bluuebunny/crossref_metadata_2025_split huggingface dataset:
Good Outcome after R-Hyper-CVAD/R-MA in High-Risk Aggressive B-Cell Lymphoma: A Single-Center Experience
Authors: Sonnevi Kristina , Ljungqvist Maria , Joelsson Joel K , Harrysson Sara , Wästerlid Tove , Bernell Per , Wahlin Björn 
Published: November 2021

Abstract
INTRODUCTION
Patients with high-risk aggressive B-cell lymphoma exhibit poor survival after R-CHOP-like immunochemotherapy. More intensive regimens yield higher rates of remission but also of complication, which have hindered their use, particularly in older patients. At Karolinska, the standard intensive regimen has been R-Hyper-CVAD/R-MA for patients with high-risk characteristics, such as high age-adjusted international prognostic index (aaIPI) and extranodal disease.
METHODS
In this analysis, high-risk disease was defined as aaIPI ≥ 2 or any extranodal involvement. We examined Karolinska's 136 patients who received at least one cycle of R-Hyper-CVAD/R-MA in first-line therapy for high-risk disease, excluding Burkitt, transformed, and primary CNS lymphoma. Patients were diagnosed between 2006 and 2020; 89 were diffuse large B-cell lymphoma, 23 high-grade B-cell lymphoma, 17 primary mediastinal B-cell lymphoma, 4 T cell/histiocyte-rich B-cell lymphoma, 2 aggressive B-cell lymphoma unspecified, 1 lymphomatoid granulomatosis grade 3. For outcome, we investigated progression-free survival (PFS).
RESULTS
In this cohort of 136 patients with high-risk disease treated with at least one cycle of R-Hyper-CVAD/R-MA, the median age was 52 years (range, 19-69); 36 patients (26%) were 61-69 years old. Lactate dehydrogenase was elevated in 92%, stage III-IV disease was seen in 93%, WHO performance status ≥2 in 49%, aaIPI = 3 in 38%, extranodal disease in 30%, CNS involvement in 17%, and Charlson comorbidity index ≥2 in 11%. At 5 years, the PFS in all patients was 72% and in the 50 patients with aaIPI = 3, 66% (Figure 1). In patients ≤60 years old, 5-year PFS was 76% (aaIPI = 3, 69%). In patients 61-69 years, the 5-year PFS was 58% (aaIPI = 3, 59%). Six out of 136 patients (4%) died from toxicity during induction therapy (3/6 were 61-69 years old).
CONCLUSIONS
This is to our knowledge the largest published single-center series of patients treated with R-Hyper-CVAD/R-MA for high-risk aggressive B-cell lymphoma. Outcome in these patients aged 19-69 years was excellent, with 5-year PFS 72%. Particularly patients with aaIPI = 3 showed rather good outcome with 5-year PFS 66%. For comparison, in Sweden the 5-year overall survival of R-CHOP-treated patients ≤60 years with aaIPI = 3 is 40% (Melén CM et al. Brit J Haematol. 614-622. 2016). We will continue to explore R-Hyper-CVAD/R-MA as primary therapy for high-risk aggressive B-cell lymphoma.
Figure 1 Figure 1.

Disclosures
Wahlin: Gilead Sciences: Research Funding; Roche: Consultancy, Research Funding.
Is Initial Dasatinib-Blinatumomab Therapy for Ph-Positive ALL in Adults Cost Effective?
Authors: Bitran Jacob D. , Nabrinsky Edward , Bufalino Shams , Knouse Phillip , Galvez Angel G. 
Published: November 2021

Abstract
Adult, Philadelphia chromosome-positive, Acute Lymphoblastic Leukemia (Ph-positive ALL) had a poor prognosis, but with the use of an initial BCR/ABL tyrosine kinase inhibitor such as Dasatinib in conjunction with chemotherapy such as hyper-CVAD, the projected 24 month disease free survival is 64%. More recently Foa et al. on behalf of the GIMEMA investigators published a phase II trial of Dasatinib and Blinatumomab as initial therapy for adults with ALL. The complete remission rate was 98%, and the projected disease-free survival at 24 months is 88%. We wished to analyze the incremental cost-effectiveness ratio (ICER) of the Dasatinib and Blinatumomab therapy as compared to Dasatinib and hyper-CVAD. The comparison is based on retail costs of chemotherapy for Dasatinib, Blinatumomab and hyperCVAD and excluded hospital and outpatient charges. The cost of hyperCVAD is based on treatment of a person with a BSA I.8m2. The retail cost of therapy is shown below.
Drug Dose Cost
Dasatinib 100 mg $505.67
Blinatumomab 1 mg $126.81
Cyclophosphamide 1,000 mg $231.00
Mesna 1,000 mg $42.89
Vincristine 2 mg $18.52
Dexamethasone 40 mg $4.12
Cytarabine 100 mg $22.88
Leucovorin 25 mg $7.48
The ICER formula is the cost of new therapy minus (-) the cost of standard therapy/quality of adjusted life new therapy - the quality of adjusted life standard (QALY). The yearly cost of Hyper-CVAD and Dasatinib is $147,288.48 per QALY, whereas, the yearly cost of Dasatinib-Blinatumomab is $187,940.46 per QALY. The difference is $42,451.98 which is less than the 50,000-threshold using cost-effective analysis. In conclusion, the combination of Dasatinib-Blinatumomab appears to be cost effective.

