was based on intermediate-dose systemic and intrathecal (IT) methotrexate (MTX) in the multicenter trial, ALL-REZ BFM 85. Because this was associated with an excess of overt second CNS relapses, cranial radiotherapy (cRT) plus prolonged triple IT therapy with MTX, cytarabine, and prednisone was instituted during the course of the subsequent trial, ALL-REZ BFM 87. Results of children with or without cRT, but otherwise identical chemotherapy, are presented here. Between April 1985 and March 1990, 93 children with their first late isolated BM relapse of ALL were entered on protocols ALL-REZ BFM 85M and ALL-REZ BFM 87. An intensive 6-month phase of multiagent chemotherapy that included 8 courses of systemic MTX (1 g/m2) plus IT MTX was followed by 2 years of conventional maintenance therapy with daily 6-thioguanine and biweekly MTX. Children with bone marrow transplantation excluded, 73 were in complete remission at the end of intensive polychemotherapy, 40 of whom received fractionated cRT plus triple IT therapy during the following 6 months; 11 did not receive cRT but prolonged triple IT; 22 received neither cRT nor prolonged triple IT. Except for a higher percentage of children who had received cRT in front-line protocols (29 of 33 v 20 of 40), the patient groups without or with salvage cRT were comparable. Of 33 children without salvage cRT, 26 relapsed, compared with 21 of 40 who had received cRT (P < .05). The difference was solely attributable to second relapses with CNS involvement (10 of 33 v 1 of 40; P < .01). Estimated 6-year event- free survival rates were .18 for children without cRT and .46 for children with cRT (P < .01). In patients without cRT, no impact of prolonged IT therapy could be shown. The data suggest that second CNS prophylaxis with cRT and prolonged triple IT therapy in children with late isolated BM relapse of ALL is effective in preventing CNS relapses, in reducing the overall relapse rate, and in increasing the overall survival rate.

scholarly journals Importance of effective central nervous system therapy in isolated bone marrow relapse of childhood acute lymphoblastic leukemia. BFM (Berlin- Frankfurt-Munster) Relapse Study Group

Blood ◽  
1994 ◽  
Vol 83 (12) ◽  
pp. 3468-3472
Author(s):  
C Buhrer ◽  
R Hartmann ◽  
R Fengler ◽  
S Schober ◽  
I Arlt ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Bone Marrow ◽  
Nervous System ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Multicenter Trial ◽  
Cranial Radiotherapy ◽  
The Difference ◽  
Multiagent Chemotherapy

Presymptomatic central nervous system (CNS) treatment in children with a late isolated first bone marrow (BM) relapse of acute lymphoblastic leukemia (ALL) was based on intermediate-dose systemic and intrathecal (IT) methotrexate (MTX) in the multicenter trial, ALL-REZ BFM 85. Because this was associated with an excess of overt second CNS relapses, cranial radiotherapy (cRT) plus prolonged triple IT therapy with MTX, cytarabine, and prednisone was instituted during the course of the subsequent trial, ALL-REZ BFM 87. Results of children with or without cRT, but otherwise identical chemotherapy, are presented here. Between April 1985 and March 1990, 93 children with their first late isolated BM relapse of ALL were entered on protocols ALL-REZ BFM 85M and ALL-REZ BFM 87. An intensive 6-month phase of multiagent chemotherapy that included 8 courses of systemic MTX (1 g/m2) plus IT MTX was followed by 2 years of conventional maintenance therapy with daily 6-thioguanine and biweekly MTX. Children with bone marrow transplantation excluded, 73 were in complete remission at the end of intensive polychemotherapy, 40 of whom received fractionated cRT plus triple IT therapy during the following 6 months; 11 did not receive cRT but prolonged triple IT; 22 received neither cRT nor prolonged triple IT. Except for a higher percentage of children who had received cRT in front-line protocols (29 of 33 v 20 of 40), the patient groups without or with salvage cRT were comparable. Of 33 children without salvage cRT, 26 relapsed, compared with 21 of 40 who had received cRT (P < .05). The difference was solely attributable to second relapses with CNS involvement (10 of 33 v 1 of 40; P < .01). Estimated 6-year event- free survival rates were .18 for children without cRT and .46 for children with cRT (P < .01). In patients without cRT, no impact of prolonged IT therapy could be shown. The data suggest that second CNS prophylaxis with cRT and prolonged triple IT therapy in children with late isolated BM relapse of ALL is effective in preventing CNS relapses, in reducing the overall relapse rate, and in increasing the overall survival rate.

