Efficacy of treatment intensity in German-speaking children with childhood apraxia of speech

Motor learning principles guide treatment of childhood apraxia of speech (CAS). Previous studies found children to benefit from higher-intensity conditions; however, they did not control for the total amount of therapy time. The aims of the article are to examine the effects of high versus low treatment frequency in intervention for CAS in German-speaking children. An alternating single-subject design with multiple baselines was applied to compare frequent, short sessions with fewer, longer sessions in terms of speech production accuracy in four children with CAS while keeping the total therapy time constant. We administered a version of integral stimulation treatment. Despite inter-individual differences, changes under both treatment conditions showed similar positive trajectories for all four children. Untreated control targets also improved across participants and conditions. Maintenance and generalization to untreated targets were observed two weeks and three months post treatment, independent of treatment intensity. Our results show no significant advantage of more intensive treatment when the total therapy time is held constant. This study contributes to the evidence base for the use of integral stimulation in treating children with CAS, and in particular those who speak languages other than English.

Romiplostim, Low-Dose Rituximab and High-Dose Dexamethasone Combination in Newly Diagnosed Immune Thrombocytopenia: Another "Total Therapy" Pilot Study

Background: Primary immune thrombocytopenia (ITP) is an acquired autoimmune disorder that results from accelerating platelet clearance, destruction, and production. Front-line therapy for newly diagnosed ITP includes corticosteroids, intravenous immune globulin, or anti-D immunoglobulin. However, after these single-agent therapies, relapses will occur in half of patients. We previously reported the safety, feasibility, and efficacy of the combination of dexamethasone, low-dose rituximab, and the thrombopoietin receptor agonist (TPO-Ra) eltrombopag as front-line treatment in newly diagnosed ITP. Romiplostim, another TPO-Ra is approved by the FDA for patients with chronic ITP. However, the safety, tolerability, and efficacy of romiplostim combined with low-dose rituximab, and high-dose dexamethasone in newly diagnosed ITP remain unknown. Objective: Our primary objectives were safety, and tolerability. Secondary objectives were initial response and relapse incidence. Methods: An open-label, single-arm study was performed in Hospital Universitario "Dr. José Eleuterio González" in Monterrey, Mexico (Clinical trials.gov NCT04588194). Eligible patients were newly diagnosed ITP patients, treatment-naïve, ≥18 years, with a platelet count ≤30×10 9/L. Patients were excluded if they had an active infection, pregnancy, or malignant disease. The treatment regimen was romiplostim (2 mcg/kg weekly, four doses), low-dose rituximab (100 mg weekly, four doses) and high-dose dexamethasone (40 mg PO, days 1-4). Dexamethasone was allowed up to 3 cycles. Partial (PR) and complete responses (CR) were defined as an increase in platelet counts ≥30×10 9/L (at least a doubling of the baseline count) and ≥100×10 9/L, respectively. Results: We included ten consecutive patients. The median age was 34.5 years (range, 17-63). Seven patients were men (70%). The median platelet account at diagnosis was 6x10 9/L (range 0-23), and median follow-up was 180 days (range 30-270). The median number of romiplostim doses was 3.5 (range 1-4), and three (30%) patients required dose adjustment due to thrombocytosis. All but one patient achieved response (CR or PR) at a median of 7 days (range 7-28). Five patients (50%) achieved CR at 28 days of treatment, and four patients (40%) PR. No significant adverse effects have occurred during treatment; one patient presented grade 1 myalgia and the other a grade 2 soft tissue infection. Five patients (50%) relapsed during follow-up. Recently, four (40%) patients remain in CR and three (30%) in PR. Conclusion: The combination of romiplostim, low-dose rituximab, and high-dose dexamethasone was safe and effective. This "total therapy" approach was associated with minimum side effects and rapid initial response. Prospective validation in a larger sample is needed. Figure 1 Figure 1. Disclosures Gomez-Almaguer: Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Bristol-Myers-Squibb: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. OffLabel Disclosure: Romiplostim in firs-line therapy for immune thrombocytopenia

A multicenter total therapy strategy for de novo adult Philadelphia chromosome positive acute lymphoblastic leukemia patients. Final results of the GIMEMA LAL1509 protocol

