Use Of Stem Cell Transplantation Research Articles

Outcomes of Contemporary Novel Agent and Stem Cell Transplantation in Relapsed/Refractory PTCL

Background Outcomes in relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL) continue to be suboptimal. In the last decade, several novel agents have been approved; however, their impact on survival remains to be defined. In this multi-center retrospective analysis, we assessed survival following initial progression with respect to novel agent exposure with and without the use of stem cell transplant (SCT). Methods Patients with PTCL diagnosed between 1998-2021 at New York Presbyterian Hospitals, Columbia and Cornell, were included after IRB approval. Medical records were reviewed for baseline characteristics and treatment parameters. In the second line setting, each patient fell into one of four categories: 1. novel agent containing regimen only ( novel-containing only), 2. novel agent containing regimen with SCT at end of second line ( novel + SCT), 3. chemotherapy alone ( chemo-only), and 4. chemotherapy with SCT at end of second line ( chemo + SCT). Event-free survival (EFS) was calculated as time from 1 st progression to 2 nd progression, re-treatment, or death. Subsequent OS (sOS) was calculated from date of first progression to death or last follow-up. Kaplan-Meier method was used to estimate survival probability. Survival difference was tested by log-rank and Cox regression analysis. Results A total of 348 patients with PTCL were identified, of which 189 had R/R disease and 184 had sufficient data for analysis. The median follow-up was 62.5m. Baseline characteristics are shown in Table 1. Most common PTCL subtypes were AITL (N=52, 28.3%), PTCL-NOS (N=39, 21.2%), ATLL (N=34, 18.5%), and ALCL (ALK- = 13, ALK+ = 11, n=24, 13%). Median age at diagnosis was 58 years. Median EFS and sOS from date of initial progression for the entire cohort was 5.0m and 25.1m, respectively. In the second-line setting, 92 (50%) received a novel-containing only, 62 (34%) patients received chemo-only, 17 (9%) received chemo + SCT, and 13 (7%) received novel + SCT. Median EFS from first progression among patients who received second-line novel + SCT was 16.0m (95% CI 6.0 - NR), chemo + SCT 15.0m (95% CI 6.2 - 24.5), novel-containing only 3.9m (95% CI 3.5 - 5.3), and chemo-only 4.1m (95% CI 2.9 - 5.1) as shown in Figure 1. Two-year EFS favored novel + SCT at 38.5m (95% CI 12.0 - 64.9) and chemo + SCT 34.0m (95% CI 10.8 - 57.1), compared to novel-containing only at 18.3m (95% CI 10.1 - 26.6) and chemo-only 11.3m (95% CI 3.0 - 19.6), with p < 0.001 across all groups. Median sOS among patients who received second-line novel + SCT was 70.7m (95% CI 16.0 - NR), chemo + SCT not reached (95% CI 15.0 - NR), novel-containing only 23.3m (95% CI 10.5 - NR), and chemo-only 16.7m (95% CI 11.7 - 27.0). Two-year sOS favored novel + SCT at 74.6m (95% CI 49.7 - 99.5) and chemo + SCT 70.4m (95% CI 48.5 - 92.2) compared to novel-containing only at 49.4m (95% CI 37.9 -61.0) and chemo-only 43.4m (95% CI 30.0 - 56.9), with p =0.014 across all groups. Conclusion This multi-center study represents one of the largest retrospective R/R PTCL cohorts in the modern era with sOS of 25.1m, which compares favorably to historical data collected a decade ago reporting a sOS of 5.5m in R/R patients receiving chemo-only (Mak 2013), however, compares similarly to more recent data from the COMPLETE study (Lansigan 2019). This improvement in sOS may reflect availability of more effective therapies for sequencing in the novel agent era. Our data suggests that SCT in second-line setting is associated with improved EFS and sOS for both those treated with novel agent containing regimens and chemotherapy. Differences are more prominent for two-year EFS and sOS, favoring SCT arms and novel agents. However, the retrospective nature of our data limits definitive conclusion of benefit derived from SCT in the second-line setting, which underscores the need for prospective studies in this area. *This work has been funded ASH RTAF

Abstract 1 Clinical and Imaging Outcomes After Allogenic Umbilical Cord Blood Transfusions in a Young Adult with Cerebral Palsy

Abstract Introduction Umbilical cord blood transplant is an emerging promising therapy for cerebral palsy. Here we report a case of a 23-year-old spastic quadriplegic young adult whose motor and cognitive function improved after allogenic umbilical cord blood transfusion. Methods The patient received three times of cord blood transfusion intravenously (2022/2/15, 2022/05/16, 2022/8/15). Each cord blood was 4/6 HLA-matched and contained 10 × 107 total nucleated cells (TNC)/kg. Results The young man was born preterm. Due to motor developmental delay, he began rehabilitation when 1-year-old. His best mobility function was GMFCS III. At the age of 18, there was a rapid decline of his mobility. EEG showed seizure like waves and TRODAT brain scan on 2018/9/28 revealed symmetric mild striatal dopaminergic neuron loss. He was totally ADL dependent and mobility and communication severely restricted due to strong spasticity and rigidity. 3 days after 1st cord blood transfusion, he walked 500 steps (1 km/h) on LOKOMAT with 100% guidance force and 50% body weight supported. In the 16th session (when he also completed the 3rd cord blood transfusion), he walked1000 steps (1.5 km/h) on LOKOMAT with 90% guidance force and 50% body weight supported. Afterward, he regained sufficient motor function to maintain daily training with traditional physiotherapy. There was no adverse event during all the transplant procedures. Brain images taken before and after cord blood transfusion were compared with a brain-age predicting model to obtain differences in predicted and chronological age in 3 sets of brain images. The result showed reduced differences between predicted and chronological brain age (Figure 1). His mother reported that he became more alert and more responsive during interaction. Discussio This case highlights the therapeutic effect of allogenic umbilical cord blood transfusion to benefit adult CP manifest deterioration in physical activity and cognitive function. The specific mechanisms involved in this process are not yet fully understood. Therefore, any use of stem cell transplantation for the treatment of cerebral palsy should be done under the guidance of good clinical practice to accumulate robust real-world data, and more research is needed to fully understand its mechanisms of action.