Disclosures
No relevant conflicts of interest to declare.
The Impact of Same Day Infusion Treatment Protocols for Uncomplicated Vaso-Occlusive Crises within an Embedded Sickle Cell Care Model
Authors: Sacknoff Stefanie , Groesbeck Jessica , Gopal Srila 
Published: November 2021

Abstract
Background: Infusion Center (IC) based care of uncomplicated sickle cell disease (SCD) vaso occlusive crises (VOCs) is very effective and results in better outcomes. At low volume sickle cell programs, it is challenging to acquire resources for a dedicated infusion program. Our goal was to create an embedded infusion program within our cancer center infusion services utilizing existing resources to improve the quality of care for our SCD patients.
Methods: A multi-disciplinary team consisting of a Nurse Case Manager, Advanced Practice Provider, MD, IC scheduler and IC charge nurse was assembled. An agreement was made between the SCD team and IC leadership that at least one time slot would be made available for a SCD VOC visit every day. A workflow was created and all team members were educated regarding the workflow. Visit numbers for IC visits, emergency department (ED) and inpatient (IP) hospitalizations were collected from the EMR and compared for pre IC development (Jan 1, 2017- Dec 31, 2018) and post IC (January 1, 2019 - Dec 31, 2020).
Results: Between 2017-2020, 182 patients with SCD were seen in the emergency room and 163 patients in our outpatient clinics. After the institution of an IC based care plan in January 2019, IC visit volume increased (270 visits pre IC vs.1076 visits post IC). ED treat and release (not requiring admissions) visits decreased from 373 visits pre IC to 286 visits post IC. The number of inpatient admissions did not change significantly during this time frame. However, the percentage of admissions from the ED increased (43% pre IC to 50% post IC), indicating a higher complexity of patients seeking care from the ED. 10 of 35 patients who used the IC in 2020 had no acute visits (ED or IP) in 2020, while these individual patients had a total of 37 ED visits in the pre IC timeframe, of which 20 were inpatient admissions with a total length of stay of 137 days and 17 treat and release episodes at the ED.
Conclusions: Our project successfully utilized existing infusion based resources to facilitate outpatient management of acute uncomplicated SCD VOCs. This project presents an effective strategy that can be utilized by smaller volume sickle cell programs who do not have a stand alone infusion program to improve the quality of care for their SCD patients.

Disclosures
Gopal: Pharming: Consultancy; GBT: Consultancy; Alexion: Speakers Bureau; Rigel Pharmaceuticals: Other: Clinical Trial, Research Funding.
There Is Association between Type of Pain and Hematologic Disorders
Authors: Levchenko Olga K. , Galstyan Gennadiy M. , Gemdzhian Eduard G. , Savchenko Valeriy G. 
Published: November 2021

