ALBERT

Beschreibung: Introduction Myelodysplastic Syndromes are diverse group of bone marrow failure syndromes and current treatment options are guided by International Prognostic scoring systems (IPSS and IPSS-R) based on clinical phenotype and cytogenetics. Deletion of long-arm of chromosome 5 is the commonest cytogenetic abnormality and confers distinct biological and clinical implications. A specific subgroup of MDS patients with isolated Del(5q) was described as a separate entity in WHO 2008 classification owing to its unique clinical features, a low risk of leukemic transformation and a relatively good prognosis. Lenalidomide is proven to induce high erythroid response rates (frequently abolishing transfusion requirements) with a median response time of over 2 years in MDS patients with Del(5q). However, with time their anaemia worsens and most patients will become transfusion dependent with subsequent iron overload. Other treatment strategies were explored for those who failed Lenalidomide. Method This retrospective multi-centre analysis involved collecting data for MDS patients with 5q abnormalities (isolated Del(5q), Del(5q) with one additional cytogenetic abnormality, or Del(5q) within a complex karyotype) diagnosed between 2006 and 2014 in the Republic of Ireland. Six haematology units participated and the data of 47 patients were available for analysis. Results The median age of diagnosis was 72(29-91) with male-female ratio of 1:1.6. A range of WHO subgroups were identified and classic 5q Syndrome was documented in only 6.4% of patients. Cytogenetic results showed 47% isolated Del(5q), 17% Del(5q) plus one other abnormality and 36% Del(5q) in a complex karyotype. Patients with isolated Del(5q) or Del(5q) plus one other abnormality had similar haemoglobin, higher neutrophil and platelet count and lower marrow blasts than those with having a complex karyotype as previously described. IPSS-R scores were available in 37 patients as very low(7), low(8), intermediate(6), high(5) and very high(11). IPSS risks were available for 40 patients as low risk(12), intermediate-1(11), Intermediate-2(8) and high risk(9). Treatment options included red cell transfusion(85%), Recombinant Erythropoietin(45%), Lenalidomide(17%), Azacitidine(36%), Intensive chemotherapy(7%), transplantation(5%) and others(21%). All 8 patients in Lenalidomide group had either isolated Del(5q) or Del(5q) plus one other abnormality and received a median of 3 cycles (range 1-50). Responses were as follows: stable disease (3,38%), complete response (3,38%), and no response (2,25%). Three patients (38%) became transfusion independent with Lenalidomide. In 16 patients treated with Azacitidine, 50% had Del(5q) in a complex karyotype and 19% had failed Lenalidomide previously. A median of 10 cycles(range 1-18) were given. Four(25%) patients achieved a complete response, 1(6%) partial response, 1(6%) haematological improvement and 8(50%) stable disease. Response patterns were similar between the two groups with a trend towards improved survival in patients with isolated Del(5q) or Del(5q) plus one other abnormality compared to those with a complex karyotype treated with Azacitidine(23 vs. 15 months, p=0.0862). Transformation to AML was observed in 44% of patients without any difference between different cytogenetic groups. Median time to AML was 14 months. Median overall survival was 15 months(range

Beschreibung: The global coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made the development of a vaccine a top biomedical priority. In this study, we developed a series of DNA vaccine candidates expressing different forms of the SARS-CoV-2 spike (S) protein and evaluated them in 35 rhesus macaques. Vaccinated animals developed humoral and cellular immune responses, including neutralizing antibody titers at levels comparable to those found in convalescent humans and macaques infected with SARS-CoV-2. After vaccination, all animals were challenged with SARS-CoV-2, and the vaccine encoding the full-length S protein resulted in 〉3.1 and 〉3.7 log10 reductions in median viral loads in bronchoalveolar lavage and nasal mucosa, respectively, as compared with viral loads in sham controls. Vaccine-elicited neutralizing antibody titers correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate vaccine protection against SARS-CoV-2 in nonhuman primates.

