Low Expression of IL-15 in Adult B-Lineage Acute Lymphoblastic Leukemia Is Associated with Central Nervous System Involvement at Initial Presentation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2389-2389
Author(s):  
Shuling Wu ◽  
Thomas Burmeister ◽  
Claudia Baldus ◽  
Stefen Schwartz ◽  
Michael Notter ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Lymphoblastic Leukemia ◽  
Initial Presentation ◽  
Leukemic Cells ◽  
Cns Involvement ◽  
Childhood All ◽  
First Relapse ◽  
B Lineage ◽  
Lower Expression

Abstract The biologic mechanisms of the development of central nervous system (CNS) involvement in acute lymphoblastic leukemia (ALL) is unknown. Risk factors associated with CNS involvement include the immunophenotype (e.g. T-ALL), high white blood cell (WBC) count and cytokine expression. Among the latter, interleukin (IL)-15 has shown to enhance the proliferation of both normal and malignant lymphocytes, thus, suggesting its potential role in leukemogenesis. It has been shown that in childhood ALL, CNS involvement is associated with higher IL-15 expression (Cario et al. 2006, Blood108a:2270). In this study, we analyzed the expression of IL-15 and its alternatively spliced variants in leukemic cells from adult ALL patients with CNS involvement (CNS+) at initial presentation (n=31) and at first relapse (n=8), as well as in patients without CNS involvement at diagnosis (CNS−; n=57). Experiments were performed by real-time RT-PCR and the values were presented ratios comparing IL-15 to expression of the reference gene belta-actin. mRNA expression levels were also correlated with protein expression by western blot analysis. We found that the expression of total IL-15 was significantly lower in ALL patients with CNS+ at initial presentation (n=31, median=0.02, range 0–0.45, P<0.001) and at first relapse (n=8; median=0.03, range 0–0.08, P=0.019), in comparison to ALL patients without CNS (n=57, median=0.08, range 0–0.91). Similarly, lower expression values of IL-15 were found in B-cell precursor (BCP)-ALL (P=0.015) as well as in the subtype of common ALL (p=0.013) with CNS+, as compared to cases without CNS-. In CNS+ ALL, patients with BCR–ABL+–BCP–ALL (n=9) had lower IL-15 expression compared to patients with BCR–ABL–BCP–ALL (n=21, P=0.017). In contrast to CNS– patients, no statistically significant difference was found regarding IL-15 expression between BCR–ABL+- and BCR–ABL–BCP–ALL. Furthermore, the expression of IL-15 was more than 5-fold higher in T–lineage ALL (n=23) than in BCP-ALL (n=72, p<0.001). Among T-lineage-ALLs, CD1+ cortical-T-ALL strongly expressed IL-15 as compared with pre-T or mature T-ALLs. The expression of both spliced variants of long signal peptide (LSP)-IL-15 and short signal peptide (SSP)-IL-15 did not differ between CNS+ and CNS– of all cases. Interestingly, the expression of LSP-IL-15 and SSP-IL-15 is higher in common or pre-B than in pro-B-leukemic cells, whereas high LSP-IL-15 was found in cortical T-ALL, but not in pre-T or mature T-ALL. In conclusion, lower expression of IL-15 in adult BCP-ALL at diagnosis was associated with CNS involvement. This unexpected difference in IL-15 expression between adult and childhood ALL may reflect differences in biologic features of leukemic cells and/or inflammation processes in the pathogenesis of CNS disease. Furthermore, the expression of IL-15 and its spilced variants was correlated with lineage commitment and differentiation status of leukemic cells in B-lineage-ALL as well as in T-ALL. It remains to be evaluated whether these prognostic and biologic findings of distinct expression pattern of IL-15 in adult ALL subtypes will have therapeutical implications for the future antileukemic strategies.

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.