Abstract
Background: Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage according to the International Association for the Study of Pain.
Aim: To estimate distinguishing features of the pain in patients with blood disorders.
Patients and Methods: The prospective exploratory study was conducted in the National Research Center for Hematology, Moscow from 11/2015 to 01/2021. In total, 40 patients (pts) with blood disorders who had a difficult-to-control pain syndrome were included in the study. There were 21 men (median age of 41.5, IQR 35.0-56.3 years) and 19 women (median age of 40, IQR 34.3-56.0 years). The pain types were determined according to clinical symptoms and the use of special questionnaires (i.e., the Douleur Neuropathique 4 Questions questionnaire for neuropathic pain). Pressure algometry was used to assess pain tolerance of the non-dominant hand by evaluating the pressure pain threshold (PPT, kg/cm 2), which is the minimum pressure required to induce pain.
Results: Four types of pain were identified: neuropathic in 9 pts (22.5%), nociceptive in 9 pts (22.5%), their mix (summing up to a half of the total number of cases ‒ 52.5%, 21 pts) and dysfunctional pain in only 1 patient (2.5%). The distribution based on the pain types was uneven (Kolmogorov test, p = 0.05). The different pain types were related with various distributions of blood disorders: lymphoid tumor (44.5%), myeloid tumor (33.3%) and not tumor (22.2%) (associated with neuropathic pain) and myeloid tumor (88.9%) and not tumor (11.1%) (associated with nociceptive pain) (Figs. 1 and 2) . The tolerance of neuropathic and nociceptive pain types turned out to be significantly different (PPT medians with 95% CI): 2.2 kg/cm 2 (1.6-3.1) vs. 4.6 kg/cm 2 (3.9-5.5), respectively, and (found in ROC-analysis) the cut-off was 3.2 kg/cm 2,AUC (the area under ROC curve) 96.3%, sensitivity and specificity 88.8% (Fig. 3 and 4). PPT cut-off points, that shares the mixed pain (median 2.7 kg/cm 2, 95 CI 1.9-3.6) on the neuropathic and nociceptive pain are: 3.2 kg/cm 2 (AUC 67.0%) and 3.8 kg/cm 2 (AUC 86.7%), respectively. Several measurements of PPT (with taking into account the cut-off) in patient, suffering from pain, can help identify with a high probability his type of pain, and accordingly (indirectly), his blood type disorder.
Conclusions: Measuring PPT in a pts with blood disorders allows to identify the type of pain (neuropathic, nociceptive, or combined), which can serve as an additional source of information for accurate diagnosis and treatment.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Predictors of Relapse Risk Do Not Influence Time to "Cure" in Children and Young Adults with Acute Lymphoblastic Leukaemia
Authors: Samarasinghe Sujith , Vora Ajay , Goulden Nicholas John , Antony Grace , Moorman Anthony V. 
Published: November 2021

Abstract
After how many years from diagnosis/completing treatment should children and young adults with acute lymphoblastic leukaemia be considered "cured"? Clinical trials generally report 5 year event free survival because the risk of relapse after that time-point is very low and this is assumed to mean cure. Indeed, the risk of relapse after four years from completing therapy was &lt;1% for patients treated on St Jude's trial Total Therapy XV and they proposed that length of follow-up should be considered to be the "time to cure". The group had previously shown that excess deaths beyond ten years in non-irradiated patients was similar to the general population whereas irradiated patients had a greater risk of excess mortality due to the development of secondary neoplasms. However, there was limited information about the time to cure and relative survival in sub-groups with variable relapse risk. We examined the long-term outcome of patients treated on an MRD stratified protocol UKALL 2003 that recruited patients between 2003-2011 to determine time to cure for the overall trial population and prognostic sub-groups defined by age, sex, immunophenotype, cytogenetics and MRD response.
There were a total of 3113 patients eligible for analysis with a median follow up of 9.4 years (only 20 patients received cranial irradiation). Relative survival rates were estimated using nationwide population mortality rates as the baseline accounting for age, sex and calendar year (Office of National Statistics 2018 release). The relative survival of UKALL2003 patients compared to equivalent children in the UK population was 96% (95% CI 95.5-96.7). Relative survival did not differ by sex but was significantly worse for patients &gt;10 years compared with younger patients (p&lt;0.001). As expected, patients with good risk cytogenetics ( ETV6-RUNX1, and high hyperdiploidy) and negative bone marrow Ig/TCR MRD at end of induction (EOI) had better relative survival rates and lower excess mortality (all p&lt;0.001) compared with patients who had adverse risk factors (high risk genetics and EOI MRD+).
To estimate the time to a cure, we calculated the conditional probability of relapse at 12 years for patients who had survived event to the start of each follow-up year. Although the initial risk of relapse differ significantly by sex, age, MRD and genetics the risk of relapse for all subgroups quickly coalesced at around 5-6 years (Figure 1). Furthermore, the time to cure, defined as a relapse risk &lt;1% (dashed blue line of figure), was similar across all the subgroups at 6-7 years.
In conclusion, the relative survival of young patients with good risk cytogenetics and EOI MRD negative status approaches that of their normal peers. However, regardless of prognosis, the time to cure is similar across risk groups.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Treatment Outcomes for Follicular Lymphoma with Progression of Disease within 24 Months of Front-Line Therapy: A Systematic Review
Authors: Siddiqui Raheel S , Shahzad Moazzam , Ahmed Saba , Zaidi Sara J , Shahid Sara , Chattha Suneeba , Khan Cyrus , Anwer Faiz 
Published: November 2021

