Doses Of Intrathecal Methotrexate Research Articles

Incidence, Method and Covariates of Central Nervous System (CNS) Prophylaxis for Diffuse Large B-Cell Lymphoma In the National Comprehensive Cancer Network (NCCN) Lymphoma Database

AbstractAbstract 1756 Background:The optimal criteria to determine which patients with diffuse large B-cell lymphoma (DLBCL) should receive central nervous system (CNS) prophylaxis remain controversial. We aimed to characterize patterns of CNS prophylaxis administration in patients with DLBCL in a large multi-institutional database. Methods:The National Comprehensive Cancer Network (NCCN) Non-Hodgkin's Lymphoma Outcomes Database is a prospective cohort study collecting clinical, treatment, and outcomes data for patients at seven participating NCCN centers. Patients who presented between January 1, 2001 and July 1, 2008 with newly-diagnosed DLBCL, without CNS disease at baseline, and who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) within 180 days of diagnosis were eligible for this analysis. We assessed clinical and sociodemographic covariates of receipt of CNS prophylaxis and type of prophylaxis received (either ≥2 doses of intrathecal methotrexate and/or cytarabine or ≥1 dose of systemic methotrexate). Extrapolating from prior studies (e.g., Boehme et al, Ann Oncol, 2007), we defined high-risk features as >1 extranodal site involvement, elevated lactate dehydrogenase (LDH), bone marrow involvement, or other high-risk site involvement (orbit, testis, peripheral blood, bone/vertebrae, nasal/paranasal sinuses), and assessed rates of CNS prophylaxis in patients with ≥1 high-risk feature. We also determined rates of CNS recurrence for patients with ≥ 2 high-risk features who received prophylaxis versus those who did not. Results:Of a total of 989 patients with DLBCL (mean age 56; 44.4 % female; 70.2% with low or low-intermediate international prognostic index (IPI) score), 117 received CNS prophylaxis (11.8% [95% Confidence Interval (CI) 9.8%-13.8%]). Considered individually, patients with bone marrow involvement, other high-risk site involvement, >1 extranodal site involvement, high versus low IPI score, and advanced stage (III or IV) were significantly more likely to receive CNS prophylaxis (all p<0.0001); those with elevated LDH or presence of B-symptoms were not. In addition, age, gender, race/ethnicity, performance status, and cancer center were not associated with CNS prophylaxis receipt. Rates of CNS prophylaxis, in descending order of frequency, are shown below for significant clinical factors:Individual Clinical Factor+ CNS prophylaxisOther high-risk site involvement36.0%Bone marrow involvement28.2%>1 Extranodal site involvement23.1%High IPI18.6%Stage III/IV15.8%Of those who received CNS prophylaxis, 71.8% received intrathecal therapy and 28.2% received systemic therapy. There were significant center-specific differences regarding type of CNS prophylaxis used (p<0.0001). In addition, other high-risk site involvement was associated with use of systemic versus intrathecal prophylaxis (p=0.04), while higher mean age was associated with the reverse (p=0.05). Patients with increasing number of the four specific high-risk features (>1 extranodal site involvement, elevated LDH, bone marrow involvement, or other high-risk site involvement) were increasingly likely to receive CNS prophylaxis (0 features: 4.3%; 1 feature: 8.1%; 2 features: 20.1%; 3 features: 31.0%; 4 features: 61.1%; p<0.0001). Of all patients with ≥1 high-risk feature (n= 617), 16.4% received CNS prophylaxis. With median follow-up of 2.5 years, there were 20 CNS recurrences (2.0% [95% CI 1.1%-2.9%]). For those with ≥2 high-risk features (n=284), rates of CNS relapse were not significantly different in those who did and did not receive prophylaxis. Conclusion:In our cohort, several classic clinical high-risk variables were associated with receipt of CNS prophylaxis. The modality of prophylaxis used, whether intrathecal or systemic, appeared predominantly mediated by site-specific clinician preference rather than clinical or sociodemographic factors. While an increasing number of widely-accepted high-risk features was associated with higher rates of CNS prophylaxis, surprisingly, a minority of patients with high-risk features received CNS prophylaxis. In conclusion, we found no standard of care for administration of CNS prophylaxis in DLBCL; moreover, as the rate of CNS recurrence was low, our data suggest the need for further evaluation of the efficacy of CNS prophylaxis in the R-CHOP era. Disclosures:No relevant conflicts of interest to declare.

Intrathecal Chemotherapy Prophylaxis for CNS Relapse of DLBCL In the RCHOP Era: A Single Center Analysis.

AbstractAbstract 2804 Introduction:The role of intrathecal (IT) chemotherapy prophylaxis for CNS relapse of diffuse large B cell lymphoma (DLBCL) is unclear. Proponents cite its safety, the lethality of CNS relapse if it occurs, and the high risk of CNS relapse among some DLBCL patients (pts). Rituximab (R)-containing therapy may be associated with a lower incidence of CNS relapse than prior regimens. To assess the efficacy of IT prophylaxis in a modern cohort, we analyzed survival and CNS relapse in DLBCL pts receiving IT prophylaxis at our center from 1998–2008. The impact of baseline clinicopathologic features and R exposure on CNS relapse risk were explored. Methods:Adult pts with DLBCL receiving IT MTX and/or Ara-c from 1998–2008 were identified from pharmacy records, with IRB approval. All pts had involvement of >1EN site, sinus/testis/epidural involvement, and/or bone marrow involvement by large cell lymphoma. Inclusion criteria: IT given as part of first-line DLBCL therapy, no other CNS prophylaxis given, at least 60 days follow-up from diagnosis. Kaplan-meier estimates of survival and CNS risk outcomes were generated. The impact of tumor cell of origin (IHC/Hans criteria), Ki67 index, age, extra-nodal (EN) sites, stage, LDH, IPI, BM involvement, RP node involvement, and first-line R on outcomes were assessed. Results:121 pts were identified, 73 of whom met inclusion criteria. The median age of reviewed patients was 63 years (range 26–84). 63% were male. 2 pts had HIV. At baseline, 59% had IPI score of 3–5, 30% had B symptoms, and 68% had elevated LDH. Median #EN sites was 2 (range 0–5). 43% had RP nodes involved. 57% had >1 EN site. 45% of pts had both elevated LDH and EN sites >1. Median Ki-67 was 80% (range 30–90%), and 26/39 (67%) assessable pts had GCB cell-of-origin DLBCL using Hans criteria. Treatment was RCHOP in 78%; it included R in 79%, and all pts received an anthracycline. IT methotrexate (MTX) 12 mg was used in all pts. 2 pts received at least 1 dose of IT ara-C. A median of 5 doses (range, 1–6) IT therapy were administered. Median follow-up is 3.7 years. 4 year OS and EFS are 77% and 58%, respectively. Five of 73 pts developed CNS relapse (3 leptomeningeal, 2 parenchymal), a relapse rate of 7% (Figure 1). CNS relapse occurred at a median 18 months from diagnosis (range, 6 – 43 months). 3 had concurrent or preceding systemic relapse; 2 relapsed only in the CNS. 3 CNS relapses occurred after initial R; all had received 3 or more doses of IT MTX. Kidney involvement was present in 2/5 CNS relapse pts, a higher proportion than others (2/68, p=.03). Kaplan-meier estimates of CNS relapse rates did not differ based on exposure to first-line R (Figure 1, p=.33). Three pts with CNS relapse died from 4–10 months from relapse. 2 pts are alive after intensive therapy (high dose IV MTX or repeat IT therapy; then salvage chemotherapy and ASCT), at 5.4 and 9.8 months from CNS relapse. Two patients required cessation of IT therapy (due to pain and spinal leak), and one died of a cryptic neurologic disorder 223 days from diagnosis while in remission; no autopsy was performed. [Display omitted] Discussion:We conclude that IT prophylaxis is a safe and reasonable strategy in the RCHOP era, when applied to pts at high risk of CNS relapse based on pattern of EN disease. The observed rate of relapse resembles that seen in a recent study incorporating IV MTX with first-line RCHOP for similarly high-risk pts (Abramson et al, Cancer June 2010). No difference in CNS relapse rate between first-line R and no R groups was observed. Prospective studies of novel first-line approaches for high-risk DLBCL pts should incorporate or allow IT prophylaxis. Disclosures:Dean:Genentech: Speakers Bureau.