Immunological aspects of hematopoietic stem cell transplantation for hematologic malignancies and some immunological peculiarities of cancer radioimmunotherapy

This literature review provides basic information about the role of hematopoietic stem cell transplantation in the treatment of myelodysplastic syndromes, acute myeloid leukemia, acute lymphoblastic leukemia. The recommendations for the use of stem cell transplantation are indicated. Conditioning regimens (myeloablative, non-myeloablative, reduced intensity), their advantages and disadvantages are considered. The issues of prevention and treatment of graft-versus-host disease, including graft preparation (T-cell depletion), extracorporeal photopheresis and mechanisms of graft-versus-tumor (-leukemia) reaction are highlighted. The historical milestones of theimmunotherapy development, the creation of therapeutic monoclonal antibodies, the development of targeted therapy, for example, conjugates of monoclonal antibodies with cytostatic drugs and radionuclides (targeted radionuclide therapy) are reported. Information about radioimmunotherapy as a method used for treatment of solid tumors and non-Hodgkin’s lymphoma, and information on the use of mesenchymal stem cells for the treatment and prevention of the graft-versus-host reaction are presented.

Treatment of Richter Transformation of Chronic Lymphocytic Leukemia in the Modern Era.

Richter Transformation (RT) refers to the development of an aggressive lymphoma in the setting of chronic lymphocytic leukemia (CLL). While many variants of RT are recognized, diffuse large B-cell lymphoma (RT-DLBCL) is the most common (80%), followed by Hodgkin's lymphoma (RT-HL, 19%). Diagnosis is based upon histologic evaluation of clinically suspicious lymph nodes. Positron emission tomography (PET) may be used to select the node of interest for biopsy. Although clonality testing is not a prerequisite of RT diagnosis, it has significant implications for survival. Clonally related DLBCL carries the worst prognosis with a median overall survival (OS) of less than one year in the era of combination chemotherapies with or without anti-CD20 antibodies. Prognosis has improved with the use of stem cell transplant and newer agents such as targeted therapy and newer forms of immunotherapy. Consideration of a clinical trial is encouraged. This review describes our current understanding of RT and focuses on treatment of RT-DLBCL, including clinical trials in progress and new therapies in development. We also report an illustrative example of a patient with clonally related DLBCL who survived two years after diagnosis without the use of combination chemotherapy.

Efficacy of Cellular Therapy for Azoospermia in Animal Models: A Systematic Review and Meta-Analysis

This study investigated the efficacy of stem cell transplantation for azoospermia, a major cause of male infertility. We conducted a systematic meta- analysis to assess the therapeutic effectiveness of stem cell transplant, using different transplant methods, injection sites, and stem cell types, and the reliability of this approach in different animal species. PubMed, the Cochrane Library, and Embase were searched for studies published from January 2006 to February 2022 that evaluated the use of stem cell transplant to treat azoospermia. We included 18 studies and conducted the analyses using Review Manager 5.2 software. Expression of the meiosis-related genes Vasa, Scp3, and Dazl and the average hematoxylin and eosin- positive staining area were improved after stem cell transplant. Subgroup analyses by mode of transplant showed higher expression of Scp3 and Dazl in the xenotransplant group. Although subgroup analyses by injection site showed that the seminiferous tubule group showed the most significant effect on Scp3 expression, spermatogenesis and repair of damaged testis were induced in the tunica albuginea group. The testicular torsion group also induced high levels of Scp3. Another subgroup analysis by stem cell type showed that umbilical cord mesenchymal stem cells promoted the highest expression of meiosis-related genes and successfully induced spermatogenesis and the repair of damaged testis. Urine-derived stem cells, spermatogonial stem cells, and amniotic fluid-derived stem cells showed significantly therapeutic effects; however, more studies are needed for definitive conclusions. Subgroup analyses by type of azoospermia animal model indicated that the use of stem cell transplant in rat or mouse models had an obvious therapeutic effect, but no significant therapeutic effect was seen in azoospermia hamsters. The meta-analysis confirmed that stem cell transplant can effectively treat azoospermia in animal models. Xenotransplant is shown to enhance the therapeutic effects of stem cell transplant on azoospermia.

Genotypic and Phenotypic Composition of Sickle Cell Disease in the Arab Population - A Systematic Review.

The protocol has been registered in the International Prospective Register of Systematic Reviews(PROSPERO):CRD42020218,666. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=218666.