High Interleukin 15 Expression Characterizes Childhood Acute Lymphoblastic Leukemia with Involvement of the Central Nervous System.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2270-2270
Author(s):  
Gunnar Cario ◽  
Anja Teichert ◽  
Peter Rhein ◽  
Andre Schrauder ◽  
Julia Skokowa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Central Nervous System ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Cns Involvement ◽  
Childhood All ◽  
Cns Disease ◽  
Inflammatory Processes ◽  
The Central Nervous System ◽  
Interleukin 15

Abstract Targeted but risk-adapted therapy to the central nervous system (CNS) has become a prerequisite for successful treatment of childhood acute lymphoblastic leukemia (ALL). Overt CNS involvement is a rare observation in childhood ALL and commonly associated with a poorer outcome when compared to CNS-negative patients. Although there are some known risk factors for CNS involvement of ALL such as T-cell-precursor immunophenotype and high initial white blood cell (WBC) count, the underlying biology leading to CNS disease is poorly understood. We hypothesized that leukemic cells crossing the blood-brain barrier early have distinct biological properties which are reflected in a specific gene expression pattern. To test this hypothesis, we generated leukemic gene expression profiles of 17 patients with CNS involvement using 26 CNS-negative patients as controls. Microarrays containing more than 39,000 distinct cDNA clones (SFGF, Stanford CA) were used. Data were analyzed applying Significance Analysis of Microarrays (PNAS2001, 98, 5116–5121). Our analytical approach identified several differentially expressed genes. To control for possible T-cell contamination of the samples, we purified leukemic cells from four samples and repeated the analysis. Interleukin 15 (IL-15) was one of the genes for which differential expression could be confirmed with an up to 10-fold higher expression in CNS-positive patients. IL-15 is a pro-inflammatory cytokine known to stimulate proliferation and activation of T-lymphocytes and polymorphonuclear cells. Of importance with regard to the CNS, IL-15 was described to be highly expressed in peripheral blood (PBL) mononuclear cells in multiple sclerosis. The high expression of IL-15 in patients with CNS involvement was confirmed in an independent set of 13 CNS-positive and 26 CNS-negative patients by quantitative RT-PCR in a similar range as described above (P Mann-Whitney U-Test = <0.001). Therefore, we postulated that inflammatory processes might be involved in the pathogenesis of CNS disease by increasing the permeability of the blood-brain-barrier and reviewed differential PBL smears of 134 CNS-positive and 335 CNS-negative ALL patients. We observed a significantly higher ratio of immature to total myeloid cells in CNS-positive samples (P = <0.001). Next, we compared IL-15 expression at initial diagnosis of CNS-negative patients subsequently relapsing with CNS involvement (n = 22) to those without CNS disease and being in long-term remission (n = 18). Again, a significantly higher IL-15 expression was detected in patients with CNS relapse (P = 0.01). We conclude that measurement of IL-15 expression could serve as an additional tool to further tailor CNS-directed therapy in children newly diagnosed with ALL. Our results support a role for inflammatory processes, but additional studies are needed to finally elucidate the role of IL-15 and inflammation in the pathogenesis of CNS disease in childhood ALL.

scholarly journals CENTRAL NERVOUS SYSTEM INVOLVEMENT IN ADULT ACUTE LYMPHOBLASTIC LEUKEMIA: DIAGNOSTIC TOOLS, PROPHYLAXIS AND THERAPY

2014 ◽  
Vol 6 (1) ◽  
pp. e2014075 ◽  
Author(s):  
Maria Ilaria Del Principe ◽  
Luca Maurillo ◽  
Francesco Buccisano ◽  
Giuseppe Sconocchia ◽  
Mariagiovanna Cefalo ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Intrathecal Injection ◽  
False Negative ◽  
Diagnostic Tools ◽  
Positive Finding ◽  
Cns Involvement ◽  
Hematopoietic Stem

In adult patients with acute lymphoblastic leukemia (ALL), Central Nervous System (CNS) involvement is associated with a very poor prognosis. The diagnostic assessment of this condition relies on the use of neuroradiology, conventional cytology (CC) and flow cytometry (FCM). Among these approaches, which is the gold standard it is still a matter of debate. Neuroradiology and CC have a limited sensitivity with a higher rate of false negative results. FCM demonstrated a superior sensitivity over CC, particularly when low levels of CNS infiltrating cells are present. Although prospective studies of large series of patients are still awaited, a positive finding by FCM appears to anticipate an adverse outcome even if CC shows no infiltration. Current strategies for adult ALL CNS-directed prophylaxis or therapy involve systemic and intrathecal chemotherapy and radiation therapy. Actually, early and frequent intrathecal injection of cytostatic combined with systemic chemotherapy is the most effective strategy to reduce the frequency of CNS involvement. In patients with CNS overt ALL, at diagnosis or upon relapse, allogenic hematopoietic stem cell transplantation might be considered. This review will discuss risk factors, diagnostic techniques for identification of CNS infiltration and modalities of prophylaxis and therapy to manage it. 