Population-Based Risks of CNS Tumors in Survivors of Childhood Cancer: The British Childhood Cancer Survivor Study

CNS tumors are the most common second primary neoplasm (SPN) observed after childhood cancer in Britain, but the relationship of risk to doses of previous radiotherapy and chemotherapy is uncertain. The British Childhood Cancer Survivor Study is a national, population-based, cohort study of 17,980 individuals surviving at least 5 years after diagnosis of childhood cancer. Linkage to national, population-based cancer registries identified 247 SPNs of the CNS. Cohort and nested case-control studies were undertaken. There were 137 meningiomas, 73 gliomas, and 37 other CNS neoplasms included in the analysis. The risk of meningioma increased strongly, linearly, and independently with each of dose of radiation to meningeal tissue and dose of intrathecal methotrexate. Those whose meningeal tissue received 0.01 to 9.99, 10.00 to 19.99, 20.00 to 29.99, 30.00 to 39.99 and≥40 Gy had risks that were two-fold, eight-fold, 52-fold, 568-fold, and 479-fold, respectively, the risks experienced by those whose meningeal tissue was unexposed. The risk of meningioma among individuals receiving 1 to 39,40 to 69, and at least 70 mg/m2 of intrathecal methotrexate was 15-fold, 11-fold, and 36-fold, respectively, the risk experienced by those unexposed. The standardized incidence ratio for gliomas was 10.8 (95% CI, 8.5 to 13.6). The risk of glioma/primitive neuroectodermal tumors increased linearly with dose of radiation, and those who had CNS tissue exposed to at least 40 Gy experienced a risk four-fold that experienced by those who had CNS tissue unexposed. The largest-ever study, to our knowledge, of CNS tumors in survivors of childhood cancer indicates that the risk of meningioma increases rapidly with increased dose of radiation to meningeal tissue and with increased dose of intrathecal methotrexate.

Epigenetic Silencing of the Pro-Apoptotic Bim Gene in Glucocorticoid Poor-Responsive Pediatric Acute Lymphoblastic Leukemia, and Its Reversal by Histone Deacetylase Inhibition.

Abstract 939 Introduction:The glucocorticoids dexamethasone and prednisolone are critical components of combination chemotherapy regimens used to treat pediatric acute lymphoblastic leukemia (ALL). While approximately 80% of patients are cured, poor response to upfront prednisolone monotherapy in 5-10% of patients is a strong predictor of adverse treatment outcome. A greater understanding of the mechanisms responsible for glucocorticoid resistance in pediatric ALL is likely to result in the design of novel strategies to overcome resistance and improve outcome for patients with refractory disease. The pro-apoptotic BH3-only BCL-2 family member BIM (BCL-2L11) has previously been identified as a critical component of glucocorticoid-induced apoptosis in normal and malignant lymphocytes. The purpose of this study was to elucidate clinically relevant mechanisms of glucocorticoid resistance in pediatric ALL, and design and test resistance reversal strategies. Patients and Methods:The study included biopsy specimens obtained at diagnosis from a cohort of patients who received 7 days of prednisolone monotherapy (60 mg/m⋀2/day) and a single age-related dose of intrathecal methotrexate, and whose prednisolone response was determined on Day 8 to be Good (PGR, peripheral blast count < 1 × 10⋀9/L, n=11) or Poor (PPR, peripheral blast count >= 1 × 10⋀9/L, n=11). The study also included biopsies from a cohort of patients who experienced early relapse (within 2 years of diagnosis, n=12). Experimental models of the disease included xenografts (n=12) established in immune-deficient (NOD/SCID) mice using direct explants of patient biopsies. Methods of analysis included: real-time quantitative RT-PCR and immunoblotting of glucocorticoid-induced mRNA and proteins following dexamethasone treatment of ex vivo cultured xenograft cells; DNA methylation analysis of the BIM 5' Untranslated Region (5'UTR) by methylated DNA immunoprecipitation (MeDIP), bisulfite sequencing, and SEQUENOM MassArray Epityper analysis; real time and array based chromatin immunoprecipitation (ChIP) analysis of histone-H3K9 acetylation, H3K4 and H3K27 tri-methylation across the entire BIM locus; as well as assessment of the histone deacetylase inhibitor SAHA (Vorinostat) to reverse dexamethasone resistance both in vitro and in vivo. Results:Dexamethasone resistance in pediatric ALL xenografts was consistently associated with failure to up-regulate BIM mRNA and protein in response to dexamethasone treatment, despite verification that other known glucocorticoid-responsive genes (GILZ, FKBP5) were highly induced in all xenografts. These results indicate specific silencing of BIM in dexamethasone-resistant xenografts rather than a dysfunctional glucocorticoid receptor, leading us to focus on epigenetic regulation of BIM transcription. DNA methylation of the BIM 5'UTR was variable between xenografts, and showed no clear association with dexamethasone resistance. In contrast, the extent of H3K9 acetylation at the BIM locus significantly correlated with the ability of dexamethasone to up-regulate BIM expression in ALL xenografts (R=0.90; P<0.001; n=12): relatively deacetylated H3K9 was associated with BIM repression, indicating that the BIM locus was in a “closed” and transcriptionally inaccessible conformation in dexamethasone-resistant xenografts. These results were in direct contrast to the other BH3-only genes examined, NOXA and PUMA, where H3K9 deacetylation was not associated with dexamethasone resistance. Moreover, H3K9 acetylation at the BIM promoter was significantly decreased in patients classified as PPRs compared with PGRs (P=0.013), while the decrease in BIM H3K9 acetylation in patients at early relapse approached a significant difference from PGRs (P=0.096). These results confirm that the results obtained with xenografts were not an artifact of engraftment. Treatment of a dexamethasone-resistant xenograft with SAHA increased BIM H3K9 acetylation, up-regulated BIM, and caused synergistic anti-leukemic efficacy with dexamethasone both in ex vivo cultures and in an in vivo model of systemic disease. Conclusions:Poor response to glucocorticoid therapy in pediatric ALL is significantly associated with epigenetic silencing of the BIM gene locus, and strategies aimed at improving glucocorticoid sensitivity and clinical outcome should consider incorporating epigenetic modifiers. Disclosures:No relevant conflicts of interest to declare.