The Age of Immune-therapy in Multiple Myeloma with a Collective Goal for a Cure

Since the year 2000, we have seen unprecedented improvement in newly diagnosed multiple myeloma in terms of progression-free survival and a doubling of overall survival in 2009 from 2.5 years to 5 years. Patients treated now expect a median survival of 7.5 years, while those receiving quadruplet therapy, stem cell transplant, and consolidation and maintenance therapy have an expected survival up to 11 years. Factors contributing to these improved outcomes include novel agents, antibodies, B-cell Maturation Agent-directed therapy, chimeric antigen receptor T-cells, bispecific antibodies, selective use of stem cell transplant, and supportive care measures such as bisphosphonates, prophylactic antimicrobials, cytokines, and intravenous immunoglobulins. Incorporation of these novel therapies in conjunction with increasing understanding of the genomic landscape of multiple myeloma and the evolving use of minimal residual disease negativity should persuade the oncology community to treat patients with high-risk smoldering multiple myeloma and guide treatment of early relapse in patients with newly diagnosed multiple myeloma. Here, we review early interventions within the context of genomic changes, minimal residual disease status, and strategies for treating high-risk smoldering multiple myeloma and standard and high-risk newly diagnosed multiple myeloma to improve progression-free survival, overall survival, and provide context for which patients may be considered cured.

Genotypic and Phenotypic Composition of Sickle Cell Disease in the Arab Population - a Systematic Review

Introduction Sickle Cell Disease (SCD), one of the common hemoglobinopathies, has a progressively increasing prevalence. Different genotypes of variants of SCD result in a spectrum of clinical manifestations. With SCD being a genetic disease, it is influenced by ethnicity and regional differences in its clinical course. There are recent advances in the management of SCD with newer therapies being introduced to the Western population. However, many of these treatments are yet to be used in the Arabic SCD population. It is important to understand the genetic variations of SCD regionally to anticipate the effectiveness of these newer modalities. This systematic review's main objective is to pool the available data on the genetic composition of SCD in the Arabic population. Methods We searched English language articles from PubMed, Scopus, and Google Scholar that reported genotypes of patients with SCD in countries of the Arab world. Demographics, prevalence, genotypes, clinical characteristics, management, and outcomes of patients were extracted and analyzed in the form of a systematic review. Descriptive and summary statistics were used to present the data and the mean (with standard deviation) and mode (with interquartile range) were reported as appropriate. Results Data for 44259 patients was extracted from 186 studies (case reports, case series, retrospective, and prospective observational studies). Male (49%) and female (51%) patients were equally reported wherever gender was available (N=13105). Most cases were reported from Saudi Arabia (>50%), and Bahrain (27.24%). The percentage of included cases was lower than 5% in Jordan, Egypt, Kuwait, and Tunisia, and less than 2% in the remaining Arab countries. Various SCD genotypes were reported in a total of 14482 patients, including Hb SS (76%) Hb Sβ0 (9.7%), and Hb Sβ+ (7.1%), while the rest of the genotypes, including HbSC, HbSD, HbSE, HbSO Arab, Hb S/α-Thal, Hb Sβ0 + α-Thal, and HBS Oman were individually reported in <4% of the cases. Major SCD complications in the Arab population included pain crises (48.25%) followed by neurological complications (33.46%), hepatobiliary complications (25.53%), musculoskeletal complications (24.73%), and hemolytic anemia (23.57%). The treatments reported for SCD included hydroxyurea (20%), blood transfusion (14.32%), and Deferasirox (3.03%). We did not find the use of stem cell transplantation or newer treatments such as L-Glutamine, Voxelotor, Crizanlizumab, or gene therapy reported in any of the studies included in our review. Conclusion SCD is a common hemoglobinopathy in the Arab population. Data with regards to its genotypic makeup in the region is scattered and is different from the other parts of the world. Many of the approved treatment modalities are yet to be reported in this patient population. This review highlights the genetic makeup of SCD in the Arab countries and common phenotypic manifestations. This data will help the direction of further research on SCD in this region, especially with respect to the upcoming era of genetic therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Stem Cell-Based Therapies for Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic, relapsing disease that severely affects patients’ quality of life. The exact cause of IBD is uncertain, but current studies suggest that abnormal activation of the immune system, genetic susceptibility, and altered intestinal flora due to mucosal barrier defects may play an essential role in the pathogenesis of IBD. Unfortunately, IBD is currently difficult to be wholly cured. Thus, more treatment options are needed for different patients. Stem cell therapy, mainly including hematopoietic stem cell therapy and mesenchymal stem cell therapy, has shown the potential to improve the clinical disease activity of patients when conventional treatments are not effective. Stem cell therapy, an emerging therapy for IBD, can alleviate mucosal inflammation through mechanisms such as immunomodulation and colonization repair. Clinical studies have confirmed the effectiveness of stem cell transplantation in refractory IBD and the ability to maintain long-term remission in some patients. However, stem cell therapy is still in the research stage, and its safety and long-term efficacy remain to be further evaluated. This article reviews the upcoming stem cell transplantation methods for clinical application and the results of ongoing clinical trials to provide ideas for the clinical use of stem cell transplantation as a potential treatment for IBD.

