ALBERT

Description: Introduction The current standard to assess chemotherapy tolerability relies on patient self-reporting. However, as the sole mechanism of managing symptom burden, this may be inconsistent and fraught with bias. Mobile wearable health devices have the ability to monitor and aggregate objective activity and sleep data over long periods of time, but have not been systematically used in the oncology clinic. The aim of the study was to assess whether the use of mobile wearable technology establishes patterns of "sleep" and "wake" states in newly diagnosed Multiple Myeloma (NDMM) patients receiving therapy, and whether these patterns differ over time. Methods Patients presenting to the myeloma clinic at Memorial Sloan Kettering Cancer Center (MSKCC) with a new diagnosis of Multiple Myeloma and smart phone or tablet (iOS or Android) compatible with the Garmin Vivofit device were offered to participate in a mobile wearable bio-monitoring study. All eligible participants were required to receive primary chemotherapy treatment at a MSKCC facility. Treatment was determined by physician. NDMM patients were assigned to one of two cohorts (20 in each; Cohort A - patients

Description: Background: Induction chemotherapy for acute myeloid leukemia (AML) is more intensive than many other cancer treatments, and may be associated with a different symptom burden. Little is known about the most prevalent symptoms during AML induction, nor how they change over time, and with remission status. Similarly, little is known about the trajectory of quality of life (QoL) and distress scores in this population. We aimed to learn more about the natural history of these issues via a prospective, longitudinal, observational patient-reported outcomes study. Methods: We enrolled 43 inpatients with AML at initiation of induction chemotherapy, and assessed their symptoms, quality of life (QoL), and distress weekly during their month-long hospitalization for induction, and monthly thereafter, using 3 validated instruments: Patient Care Monitor v2.0 (PCM); Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu); and NCCN distress thermometer (DT). We used descriptive statistics and ANOVA to analyze results. Results: Mean age of study participants was 59.4 (SD 13.4); 21 (49%) were female. Patients were mostly high-risk for recurrence, with 25 (58%) being ≥60 years old, 19 (44%) having high-risk cytogenetics, and 10 (23%) having relapsed disease. Among relapsed patients, the mean number of prior treatments was 2.7 (SD 1.3). At the time of this analysis, 5 patients (18%) had gone on to receive a stem cell transplant. As expected, symptoms were most prominent during the second and third weeks of treatment. However, across all 4 weeks of induction patients consistently reported 5 symptoms at a moderate or severe level (scores of 4 to 6, or 7 to 10 out of 10, respectively), including: poor appetite (35%), dry mouth (37%), difficulty sleeping (38%), dysgeusia (44%), and fatigue (56%). Other prominent moderate-to-severe symptoms included diarrhea (35%), daytime sleepiness (30%), and nausea (27.5%), despite standard supportive care. Mean QoL by FACT-Leu worsened substantially from week 1 (121.8, SD 27.6) to week 2 (108.2, SD 26.3), and then slowly recovered thereafter, improving to better than baseline by month 3 and continuing to improve throughout 1-year of follow-up (p

Description: The IGHV4-34 gene is very frequent (~10%) in the B cell receptor immunoglobulin (BcR IG) gene repertoire of chronic lymphocytic leukemia (CLL). Over 30% of IGHV4-34 CLL cases can be assigned to different subsets with stereotyped BcR IG. The largest is subset #4 which represents ~1% of all CLL and ~10% of IGHV4-34 CLL and is considered a prototype for indolent disease. The BcR IG of a great majority (~85%) of IGHV4-34 CLL cases carry a significant load of somatic hypermutation (SHM), often with distinctive SHM patterns. This holds especially true for stereotyped subsets and is suggestive of particular modes of interactions with the selecting antigen(s). In detail, subsets #4 and #16, both involving IgG-switched cases (IgG-CLL), exhibit the greatest sequence similarity in SHM profiles, whereas they differ in this respect from IgM/D subsets #29 and #201. Prompted by these observations, here we explored the extent that these subset-biased SHM profiles in different IGHV4-34 stereotyped subsets were reflected in distinct demographics, clinical presentation, genomic aberrations and outcomes. Within a multi-institutional series of 20,331 CLL patients, 1790 (8.8%) expressed IGHV4-34 BcR IG. Following established bioinformatics approaches for the identification of BcR IG stereotypy, 573/1790 IGHV4-34 CLL cases (32%) were assigned to stereotyped subsets; of these, 340 cases (19% of all IGHV4-34 CLL and 60% of stereotyped IGHV4-34 cases) belonged to subsets #4, #16, #29 and #201, all concerning IGHV-mutated CLL (M-CLL). Clinicobiological information was available for 275/340 patients: #4, n=150; #16, n=44; #29, n=39; and #201, n=42. Comparisons between subsets revealed no differences in gender and age distribution. Interestingly, however, 36-43% of each subset cases were young for CLL (defined as patients aged ≤55 years), which is higher compared to general CLL cohorts, where young patients generally account for ~25% of cases. In contrast, significant differences were identified between subsets regarding: (i) disease stage at diagnosis, with 〉90% of IgG subsets #4 and #16 diagnosed at Binet stage A versus 83% in subset #201 and 74% in subset #29 (p=0.029); (ii) CD38 expression, ranging from 1% in subset #4 to 10% in subset #201 (p=0.013); (iii) the distribution of del(13q), peaking at a remarkable 92% in subset #29 versus only 37% in subset #16 (p