Report On Excessive Induction Toxicity in Infants with ALL Enrolled On COG Protocol AALL0631: A Children's Oncology Group Study.

Abstract 3091Poster Board III-28Infants (age ≤ 1 year) with ALL are treated on separate protocols due to distinctive host characteristics and leukemia biology [frequent MLL rearrangements (MLL-r), high relapse rates]. AALL0631 is a treatment protocol for newly diagnosed infant ALL that stratifies patients by age at diagnosis and MLL status into three risk groups: high risk (HR) – age < 90 days, MLL- r; intermediate risk (IR) – age ≥ 90 days, MLL-r; standard risk (SR) – any age, MLL wild-type. All patients receive a common induction chemotherapy course. Post-induction chemotherapy is risk-stratified: SR patients receive relatively less intensive post-induction chemotherapy, and IR and HR patients receive more intensive post-induction chemotherapy and are eligible for randomization to also receive a FLT3 inhibitor (lestaurtinib).AALL0631 induction is based on the predecessor COG P9407 trial. In P9407, excessive induction toxicity was initially encountered, particularly among infants < 90 days of age, prompting changes to induction and prospective safety monitoring rules. A cohort of 142 eligible patients subsequently enrolled (cohort 3, or c3) did not trigger these stopping rules, and enrollment concluded on 10/20/2006. In AALL0631, two changes were made to induction compared to P9407c3: (1) daunomycin dose was reduced 15% to reduce the risk of mucositis; (2) E. coli asparaginase (8 doses over days 4 - 19) was replaced with PEG asparaginase (1 dose on day 4). Four of the first 26 patients enrolled on AALL0631 died of infections during induction, and one patient discontinued protocol therapy during induction due to severe non-fatal toxicity; all toxicities occurred prior to administration of lestaurtinib. This prompted suspension of the protocol on 11/19/2008, and a comprehensive review of induction toxicity for infants treated on AALL0631, P9407c3 and Interfant-99 (a published international cooperative group ALL study with 482 infants enrolled).Differences in Interfant-99 induction compared to COG AALL0631 include: 1) an initial 7 day prednisone-only “prophase” ; 2) 3- to 4-fold lower doses of daunorubicin; 3) use of low dose cytarabine; 4)no use of cyclophosphamide; 5) 2- to 3-fold lower doses of intrathecal methotrexate and cytarabine, and 6) use of native as opposed to PEG L-asparaginase.The details of the 5 severe induction toxicities on AALL0631 are below (Table 1):TABLE 1Age at dx (days)Type of toxicityFatal?1Infection (fungal – Aspergillus fumigatus)Y2Severe hepatotoxicity/hyperbilirubinemiaN92Infection (fungal – Candida tropicalis)Y285Infection (bacterial – Pseudomonas aeruginosa)Y289Infection (bacterial – Bacillus species)YNon-fatal infections have also been prevalent. Table 2 summarizes the grade 3 or greater infectious adverse events (AE) that have been reported during induction therapy on AALL0631.TABLE 2Organism TypeAEFatal AE% of AE# of Patients% of PatientsBacteria19276%1558%Blood16264%1350%Urine3012%28%Fungi4216%415%Viral208%28%Totals254100%18*69%*Of the 16 bacterial blood isolates, 12 (75%) were gram positive; of these, 6 (50%) were Viridans group streptococci.Since toxicities appeared to vary by age, we analyzed induction deaths by age group as shown in Table 3.*these are not simple sums, since some patients had multiple AEsTable 3AALL0631P9407c3Both COGInterfant99AgeNDeathsRateNDeathsRateNDeathsRateNDeathsRate< =302150%6117%8225%30310%0-72150%2150%4250%9222%8-3000-400%400%2115%> 3024313%13654%16085%452194%≥ 9022314%11544%13774%370nd-Infants ≤ 7 days old have a high risk of induction death with all regimens (overall 31%). For infants ≤ 30 days old, P9407c3 and AALL0631 have a higher induction death rate than Interfant-99 [OR 3.6 (0.5-27), p=.23] although the numbers are small. For infants > 30 days, AALL0631 has a higher induction death rate than P9407c3 [OR 3.7 (0.83-16.8), p=0.1] or Interfant-99 [OR 3.3 (0.89-11.9), p=0.09]. For infants ≥ 90 days, AALL0631 has a higher induction death rate than P9407c3 [OR 4.4 (0.9-21.1), p=0.08].As a result of this analysis, we decided to make the following major changes to AALL0631: 1) adopt the Interfant-99 induction regimen for all age groups, but dose reduce an additional 25% for infants ≤ 7 days old; 2) enhance supportive care guidelines regarding infection prevention; 3) include a prospective induction death toxicity monitoring plan. DisclosuresZaoutis:Merck & Co.: Research Funding; Cephalon: Research Funding; Enzon: Research Funding.