PB1807: OUTCOME OF CORE BINDING FACTOR ACUTE MYELOID LEUKEMIA IN CHILDREN AND ADOLESCENTS: A SINGLE CENTER EXPERIENCE

Background: Core binding factor acute myeloid leukemia (CBF-AML) is a subgroup of AML, mainly defined by two gene rearrangements affecting CBF;t (8; 21)/RUNX1-RUNX1T1 and inv (16)/CBFB-MYH11. CBF-AML is considered as a favorable cytogenetic group. However, one-third of these patients relapse succeeding treatment. Aims: The main of this study is to evaluate the clinical characteristics and the outcome of this group of patients in our center. Methods: This retrospective study included all CBF-AML diagnosed between 2002 and 2020 in the hematology department of the University Hospital of Sousse. Patients were aged 20 years or less. The diagnosis was confirmed according to the WHO classification of hematological malignancies based on cytology and immune-phenotyping. An initial karyotype during diagnosis was performed in all the cases to classify the cases according to the prognostic MRC classification. Patients were treated by the standard chemotherapy regimen. Promyelocytic leukemia and secondary leukemia were excluded. Statistical analysis was performed using the Kaplan Meier method. Results: Among the 66 children and adolescents diagnosed with AML 15 had CBF AML (23%). 60% were male. The median age was 9 years (3-16). WBC at diagnosis was<4000 in 5 cases, 4000-10000 in 2 cases, between 10000-50000 in 7 cases, and >50000 in 1 case. Disseminated intravascular coagulation was noted in 2 cases. Twelve patients had t(8,21) and 3 patients had inv(16). 75% achieved complete remission after induction. 2 patients had a refractory disease (12,5%). Treatment-related mortality was 12,5% and meantime to relapse was 6,2 months in 5 patients (45%). Three patients responded to salvage chemotherapy (60%) and 2 died (40%). Hematopoietic stem cell transplantation (HSCT) was performed in only 2 patients. For the 3 others, HSCT was not feasible because of the absence of compatible matched related donors. The 5-year overall survival and relapse-free survivals were 55,7% and 58,3% respectively. Summary/Conclusion: Compared to the literature, the frequency of CBF-AML and epidemiological features were very similar. Furthermore, the majority had t (8, 21) in karyotype. Complete remission rate was slightly lower in our study (73% vs 85-96%), Treatment-related mortality was higher (12% vs 3-10%) which may be explained by the absence of protective isolation in the earlier years of the study. Regrettably, PFS was inferior to data from the literature (70-80%). The early use of stem cell transplants could improve our results.

Efficacy of expressive helping in adult hematologic cancer patients undergoing stem cell transplant: protocol for the Writing for Insight, Strength, and Ease (WISE) study\u2019s two-arm randomized controlled trial

BackgroundDuring, shortly after, and sometimes for years after hematopoietic stem cell transplant, a large proportion of hematological cancer patients undergoing transplant report significant physical and psychological symptoms and reduced health-related quality of life. To address these survivorship problems, we developed a low-burden, brief psychological intervention called expressive helping that includes two theory- and evidence-based components designed to work together synergistically: emotionally expressive writing and peer support writing. Building on evidence from a prior randomized control trial showing reductions in physical symptoms and distress in long-term transplant survivors with persistent survivorship problems, the Writing for Insight, Strength, and Ease (WISE) trial will evaluate the efficacy of expressive helping when used during transplant and in the early post-transplant period, when symptoms peak, and when intervention could prevent development of persistent symptoms.MethodsWISE is a multi-site, two-arm randomized controlled efficacy trial. Adult hematological cancer patients scheduled for a hematopoietic stem cell transplant will complete baseline measures and then, after hospitalization but prior to transplant, they will be randomized to complete either expressive helping or a time and attention “neutral writing” task. Both expressive helping and neutral writing involve four brief writing sessions, beginning immediately after randomization and ending approximately 4 weeks after hospital discharge. Measures of symptom burden (primary outcome), distress, health-related quality of life, and fatigue (secondary outcomes) will be administered in seven assessments coinciding with medically relevant time points from baseline and to a year post-intervention.DiscussionThe steady and continuing increase in use of stem cell transplantation has created growing need for efficacious, accessible interventions to reduce the short- and long-term negative physical and psychosocial effects of this challenging but potentially life-saving treatment. Expressive helping is a psychological intervention that was designed to fill this gap. It has been shown to be efficacious in long-term transplant survivors but could have even greater impact if it is capable of reducing symptoms during and soon after transplant. The WISE study will evaluate these benefits in a rigorous randomized controlled trial.Trial registrationClinicaltrial.govNCT03800758. Registered January 11, 2019

Increased Risk of Second Primary Malignancy and Mortality at ten Years After Stem Cell Transplant for Multiple Myeloma: An Analysis of 14,532 Patients.

BackgroundThe landscape for patients with multiple myeloma has improved dramatically over the last 15 years. Immunomodulatory imide drugs (IMiDs) have shown great efficacy in both the setting of initial therapy and as maintenance after autologous stem cell transplant (ASCT). Concern has arisen, however, regarding the risk of second primary malignancies (SPMs) that appear to be associated with the use of IMiD agents. SPMs are a known sequela of multiple myeloma treatment, particularly as a consequence of maintenance lenalidomide status-post stem cell transplant (SCT). The benefit of SCT has become less clear with the utilization of newer, more effective initial therapies.ObjectivesTo determine the effect of SCT on SPM risk and overall survival in multiple myeloma patients at 5 and 10 years after treatment initiation.MethodsWe used TriNetX, a global federated health research network providing access to electronic medical records (diagnoses, procedures, medications, laboratory values, genomic information) from approximately 58 million patients in 49 large healthcare organizations. We created two patient cohorts who had all received treatment with thalidomide, lenalidomide, or pomalidomide. One cohort had received SCT while the other had not. Both cohorts were then analyzed for the development of all non-myeloma malignancies which occurred at least one year after initiation of treatment.ResultsAt 5 years, SPMs were 5.8% more likely in patients who received stem cell transplant (22.4% vs 16.6%, RR 0.741, p value <0.0001) but 5-year survival favored transplanted patients by 2.38% (64.85% vs 62.474%, p value 0.0044). 10-year survival favored patients who did not receive transplant by 1.44% (42.279% vs 40.838%, p value 0.0279). The Kaplan-Meier curves cross at year 6.ConclusionsIt has previously been shown that the use of alkylating agents in myeloma patients significantly increases the risk of SPM, but that difference had curiously not been shown to have a negative impact on survival. Our analysis shows that this negative survival impact does exist but requires six or more years of follow up to become evident. Recent analyses from studies using older regimens show no overall survival benefit from the use of stem cell transplant. As non-transplant regimens become more effective at producing minimal residual disease (MRD) negativity, it seems that transplantation for myeloma patients will soon be regarded as unnecessary or even detrimental.