Abstract
Background:
Progression of disease (POD24) within 24 months after front-line therapy in patients with Follicular lymphoma (FL) is associated with poor prognosis compared to delayed progression. There is a scarcity of data regarding the best treatment approach for these patients. We performed this systematic review to assess the efficacy of various therapeutic regimens used for the treatment of FL with POD24.
Methodology:
Three databases (PubMed, Cochrane Library, ClinicalTrials.gov) were searched in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines using the MeSH terms and keywords for: "Follicular Lymphoma" AND "recurrence" AND "therapy". The literature search was performed from Jan 01, 2010, to May 8, 2021. A total of 1832 studies were screened, and duplicates, reviews, and irrelevant articles were excluded. We included prospective and retrospective clinical trials presenting separate treatment outcomes of FL with POD24. A total of 3 studies were selected for inclusion after the application of inclusion and exclusion criteria.
Results:
A total of 167 patients from 3 studies were included for this review. In a retrospective study, High dose chemotherapy with autologous stem cell transplantation (HDC/ AutoSCT) for patients (n=17) with rituximab resistant FL with POD24 showed an objective response rate (ORR) of 88%, complete response (CR) of 29%, and partial response (PR) of 59%. In a phase III study of rituximab sensitive patients, 12 cycles of a combination of lenalidomide and rituximab (n=56) showed ORR of 80 %, CR of 30%, and PR of 50% whereas 12 cycles of Rituximab and placebo showed ORR, CR, and PR of 51%, 18%, and 33% respectively. In a retrospective post hoc analysis of subgroups of phase II clinical trial (n=37), Idelalisib showed an ORR of 56%, CR of 13%, and PR of 43% in rituximab-resistant patients. (Table 1)
Conclusion:
FL with POD24 is a poor prognostic factor for which therapeutic data is limited and uniform treatment recommendations are not available. Further prospective clinical trials with randomization and blinding are needed.
Figure 1 Figure 1.

Disclosures
Khan: Abbvie: Research Funding, Speakers Bureau; Astrazeneca: Research Funding, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; Epizyme: Research Funding, Speakers Bureau; Genentech: Research Funding, Speakers Bureau; GSK: Research Funding, Speakers Bureau; Karyopharm: Speakers Bureau; Kite: Speakers Bureau; Morphosys: Speakers Bureau; Sanofi: Speakers Bureau; SeaGen: Speakers Bureau. Anwer: GlaxoSmithKline: Research Funding; Janssen pharmaceutical: Honoraria, Research Funding; BMS / Celgene: Honoraria, Research Funding; Allogene Therapeutics: Research Funding.
Genomic Heterogeneity and Clonal Evolution in High Hyperdiploid Childhood Acute Lymphoblastic Leukemia
Authors: Woodward Eleanor L , Yang Minjun , Moura-Castro Larissa H , Spierings Diana CJ , van den Bos Hilda , Foijer Floris , Paulsson Kajsa 
Published: November 2021

Abstract
High hyperdiploid (HeH) B-cell precursor acute lymphoblastic leukemia (BCP ALL) is characterized by a very specific nonrandom gain of chromosomes; a feature distinct from other types of aneuploid tumor types that usually display very heterogeneous gains and losses of chromosomes. Gains of chromosomes X, 4, 6, 10, 14, 17, and 18 are seen in more than 75% of cases of HeH childhood ALL, and of chromosome 21 in 100% of cases. In contrast to many aneuploid malignancies, there has been little evidence of chromosomal instability (CIN) in HeH ALL and the mechanisms leading to these chromosomal gains remain unknown. The aim of this project was to determine the level of genomic heterogeneity in HeH ALL. In order to do this, we performed low-pass whole genome sequencing (WGS) of single cells isolated from diagnostic bone marrow samples from HeH ALL patients to investigate cell-to-cell heterogeneity. Single nuclei in G 1 phase from nine diagnostic childhood HeH ALL samples were isolated using fluorescence-activated cell sorting and DNA libraries were constructed for low-pass WGS. Copy number analysis for each individual cell was performed in-house using the software programs AneuFinder and Ginkgo. Homolog inheritance of chromosomes gained or lost was determined by screening for heterozygous variants and calculation of the variant allele frequencies (VAF). Sequencing 2,572 single cells showed that the nine HeH ALL patients were all relatively homogenous at the trunk of their evolution tree and that the bulk of chromosomal gains were stable and unchanging. Structural aberrations, visible as partial chromosome copy number changes, were detected at diagnosis in most cases, with a greater number of structural aberrations detected in patients with greater numbers of sub-clones (defined as three or more cells presenting with the same numerical and structural aberrations). Unique numerical chromosomal aberrations detected in two or fewer cells were relatively random and therefore indicative of nondisjunction events in recent cell divisions rather than being part of the clonal evolution of the leukemia. These results indicate very low heterogeneity in HeH ALL and suggests that the genome of these leukemias is relatively stable.