Risk of Relapse of Childhood Acute Lymphoblastic Leukemia Is Predicted By Flow Cytometric Measurement of Residual Disease on Day 15 Bone Marrow

Speed of blast clearance is an indicator of outcome in childhood acute lymphoblastic leukemia (ALL). Availability of measurement of minimal residual disease (MRD) at an early time point with a reduced-cost method is of clinical relevance. In the AIEOP-BFM-ALL (Associazione Italiana Ematologia Oncologia Pediatrica and Berlin-Frankfurt-Münster Study Group) 2000 trial, patients were stratified by levels of polymerase chain reaction (PCR) MRD at day +33 and +78. AIEOP studied the prognostic impact of MRD measured by flow cytometry (FCM) at day 15 of induction therapy. Bone marrow samples from 830 Italian patients were collected on day 15, after 14 days of steroids, and one dose of intrathecal methotrexate, vincristine, daunorubicine, and asparaginase. Cells were analyzed by four-color FCM for detection of leukemia-associated immunophenotypes. Three patient risk groups were identified by FCM: standard (< 0.1% blast cells; 42% of the total), intermediate (0.1 to < 10%; 47%), and high (> or = 10%; 11%). Their 5-year cumulative incidences of relapse were 7.5% (SE, 1.5), 17.5% (SE, 2.1), and 47.2% (SE, 5.9), respectively. In multivariate analysis, FCM was the most important prognostic factor among those available by day 15, with two-fold and five-fold increase in the risk of relapse compared with patients with less than 0.1%. PCR MRD, when added to the model, had significant prognostic impact; yet high levels of FCM MRD retained an independent ability to detect a significantly higher risk of relapse. Measurement of FCM MRD in day 15 bone marrow was the most powerful early predictor of relapse, applicable to virtually all patients; it may complement PCR MRD-based stratification including later time points, thus allowing additional treatment tailoring.

Improved Outcome for Children and Young Adults with T-Cell Acute Lymphoblastic Leukaemia (ALL): Results of the United Kingdom Medical Research Council (MRC) Trial UKALL 2003.

UKALL 2003 is an ongoing randomised controlled trial investigating whether treatment can be adjusted according to Minimal Residual Disease (MRD) levels measured by RQPCR at the end of induction and week 11 in children and young adults (up to age 25 years) with ALL. Although the results of the randomised interventions remain blinded, we have observed a significant improvement in 4 year event-free (EFS) and overall survival (OS) in the trial overall compared with its predecessor, ALL 97/99. Here we report a comparison of the outcome for T cell patients in the two trials, in whom the majority of events occur within 3 years.Both UKALL 2003 and ALL97/99 included risk stratification by NCI risk, blast karyotype, and morphological marrow response at day 8/15 of induction to allocate patients to one of 3 treatment regimens (A, B and C – escalating intensity from A to C). NCI standard risk (SR) patients received a 3 drug induction whilst high risk (SR) patients received 4 drugs including daunorubicin. Patients with a slow early response at day 8 (NCI HR) or day 15 (NCI SR) of induction and those with poor risk cytogenetics were transferred to Regimen C. The only differences in treatment administered to all patients between the two trials was the use of Pegylated E. Coli Asparaginase (Peg-ASP) (Oncospar, Medac UK) and Dexamethasone in UKALL 2003 instead of native E. Coli Asparaginase and a Dexamethasone vs Prednisolone randomisation respectively in ALL97/99. Only patients with overt CNS disease (CNS3) at presentation received cranial radiotherapy and high dose Methotrexate was not part of the protocol in either trial. CNS directed therapy comprised 19 – 26 doses of intrathecal methotrexate given over 2 – 3 years depending on regimen and gender. Less than 2% of patients, with high risk cytogenetics or day 28 BM3 marrow, were eligible for first remission transplantation.The outcome for 190 (12%) T-cell patients recruited to UKALL 2003 at 30/10/07 was compared with 92 (10%) patients in ALL97/99. In UKALL 2003, the proportions of T-cell ALL patients treated on the 3 regimens was A= 14%, B= 54% and C= 32% (51%, 26% and 23% respectively in trial overall). For ALL97/99 this was A=14%, B=57% and C=29% (59%, 24% and 16% respectively for the trial overall). EFS and OS are significantly better for T-cell patients in UKALL 2003 (3 year: EFS 86% (se 3.3), OS 90% (se 2.8)) compared with ALL97/99 (EFS 73% (se 4.6), OS 78% (se 4.3)) (p = 0.03 for EFS, p=0.04 for OS). The actuarial incidence of CNS relapse in UKALL 2003 and ALL 97/99 respectively was 3% vs 4% isolated (p=0.7) and 4% vs 7% any CNS (p =0.3). There is a suggestion of a difference in the effect of WCC (<100, ≥ 100) by age on EFS in T-cell patients in both trials, with the effect of WCC not seen in those aged <10, p(heterogeneity)=0.01. Treatment related mortality for T-cell patients was similar in both trials. Only a third of T-cell patients have been entered into the MRD randomisations, hence the observed differences in outcome are unlikely to be due to the randomised interventions.Over 85% of children and young adults with T-cell ALL at all ages and presenting white cell count can be cured without cranial radiotherapy or high dose methotrexate. The observed improvements in outcome are likely to be due to the use of Dexamethasone and Pegylated asparaginase.

Efficacy and Toxicity of Pegylated Asparaginase in the Treatment of Children and Young Adults with Acute Lymphoblastic Leukaemia: Results of the United Kingdom Medical Research Council (MRC) Trial UKALL 2003.