scholarly journals Abducens Nerve Palsy as Initial Presentation of Multiple Myeloma and Intracranial Plasmacytoma

2018 ◽  
Vol 7 (9) ◽  
pp. 253
Author(s):  
Elochukwu Ibekwe ◽  
Neil Horsley ◽  
Lan Jiang ◽  
Nadine-Stella Achenjang ◽  
Azubuogu Anudu ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Multiple Myeloma ◽  
Nervous System ◽  
Case Report ◽  
Nerve Palsy ◽  
Abducens Nerve ◽  
Initial Presentation ◽  
Solitary Plasmacytoma ◽  
Cns Involvement ◽  
The Right

Central Nervous System (CNS) involvement in multiple myeloma and/or multifocal solitary plasmacytoma is rare. Although they are unique entities, multiple myeloma (MM) and plasmacytoma represent a spectrum of plasma cell neoplastic diseases that can sometimes occur concurrently. Plasmacytomas very often present as late-stage sequelae of MM. In this case report, we report a 53-year-old female presenting with right abducens cranial nerve (CN) VI palsy as an initial presentation secondary to lesion of the right clivus.

Folate Pathway Gene Expression Differs in Genetic Subtypes of Acute Lymphoblastic Leukemia and Influences Methotrexate Pharmacodynamics.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 452-452
Author(s):  
Leo Kager ◽  
Meyling H. Cheok ◽  
Wenjian Yang ◽  
Gianluigi Zaza ◽  
Ching-Hon Pui ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells ◽  
Cancer Resistance ◽  
Childhood All ◽  
Pathway Gene ◽  
Folate Pathway ◽  
B Lineage ◽  
Lower Expression

Abstract Methotrexate (MTX) is an essential treatment component for acute lymphoblastic leukemia (ALL). The ability of leukemia cells to accumulate MTX in its polyglutamylated form (MTXPG) is recognized as an important determinant of its antileukemic effect. We measured in vivo MTXPG accumulation in leukemia cells from 101 children with ALL, and established that blasts of B-lineage ALL with either the TEL-AML1 (n=24 patients, median 911, range 338 to 5906 pmol/109 blasts) or E2A-PBX1 gene fusion (n=5, median 553, range 364 to 800 pmol/109 blasts) or T-lineage ALL (n=14, median 572, range 284 to 1468 pmol/109 blasts) accumulate significantly lower MTXPG, compared to those of other B-lineage ALL (BNHD, n=39, median 2210, range 186 to 9722 pmol/109 blasts) or hyperdiploid ALL (BHD, n=19, median 4375, range 377 to 9206 pmol/109 blasts) (E2A-PBX1 versus BHD, p=0.008; E2A-PBX1 vs. BNHD, p=0.010; TEL-AML1 vs. BHD, p&lt;0.001; TEL-AML1 vs. BNHD, p=0.004; T-ALL vs. BHD and BNHD, p&lt;0.001; p-values are from pair-wise comparisons using Wilcoxon rank sum test, adjusted for multiple testing using Holm’s method). To elucidate mechanisms underlying these differences in MTXPG accumulation, we used oligonucleotide microarrays (Affymetrix® HG-U133A) to analyze expression of 32 folate pathway genes (53 probe sets) in diagnostic bone marrow blasts from 197 children with ALL. This revealed ALL subtype-specific patterns of folate metabolism gene expression and identified differences in gene expression that discriminated the MTXPG accumulation phenotype in ALL cells. We found significantly lower expression of the reduced folate carrier (SLC19A1, MTX uptake transporter) in E2A-PBX1 ALL; significantly higher expression of breast cancer resistance protein (ABCG2, MTX efflux transporter) in TEL-AML1 ALL; and lower expression of FPGS (catalyzes formation of MTXPG) in T-ALL; consistent with lower MTXPG accumulation in these ALL subtypes. These findings reveal distinct mechanisms of subtype-specific differences in MTXPG accumulation and point to new strategies to overcome this potential cause of treatment failure in childhood ALL.