Beschreibung: An understanding of protective immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for vaccine and public health strategies aimed at ending the global coronavirus disease 2019 (COVID-19) pandemic. A key unanswered question is whether infection with SARS-CoV-2 results in protective immunity against reexposure. We developed a rhesus macaque model of SARS-CoV-2 infection and observed that macaques had high viral loads in the upper and lower respiratory tract, humoral and cellular immune responses, and pathologic evidence of viral pneumonia. After the initial viral clearance, animals were rechallenged with SARS-CoV-2 and showed 5 log10 reductions in median viral loads in bronchoalveolar lavage and nasal mucosa compared with after the primary infection. Anamnestic immune responses after rechallenge suggested that protection was mediated by immunologic control. These data show that SARS-CoV-2 infection induced protective immunity against reexposure in nonhuman primates.

Beschreibung: Ice-nucleating particles (INPs) have the potential to remove much of the liquid water in climatically important mid- to high-latitude shallow supercooled clouds, markedly reducing their albedo. The INP sources at these latitudes are very poorly defined, but it is known that there are substantial dust sources across the high latitudes, such as Iceland. Here, we show that Icelandic dust emissions are sporadically an important source of INPs at mid to high latitudes by combining ice-nucleating active site density measurements of aircraft-collected Icelandic dust samples with a global aerosol model. Because Iceland is only one of many high-latitude dust sources, we anticipate that the combined effect of all these sources may strongly contribute to the INP population in the mid- and high-latitude northern hemisphere. This is important because these emissions are directly relevant for the cloud-phase climate feedback and because high-latitude dust emissions are expected to increase in a warmer climate.

Beschreibung: Introduction: Although recent studies have refined the classification of B-progenitor and T-lineage acute lymphoblastic leukemia into gene-expression based subgroups, a comprehensive integration of significantly mutated genes and pathways for each subgroup is needed to understand disease etiology. Methods: We studied 2789 children, adolescents and young adults (AYA) with newly diagnosed B-ALL (n=2,322 cases) or T-ALL (n=467) treated on Children's Oncology Group (n=1,872) and St. Jude Children's Research Hospital trials (n=917). The cohort comprised childhood NCI standard-risk (41.8%; age range 1-9.99 yrs, WBC ≤ 50,000/ml), childhood NCI high-risk (44.5%; age range ≥10 to 15.99 yrs) and AYA (9.9%; age range 16-30.7 yrs). Genomic analysis was performed on tumor and matched-remission samples using whole transcriptome sequencing (RNA-seq; tumor only; n=1,922), whole exome sequencing (n=1,659), whole genome sequencing (n=757), and single nucleotide polymorphism array (n=1,909). Results: For B-ALL, 2104 cases (90.6%) were classified into 26 subgroups based on RNA-seq gene expression data and aneuploidy or other gross chromosomal abnormalities (iAMP21, Down syndrome, dicentric), deregulation of known transcription factors by rearrangement or mutation (PAX5 P80R, IKZF1 N159Y), or activation of kinase alterations (Ph+, Ph-like). For T-ALL, cases were classified into 9 previously described subtypes based on dysregulation of transcription factor genes and gene expression. In 1,659 cases subject to exome sequencing (1259 B-ALL, 405 T-ALL) we identified 18,954 nonsynonymous single