Pegylated E. Coli Asparaginase (Peg-ASP) (Oncospar, Medac UK) 1000 units/m2 administered intra-muscularly replaced native E. Coli Asparaginase (Elspar, MSD) throughout treatment in the current UK trial for children and young adults with ALL, UKALL 2003. The trial opened in October 2003 to patients aged 1 – 21 years (increased to 25 years recently). Included in these analyses are the 1542 patients enrolled and followed up to 31/10/2007. Standard and Intermediate risk patients receive two doses Peg-ASP in induction at days 4 and 18 and a single dose on day 4 of each of two delayed intensifications. High risk patients receive an additional 8 doses during consolidation, interim maintenance and 2 delayed intensification courses. Although results of the randomised interventions remain blinded, overall event free survival (EFS) is significantly better for patients in UKALL 2003 compared with its predecessor, ALL 97/99 (3 year EFS: 92% (se 0.9) vs 87% (se 1.1) - p=0.005), particularly for patients in NCI high risk, T cell and slow early response categories.Both trials included risk stratification by NCI risk, blast karyotype, and morphological marrow response at day 8/15 of induction to allocate patients to one of 3 treatment regimens (A, B and C – escalating intensity from A to C). NCI standard risk (SR) patients received a 3 drug induction whilst high risk (SR) patients received 4 drugs including daunorubicin. Patients with a slow early response at day 8 (NCI HR) or day 15 (NCI SR) of induction were transferred to Regimen C. The only difference between the trials in treatment administered to all patients was the use of Peg-ASP and dexamethasone in UKALL 2003 instead of native E. Coli asparaginase and a dexamethasone vs prednisolone randomisation in ALL97/99. Only patients with overt CNS disease (CNS3) at presentation received cranial radiotherapy, and high dose Methotrexate was not part of the protocol in either trial. CNS directed therapy comprised 19 – 26 doses of intrathecal methotrexate given over 2 – 3 years depending on regimen and gender.Comparison of cohorts receiving otherwise similar treatment in the two trials suggests that Peg-ASP is an important contributor to the improved outcome seen in the high risk subgroups. In NCI HR patients, EFS is significantly better in UKALL2003 (3 year EFS: 88% (se 1.6)) compared with ALL97/99 patients who received Elspar and dexamethasone (79% (se 3.8)) (p=0.01). For T-cell patients, 3 year EFS in UKALL2003 is 86% (se 3.3), and 72% (se 9.0) in ALL97/99 (p=0.1). The incidence of Peg-ASP related serious toxicities has been relatively low: thrombosis 3% (CNS <1%), clinical hypersensitivity 1.5% and pancreatitis 1%. There is no indication that older children and young adults are at higher risk of these toxicities except possibly pancreatitis, although numbers are too small to permit statistical analysis.As part of an intensive front-line treatment protocol, Peg-ASP has contributed to improved outcome with acceptable toxicity in a large cohort of children and young adults with ALL.

Incidence and Outcome of Osteonecrosis in Children and Young Adults with Acute Lymphoblastic Leukaemia Treated on a Dexamethasone Containing Protocol: Results of the Medical Research Council UK Trial ALL 2003.

There is concern that dexamethasone is associated with a higher risk of ostenecrosis than prednisolone when used in older children and young adults with Acute Lymphoblastic Leukaemia. UKALL 2003 is an ongoing randomised controlled trial in which patients receive dexamethasone 6 mg/m2 for 29 days during induction and 5 days each month during maintenance in combination with Vincristine. Additionally, they receive 10 mg/m2 for 14 days in an alternate week schedule during each of two delayed intensifications. The trial is investigating whether treatment can be adjusted according to Minimal Residual Disease (MRD) levels in children and young adults with ALL. The trial opened in October 2003 to patients aged 1 – 21 years (increased to 25 years recently) and at 30/06/08 had accrued 1864 patients.Intensity of treatment is determined by risk stratification based on NCI risk, blast karyotype, and morphological marrow response at day 8/15 of induction to allocate patients to one of 3 treatment regimens (A, B and C – escalating intensity from A to C). NCI standard risk (SR) patients receive a 3 drug induction whilst high risk (HR) patients receive 4 drugs including daunorubicin. Pegylated E. Coli Asparaginase (Medac, Oncospar) is used throughout treatment. Only patients with overt CNS disease (CNS3) at presentation receive cranial radiotherapy, and high dose Methotrexate is not part of the protocol, although Regimen C includes escalating intermediate dose IV Methotrexate without folinic acid rescue given during two courses of Capizzi interim maintenance . CNS directed therapy comprises 19 – 26 doses of intrathecal methotrexate given over 2 – 3years depending on regimen and gender.The actuarial incidence of symptomatic AVN (confirmed on MRI) is 4% overall and 1%, 13% and 16% in patients < 10 years, 10–15 years and > 16 years respectively (p <0.00005 ≤ 10 vs > 10). There is no difference in incidence by sex (M vs F 3.5% vs 4%, P =0.7) or treatment intensity (A= 1%, B =8%, C = 6%, p (stratified by age) = 0.7). Onset of symptoms was during maintenance in the vast majority of affected patients (40/41). The sites involved were hips = 19, knees = 14, ankles/feet = 7, shoulders = 4, elbows = 4, spine = 3 and multi-focal = 13. Management varied from centre to centre and consisted of switching to prednisolone or stopping steroids followed by no further treatment in 19, surgery in 8 (core decompression = 4, hip replacement = 4) and administration of bisphosphonates in 2 cases. Eighteen patients have resulting moderate to severe disability, 5 have recovered and the remaining have ongoing need for analgesia after a median follow-up of 33 weeks.AVN is a problem predominantly of older children and young adults. The incidence associated with a dexamethasone containing protocol in that age group is similar to that reported with prednisolone (CCG 1882, J Clin Oncol 18:3262–3272).

Increased Incidence of Osteonecrosis (ON) with a Dexamethasone (DEX) Induction for High Risk Acute Lymphoblastic Leukemia (HR-ALL): A Report from the Children's Oncology Group (COG).

Treatment with DEX, rather than prednisone (PRED), improves outcome for children with standard risk ALL. However, DEX exposure is strongly associated with the development of therapy-related ON, particularly in adolescents. Previous COG HR-ALL studies have shown a lower ON risk for patients receiving 1 vs. 2 delayed intensification (DI) phases, and for DI using discontinuous DEX (days 1–7 & 15–21) vs. continuous DEX (days 1–21), suggesting a strategy for giving the drug with acceptable toxicity. The HRALL study COG AALL0232 utilizes a modified augmented BFM backbone that compares in a 2x2 randomized design:induction DEX (10 mg/M2/day x14 days) vs PRED (60 mg/M2/day x28 days), andinterim maintenance (IM) escalating-dose “Capizzi” methotrexate vs. high-dose (HD) MTX.Induction rapid early responders (RER) receive single DI while slow responders receive double DI; all patients receive monthly 5-day DEX pulses during maintenance. To limit ON risk in adolescents, in the initial study design children ≥ 13y received discontinuous DEX during single or double DI; those <13y received continuous DEX. In 10/2006 the study was amended due to an unexpectedly high ON incidence in patients 10–12y receiving continuous DEX (28% @ 18 months) compared with historical controls given discontinuous DEX (3.4%). Subsequently all patients ≥ 10y have received discontinuous DEX; it is too early to assess the impact of this change. A comprehensive interim ON analysis was completed 4/2008 (reported as 24-month cumulative incidences). Overall ON incidence is 10.4% (110/1647), and is higher for those age ≥ 10 vs. <10y (15.2 vs 2.6%, p<0.0001, RHR=6.38); 99/110 cases of ON occurred in the older cohort. Among all patients, ON incidence is higher in DEX vs. PRED regimens (11.6 vs 8.7%, p=0.014, RHR 1.64); rates are similar for Capizzi MTX vs. HD-MTX regimens (10.4 vs 9.8%). Among patients ≥ 13y, incidence is higher in DEX vs. PRED regimens (18.9 vs 9.9%, p=0.02, RHR 1.97). There is no difference between regimens for children <10y. Among randomized RER patients ≥ 10y, incidence is higher in DEX vs. PRED regimens (17.2 vs 12.6%, p=0.006, RHR=1.79). For historical comparison, ON incidences by age cohort for RER patients on AALL0232 regimen PC (PRED + Capizzi MTX) vs. CCG-1961 regimen D (double DI with discontinuous DEX) were: <10y 4.1±3.4 vs. 2.0±1.4%, 10–12y 21.9±10.6 vs. 7.1±2.8%, and ≥ 13y 7.1±10.1 vs. 6.6±3.8%. To address these findings, the study was amended 6/2008. Patients ≥ 10y will be non-randomly assigned to induction PRED; the induction steroid randomization will continue for younger patients. Patients of all ages will receive discontinuous DEX during DI and PRED pulses during maintenance. Of note, compared with CCG-1961 the AALL0232 augmented BFM backbone was non-randomly modified in several ways that may affect ON incidence, including the use of pegaspargase during induction, a higher 15 mg intrathecal methotrexate dose for those age ≥ 9y, and monthly DEX instead of PRED maintenance pulses. Heightened awareness among caregivers may also have led to increased recognition and reporting of this toxicity. Using CTCAE v3.0 criteria, clinical ON severity among the 110 patients is: 3% grade 1, 60% grade 2, 35% grade 3, and 2% grade 4. Data regarding surgical intervention are being collected. These findings will directly influence the design of future trials in an effort to lessen the incidence and burden of this toxicity.