scholarly journals Central nervous system relapses after bone marrow transplantation for acute lymphoblastic leukemia in remission

Cancer ◽  
1989 ◽  
Vol 64 (9) ◽  
pp. 1796-1804 ◽  
Author(s):  
Gérard Ganem ◽  
Mathieu Kuentz ◽  
FrançOise Bernaudin ◽  
Abdelkader Gharbi ◽  
Catherine Cordonnier ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Bone Marrow ◽  
Nervous System ◽  
Acute Lymphoblastic Leukemia ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Lymphoblastic Leukemia

scholarly journals Outcomes after late bone marrow and very early central nervous system relapse of childhood B-acute lymphoblastic leukemia: a report from the Children's Oncology Group phase III study AALL0433

Haematologica ◽  
2020 ◽  
Vol 106 (1) ◽  
pp. 46-55 ◽  
Author(s):  
Glen Lew ◽  
Yichen Chen ◽  
Xiaomin Lu ◽  
Susan R. Rheingold ◽  
James A. Whitlock ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Bone Marrow ◽  
Nervous System ◽  
Acute Lymphoblastic Leukemia ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Central Nervous System Relapse ◽  
Oncology Group

Outcomes after relapse of childhood B-acute lymphoblastic leukemia (B-ALL) are poor, and optimal therapy is unclear. Children’s Oncology Group study AALL0433 evaluated a new platform for relapsed ALL. Between March 2007 and October 2013 AALL0433 enrolled 275 participants with late bone marrow or very early isolated central nervous system (iCNS) relapse of childhood B-ALL. Patients were randomized to receive standard versus intensive vincristine dosing; this randomization closed due to excess peripheral neuropathy in 2010. Patients with matched sibling donors received allogeneic hematopoietic cell transplantation (HCT) after the first three blocks of therapy. The prognostic value of minimal residual disease (MRD) was also evaluated in this study. The 3-year event free and overall survival (EFS/OS) for the 271 eligible patients were 63.6% +/- 3.0% and 72.3% +/- 2.8% respectively. MRD at the end of Induction-1 was highly predictive of outcome, with 3-year EFS/OS of 84.9 +/- 4.0% and 93.8 +/- 2.7% for patients with MRD <0.1%, vs. 53.7 +/- 7.8% and 60.6 +/- 7.8% for patients with MRD ≥0.1% (p<0.0001). Patients who received HCT vs. chemotherapy alone had an improved 3-year disease-free survival (77.5 +/- 6.2% vs. 66.9 +/- 4.5%, p=0.03) but not OS (81.5 +/- 5.8% for HCT vs. 85.8 +/- 3.4% for chemotherapy, p=0.46). Patients with early iCNS relapse fared poorly, with a 3-year EFS/OS of 41.4% +/- 9.2% and 51.7% +/- 9.3%, respectively. Infectious toxicities of the chemotherapy platform were significant. The AALL0433 chemotherapy platform is efficacious for late bone marrow relapse of B-ALL, but with significant toxicities. The MRD threshold of 0.1% at the end of Induction-1 was highly predictive of outcome. The optimal role for HCT for this patient population remains uncertain. This trial is registered at clinicaltrials.gov (NCT# 00381680).

scholarly journals Central Nervous System Involvement Detected By Flow Cytometry Is a Risk Factor for Relapse in Childhood Acute Lymphoblastic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 657-657 ◽  
Author(s):  
Maria Thastrup ◽  
Hanne Vibeke Marquart ◽  
Mette Levinsen ◽  
Kathrine Grell ◽  
Jonas Abrahamsson ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Bone Marrow ◽  
Nervous System ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cox Model ◽  
Lymphoblastic Leukemia ◽  
Cns Involvement ◽  
Fcm Analysis ◽  
Risk Of Relapse