Gemtuzumab Ozogamicin (GO) In Children With De Novo Acute Myeloid Leukemia (AML) Improves Event-Free Survival (EFS) By Reducing Relapse Risk – Results From The Randomized Phase III Children's Oncology Group (COG) Trial, AAML0531

▪ BackgroundEscalation of treatment intensity for childhood acute myeloid leukemia has improved EFS but with excessive toxicity and toxic mortality (TM), compelling a search for more targeted less toxic alternatives. ObjectiveTo determine if the addition of GO to standard chemotherapy improves EFS in pediatric AML. MethodsPatients < 30 years of age were randomly assigned to receive standard therapy alone (noGO) or to receive two doses of GO 3 mg/m2/dose on day 6 of Induction I (IndI) and on day 7 of Intensification II (IntII) in a 5 cycle chemotherapy backbone previously piloted by COG (Cooper et al, Cancer 2012). Use of stem cell transplant (SCT) was stratified by overall risk group assignment (based on cytogenetics, FLT3-ITD high allelic ratio (HAR), and IndI response) in which high risk patients were allocated to best allogeneic donor SCT after Int I, low risk (LR) patients received chemotherapy only, and intermediate risk (IR) were assigned to SCT if there was a matched family donor (MFD). ResultsBetween 2006-2010, 1022 of 1070 enrolled non-DS pts were eligible for analysis; characteristics are presented in Table 1. Median follow-up was 3.6 (range 0-6.4) years for those alive.Protocol therapy was well tolerated with a TM of 2% in induction and 5% overall with no difference by study arm. VOD was observed in 3% (severe in 0.6%) with no difference by study arm. From time of enrollment, GO was significantly associated with better overall EFS (hazard ratio (HzR) 0.83 (95% CI: 0.7-0.99; p=.04) and relapse-free survival (HzR 0.74 (0.6-0.93; p=.01)) whereas OS was not significantly improved (HzR 0.91 (0.74-1.13)). At 3 yr, noGO v GO EFS was 47 v 53%, p=.05 and OS was 65 v 69%, p=.18. In multivariate analyses, GO was significantly associated with improved EFS than standard therapy after adjustment for significant adverse risk factors: age <2yr, initial WBC>100,000x109/L, and black race. GO was not associated with significantly better induction complete remission (CR) when compared to standard therapy (88% v 85%; p=NS). Table 2 illustrates the overall results by randomized arm and by overall risk group from time of CR showing a consistent reduction in relapse risk in all risk groups. Further risk group analysis found several unique results. In the LR group, relapse rates (RR) trended lower in the GO arm but the benefit was reduced by TM during Int 2 & 3 that was significantly worse in the GO arm (3 v 10%, p=.02). In the IR group, EFS, RR, and OS trended towards improvement with GO. However when pts were censored at the time of SCT (as treated), the outcomes were not significantly different between arms (log-rank p=.14 EFS and p=.81 OS). Table 1 shows an imbalance for SCT received in assigned IR pts with fewer actually receiving SCT in the noGO arm. As such, Table 2 shows outcomes by intent-to-treat for IR pts with MFD censored and by as treated for IR pts receiving MFD SCT. Noteworthy in the IR group alone who did receive a SCT, GO arm pts had a significantly better DFS than the noGO arm (intent to treat: p=.022; as treated: p=.044). However, for the IR pts randomized to the noGO arm, SCT failed to provide benefit. For HR pts achieving CR they as well trended towards better survival & RR in the GO arm. ConclusionGO improves EFS in children, adolescents and young adults with AML by reducing the risk of relapse among those achieving remission. Disclosures:No relevant conflicts of interest to declare.

Efficacy of VDT PACE-like Regimens in Treatment of Relapsed/Refractory Multiple Myeloma—a Single Center Experience