Intrathecal trastuzumab (Herceptin) and methotrexate for meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer: a case report

Leptomeningeal carcinomatosis represents a rare manifestation of metastatic breast cancer (MBC). We herewith report on a patient suffering from HER2 overexpressing MBC who received intrathecal methotrexate and trastuzumab for meningeal carcinomatosis. A 48-year-old woman was diagnosed with breast cancer in December 2002. Following surgery, six cycles of adjuvant FE100C plus irradiation and, subsequently for 1 year, trastuzumab were given. As a result of disseminated metastatic spread in October 2005, the patient received whole-brain radiotherapy for symptomatic central nervous system involvement, and was put on several trastuzumab-based combination regimens (capecitabine, vinorelbine, paclitaxel). In June 2006, the patient developed clinical signs of terminal cone involvement with overflow incontinence and paraparesis of the legs. Immediate radiation led to partial relief from clinical symptoms. Subsequently, the patient was put on the tyrosine kinase inhibitor lapatinib and capecitabine (August to October 2007), but on November 6th the patient suffered again from overflow incontinence and weakness of the legs. Failing to respond to lapatinib, the patient received gemcitabine/cisplatin and, additionally, was recommenced on intravenous trastuzumab. Owing to progressive leptomeningeal disease, the patient received repeated doses of intrathecal methotrexate and trastuzumab. Within 2 weeks and four intrathecal treatments, cerebrospinal fluid cytology showed the absence of tumor cells. Moreover, a striking clinical improvement with resolution of the paraparesis of the legs and overflow incontinence was observed. This case report gives details regarding the clinical course of a breast cancer patient who received intrathecal trastuzumab and methotrexate via lumbar puncture for meningeal carcinomatosis of HER2-overexpressing MBC.

A Case of Peripheral Neuropathy Combined with Leukoencephalopathy after Injection with Intrathecal Methotrexate and Vincristine.

Vincristine and methotrexate are the anchor drugs in the treatment of acute lymphocytic leukemia. The neurological complications caused by either vincristine or methotrexate have been well documented. A 10 year-old girl diagnosed acute lymphocytic leukemia without central nervous involvement and treated with CCG 1882 based therapy. She suffered from ascending paralysis from lower extremities without seizure or mental change three days after the fifth dose of vincristine and the fifth dose of intrathecal methotrexate during consolidation chemotherapy composed of 3-drug(vincristine, methotrexate, and L-asparaginase). Two days later, she developed dysarthria and respiratory discomfort. Her neurological examination showed a symmetric, flaccid, quadriparesis with loss of deep tendon reflex. But, she did not have sensory loss. We thought Guillain-Barre syndrome as first impression and carried out diagnostic evaluation. Viral study revealed no abnormality and cerebrospinal fluid study was not consistent with Guillain-Barre syndrome or infectious disease. Diffusion weighted magnetic resonance imaging showed a well-demarcated area of moderately high signal intensity in the white mater of the both parietal lobes. Neuromuscular conduction test revealed severe amplitude reduction in motor nerve action potential meaning on peripheral polyneuropathy. These findings were corresponded with drug-induced peripheral neuropathy and chemotherapy-related leukoencephalopathy that was detected incidentally. She did not receive further doses of vincristine and intrathecal methotrexate during the consolidation phase. There was gradual improvement of the weakness in the both lower and upper limbs for 3 months. She was recovery to walk with minimal support. We report peripheral neuropathy combined with subclinical leukoencephalopahty after injection with intrathecal methotrexate and vincristine.

Cytoprotective Effect of Palifermin on Gastrointestinal Mucous Membrane Enabled Non-Myeloablative Chemotherapy Administration in ALL Patient with High Risk of Gastrointestinal Toxicity.

Palifermin (Keratinocyte Growth Factor, KGF) is indicated to decrease the incidence, persistence and severity of mucositis in patients with hematologic malignancies receiving myeloablative chemotherapy with consecutive hematopoietic stem cell support. Hereby we present a clinical case of acute lymphoblastic leukemia (ALL) patient with a high risk of gastrointestinal complications who received intensive reinduction and consolidation chemotherapy together with KGF. 21-years old male with common ALL (BCR/ABL negative) with primary central nervous system (CSN) infiltration diagnosed in 2003, received two doses of standard induction therapy (vincristine + epirubicin) and four doses of intrathecal methotrexate (4 x 20mg) and arabinoside cytosine (4 x 50mg) with consecutive development of severe intestinal mucositis resulted in ileus perforation. After repeated procedure of laparotomy surgery the extended right hemicolectomy must had been performed. The patient remained in complete remission (CR) and was disqualified for following chemotherapy. After 23 months the patient relapsed with 90% of bone marrow infiltration and right testis involvement. Local irradiation was performed. Because of a high risk of severe life-threatening intestinal mucositis KGF was administered together with the second induction therapy according to PALG4-2002 protocol (Polish Adult Leukemia Group www.palg.pl). Patient's informed consent and local Ethics Committee approval were obtained. KGF was administered 60μg/kg during three consecutive days before each cytostatics infusion with retaining of 24–48 hrs period between KGF and chemotherapy dose. No gastrointestinal side effects were observed, thus consolidation chemotherapy with non-reduced doses was performed. The only side effects that occurred during the treatment were taste alteration and subjective sensation of gustatory buds hypertrophy. A generalized intense bone pain during concomitant administration of KGF and granulocyte-colony stimulating factor (G-CSF) was observed. This seems to be significant because the symptom did not appear when the two drugs were administered separately. Currently the patient remains in CR and is qualified as eligible for allogeneic stem cell transplantation (SCT). A cytoprotective activity of KGF on distal parts of gastrointestinal tract has been concluded based on the case of intensive chemotherapy administered together with KGF in patient with high risk of severe chemotherapy-related intestinal mucositis. That may allow significantly reduce incidence and severity of gastrointestinal mucositis not only in patients receiving myeloablative chemotherapy but also in those who developed chemotherapy-related severe mucositis after non-myeloablative treatment. The excellent chemotherapy tolerability without any serious complication and no gastrointestinal side effects allows taking into consideration KGF administration in patients with hematological malignancies and high risk of severe mucositis.