Abstract Background: Central nervous system (CNS) involvement is common in childhood acute lymphoblastic leukemia (ALL). Today all patients receive intensive prophylactic CNS-directed therapy, which is associated with short- and long-term neurotoxicity. The conventional method for diagnosing CNS leukemia is by microscopic examination of cytospin preparations of cerebrospinal fluid (CSF). Both high (CNS3: ≥5 x 109 cells/L) and low level CNS disease (CNS2: <5 x 109 cells/L) indicate intensified CNS-directed therapy. The CNS is involved in 30-40% of relapses, and most occur in patients classified as CNS negative by cytospin (CNS1). We investigated if sensitive flow cytometric (FCM) analysis of CSF at diagnosis improves detection of CNS involvement and prediction of relapse risk. Methods: Cytospin results were collected from local oncology clinics for patients treated according to the Nordic Society of Pediatric Hematology (NOPHO) ALL2008 protocol from July 2008 to December 2017 (N=1841). CSF samples for FCM were obtained from patients enrolled from September 2012 to December 2017 at 17 participating centers (N=669). CSF samples were collected into Transfix® tubes (Intermedico Ltd., Hellerup, Denmark) and shipped to Rigshospitalet, Copenhagen, Denmark for centralized analysis as previously described (Levinsen at al., Pediatr Blood Cancer 2016). FCM positivity required detection of ≥10 cells with a leukemia-associated phenotype. CSF FCM results were blinded to the treating physician. Time to relapse was analyzed using Cox proportional hazards models with delayed entry at remission and with death and second malignant neoplasm as competing events. Results: At diagnosis, 241 of 1841 (13.1%; CNS2: 8.9% and CNS3: 4.2%) patients were positive by cytospin, whereas 167 of 669 (25.0%) patients were positive by FCM. FCM positivity was not associated with shipment duration (median: 2 days). In total, 191 of the 669 patients (28.6%) were CNS positive by cytospin and/or FCM. CNS positivity was associated with higher white blood cell (WBC) count at diagnosis, T-cell ALL, lack of t(12;21), and traumatic lumbar puncture (TLP) (all comparisons: p < 0.001). However, patients with CNS positivity did not differ in their end of induction bone-marrow minimal residual disease (MRD) levels compared to the remaining patients (cytospin: median MRD 1.2 x 10-4 vs. 0.9 x 10-4, p = 0.058; FCM: median MRD 2.0 x 10-4 vs. 1.7 x 10-4, p = 0.62). During follow-up, 30 patients relapsed with nine of the relapses involving the CNS and 16 relapses isolated to the bone-marrow. The 4-year cumulative incidence of any relapse was higher for patients who were CNS positive by cytospin (16.1% vs. 8.9%), FCM (18.6% vs. 6.0%), and combined cytospin/FCM (19.0% vs. 5.5%) (Figure 1a). Simple Cox regressions yielded relapse hazard ratio (HR) estimates of CNS positivity at diagnosis of 2.4 for cytospin (95% CI 1.0-5.7, p = 0.04), 3.5 for FCM (95% CI 1.7-7.2, p < 0.001), and 4.1 for combined cytospin/FCM (95% CI 2.0-8.7, p < 0.001). Cytospin and/or FCM was associated with increased risk of both isolated bone-marrow relapse (16 events, HR 3.1, 95% CI 1.2-8.4, p = 0.024) and of any CNS relapse (9 events, HR 4.9, 95% CI 1.2-19.5, p = 0.025). In a multiple Cox model stratified by immunophenotype and risk group, predictors of relapse were age (per year: HR 1.1, 95% CI 1.0-1.2, p = 0.003), WBC at diagnosis (per doubling: HR 1.3, 95% CI 1.1-1.6, p = 0.005), and cytospin and/or FCM (HR 3.2, 95% CI 1.4-7.2, p = 0.006) (Figure 1b). Cytospin and/or FCM was associated with a significantly higher risk of relapse for BCP-ALL (N=581; 23 relapses; HR 4.5, 95% CI 1.9-10.4, p = < 0.001). For T-cell ALL no significant association was observed (N=85; 7 relapses; HR 1.6, 95% CI 0.3-8.2, p = 0.58), however the number of T-cell ALL was too small to allow reliable conclusions. In a simple Cox model, TLP was associated with a significantly higher risk of relapse than no TLP (HR 2.7, 95% CI 1.3-5.9, p = 0.011), but this was only the case for patients who were positive by FCM (FCM pos: HR 2.7, 95% CI 1.0-7.0, p = 0.043; FCM neg: 0.7, 95% CI 0.1-5.0, p = 0.68). Conclusion: FCM markedly increases the detection rate for CNS involvement at diagnosis, and distinguish between patients at high and low risk of relapse. Diagnosis of CNS leukemia by combined cytospin and FCM analysis should be the standard for accurate classification of CNS status, which will enable better stratification of CNS-directed and systemic therapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Central Nervous System Infiltration in Acute Lymphoblastic Leukemia in a Dog