nucleotide variants (SNV) and 2,329 insertion-deletion mutations (indels) in 8,985 genes. Overall, 161 potential driver genes were identified by the mutation-significance detection tool MutSigCV or by presence of pathogenic variants in known cancer genes. Integration of sequence mutations and DNA copy number alteration data in B-ALL identified 7 recurrently mutated pathways: transcriptional regulation (40.6%), cell cycle and tumor suppression (38.0%), B-cell development (34.5%), epigenetic regulation (24.7%), Ras signaling (33.0%), JAK-STAT signaling (12.0%) and protein modification (ubiquitination or SUMOylation, 5.0%). The top 10 genes altered by deletion or mutation in B-ALL were CDKN2A/B (30.1%), ETV6 (27.0%), PAX5 (24.6%), CDKN1B (20.3%), IKZF1 (17.6%), KRAS (16.5%), NRAS (14.6%), BTG1 (7.5%) histone genes on chromosome 6 (6.9%) and FLT3 (6.1%), and for T-ALL, CDKN2A/B (74.7%), NOTCH1 (68.2%), FBXW7 (21.3%), PTEN (20.5%) and PHF6 (18.2%) (Figure 1A). We identified 17 putative novel driver genes involved in ubiquitination (UBE2D3, UBE2A, UHRF1, and USP1), SUMOylation (SAE1, UBE2I), transcriptional regulation (ZMYM2, HMGB1), immune function (B2M), migration (CXCR4), epigenetic regulation (DOT1L) and mitochondrial function (LETM1). We also observed variation in the frequency of genes and pathways altered across B-ALL subtypes (Figure 1B). Interestingly, alteration of SAE1 and UBA2, novel genes that form a heterodimeric complex important for SUMOylation, and UHRF1 were enriched in ETV6-RUNX1 cases. Deletions of LETM1, ZMYM2 and CHD4 were associated with near haploid and low hypodiploid cases. Deletion of histone genes on chromosome 6 and alterations of HDAC7 were enriched in Ph+ and Ph-like ALL. Mutations in the RNA-binding protein ZFP36L2 were observed in PAX5alt, DUX4 and MEF2D subgroups. Genomic subtypes were prognostic. ETV6-RUNX1, hyperdiploid, DUX4 and ZNF384 ALL were associated with good outcome (5-yr EFS 91.1%, 87.2%, 91.9% and 85.7%, respectively), ETV6-RUNX1-like, iAMP21, low hyperdiploid, PAX5 P80R and PAX5alt were associated with intermediate outcome (5-yr EFS 68.6%, 72.2%, 70.8%, 77.0% and 70.9%, respectively), whilst KMT2A, MEF2D, Ph-like CRLF2 and Ph-like other conferred a poor prognosis (55.5%, 67.1%, 51.5% and 62.1%, respectively). TCF3-HLF and near haploid had the worst outcome with 5-yr EFS rates of 27.3% and 47.2%, respectively. Conclusions: These findings provide a comprehensive landscape of genomic alterations in childhood ALL. The associations of mutations with ALL subtypes highlights the need for specific patterns of cooperating mutations in the development of leukemia, which may help identify vulnerabilities for therapy intervention. Disclosures Gastier-Foster: Bristol Myers Squibb (BMS): Other: Commercial Research; Incyte Corporation: Other: Commercial Research. Willman:to come: Patents & Royalties; to come: Membership on an entity's Board of Directors or advisory committees; to come: Research Funding. Raetz:Pfizer: Research Funding. Borowitz:Beckman Coulter: Honoraria. Zweidler-McKay:ImmunoGen: Employment. Angiolillo:Servier Pharmaceuticals: Consultancy. Relling:Servier Pharmaceuticals: Research Funding. Hunger:Jazz: Honoraria; Amgen: Consultancy, Equity Ownership; Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Loh:Medisix Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees. Mullighan:Amgen: Honoraria, Other: speaker, sponsored travel; Loxo Oncology: Research Funding; AbbVie: Research Funding; Pfizer: Honoraria, Other: speaker, sponsored travel, Research Funding; Illumina: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored travel.