Prospective Management of Primary Testicular Lymphoma (PTL) with Doxorubicin-Based Chemotherapy, Prophylactic Intrathecal (IT) Methotrexate and Radiotherapy (RT), but without Rituximab: Results from IELSG.

Introduction: PTL is a rare extranodal lymphoma characterized by a continuous pattern of systemic relapses in spite of doxorubicin-based therapy. There are also frequent relapses in the contralateral testis and the central nervous system (CNS). Therefore we decided to determine whether prophylaxis of the CNS and the contralateral testis would modify the pattern of relapse of PTL.Patients and methods: From 1993 to February 2002 in IELSG member institutions patients with PTL (presenting with testicular enlargement) were managed with doxorubicin-based therapy according to institutional policy, with the addition of four doses of IT methotrexate (15 mg) during the first 6 weeks. At the end of chemotherapy scrotal RT (30 Gy) was given to all patients and 30–36 Gy nodal RT to those with stage II disease. Rituximab was not used in this cohort because it was not yet generally available for patients with diffuse large B-cell lymphoma.Results: There were twenty seven patients; two refused chemotherapy and/or RT/IT therapy and one RT, leaving 24 eligible for analysis. Median age was 60 years (range 31–80). Ann Arbor stage was I in 17, II in four, and four in three patients. B-symptoms were present in one patient. The right testis was involved in 13 and the left in 11 patients. Serum LDH was elevated in four of 21 with available values. No patient had CNS involvement at diagnosis. Pathology was diffuse large B-cell lymphoma in all patients. Treatment was CHOP in 21, alternating triple therapy in two, and hyper-CVAD in one patient. Three patients died during therapy: one from neutropenic sepsis and two from toxicity of systemic methotrexate. The remaining 21 patients achieved a complete remission. With a median follow-up of 57 months (range 8–123) for survivors, seven patients have relapsed, three in the CNS. There were no testicular relapses. Eight patients have died: three from toxicity during induction, three from relapsed lymphoma, one from gastric carcinoma and one from sudden death, both in complete remission. At 5 years the projected progression-free survival was 78%, and survival 66%, but both without an apparent plateau. Freedom from progression in the CNS was 84%, with a plateau.Conclusions: Patients with PTL treated prospectively with doxorubicin-based therapy before the availability of rituximab exhibit the continuous pattern of relapse previously reported. Scrotal RT seems eliminate testicular relapses, and prophylactic IT methotrexate seems to reduce, but not eliminated CNS relapses. These need to be confirmed by longer follow-up. The ongoing IELSG-10 should determine whether the addition of rituximab alters the continuous pattern of systemic relapses. Future studies should determine the molecular basis of the continuous relapses and minimize both systemic and CNS relapses.

Pharmacokinetic interaction between methotrexate and piperacillin/tazobactam resulting in prolonged toxic concentrations of methotrexate

Sir, Methotrexate is an antimetabolite commonly used to treat a number of malignancies including acute lymphoblastic leukaemia, high-grade lymphomas and germ cell tumours. In high doses methotrexate has been shown to result in significant myelosuppression, mucositis, hepatotoxicity and renal failure. Methotrexate is eliminated mainly unchanged in the urine by glomerular filtration and proximal tubular transport. We identified a 50-year-old female with newly diagnosed Burkitt’s lymphoma who was treated with alternating monthly cycles of IVAC (ifosfamide, etoposide and high-dose cytarabine) and CODOX-M (cyclophosphamide, doxorubicin, vincristine and high-dose methotrexate). Cerebral spinal fluid disease was treated with alternating weekly intrathecal administration of methotrexate or cytarabine. The patient’s course was complicated by a febrile neutropenic event on day +10 of her first cycle of chemotherapy and piperacillin/tazobactam was initiated as empirical therapy. Long-term therapy with piperacillin/tazobactam was necessary due to the formation of cavitary pneumonia secondary to Pseudomonas aeruginosa. A significant drug interaction was suspected during the patient’s first cycle of CODOX-M. The serum methotrexate concentration failed to decrease below 0.05 mmol/L and appeared to plateau around 0.2 mmol/L (Figure 1). Cytotoxic methotrexate concentrations were sustained for 8 days and were only abated (i.e. fell below 0.05 mmol/L) by the discontinuation of piperacillin/tazobactam. During the patient’s second cycle of CODOX-M, piperacillin/tazobactam was not administered and serum methotrexate levels declined appropriately. The patient’s serum creatinine concentrations (average and standard deviation of 0.46 – 0.07 mg/dL first cycle and 0.47 – 0.03 mg/dL second cycle) and concurrent medications, aside from piperacillin/tazobactam, did not differ between the two cycles of CODOX-M. Methotrexate total body clearance fell to only 3% of normal in the presence of piperacillin/tazobactam (Table 1). Following the patient’s next scheduled dose of intrathecal methotrexate, the peak serum methotrexate concentration was measured to be 0.44 mmol/L, well within the cytotoxic range. Fortunately, the patient was no longer receiving piperacillin/ tazobactam at that time, and serum methotrexate levels fell to below 0.05 mmol/L within 24 h. Many agents are known to prolong methotrexate elimination including probenecid, salicylates, non-steroidal anti-inflammatory drugs (NSAIDs) and weak organic acids. Penicillin is known to abolish tubular secretion of methotrexate in monkeys and reduce human organic anion transporter (hOAT)-mediated methotrexate elimination in an in vitro mouse model. Piperacillin was shown to reduce renal methotrexate clearance in rabbits as early as 1986. Only a single clinical case report of a piperacillin–methotrexate interaction has ever been documented. The weak organic acid and penicillin derivative, tazobactam, is also eliminated by glomerular filtration and tubular secretion; however, no evidence is available regarding its potential ability to impair methotrexate elimination. 0.01 0.1 1 10 10