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.

Central Nervous System Relapse In Adults With Acute Lymphoblastic Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3311-3311
Author(s):  
Amir Hamdi ◽  
Raya Mawad ◽  
Antonio Di Stasi ◽  
Roland Bassett ◽  
Roberto Ferro ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cumulative Incidence ◽  
Lymphoblastic Leukemia ◽  
Conditioning Regimen ◽  
Cns Involvement ◽  
Hematopoietic Stem ◽  
Cns Prophylaxis ◽  
Cns Relapse ◽  
History Of ◽  
First Relapse

Abstract Introduction Central nervous system (CNS) recurrence after allogeneic hematopoietic stem cell transplantation (HSCT) confers a poor prognosis in adult patients with acute lymphoblastic leukemia (ALL). Preventing CNS recurrence after HSCT remains a therapeutic challenge, and criteria for post-HSCT CNS prophylaxis have not been addressed. Our goal was to investigate the post-HSCT outcome of ALL patients and identify patient groups who may benefit from post-HSCT CNS prophylaxis. Methods In this two-center retrospective study, we studied all adult (age≥18) ALL patients who underwent HSCT at MD Anderson Cancer Center or Fred Hutchinson Cancer Research Center between 1997 and 2011. We included all adult ALL patients who were transplanted in the first or second complete remission (CR) and who received any prophylactic or therapeutic CNS therapy before HSCT. We assessed the cumulative incidence of systemic and CNS relapses in a competing risks framework with a competing risk of non-relapse death. Since data from second and subsequent relapses were not available, patients whose first relapse did not include CNS involvement were censored at the time of relapse. To analyze the association between post-HSCT CNS prophylactic therapy and CNS relapse, we used a landmark analysis, including only patients who had not relapsed or died by 3 months post HSCT. Results We included 415 adult ALL patients (239 in CR1 and 176 in CR2) who were transplanted with a myeloablative total body irradiation based (MA-TBI, n=252), myeloablative non-TBI based (MA-nonTBI, n= 130), or reduced intensity conditioning regimen (RIC, n=33). Median age at HSCT was 37 years (range 18-70; 59% male). Sixty seven patients (16%) had a history of pre-HSCT CNS involvement either at diagnosis or at time of first relapse, while 339 patients (81%) had no CNS disease at any time before HSCT. Overall 175 patients (42%) received CNS prophylaxis after HSCT. CNS prophylaxis included intrathecal methotrexate, cytarabine, or both agents. Two patients received prophylactic cerebrospinal radiotherapy. The median follow-up for the 189 surviving patients was 4.2 years. Sixteen patients (3.8% of all patients, 13.2% of all relapses) developed CNS relapse (11 isolated and 5 combined with marrow relapse) at a median of 231 days (range 38-1397) after HSCT. Seven of these patients had pre-HSCT CNS disease. The 4-year cumulative incidence of relapse after HSCT among all patients was 31.7% and 28.2% for patients with and without CNS prophylaxis after HSCT, respectively (P=0.51). The 4-year cumulative incidence of CNS relapse was 6% and 2.6% for patients with and without CNS prophylaxis after HSCT, respectively (P=0.16) (Figure 1). When the analysis was limited to the patients without prior CNS involvement, there was still no benefit to post-HSCT CNS prophylaxis (P=0.63). Patients with a prior history of CNS involvement with leukemia had a significantly higher rate for CNS relapse, 11.6% vs. 2.7% (P=0.003) (Figure 2). The 4-year rate of CNS relapse was not impacted by intensity of the HSCT conditioning regimen and was 3%, 4%, and 6.5% for RIC, MA-TBI, and MA-nonTBI, respectively. Conclusion CNS relapse is an uncommon event following HSCT for ALL in CR1 or CR2. Furthermore, neither the intensity of the HSCT conditioning regimen nor the routine use of post-HSCT CNS prophylaxis made a significant difference in the rate of post-HSCT CNS relapse in patients who had received CNS prophylaxis prior to HSCT. Not surprisingly, patients with a pre-HSCT history of CNS involvement had a significantly higher risk of CNS relapse after HSCT. Disclosures: No relevant conflicts of interest to declare.

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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