Beschreibung: Introduction: Adolescent and young adult (AYA) patients (〉16 years of age) with high-risk B acute lymphoblastic leukemia (HR B-ALL) have inferior outcomes compared to HR B-ALL patients 1-15 years of age, primarily due to relapse and toxicity. In a prior Children's Oncology Group (COG) HR B-ALL study 1961 (1996 - 2002), 12.7% of patients were AYA (ages 16 - 21 years) with 5-year event-free survival (EFS) and overall survival (OS) of 71.5% and 77.5% respectively. Here we report the outcomes of the most recently completed HR B-ALL COG study AALL0232, comparing AYA and younger patients. Methods: COG study AALL0232 was a Phase 3 randomized trial for patients 1-30 years of age with newly diagnosed HR B-ALL utilizing a 2 x 2 factorial design with an augmented intensityBerlin-Frankfurt-Münster (BFM) backbone. Patients were randomized to two weeks of dexamethasone versus four weeks of prednisone during Induction therapy and high dose methotrexate (HD-MTX) versus escalating Capizzi methotrexate plus pegaspargase (C-MTX) during Interim Maintenance I. Between 2004 and 2011, 3,154 patients enrolled, with 3,081 eligible and evaluable for induction. AYA patients comprised 20% (16-21 years, n= 558; 22-30 years, n=47). Results: The study was amended in 2008 due to an excess incidence of osteonecrosis observed in patients older than 10 years of age who were randomized to dexamethasone. Thereafter, they were nonrandomly assigned to prednisone during induction. The dexamethasone delivered during delayed intensification was also rescheduled from continuous (days 1-14) to discontinuous (days 1-8 and 15-22) delivery. 5-year EFS and OS were 65.1% and 76.9% for AYA patients compared to 77.9% and 87.1% for younger patients (p

Beschreibung: Introduction: Acute myeloid leukemia (AML) comprises 5% of pediatric cancers and reports 5 year event free survival (EFS) of approximately 50% and overall survival (OS) of 60-70% following intensive multi-agent chemotherapy. Anthracyclines have been the cornerstone in upfront treatment of AML since the 1960's and continue to be used today in upfront trials for AML. Anthracycline induced cardiotoxicity remains a significant contributor to late morbidity/mortality in children and young adults with AML. The cardioprotectant dexrazoxane (Zinecard) can be used as prophylaxis to diminish the risk for cardiomyopathy but whether it affects the risk of relapse in pediatric AML is unproven. Our institution adopted the use of dexrazoxane prior to administration of any non-liposomal anthracycline for all patients in 2011. We are therefore reporting the differences in cardiac and treatment outcomes in children and young adults with AML treated with and without dexrazoxane from 2008 to 2013. Methods: We performed a retrospective chart review of children ages 0 to 21 years who received their therapy for AML at the Children's Hospital of Wisconsin (CHW) between January 1, 2008 and December 31, 2013. This study was approved by the CHW institutional review board prior to our data collection. Descriptive statistics were used to describe the study population. Echocardiogram statistics were generated with each model based on the least squares means and then transformed back to its original unit. A log rank test was used to detect differences between populations. Based on number of patients, a hazard ratio of 3 will achieve 85% power to detect a significant difference between groups. Results: Forty-four patients with AML were treated at CHW during 2008 - 2013 with 28 (64%) receiving dexrazoxane cardioprotectant and 16 (36%) did not. The median age at diagnosis was 8.1 years (5 months - 21.7 years) and 55% (n=24) were female. Six (14%) patients underwent transplantation in first complete remission and 6 (14%) underwent transplantation following relapse. No patients had history of cardiac disease, cardiac surgery or hypertension prior to treatment. We identified no statistical difference in relapse free survival (RFS) p〉0.40), EFS (p〉0.48) or OS (p〉0.53) between groups. However, there was a significant decrease in the ejection fraction (EF %) (p=0.0018) and a significant decrease in shortening fraction (SF %) (p=0.0108) trends over time in the non-dexrazoxane group compared to patients who received dexrazoxane (Figures 1 & 2). Conclusion: Utilization of the cardioprotectant dexrazoxane prior to anthracycline chemotherapy in pediatric patients with AML demonstrated no significant difference in RFS or OS relative to our institutional controls and appeared to improve cardiac function. Further studies are needed to confirm these findings. Disclosures No relevant conflicts of interest to declare.