The GIMEMA LAL1509 protocol, designed for adult (≥18-60 years) de novo Ph+ acute lymphoblastic leukemia patients, was based on a dasatinib plus steroids induction - with central nervous system prophylaxis - followed by dasatinib alone in patients in complete molecular response or chemotherapy and/or allogeneic transplantation in patients not reaching a complete molecular response. Sixty patients (median age 41.9 years) were enrolled: 33 were p190+, 18 p210+ and 9 p190/p210+. At the end of induction (day +85), 58 patients (97%) achieved a complete hematologic remission. No deaths in induction were recorded. Eleven patients (18.3%) obtained a complete molecular response. Among non-complete molecular responders (n=47), 22 underwent an allogeneic transplant. Seventeen hematologic relapses occurred (median 7 months, range 3-40.1), 13 during consolidation and 4 post-transplant. ABL1 mutations (5 T315I, 3 V299L, 1 E281K and 1 G254E) were found in 10/13 relapsed cases. With a median follow-up of 57.4 months (range: 4.2-75.6), overall survival and disease-free survival are 56.3% and 47.2%. A better diseasefree survival was observed in patients who obtained a molecular response at day +85 compared to cases who did not. The presence of additional copy number aberrations - IKZF1 plus CDKN2A/B and/or PAX5 deletions - was the most important unfavorable prognostic factor on overall and disease-free survival (p=0.005 and p=0.0008). This study shows that in adult Ph+ ALL long-term survivals can be achieved with a total-therapy strategy based on a chemo-free induction and, in complete molecular responders, also without further systemic chemotherapy. Finally, the screening of additional copy number aberrations should be included in the diagnostic work-up. EudraCT 2010-019119-39

Rehabilitation Therapy Staffing Composition and Post-Acute Care Quality in Skilled Nursing Facilities

Rehabilitation therapy staffing is crucial in achieving high quality of post-acute care (PAC) in skilled nursing facilities (SNFs), but few studies have explored therapy staffing composition and how it relates to SNFs’ PAC quality. This study describes SNFs’ therapy staffing composition and its association with facility-level PAC fall rates. Our study was a cross-sectional study using facility-level data (Q3 2017-Q2 2018). Data sources include Nursing Home Compare, Payroll-Based Journal data, Area Health Resource File and LTCFocUS.org. The first independent variable was the share of total therapy staff in the direct care team, a ratio between total therapy staffing hours and total direct care hours (includes nursing).To further understand the composition of therapy staff with different qualifications within the therapy team, two variables were generated: 1) proportion of higher skilled therapy staff (i.e. assistant, therapist) hours of total therapy hours; and 2) assistant to therapist ratio. Multivariate linear regression modeling was used, controlling for other characteristics and state fixed effects. Our results show SNF therapy staffing compositions varied significantly by profit status, chain affiliation, and urban/rural location. Further, SNFs with higher shares of therapy staff and higher skilled staff had significantly lower fall rates. However, SNFs with higher assistant-to-therapist ratios had higher fall rates. Our results demonstrated the value of having a multidisciplinary team with higher skilled staff. The results also supported researchers’ concerns that recent Medicare payment change (i.e. the Patient Driven Payment Model) may negatively impact quality by reinforcing providers’ incentives of reducing rehabilitation staffing and/or using lower-skilled staff.

Late Relapsing Multiple Myeloma ≥ 10 Years after Treatment on Total Therapy Protocols Are Associated with Good Outcome