Disclosures
No relevant conflicts of interest to declare.
Highly Sensitive and Rapid Diagnosis of Mutations in Hematological Malignancies By CRISPR Technology
Authors: Liu Yin , Chen Yanling , Dang Lu , Huang Xingxu , Wang Xinjie , Zhou Fuling 
Published: November 2021

Abstract
With the rapid development of genomics and molecular diagnosis technologies, the treatment of hematological malignancies has entered the era of precision medicine, where individualized treatment is provided based on the unique genetic profile of each patient. Commonly-used techniques for gene mutation detection include polymerase chain reaction (PCR), sequencing approaches and real-time fluorescence quantitative PCR. However, these methods have drawbacks in sensitivity, specificity, or speed. Here, we established a mutation detection method based on CRISPR technology, which can achieve a highly sensitive, specific, and rapid diagnosis. Through a rapid release of genomic DNA, isothermal amplification, mutation enrichment, and Cas12a fluorescence reaction, this method can complete the whole diagnosis process from drawing blood to obtaining the results within one hour, without any large instruments or expensive reagents. Taking the detection of FLT3 gene D835Y/V/H/F drug-resistant mutations as an example, the sensitivity can reach 0.001%, which means 10 copies of mutation template can be detected from 999,990 copies of wild-type template. Then we used this method to detect 112 patients with acute myeloid leukemia, resulting in 11 FLT3-D835Y/V/H/F positive cases, which were verified by next-generation sequencing while missed by Sanger sequencing. We also applied this method to detect other common mutations in hematological malignancies, including NRAS gene G12D, IDH2 gene R172K, and JAK2 gene V617F. These results fully proved the high sensitivity, specificity, efficiency and universality of this method. Thus it has the potential to become a novel molecular diagnostic technology, and help point-of-care, early screening, prognosis determination and medication guidance in hematological malignancies.

Disclosures
No relevant conflicts of interest to declare.
Modeling Future Blood Requirements in Patients with Transfusion-Dependent β-Thalassemia in Greece
Authors: Souliotis Kyriakos , Golna Christina , Gountas Ilias , Tsironi Maria 
Published: November 2021

Abstract
Introduction : In Greece, official data confirm that blood supply is consistently declining, primarily because of decreased voluntary blood donations. At this rate, it is unclear whether there will be sufficient red blood cell (RBC) units to meet future demand for patients with β-thalassemia. We modeled future blood demand in patients with transfusion-dependent β-thalassemia (TDT) over the next 15 years to assess whether such a demand can be met.
Methods: A discrete time, stochastic, individual-based model, was developed to assess future blood needs of patients with TDT in Greece. The model adopted a cohort approach and patients enter the model shortly after birth and exit at death. The model was seeded with data from the National Registry for Hemoglobinopathies in Greece (NRHG; patient population) and data from the National Blood Centre (RBC units) (Table). To quantify the decrease in TDT incidence, a linear regression model was fitted to the incident cases as described by Voskaridou (Voskaridou E, et al. Ann Hematol 2019;98:55-66). The calculated annual reduction rate was then applied to the observed thalassemia major (TM) and thalassemia intermedia (TI) incident cases for 2012 (Voskaridou E, et al. Ann Hematol 2012;91:1451-1458). The model assumes the reduction would continue through to 2020, from which time the incidence curve would be constant.
Results: The model estimates a decrease in both target population, primarily due to the implementation of the national prenatal screening program and TM related mortality, (9.2%, 18.6%, and 26.0% in 2025, 2030, and 2034, respectively) and in demand for RBC units (100,665, 89,428 and 80,565, respectively) over the next 15 years. After accounting for any blood donated, based on latest (2017) data as projected to 2020, Greece is expected to be short of 56,716 RBC units to meet needs of patients with TDT in 2020. By 2025, 2030, and 2034, cumulative required RBC units for patients with TDT are estimated to be 307,150, 501,698, and 617,074, respectively. Assuming RBC units are divided among patients ≥ 18 years and those &lt; 18 years in line with the population mix in the NRHG, cumulative RBC units required for adult patients with TDT are estimated to be 292,837, 464,337, and 554,083 by 2025, 2030, and 2034, respectively.
Conclusions: Though blood demand for patients with TDT is expected to decrease in line with a decrease in the patient population, it will remain a challenge for the healthcare system in Greece to meet the demand, primarily due to a continuing shortage of available RBC units from voluntary donations. This annual deficit is estimated to accumulate to over 600,000 units over the next 15 years.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.