2021 ◽  
Vol 49 ◽  
Author(s):  
Giovana Scuissiatto De Souza ◽  
Gabriela Oliveira da Paz Augusto Pinto ◽  
Weslley Junior De Oliveira ◽  
Rosangela Locatelli-Dittrich
Keyword(s):  
Central Nervous System ◽  
Bone Marrow ◽  
Alkaline Phosphatase ◽  
Nervous System ◽  
Acute Lymphoblastic Leukemia ◽  
Blood Count ◽  
Complete Blood Count ◽  
Lymphoblastic Leukemia ◽  
Neurological Signs ◽  
Csf Analysis

Background: Acute lymphoblastic leukemia (ALL) is a malignant neoplasia in which there is proliferation of lymphoid progenitor cells in the bone marrow, blood, and extramedullary sites. This disorder has a fast and progressive development; in dogs, cases of infiltration of ALL cells in the central nervous system (CNS) are uncommon and rare. Diagnosis can be achieved with the help of the clinical history and physical, radiographic, hematological, myelographic, and cerebrospinal fluid (CSF) tests in patients with or without neurological clinical signs. The present report aims to describe a case of ALL and the presence of lymphoblasts in the CSF of a dog with neurological clinical signs.Case: An 8-year-old Lhasa Apso dog was examined at the Veterinary Hospital of Universidade Federal do Paraná, Curitiba campus. At the physical examination, the animal exhibited apathy and paralysis of pelvic limbs, which progressed to tetraplegia. Abdominal palpation revealed presence of hepatosplenomegaly and absence of lymphadenomegaly. No alterations were observed in radiographs of the cervical, thoracic or lumbar spine. A complete blood count revealed presence of non-regenerative anemia (hematocrit = 22%), extreme lymphocytosis (185,229 cells/µL), lymphoblasts at a level of 72% (133,364 cells/µL), and thrombocytopenia (66,000 platelets/µL). The biochemical tests revealed increased alkaline phosphatase (859 IU/L). The levels of alanine aminotransferase, creatinine, urea, total protein, albumin, and globulin were normal. The diagnosis of ALL was achieved with the help of a myelogram. The myelogram findings included 39% of mature lymphocytes and 59% of lymphoblasts exhibiting large size, spherical shape, poorly delimited borders, with a high nucleus/cytoplasm ratio, marked cytoplasmic basophilia, and 2 to 3 evident nucleoli; metarubricytes (1%) and promyelocytes (0.6%) were also observed. The CSF contained an increased number of nucleated cells (27 cells/µL) comprising lymphocytes (43%), macrophages (33%), and segmented neutrophils (24%). Of the 11.6 lymphocytes per µL of CSF, 8.1 were lymphoblasts, which indicates infiltration of ALL cells in the CNS. The animal died one day after collection of bone barrow and CSF. Discussion: Relevant alterations observed in this case included the neurological signs caused by the infiltration of neoplastic cells in the CNS, severe leukocytosis and lymphocytosis, with large amounts of lymphoblasts in the blood and predominance of lymphoblasts in the bone marrow, which are alterations typically found in ALL. The animal also exhibited non-regenerative anemia and thrombocytopenia, which were secondary to infiltration of leukemic cells in the bone marrow. The CSF exhibited pleocytosis (27 cells/ µL), and 30% of the cells observed were lymphoblasts. Lymphoblast infiltration in the CNS of leukemic dogs is rare, and other studies have reported absence of neurological signs or neurological signs different from those observed in the present study. CSF analysis in indicated in cases of leukemia to assess leukemic cell infiltration in the CNS. In the case reported here, the plasma level of alkaline phosphatase was increased (859 IU/L) as a consequence of hepatomegaly and hepatic cholestasis. ALL is a very aggressive, proliferative neoplasia, and the resulting lymphoblasts infiltrated the CNS of the animal. In cases of ALL, performing complete blood count, myelogram, and CSF analysis is indicated whether the patients exhibit neurological signs or not.