Beschreibung: Introduction: Longitudinal changes in health-related quality of life (HRQoL) are important in patients with chronic lymphocytic leukemia (CLL). GIBB (NCT02320487) is an open-label, single-arm phase II study of obinutuzumab (GA101; G) in combination with bendamustine (G-Benda) in patients with previously untreated CLL. A previous report from the GIBB study demonstrated an investigator-assessed objective response rate of 89.2%, a complete response rate of 49.0%, and no unexpected safety signals with G-Benda (Sharman et al. J Clin Oncol 2017). Here we report the final HRQoL data over 3 years from the GIBB study. Methods: Enrolled patients received G-Benda by intravenous infusion over six 28-day cycles: G 100mg on Day (D)1, 900mg on D2, and 1000mg on D8 and D15 of Cycle (C)1, then 1000mg on D1 of C2-6; benda 90mg/m2 on D2-3 of C1, and on D1-2 of C2-6. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) includes a global health status measure, 5 functional scales (physical, emotional, cognitive, social, and role functioning), 8 symptom scales/items (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, and diarrhea), and an item on financial difficulties (Aaronson et al. J Natl Cancer Inst 1993). The EORTC Quality of Life Questionnaire-Chronic Lymphocytic Leukemia 16 (QLQ-CLL16) is a 16-item module, specific to CLL, containing 4 multi-item scales (fatigue, treatment side effects, disease symptoms, and infection) and 2 single items (social activities and future health worries). Both questionnaires were completed by patients on C1D1 (baseline), C3D1, and C6D1, at the end of induction (EOI) treatment (defined as +28 days from C6D1 or early treatment termination visit), at the response visit (defined as 2-3 months after the EOI treatment for all patients who received study treatment and had not experienced disease progression), and every 3 months thereafter at follow-up visits for up to 2 years. In total, there were 14 timepoints where data were collected. HRQoL scores were linear transformed to a 0-100-point scale. Mean baseline scores and mean score changes from baseline at each visit were evaluated. A threshold of ≥10-point change in score represents a clinically meaningful difference. For symptoms, negative change scores from baseline reflect an improvement in symptom burden. For global health status and functioning, positive change scores from baseline reflect improvements. Results: The trial enrolled 102 patients. Median age was 61 years and 68.4% of patients were male. Ninety-eight patients (96%) completed a questionnaire at baseline and at least 1 other questionnaire during a follow-up visit. Questionnaire completion rates at 14 time points ranged from 96% at baseline to 66% at 27 months follow-up (Table 1). According to the EORTC QLQ-C30 (Figure 1), improvements were observed for global health status at all follow-up visits, and clinically meaningful improvements were observed at the response visit, 3 months follow-up, and 27 months follow-up. Clinically meaningful improvements in role functioning were observed at EOI and persisted throughout the 27-month follow-up. For fatigue, clinically meaningful improvements were observed at every visit starting from the end of treatment (EOT) visit. Improvements were also observed for insomnia with mean reductions from baseline ≥10 points at various time points during follow-up. There was no worsening in other patient-reported symptoms or functional status over time. Similarly, with the EORTC QLQ-CLL16 (Figure 2), clinically meaningful improvements in symptoms were observed for fatigue, disease symptoms, and future health worries during treatment, at the EOT and/or throughout the follow-up. The largest improvement was observed for fatigue (-24.7) at the 24-month follow-up and future health worries (-25.4) at the 27-month follow-up. Conclusions: We previously reported that G-Benda is an effective regimen for first-line treatment of CLL with no unexpected safety signals. The HRQoL data from the GIBB trial suggest that G-Benda treatment consistently improved patient HRQoL over time. Several clinically meaningful improvements were observed in HRQoL, including global health status, functioning, symptoms, and future health worries. Disclosures Danilov: AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; MEI: Research Funding; Bristol-Meyers Squibb: Research Funding; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Takeda Oncology: Research Funding; Genentech: Consultancy, Research Funding; Bristol-Meyers Squibb: Research Funding; Takeda Oncology: Research Funding; Aptose Biosciences: Research Funding; Aptose Biosciences: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy; Curis: Consultancy; Seattle Genetics: Consultancy; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Gilead Sciences: Consultancy, Research Funding; Bayer Oncology: Consultancy, Research Funding; Curis: Consultancy; Seattle Genetics: Consultancy; MEI: Research Funding; TG Therapeutics: Consultancy; Celgene: Consultancy; Gilead Sciences: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Abbvie: Consultancy; Abbvie: Consultancy. Yimer:AstraZeneca: Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Honoraria; Celgene: Honoraria; Clovis Oncology: Equity Ownership; Puma Biotechnology: Equity Ownership; Amgen: Consultancy. Boxer:Gerson Lerman: Consultancy; Best Doctors: Consultancy; Takeda: Honoraria, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau. Burke:Celgene: Consultancy; Gilead: Consultancy; Roche/Genentech: Consultancy. Babu:Genentech: Research Funding. Li:Genentech: Employment; Roche: Equity Ownership. Mun:Genentech: Employment, Equity Ownership. Trask:Genentech: Employment, Equity Ownership. Masaquel:Roche: Equity Ownership; Genentech: Employment. Sharman:Acerta: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated: in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia; in combination with bendamustine followed by GAZYVA monotherapy, for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen

Beschreibung: Introduction In a subset of multiple myeloma (MM) patients the t(4;14) deregulates the histone methyltransferase, MMSET and growth factor receptor, FGFR3 and has been associated with poor prognosis. In some patients this has been ameliorated by the introduction of proteasome inhibitors but 50% of t(4;14) cases have a high-risk gene expression profile (GEP70) at presentation and derive less benefit from their use. The t(4;14), therefore, constitutes a very significant target for therapy. Despite international efforts at drug design it has proven difficult to target MMSET directly. Targeting FGFR3 has been attempted and may be effective when the gene is mutated, but this only occurs in a small proportion. We have used multi-level molecular (proteomic, gene expression, metabolomic) and phenotypic analysis to identify downstream molecules upregulated in t(4;14) MM as an alternative approach to defining novel targets for therapy. Materials/Methods The MM cell line KMS11 has t(4;14) which re-locates MMSET downstream of the immunoglobulin heavy chain gene enhancer. From KMS11 the isogenic paired cell lines non-translocated allele knock out (NTKO, retains high MMSET expression) and translocated allele knock out (TKO, low MMSET expression) have been derived using homologous recombination (Lauring et al, Blood 2008). We performed Affymetrix GEP (HG_U133_plus_2) on mRNA extracted from KMS11, NTKO and TKO cells in triplicate and analysed using Partek®. Probes were included in the analysis if they had fold change (FC) 〉2 or

Beschreibung: Precursor-B acute lymphoblastic leukemia (pre-B ALL) is the most common malignancy in children and can be cured in a majority of patients. However, cure remains elusive in approximately 20% of patients for reasons that are not well understood. Moxetumomab pasudotox is one of several CD22-targeting therapies currently under investigation in clinical trials for subjects with B-cell malignancies, including pediatric subjects with pre-B ALL. Moxetumomab pasudotox (MP) is a second-generation immunotoxin composed of disulfide-stabilized, affinity matured VL and VH regions of the mouse anti CD22 monoclonal antibody RFB4 fused to PE38, a truncated form of Pseudomonas exotoxin E. We evaluated in vitro activity of MP against six pre-B ALL cell lines (697, Nalm6, MHH-Call3, RS4;11, SupB15, REH), as well as freshly isolated patient blasts. We found the most sensitive cell line to be Reh, followed by 697, MHH-Call3, and the least sensitive cell lines to be Nalm6 and RS4;11. Toxicity of MP on ALL cell lines and patient blasts was not well-correlated with the number of the CD22 receptors present on the cell surface. However, we found that cleavage of MP by ALL cell lines into active toxin correlated with uptake and inhibition of protein synthesis. Using ALL cell lines, we also demonstrated that binding and internalization of MP/CD22 complexes was correlated with pre-B ALL cell line responses to MP. In addition, the Fv MP/CD22 complexes internalized more slowly than the parent RFB4 antibody/CD22 complexes. In addition to evaluating cell lines, we applied similar assays to 7 patient samples of bone marrow blasts, where we evaluated bound and internalized MP with cellular toxicity up to 72 hours. Our results suggest that some of the heterogeneity observed in in vitro responses to treatment with MP may be related to differences in internalization. Additional studies evaluating intracellular cleavage and trafficking/processing of MP in cell lines and patient blasts is ongoing. These studies, combined with planned in vivo studies evaluating MP antitumor efficacy using ALL cell lines and patient blasts, will provide a more comprehensive picture for differences in ALL response to treatment with MP. TLaVallee currently affiliated with Kolltan Pharmaceuticals, New Haven, CT, USA; work related to this abstract occurred at MedImmune. Disclosures: Burke: MedImmune: Employment. LaVallee:MedImmune: full employee when work was conducted Other.