Description: Notch1-mutated T-ALL is an aggressive hematologic malignancy lacking targeted therapeutic options. Genomic alterations in Notch1-gene and its activated downstream pathways are associated with metabolic stress response and heightened glutamine (Gln) utilization to fuel oxidative phosphorylation (OxPhos) (Kishton at al., Cell Metabolism 2016, 23:649, Herranz at al., Nat Med, 2015, 21(10): 1182-1189). Hence, targeting NOTCH1-associated OxPhos and/or Gln dependency could constitute a plausible therapeutic strategy for T-ALL. In this study we examined metabolic vulnerabilities of NOTCH1-driven T-ALL and tested pre-clinical efficacy of novel mitochondrial complex I (OxPhosi) IACS-010759 and of glutaminase inhibitor CB-839 (GLSi) in T-ALL models including Notch1-mutated T-ALL cell lines, patient-derived xenograft (PDX) and primary T-ALL cells. We have previously reported and confirmed in this expanded study the anti-leukemia efficacy of IACS-010759 (EC50s 0.1-15 nM) (Molina at al., Nat Med, 2018, 24: 1036; Baran at al., Blood, 2018, 132:4020). Metabolic characterization demonstrated that OxPhosi caused striking dose-dependent decrease in basal and maximal oxygen consumption rate (OCR), ATP and NADH generation in T-ALL cell lines and primary T-ALL samples (p

Description: Key Points In B-ALL, cells that express a functional pre-BCR ibrutinib abrogate leukemia cell growth in vitro and in vivo. Effects of ibrutinib in B-ALL not only are mediated through inhibition of BTK but also involve BLK inhibition.