Introduction: Intensive cytotoxic chemotherapy for multiple myeloma (MM) using VDT PACE regimen (bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide) and its modifications (together called VDT PACE-like regimens-VPLRs) have been studied only as part of Total Therapy protocols. Institutional experience with VPLRs is limited. We aimed to analyze the outcomes of patients with MM who received VPLRs at our center.Methods: We reviewed the records of patients who received VPLRs at Mayo Clinic, Rochester from 10/2006 to 03/2017 in an intent-to-treat analysis. We collected data on patient characteristics, prior therapy, drugs used, response to VPLR, timing of progression and next therapy, use of stem cell transplant (SCT) after VPLR, hospital stay and readmission during first cycle (C1), and survival at last follow-up. Revised international staging system (RISS) stage at starting VPLR was calculated if required data were available. Survival outcomes were calculated from initiation of VPLR using Kaplan Meier method. We analyzed for factors affecting survival from initiation of VPLRs using Cox proportional hazards model.Results: We identified 143 patients who received VPLRs, of whom 141 (98.6%) had relapsed/refractory MM (RRMM) and 2 (1.4%) had newly diagnosed MM. We included only patients with RRMM in further analysis. Patient characteristics at initiation of VPLR are shown in Table 1 . Ninety five (67.4%) patients received VDT PACE, 20 (14.2%) received VD PACE and 26 (18.4) received other VPLRs. Patients received a median of 1 cycle (range, 1-9) of VPLR. Forty five (31.9%) patients received ≥2 cycles of therapy. Of the 135 evaluable patients, after C1, we observed ≥minimal response (MR) in 88 (65.2%), ≥partial response (PR) in 69 (51.1%) and ≥very good PR (VGPR) in 10 (7.4%) patients. After entire course of VPLR, we observed ≥MR in 93(68.9%), ≥PR in 74 (54.8%) and ≥VGPR in 14 (10.4%) patients. Estimated median progression-free survival was 3.1 months (95%CI, 1.9-3.9) and time to next treatment was 1.9 months (95%CI, 1.7-2.2). Median overall survival (OS) was 8.1 months (95%CI, 6.2-9.9) from initiation of VPLR. Among 116 patients who received further therapy after VPLR, 71 (61.2%) received systemic chemotherapy as next line, while 38 (32.7%) and 7 (6%) received autologous SCT and allogeneic SCT respectively. Median OS for those who received SCT vs those who received chemotherapy after VPLR was 15.1 months (95%CI, 10.3-20.8) vs 7.3 months (95%CI, 5.6-9.5) (p<0.01). Twenty nine (20.6%) patients died within 100 days of initiating VPLR.Patients were hospitalized for a median of 6 days (range, 4-42) during actual administration of drugs in C1. Seventy seven (55.4%) patients had re-admission after administration of chemotherapy in C1 with a median of 1 (range, 1-3) re-admission. Median cumulative duration of hospital stay was 9 days (range, 4-42) during C1. Neutropenic fever and nephrotoxicity were seen during C1 in 51 (36.9%) and 20 (14.8%) patients respectively, among those with available data. Median time to recovery of neutrophil count and platelet count from initiating VPLR were 18 (range, 12-44) and 21 (range, 11-45) days respectively. OS was short in patients who had ≥2 re-admissions [3.1 (95%CI, 1.8-8.3) vs 8.4 (95%CI, 7.3-10.9) months; p=0.02] and those who developed neutropenic fever [5.9 (95%CI, 3.4-9.6) vs 8.4 (95%CI, 7.4- 12.8) months; p=0.02] during C1.We used age ≥65 years vs <65, serum creatinine >2 mg/dL vs ≤2 mg/dL, RISS III vs I/II stage, presence vs absence of extramedullary disease, high risk vs standard risk cytogenetics and being refractory to a proteasome inhibitor and an immunomodulatory drug, as independent variables in univariate analysis. Age ≥60 years (p<0.01) and RISS III stage (p=0.01) were associated with reduced OS. In multivariate Cox proportional model, age ≥65 [hazard ratio- 2.3 (95% CI, 1.4-3.7); p<0.01] and RISS III stage [hazard ratio- 2.4 (95% CI, 1.3-4.0); p<0.01] predicted shortened OS.Conclusions: VPLRs provide an effective combination in RRMM. OS was better among patients who underwent an SCT after VPLR. Age ≥60 years and RISS III stage predicted reduced OS from initiation of VPLR. Complications including neutropenic fever and two or more re-admissions during first cycle of VPLR were associated with reduced OS. [Display omitted] DisclosuresGertz:Millennium: Consultancy, Honoraria; Celgene, Novartis, Smith-Kline, Prothena, Ionis, Amgen: Honoraria. Dingli:Takeda: Consultancy; Karyopharm Therapeutics: Research Funding; Alexion Pharmaceuticals: Consultancy; Janssen: Consultancy; Millenium: Consultancy. Dispenzieri:Celgene, Millenium, Pfizer, Janssen: Research Funding. Russell:Imanis Life Sciences: Equity Ownership; Vyriad: Equity Ownership. Kapoor:Takeda, Celgene and Amgen: Research Funding. Kumar:Skyline: Honoraria; Celgene, Millennium/Takeda, Onyx, AbbVie, Janssen, Sanofi, Novartis, Amgen, Genentech, Merck, Oncopeptides, Roche, Skyline Diagnostics: Research Funding; Celgene, Millennium, BMS, Onyx, Janssen, Noxxon, AbbVie, Amgen, Merck, Oncopeptides, Skyline Diagnostics, Takeda: Consultancy.

A Phase Ib Study to Assess the Safety and Tolerability of Ruxolitinib in Combination with Azacitidine in Patients with Advanced Phase Myeloproliferative Neoplasms (MPN), Including Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukaemia (AML) Arising from MPN (The Bloodwise / TAP PHAZAR Study on Behalf of the UK MPN CSG)

A Phase Ib Study to Assess the Safety and Tolerability of Ruxolitinib in Combination with Azacitidine in Patients with Advanced Phase Myeloproliferative Neoplasms (MPN), Including Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukaemia (AML) Arising from MPN (The Bloodwise / TAP PHAZAR Study on Behalf of the UK MPN CSG)

Stem Cell Repair of the Microvascular Damage in Stroke.