Introduction Novel agents are incorporated into a backbone of multi-agent chemotherapy and tandem transplantation in successive Total Therapy (TT) protocols for multiple myeloma (MM) patients. The TT protocols extend the duration of remission with a significant proportion of patients achieving long-term disease control. However, a small percentage of patients have documented late relapse and we theorize that these relapses are indolent with overall good clinical outcome. While even a late relapse is seemingly an undesirable outcome, defining the clinical implications is imperative to understanding the impact on long-term prognosis and management. Methods Our MM database was interrogated to identify patients that presented with relapsing disease ≥ 10 years from diagnosis and were treated on TT protocols. All patients had myeloma markers every 2 to 3 months and bone marrows with either PET-CT or MRI at least once a year. In the group of patients with documented relapse, we obtained the pattern of relapse, clinical and laboratory markers, cytogenetics, FISH, gene expression profile (GEP), bone marrow (BM) minimal residual disease (MRD), imaging (PET-CT and MRI, use of salvage transplant, and response assessment including best response to treatment. Patterns of relapses were evaluated based on elevated serum myeloma markers, BM plasmacytosis and presence of macrofocal relapse/extramedullary disease. Clinical relapses were classified based on the International Myeloma Working Group criteria. Indolent relapse was defined as a biochemical relapse with a rising M-protein or free light chains, less than 30% bone marrow plasmacytosis involvement, absence of focal lesion on imaging and of CRAB criteria, low riskGEP70 signature at relapse or no abnormal metaphase cytogenetics. Results A total of 2055 patients were enrolled and treated on successive TT protocols (TT1 to TT7) of which 658 patients had ≥10 years follow up from initial study enrollment. Among these 658 patients, 8% (53/658) had a clinical relapse ≥ 10 years from diagnosis. The median time to clinical relapse was 11. 8 years (range, 9.8 - 17.6). Median age at the time of relapse was 67.7 years with 28% being females. Gene expression profiling showed that 45% (24/53) belonged to the molecular CD2 and LB subgroups. The most common pattern of relapse is with BM plasmacytosis in 49% (26/53) with 36% (19/53) presenting with CRAB clinical features. Focal lesions by MRI and/or CT-PET were present in 35.8% (19/53). Overall, 56.6% (30/53) of patients had indolent relapses; of these 9 and 7 belonged to the CD2 and LB molecular subgroups, respectively. BM MRD assessment by 8-color flow cytometry was available in 17 patients and MRD positivity preceded clinical relapse by a median 17.9 months (range: 0 - 60.8). Forty-one patients required treatment for disease relapse with 11 patients managed expectantly without treatment. While most patients (73.1%, 30/41) received initial treatment with either PI/IMiD/PI IMiD combinations, 8 patients later underwent salvage ASCT. A response of ≥ VGPR was attained in 70% (31/47) of the treated patients with the large majority (87%) achieving a sCR/CR. The overall survival from relapse at 5 years was 73.3% (95% CI: 55.0% to 85.1%). A total of 14/53 patients died during follow-up;7 patients died to progressive disease; 6 of these 7 presented with focal lesions detected on imaging and had an aggressive relapse. Three patients died to treatment related complications, 1 had an unrelated pneumonia, the cause of death was indeterminate in 2 and unknown in 1. Overall, in these 14 patients, median time to death from initial diagnosis was 15.4 years (range: 11.8 - 18.0) and a median time to death from relapse was 3.2 years (range: 0.3 - 6.0). Conclusions Late relapses (>10 years) in MM are a rare event occurring in 8% of long-term survivors and accounting for 2.6% of all patients treated on the TT protocols. Intriguingly, most patients with late relapsing MM belong to the GEP subtype LB and CD2 and accounted for 51% of the indolent relapses. These findings have clinical implications and emphasizes the importance of extended and close follow-up even in patients with prolonged clinical remission. Disclosures van Rhee: Karyopharm: Consultancy; Adaptive Biotech: Consultancy; Takeda: Consultancy; EUSA: Consultancy; CDCN: Consultancy.

Improved CNS Control of Childhood Acute Lymphoblastic Leukemia Without Cranial Irradiation: St Jude Total Therapy Study 16

PURPOSE Despite contemporary treatment, up to 10% of children with acute lymphoblastic leukemia still experience relapse. We evaluated whether a higher dosage of PEG-asparaginase and early intensification of triple intrathecal therapy would improve systemic and CNS control. PATIENTS AND METHODS Between 2007 and 2017, 598 consecutive patients age 0 to 18 years received risk-directed chemotherapy without prophylactic cranial irradiation in the St Jude Total Therapy Study 16. Patients were randomly assigned to receive PEG-asparaginase 3,500 U/m2 versus the conventional 2,500 U/m2. Patients presenting features that were associated with increased risk of CNS relapse received two extra doses of intrathecal therapy during the first 2 weeks of remission induction. RESULTS The 5-year event-free survival and overall survival rates for the 598 patients were 88.2% (95% CI, 84.9% to 91.5%) and 94.1% (95% CI, 91.7% to 96.5%), respectively. Cumulative risk of any—isolated or combined—CNS relapse was 1.5% (95% CI, 0.5% to 2.5%). Higher doses of PEG-asparaginase did not affect treatment outcome. T-cell phenotype was the only independent risk factor for any CNS relapse (hazard ratio, 5.15; 95% CI, 1.3 to 20.6; P = . 021). Among 359 patients with features that were associated with increased risk for CNS relapse, the 5-year rate of any CNS relapse was significantly lower than that among 248 patients with the same features treated in the previous Total Therapy Study 15 (1.8% [95% CI, 0.4% to 3.3%] v 5.7% [95% CI, 2.8% to 8.6%]; P = .008). There were no significant differences in the cumulative risk of seizure or infection during induction between patients who did or did not receive the two extra doses of intrathecal treatment. CONCLUSION Higher doses of PEG-asparaginase failed to improve outcome, but additional intrathecal therapy during early induction seemed to contribute to improved CNS control without excessive toxicity for high-risk patients.