Description: CD19-directed chimeric antigen receptor T cell (CAR-T) therapy has shown impressive results in children and adults with relapsed or refractory B-ALL or diffuse large B-cell lymphoma. However, 30 - 70% of initial responders will eventually relapse with CD19 antigen loss (CD19Neg) (Maude SL, et al. N Engl J Med. 2018). To avoid CD19Neg relapse, patients may undergo a hematopoietic stem cell transplant (HSCT). HSCT is an expensive and often morbid procedure that many physicians would prefer to avoid. The development of tools to accurately predict which patients are at risk for CD19Neg relapse would guide treatment decisions regarding HSCT or alternative therapies. Since CD19Neg relapses also occur in patients treated with other CD19-directed immunotherapies, like blinatumomab (Mejstríková E, et al. Blood Cancer J. 2017), a predictive model to detect patients at risk of CD19Neg relapse would have broader therapeutic impact. To address this problem, we performed CyTOF and RNA-seq analysis from paired patient samples collected before CD19-directed CAR-T administration and after CD19Neg relapse. High dimensional phenotyping by CyTOF clustered patient samples based on their mechanism of CD19 expression loss (frameshift mutation versus expression of intracellular isoforms), even before CAR-T administration. In addition, we identified identical immunoglobulin heavy and light chain RNA sequences before CAR-T administration and after CD19Neg relapse, suggesting that the clones destined to cause relapse are present at the time of CAR-T administration. Altogether, these results support our hypothesis that resistant tumor cells are present before CAR-T administration and could be discovered and interrogated for CD19Neg relapse prediction. To identify cell subpopulations responsible for driving CD19Neg relapse, we used the B cell developmental classifier previously developed in our lab (Good Z, et al. Nat Med. 2018). We observed a significant increase in the Early-non-BI population (CD38Pos CD24Pos CD19Neg CD20Neg CD3Neg CD16Neg CD61Neg cells) after CD19Neg relapse, suggesting that CD19 loss is associated with the loss of other B cell features. Since our classifier relies on CD19 to classify cells, we compared the resulting classification of cells when CD19 was included or excluded in the classifier. This change had minimal impact in cell classification from healthy bone marrow controls. However, when applied to the samples collected before CAR-T administration, we found a subpopulation of CD19Pos Pro-B cells that classified as Early-non-BI cells when CD19 was excluded from the classification. We hypothesize that these Pro-B "discordant" cells are those that lose CD19 expression to escape the immune pressure exerted by the CD19-directed CAR-T and mediate CD19Neg relapse. Further, we found Pro-B "discordant" cells in 77% of independent cohort of 22 B-ALL samples collected at the time of diagnosis, suggesting these cells exist in de novo B-ALL. We likewise identified a CD19Neg IgMPos Early-non-BI subpopulation in 4 healthy bone marrow and further studies are ongoing to characterize these cells. We continue to interrogate this candidate population as that responsible for CD19Neg relapse after CAR-T cell therapy. In addition, we performed differential expression analysis between paired samples collected before (CD19Pos) and after (CD19Neg) CAR-T therapy. Through the application of the developmental classifier, we identified that CD19 loss is associated with upregulation of key B cell transcription factors IKAROS, PAX5 and glucocorticoid receptor in the pre-pro-B to Pre-B stages. Moreover, after CD19 loss, there are also increases in levels of phosphorylated proteins pSYK, pSRC and pSTAT5, involved in IL7 receptor and pre-BCR signaling pathways, essential for B cell development. This suggests that CD19Neg cells activate unique tumorigenic pathways that may provide novel therapeutic opportunities. Exploration and validation of these therapeutic targets could significantly improve clinical outcome and care of patients with CD19Neg B-ALL. In conclusion, these results support the feasibility to predict patients at risk for CD19Neg relapse together with the mechanism behind it. Future studies will be conducted to confirm unique tumorigenic pathways in CD19Neg B cells and determine their therapeutic potential. Disclosures Mullighan: Illumina: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored travel; Amgen: Honoraria, Other: speaker, sponsored travel; AbbVie: Research Funding; Pfizer: Honoraria, Other: speaker, sponsored travel, Research Funding; Loxo Oncology: Research Funding. Grupp:Humanigen: Consultancy; CBMG: Consultancy; Novartis: Consultancy, Research Funding; Roche: Consultancy; GSK: Consultancy; Novartis: Research Funding; Kite: Research Funding; Servier: Research Funding; Jazz: Other: study steering committees or scientific advisory boards; Adaptimmune: Other: study steering committees or scientific advisory boards; Cure Genetics: Consultancy.