Stroke is a life-threatening disease that leads to mortality, with survivors subjected to long-term disability. Microvascular damage is implicated as a key pathological feature, as well as a therapeutic target for stroke. In this review, we present evidence detailing subacute diaschisis in a focal ischemic stroke rat model with a focus on blood–brain barrier (BBB) integrity and related pathogenic processes in contralateral brain areas. Additionally, we discuss BBB competence in chronic diaschisis in a similar rat stroke model, highlighting the pathological changes in contralateral brain areas that indicate progressive morphological brain disturbances overtime after stroke onset. With diaschisis closely approximating stroke onset and progression, it stands as a treatment of interest for stroke. Indeed, the use of stem cell transplantation for the repair of microvascular damage has been investigated, demonstrating that bone marrow stem cells intravenously transplanted into rats 48 h post-stroke survive and integrate into the microvasculature. Ultrastructural analysis of transplanted stroke brains reveals that microvessels display a near-normal morphology of endothelial cells and their mitochondria. Cell-based therapeutics represent a new mechanism in BBB and microvascular repair for stroke.

Stem Cell Transplant Minimizes Insurance Coverage-Driven Outcome Disparities for Multiple Myeloma Patients

Advent of novel anti-myeloma agents and broader use of stem cell transplant has led to significant improvement in survival of patients (pts) with Multiple Myeloma (MM). However, there are well-described issues with affordability of novel drugs and rapidly escalating price of these agents (Shih et al. JCO 2017), leading to significant disparity among different sociodemographic groups. Hereby, we interrogated the National Cancer Database (NCDB) (which covers 70% of MM patient diagnosed nationwide) to assess impact of insurance type on survival. We also sought to investigate if autologous transplant may overcome socioeconomic effects on survival, by potentially minimizing the need for chronic use of expensive drugs. Methods: Data from 117,926 MM pts diagnosed with MM (ICD-O 9732) between 2005 and 2014 were analyzed. Results: Median age at diagnosis was 67 (19-90); 55% were males. 57% of pts lived in areas where the median income was Conclusions: Although insurance type and regional income are associated with MM survival among pts who relied on non-transplant modalities, there was no significant impact of these socioeconomic factors on survival of pts that received an autologous transplant in this large database. This finding merits further investigation.

Clinical and Prognostic Impact of (11;14)(q13;q32) Translocation on Patients with Multiple Myeloma

Introduction. Translocations involving chromosome 14 at band q32, the immunoglobulin heavy chain (IgH) locus, are considered to be the most important initiating events for the development of multiple myeloma (MM). Among the IgH translocations in MM, t(11;14)(q13;q32) is the most frequently reported, and associated with a lymphoplasmacytic morphology. This translocation have been traditionally considered as standard-risk chromosomal abnormality compared to other translocations such as t(4;14) or t(14;16), although some controversies on the prognostic impact of this translocation still remain. This study aimed to clarify the clinical and prognostic impact of t(11;14) in Japanese patients in relation to other clinical variables such as immunophenotype of the tumor cells, other cytogenetic abnormalities, and use of stem cell transplantation (SCT). Patients and methods. Among the 244 consecutive patients with newly diagnosed MM, treated at Kameda Medical Center between April 2009 and July 2019, 234 patients, having cytogenetic analysis data (including t(11;14), t(4;14), t(14;16), and del(17p) by interphase fluorescence in situ hybridization (iFISH)) fully available, were included in this study. Data regarding the patients' clinical and laboratory characteristics, including the International Staging System (ISS), immunophenotype of the tumor cells, baseline circulating plasma cells (CPCs), treatment responses, disease progression, and survival status, were collected. iFISH was performed with CD138-purified bone marrow plasma cells, and the cut off values for translocation were ≥ 10% and for del(17p) ≥ 20%. Using multicolor flow cytometry, surface marker analysis of bone marrow samples and quantification of pre-treatment CPCs on peripheral blood mononuclear cells were simultaneously performed. CPCs were reported as the percentage of total mononuclear cells. Patients were considered to be negative for clonal CPCs at a sensitivity of 10−4 (0.01%) clonal plasma cells for all events evaluated. Results. The incidence of patients harboring t(11;14) was 24.4% (n = 57); t(11;14) was detected significantly high in light-chain-only subtypes (P &lt; 0.001). We compared clinical characteristics of patients carrying t(11;14) with others. Myeloma cells with t(11;14) were associated with negative expression of CD56 (P &lt; 0.001), CD117 (P = 0.046), and CD200 (P = 0.006), and positive expression of CD20 (P = 0.01) and CD81 (P = 0.035). Patients with t(11;14) were associated with positive CPCs (P = 0.011). In order to focus on the impact of t(11;14), we divided the patients into 4 groups: (A) no specific cytogenetic abnormality listed above (n = 137), (B) t(11;14) group (n = 57), (C) t(4;14) or t(14;16) group (n = 29), and (D) del(17p) only (n = 10), and the clinical characteristics and survival of the patients were compared across the three groups (A), (B), and (C). Almost all the patients (&gt; 95%) in this cohort received bortezomib-based therapy. Median progression-free survival (PFS) and overall survival (OS) of patients in (A), (B), and (C) groups were 55.6, 34.2, and 30.2 months (m) (A vs. B, P = 0.036, and A vs. C, P = 0.031), and not reached, 51.2, and 79.8 m (A vs. B, P = 0.11, and A vs. C, P = 1.00), respectively. However, patients harboring t(11;14) were further divided into CD20-positive and -negative groups, the latter having poor prognosis (36.1 vs. 26.7, P = 1.0 for median PFS, and not reached vs. 44.2, P = 0.029 for median OS). Compared to other groups, patients without CD20 expression had significantly shorter OS (vs. A, vs. B, P = 0.024, 0.035, respectively), whereas those with CD20 expression tended to have longer OS, without statistical significance (Figure 1).Univariate analysis revealed ISS stage III, creatinine &gt; 2.0 mg/dL, use of SCT, t(11;14) without CD20 expression, and age ≥ 70 years to be associated with shorter OS, whereas multivariate analysis demonstrated ISS stage III, use of SCT, and t(11;14) without expression CD20 (HR 1.88; 95% CI 1.10-3.21; P = 0.021) to be independent prognostic factors for poor OS. Conclusions. Our findings demonstrated that patients harboring t(11;14) had distinct clinical and immunophenotypic characteristics, two subsets of the disease entities with a clearly different survival according to CD20 expression. Disclosures Matsue: Ono Pharmaceutical: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Novartis Pharma K.K: Honoraria; Celgene: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria.