The Role of PHF19 As a Promoter of Tumorigenicity and Therapeutic Target in Multiple Myeloma

Introduction - Multiple Myeloma (MM) is a hematologic malignancy characterized by clonal growth of differentiated plasma cells (PCs). Despite improvement in MM therapy, the disease remains mostly incurable and is characterized by recurrent relapses with development of resistant clones that eventually lead to patient death. The pathways that lead to resistant and aggressive MM are not fully understood highlighting the need to improve our understanding of MM biology to identify potential new pathways and therapeutical targets. PHD Finger Protein 19 (PHF19) is a regulator of Polycomb Repressive Complex 2 (PRC2), the sole methyltransferase complex capable of catalyzing H3K27me3 to induce and enforce gene repression. PRC2 employs enhancer of zeste homolog 1 and 2 (EZH1/EZH2) as enzymatic subunits to hypermethylate H3K27. While overexpression and gain of function mutations of EZH1/2 have been observed in many cancers the role of this particular pathway in MM remains poorly understood. In the present study, we report on PHF19 as a new candidate gene to play a potential crucial role in MM oncogenesis. Methods- Gene expression profiling (GEP; Affymetrix U133 Plus 2.0) was performed on 739 MM patients (from total therapy trials [TT] 3-5; low risk MM n=636, high risk MM n=103), 42 patients with monoclonal gammopathy of undetermined significance (MGUS), 73 smoldering MM patients, 42 patients with primary plasma cell leukemia and 34 healthy donors. Myeloma risk was determined by the GEP 70 signature as previously defined. To test the implications of functional PHF19 knock down (KD) we used TRIPZ inducible PHF19 shRNA vs. scrambled control (Dharmacon) in two MM cell lines (JJN3 and ARP1). Real time PCR as well as western blotting was used to confirm PHF19 KD as well as to elucidate the effect on H3K27me3 (Cell Signaling). Functional in vitro studies included proliferation (Promega), clonogenic assays (StemCell), cell cycle and apoptosis assays (both Invitrogen). In vivo studies were performed using SCID mice that were subjected to tail vain injection with PHF19 KD JJN3 cells (n=10) or scrambled shRNA control (n=10). Weekly ELISA (Bethyl) and in vivo imaging (Xenogen) were performed and survival was recorded. Results- GEP of the previously mentioned patient populations and healthy controls identified PHF19 (chr9q33.2) as a candidate gene that was consistently dysregulated in MM patients. Mean expression levels at different MM stages correlated with disease aggressiveness (ANOVA, p<0.0001), Figure 1. High expression of PHF19 (log2>10.46) at diagnosis correlated significantly with adverse clinical parameters, including ISS III, anemia and elevated LDH, as well as worse overall survival (5 yr OS = 29% for patients with high PHF19 expression vs 77% for patients with low PHF19 expression [log2<10.46], p< 0.0001). These results led us to test the implications of functional PHF19 KD using TRIPZ inducible PHF19 shRNA vs. scrambled control in the JJN3 and ARP1 MM cell lines. PHF19 KD led to a drastic reduction of H3K27me3 thereby resulting in significantly reduced proliferation via cell cycle arrest, while apoptosis was not substantially altered. Clonogenic assays showed a significant reduction in colony numbers and size of MM cells with PHF19 KD compared to the control (>75% reduction in both cell lines, p<0.05). Xenograft studies showed consistently less tumor burden in the mice injected with PHF19 KD cells compared to scrambled control, evident through ELISA testing for IgG Kappa (Median =180 mg/ml for scrambled control vs 80 mg/ml for PHF19 KD at week 8, p=0.07) and bioimaging (Median bioilumisence 2.1x108 p/s for scrambled control vs. 0.8x108 p/s for PHF19 KD at week 8, non-significant). Median OS in mice injected with PHF19 KD cell was substantially longer (66 days) compared to mice subjected to scrambled control cells (54 days), p=0.052. Conclusion- In summary we show that PHF19 is upregulated in malignant plasma cells of MM patients and that PHF19 expression levels increase with advanced MM stages. High PHF19 expression was a marker of adverse prognosis in our total therapy (TT 3-5) cohort. Most importantly, in-vitro and in-vivo functional studies showed that PHF19 has important biological functions in MM. These results suggest that epigenetic regulation through histone methylation, in particular, H3K27 trimethylation, plays a crucial role in MM and the affected downstream pathways should be further elucidated. Disclosures Boyle: Janssen: Honoraria, Other: Travel; Abbvie: Honoraria; Amgen: Honoraria, Other: travel; Takeda: Honoraria, Other: travel; Celgene Corporation: Honoraria, Other: Travel. van Rhee:Kite Pharma: Consultancy; Adicet Bio: Consultancy; Karyopharm Therapeutics: Consultancy; Takeda: Consultancy; Sanofi Genzyme: Consultancy; Castleman Disease Collaborative Network: Consultancy; EUSA: Consultancy. Walker:Celgene: Research Funding.