Description: Background: Data on overall survival (OS) and adverse events (AEs) in patients with chronic lymphocytic leukemia (CLL) are mostly available from controlled trials, with limited data from routine clinical practice. We therefore conducted a population-based retrospective cohort study to assess OS, incidence of AEs, and economic burden in patients treated for CLL. Methods: Patients with CLL receiving ≥ 1 systemic therapy from 2013-2015 were selected from the Medicare claims database and followed through 2016. The date of the start of first observed therapy served as the index date. Patients were required to have at least 12 months of continuous Medicare enrollment with no evidence of systemic therapy for CLL and/or SCT before the index date. An observed therapy regimen was defined as the combination of all agents received within 35 days after (and including) the first claim for a systemic therapy drug. Therapy was considered ended upon switch to a different regimen or a gap ≥ 90 days after the last treatment. OS was assessed from the index date until the last follow-up or death using the Kaplan-Meier method. Incidence of hematologic and nonhematologic AEs during treatments were assessed for the most commonly observed regimens. The incidence of AEs was based on the presence of at least one claim containing an AE-specific diagnosis code during the treatment, regardless of any history of the AE before treatment initiation. All-cause direct medical costs were assessed from the Medicare's perspective. Results: We analyzed 7965 patients (median age=76 years) who met the inclusion criteria. In the overall study follow-up (across all observed therapy lines), ibrutinib monotherapy (Ibr; n=2708) was the most frequent regimen, followed by chlorambucil monotherapy (Clb; n=1620) and bendamustine/rituximab (BR; n=1485). Median length of follow-up from the index date was 19 months for Ibr, 21 months for Clb, and 24 months for BR. Median OS was reached only for Clb (40.8 months [95% CI = 38.6-not reached]). 24-month OS rates for Ibr, Clb, and BR recipients were 69% (95% CI = 68%-71%), 68% (95% CI = 65%-71%), and 79% (95% CI = 77%-81%), respectively. The incidence of the most frequent AEs (occurrence in 〉10% of patients) are presented in Table1 1; estimates in bold indicate that the incidence of the AE was higher by ≥ 5 percentage points than in the noted trials (Woyach, 2018, N Engl J Med; Burger, 2015, N Engl J Med). The mean per patient per month costs, among all patients, were $1,915 (SD = $2,453) during the baseline period and $8,974 (SD = $11,562) during the period after initiation of the first observed CLL-directed systemic therapy. Mean monthly all-cause costs increased by the number of AEs (from $5,144 [SD = $5,409] among those with 1-2 AEs to $10,077 [SD = $12,542] among those with ≥6 AEs). Conclusion: To our knowledge, this is the largest contemporary observational study reporting outcomes among CLL patients initiating treatments in a real-world setting. Over two-thirds of patients survived ≥2 years after start of the first observed therapy during the study period. Incidence for several hematologic and nonhematologic AEs during the common CLL therapies observed in this study appear to be higher than those reported in the noted clinical trials, highlighting potentially greater susceptibility to these AEs and an unmet medical need in Medicare patients with CLL treated in routine practice. This study also highlights a substantial economic burden that exists in the period after initiation of treatment for CLL. Disclosures Goyal: RTI Health Solutions: Employment. Nagar:RTI Health Solutions: Employment. Kabadi:AstraZeneca: Employment, Equity Ownership. Davis:RTI Health Solutions: Employment. Le:AstraZeneca: Employment, Other: Stocks. Kaye:RTI Health Solutions: Employment.

Description: Background: Nephropathy in sickle cell anemia (SCA) begins in childhood and portends chronic kidney disease, renal failure, and early mortality among affected adults. Individuals of African descent have disproportionately higher rates of developing non-diabetic renal disease. Several candidate genetic variants have been identified, including some specific to African Americans, which are associated with the development of albuminuria and renal disease. The influence of genetic polymorphisms on albuminuria and elevated glomerular filtration rate (GFR) in children with SCA, both early signs of sickle nephropathy, has not been investigated. Objectives: To determine the influence of selected single nucleotide polymorphisms (SNPs) on the development of albuminuria and elevated GFR in children with SCA; to identify novel genetic variants influencing albuminuria and GFR by whole exome sequencing (WES). Design/Methods: Genomic DNA was collected on children with SCA enrolled in two prospective studies with pre-hydroxyurea renal assessments (n=185): (1) Hydroxyurea Study of Long-Term Effects (HUSTLE, NCT00305175, n=79) with no prior disease-modifying therapy; and (2) Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea (TWiTCH, NCT 01425307, n=106) on chronic transfusions for abnormal TCD velocities. Albuminuria was defined as ≥30mg albumin/gm creatinine on the pre-hydroxyurea urine specimen. GFR was measured in HUSTLE using plasma DTPA (technetium 99m-labeled diethylenetriaminepentaacetic acid) clearance, and estimated GFR (eGFR) in TWiTCH based on serum creatinine. DNA samples were genotyped for 8 candidate SNPs previously associated with renal disease, using PCR-based allelic discrimination, bidirectional Sanger sequencing, and analysis of variable number tandem repeats (VNTR). Associations between albuminuria and genetic polymorphisms were tested using an additive model and correlation trend test. Linked WES data from the same patients were analyzed to identify other variants associated with albuminuria and GFR. Results: Albuminuria was present in 13.1% of patients, including 16.3% in HUSTLE and 11.0% in TWiTCH. APOL1 genetic variants were common (G1 allele frequency = 21.9%, G2 allele = 16.0%, Table) and similar to published cohorts. Children with two APOL1 G1 alleles had an increased risk of albuminuria that approached statistical significance (p=0.053). Conversely, the presence of the DARC SNP that confers Duffy antigen expression had a protective effect (p=.038). WES analysis did not identify additional non-synonymous APOL1 variants linked with albuminuria. However, 93 non-synonymous variants were associated with DTPA GFR (p