scholarly journals Cell-Free DNA As a Biomarker for Acute Lymphoblastic Leukemia Relapse in the Central Nervous System

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-8
Author(s):  
Meghan Haney ◽  
Henry Moore ◽  
Shilpa Sampathi ◽  
Yelena Chernyavskaya ◽  
Tom Badgett ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Bone Marrow ◽  
Nervous System ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Cns Disease ◽  
The Central Nervous System ◽  
Cell Clonality ◽  
Over Time

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, with a relapse rate of 15%. The presence of lymphoblasts in the central nervous system (CNS) is a negative prognostic indicator and a frequent site of disease relapse. CNS disease is defined as more than five white blood cells in the cerebrospinal fluid (CSF) with positive lymphoblast cytomorphology. Often leukemic blasts are detected by flow cytometry of the CSF prior to reaching the five white blood cell threshold, requiring repeat lumbar punctures at 2-4 week intervals until the arbitrarily defined clinical criteria for diagnosis are met. Additionally, more than 50% of autopsied brains from ALL patients show evidence of CNS disease, despite non-detectable CNS involvement via cytology of CSF. These data suggest that patients may be harboring CNS disease before it expands enough to be clinically diagnosed. We have developed a new assay that may allow for earlier detection of CNS disease and relapse by quantifying cell-free, circulating tumor DNA (ctDNA) in the CSF. ctDNA is a proven biomarker of relapse and metastasis in solid tumors in pre-clinical testing; however, its utility at predicting CNS disease in ALL has not been examined. We examined two possible methods for using ctDNA as a biomarker: leukemia cell clonality and DNA methylation profiling. We collected bone marrow aspirate, blood, and CSF samples from 11 newly diagnosed patients prior to the start of chemotherapy treatment to use as a training data set. ctDNA was isolated from blood and CSF samples at diagnosis and throughout treatment. Genomic DNA was isolated from bone marrow and peripheral blood mononuclear cell (PBMC) samples at diagnosis. For leukemia cell clonality assays, Invivoscribe Lymphotrack PCR assays combined with MinION (Oxford Nanopore Technologies) sequencing were used to identify the VDJ sequence of the immunoglobulin (B-ALL) or T-cell receptor (T-ALL) rearrangements in the clones comprising each leukemia. Throughout the course of treatment, ctDNA samples were run on the MinION sequencer, examining the abundance of major clones present and ctDNA quantification was done on patient plasma and CSF samples over time. While this assay relies on patient specific VDJ sequencing, we are also in the process of developing a more universal assay that utilizes recurrent methylation changes in T-ALL or B-ALL, compared to normal PBMCs. We performed methylation sequencing on 3 control PBMC samples and 7 ALL patient samples to identify differentially methylated regions (DMRs) present specifically in ALL samples. This sequencing identified 9,222 DMRs present in the ALL samples. These sites were then compared with publicly available datasets, yielding 55 overlapping regions and 19 specific overlapping methylation sites commonly present in ALL samples and not in PBMCs. We are now in the process of validating these differentially methylated sites by droplet digital polymerase chain reaction (ddPCR) to come up with a panel of biomarkers to track ALL disease over time. The end goal of our study is to develop an assay to rapidly detect relapse and CNS disease in ALL that is more sensitive and less invasive than the current clinical assays. Earlier detection of relapse and CNS disease will provide patients with more treatment options, which may ultimately improve patient outcome. Results will ultimately be correlated with patient response to therapy, the presence of CNS disease, and overall outcomes as determined by standard clinical diagnostic procedures. Disclosures No relevant conflicts of interest to declare.

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