Application of intrathecal trastuzumab (Herceptin™) for treatment of meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer

Leptomeningeal carcinomatosis represents a rare manifestation of metastatic breast cancer (MBC). A 39-year-old female presenting with HER2-overexpressing MBC and suffering from meningeal carcinomatosis was treated with the humanized antibody trastuzumab directed to HER2 by intrathecal administration. The patient was diagnosed with HER2-overexpressing stage III breast cancer in December 2003. In August 2004, the patient developed a singular intracerebral metastasis which was resected by neurosurgery followed by whole-brain radiotherapy. Since MRI and cerebrospinal fluid (CSF) analyses indicated meningeal carcinomatosis, the patient was commenced on trastuzumab (6 mg/kg q3w) and capecitabine (2.500 mg/m2 d1-14, q3w). Prompted by clinical deterioration, 5 repeated doses of intrathecal methotrexate (15 mg/dose) were administered, yet without clinical improvement. There is initial evidence that trastuzumab does not reach an adequate concentration in CSF after intravenous application. Nevertheless, infiltration of trastuzumab into CSF is facilitated under conditions of an impaired blood-brain barrier, as it is known for meningeal carcinomatosis. For patients with leptomeningeal disease, intrathecal application of trastuzumab may provide an interesting therapeutical approach for patients with HER2 overexpressing metastatic breast cancer. Therefore, an Ommaya reservoir for intrathecal treatment with trastuzumab was placed surgically and intrathecal therapy was begun with escalating doses of trastuzumab (5-20 mg), which proved to be effective and well tolerated by the patient. Within 2 weeks after treatment, the patients' condition improved significantly and cell counts in CSF obtained from the Ommaya reservoir remained low for 11 months after first diagnosis of meningeal carcinomatosis when clinical symptoms and MRI indicated progression of meningeal and cerebral disease.

Sustained Visual Recovery After Treatment With Intrathecal Methotrexate in a Case of Optic Neuropathy Caused by Chronic Lymphocytic Leukemia

A 68-year-old woman with chronic lymphocytic leukemia (CLL) had acute optic neuropathy associated with cerebrospinal fluid evidence of meningeal spread of CLL. There was no evidence of a hematologic relapse. After undergoing four weekly doses of intrathecal methotrexate, vision improved dramatically and spinal fluid became normal. Four years later, she has near normal vision in the affected eye and remains in hematologic remission. This is the first reported case of successful treatment of optic neuropathy in CLL with intrathecal methotrexate alone.

Gene Expression Analysis of Leukemic Blasts Persisting at Day 8 of Induction Therapy in Childhood ALL.

In childhood acute lymphoblastic leukemia (ALL), early response to therapy is of crucial prognostic significance. In the frontline ALL-BFM (Berlin-Frankfurt-Münster) trial, treatment stratification is based on blast count estimation in peripheral blood at day 8 of induction prephase with prednisone and one dose of intrathecal methotrexate at day 1. To approach yet unknown mechanisms of therapy resistance and to characterize cells persisting under therapy on molecular level, we investigated gene expression profiles of leukemic blasts at day 8 of therapy (“day 8” cells) and their changes as compared with blast cells at initial diagnosis (“day 0” cells). To this end, an experimental procedure has been established including flow sorting of leukemic cells by their leukemia-associated immunophenotype and preparation of cRNA, starting from a small number of cells and using an additional amplification step. Experiments have shown that flow sorting procedure does not affect RNA quality, and this experimental approach facilitates investigation of patient samples with blast cell counts as low as 50 blast cells/μl. Blast cells from ten patients with B-cell precursor ALL were investigated using Affymetrix HG U133A microarrays, and gene expression data were processed by normalization procedure on probe level by variance stabilization. Genes commonly up- or downregulated in blast cells under therapy were identified in matched pairs of day 8 and day 0 samples using Significance Analysis of Microarrays (SAM) and a filtering criterion of at least two-fold mean change. By this procedure a group of 84 genes with a false discovery rate of less than 10 % was identified. In this group, 24 genes, reportedly involved at different levels of the cell cycle regulation, including cell cycle progression (CDC2, cyclin B2), DNA replication (e.g. thymidylate synthetase TYMS, ribonucleotide reductase RRM2, proteins MCM 4 and 6) and execution of mitosis (e.g. cell cycle checkpoint kinases CHEK1 and BUB1B, kinesin-like proteins 1 and 7, and MAD2L1), were found to be downregulated in the day 8 cells. In contrast, genes (n=7) encoding for proteins involved in survival signaling (e.g. IL-4/IL-13 common receptor chain, membrane-spanning 4-domains MS4A1 and CD20) showed increased expression in day 8 blasts. Taken together, the described experimental approach enabled gene expression analysis of ALL cells persisting under therapy and pointed to increased survival signaling in day 8 blasts and their preferential positioning in the G1 cell cycle phase.

Fatal Acute Encephalomyelitis After a Single Dose of Intrathecal Methotrexate

A 40-year-old Hispanic man with acute lymphoblastic leukemia was treated with a single dose of intrathecal methotrexate 12 mg for prophylaxis against leptomeningeal spread of tumor. The day after methotrexate administration, the patient complained of severe back pain and urinary retention. The diagnosis of encephalomyelitis was made on day 3 after methotrexate administration, and by day 6 mechanical ventilation was begun secondary to ascending paralysis. By day 8 the patient was comatose, with minimal signs of brain activity and little hope for recovery; on day 12 he died. Although neurotoxicity is a frequent complication of methotrexate therapy, fatal acute neurotoxicity is extremely uncommon, especially in adults. The mechanisms of methotrexate toxicity remain unclear, and no effective treatment exists to prevent its occurrence. This patient rapidly progressed from mild neurotoxicity to fatal encephalopathy after one dose of intrathecal methotrexate during his third cycle of chemotherapy. Clinicians should be aware of the signs and symptoms of neurotoxicity during treatment, as well as predisposing factors that put patients receiving methotrexate at risk for neurotoxic effects.

American Society of Pediatric Hematology/Oncology 17th Annual Meeting. San Francisco, California, USA. April 29 - May 2, 2004. Abstracts.

American Society of Pediatric Hematology/Oncology 17th Annual Meeting. San Francisco, California, USA. April 29 - May 2, 2004. Abstracts.