Description: The regulatory function of recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) on granulocyte production in vivo was evaluated in an autologous bone marrow transplantation model using rhesus monkeys. Monkeys were exposed to 9.0 Gy total body irradiation and then transplanted with 5.0 x 10(7) low-density bone marrow cells/kg. Alzet miniosmotic pumps were subcutaneously implanted to deliver rhGM-CSF at a rate of 50,400 U/kg/d. Minipumps, containing either rhGM-CSF or saline, were implanted between zero and five days after transplantation for seven days. Kinetic recoveries of peripheral blood cells after either saline or rhGM-CSF treatment were compared. Treatment with rhGM-CSF accelerated the recovery of neutrophils. Neutrophils in rhGM-CSF-treated animals recovered to 80% (3.4 x 10(3)/mm3) pre-irradiation control levels by day 20, in comparison with only 33% (0.9 x 10(3)/mm3) recovery for saline control monkeys. In addition, the recovery of neutrophils was enhanced over that of the controls, reaching 140% v 70% on day 30. Another prominent feature of rhGM-CSF-treated monkeys was the accelerated recovery of platelets, reaching near 50% normal levels by day 24 in comparison with 20% of normal levels for controls. The infusion of rhGM-CSF was shown to be an effective regulator of early hematopoietic regeneration, leading to the accelerated recovery of both neutrophils and platelets and then providing a consistent sustained increase of neutrophils even in the absence of rhGM-CSF.

Description: Purpose: We assessed the survival outcome of patients with anaplastic large cell lymphoma (ALCL) who experienced disease progression or relapse after first line and subsequent therapy. We sought to evaluate the impact of brentuximab vedotin (BV), and survival outcome of patients with ALCL who experienced progression after BV. Patients and Methods: A total of 176 patients (74 ALK+, 102 ALK-) initially diagnosed between 1999 and 2014 were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) after the progression/relapse following first-line chemotherapy (PFS1 and OS1), after first salvage therapy (PFS2 and OS2) and after second salvage therapy (PFS3 and OS3) were calculated. Outcome was separately analyzed according to the ALK status focusing on the use of BV. Results: The median age of the patients was 50 (range: 18-89). With a median follow up of 64 months, 111 patients (38 ALK+, 73 ALK-) experienced progression/relapse after the first-line therapy, of which 4 ALK- patients were post upfront stem cell transplant (SCT). Thirty and 15 patients eventually underwent autologous and allogeneic SCT after salvage chemotherapy, respectively. The median PFS1 and OS1 in patients with ALK+ALCL and ALK-ALCL were 8.4 and 28.5 months, and 13.1 and 47.7 months, respectively. In patients with ALK+ALCL, the median PFS1, PFS2 and PFS3 were 53.6, 5.2 and 2.3 months, respectively. The median OS1, OS2 and OS3 were not reached, 47.3 and 6.1 months, respectively. In patients with ALK-ALCL, the median PFS1, PFS2 and PFS3 were 12.9, 3.0 and 2.0 months, respectively. The median OS1, OS2 and OS3 were 54.3, 10.8 and 5.8 months, respectively. Interestingly, there were no significant difference in PFS2 between ALK+ALCL and ALK-ALCL. However, OS2 was significantly longer in patients with ALK+ALCL, suggesting possibly continued chemosensitivity of recurrent ALK+ALCL. A total of 30 patients received BV in 1st salvage (15 patients) and after 2nd salvage (15 patients).The use of BV at 1st salvage was associated with significantly longer PFS2 and OS2 both in patients with ALK-ALCL but not with ALK+ALCL likely due to small number of cases. Mutivariate analysis adjusting baseline PIT risk factors and the duration of the response to first line therapy revealed that use of BV (at any point in the salvage setting) is significantly associated with longer OS2 (HR: 0.43, 95%CI: 0.23-0.80). Overall, 12 patients experienced relapse/progression after BV treatment. The median OS after BV failure was 1.4 months (95%CI: 0.5-9.5 months) (Figure). Summary: Survival outcome for relapsed/refractory patients with ALK+ and ALK- patients is improved with BV. However, survival outcome after BV failure is very poor. A new treatment strategies to consolidate or maintain the response after BV and to develop more safe and better therapeutic options are needed. Figure 1. Figure 1. Disclosures Fanale: Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Genentech: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Molecular Templates: Research Funding; ADC Therapeutics: Research Funding; Onyx: Research Funding; Gilead: Research Funding. Westin:Spectrum: Research Funding. Nastoupil:Celgene: Honoraria; Genentech: Honoraria; AbbVie: Research Funding; Janssen: Research Funding; TG Therapeutics: Research Funding. Wang:Celgene: Research Funding.