Annotation of Somatic Genomic Variants in Hematologic Diseases Using OncoKB, a Precision Oncology Knowledgebase

Background: Over 300 somatic molecular variants in hematologic diseases are either specified as diagnostic criteria in the World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues, recognized as potentially actionable biomarkers in the National Comprehensive Cancer Network (NCCN) compendia, or supported by published well-powered clinical studies. Moreover, new molecular alterations with potential clinical implications in hematologic disease are continuously emerging in the scientific literature. These have critical use for a wide spectrum of clinicians, including hematopathologists who diagnose patient-specific hematologic malignancies, heme-oncologists who direct patient care, and clinical trial nurses who assist patients in finding appropriate clinical trials. Importantly, the utility of this information critically depends on the clinician's ability to interpret the significance of variants in a point-of-care setting. Therefore, there is an urgent and unmet need for a clinical decision support system that 1) distills the clinical implications associated with molecular alterations into a standardized and easily interpretable format and 2) democratizes access of this information to all members of the heme-oncology community. Methods: OncoKB is an established expert-guided precision oncology knowledge base that annotates the oncogenic effect and therapeutic implications of somatic molecular alterations (Chakravarty, D. et al., JCOPO, 2017). Previously, OncoKB was focused primarily on solid tumor mutation annotation. Recently, we expanded OncoKB to include alterations in hematologic malignancies. The heme-specific annotation efforts were guided by heme-oncology and hematopathology physician scientists at Memorial Sloan Kettering (MSK). Supplementing the previously published therapeutic levels of evidence (Fig. 1a), we further added level of evidence systems for diagnostic and prognostic implications (Fig. 1b, c). These three sets of evidence levels are consistent with the criteria set forth by the joint consensus of the ASCO/CAP/AMP guidelines (Li, MM. et al., J Mol Diagn, 2017). We assigned the newly curated heme-specific molecular alterations with diagnostic, prognostic or therapeutic levels of evidence, when applicable. Finally, we annotated and analyzed 1569 hematologic tumor samples from the AACR Project GENIE (release 6.1) with these levels of evidence. Results: In addition to alterations with both solid and heme clinical implications already curated in OncoKB, we annotated 288 unique heme-specific mutations, fusions, and copy number alterations in 156 newly curated cancer-associated genes. Based on MSK-expert consensus, the WHO and NCCN guidelines, and the scientific literature, we identified a total of 192 alterations with unique diagnostic levels of evidence, 65 alterations with unique prognostic levels of evidence and 55 alterations with unique therapeutic levels of evidence across 13 major hematologic tumor types (Fig. 2). To test the utility of OncoKB, we annotated all genomic events in 1569 heme cancer samples in 89 hematologic malignancies in the AACR GENIE cohort (V6.1) (Fig. 3a). Thirty-eight percent of samples harbored at least one potentially actionable alteration, and 8% were predictive of clinical benefit from an FDA-approved drug (Fig. 3b). Conclusions: OncoKB heme data is publicly available both through the web resource http://oncokb.org and through incorporation into the cBioPortal for Cancer Genomics. Heme-specific molecular alterations are used to make an accurate diagnosis, inform prognosis, optimize the use of stem cell transplant, and to link patients with the optimal mechanism-based therapies in the clinical trial setting and in routine clinical practice. This is the first study to annotate and analyze actionability of heme samples. In this proof-of-principle study, we demonstrate the ability to annotate clinical samples with their diagnostic, prognostic and therapeutic implications in a point-of-care setting. Disclosures Roshal: Celgene: Other: Provision of Services; Auron Therapeutics: Equity Ownership, Other: Provision of services; Physicians' Education Resource: Other: Provision of services. Ho:Invivoscribe, Inc.: Honoraria. Knorr:Fate Therapeutics: Patents &amp; Royalties. LaFave:Epizyme: Patents &amp; Royalties. Arcila:Invivoscribe, Inc.: Consultancy, Honoraria. Berger:Roche: Consultancy. Solit:Pfizer: Consultancy; Lilly Oncology: Honoraria; Vivideon Therapeutics: Consultancy; Loxo Oncology: Consultancy, Equity Ownership; Illumina: Consultancy. Dogan:Celgene: Consultancy; Seattle Genetics: Consultancy; Corvus Pharmaceuticals: Consultancy; Roche: Consultancy, Research Funding; Novartis: Consultancy; Takeda: Consultancy. Levine:C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Qiagen: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Loxo: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Gilead: Consultancy; Imago Biosciences: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Lilly: Honoraria; Prelude Therapeutics: Research Funding; Roche: Consultancy, Research Funding.

Stem Cell Transplant Minimizes Insurance Coverage-Driven Outcomes Disparities for Multiple Myeloma Patients

Advent of novel anti-myeloma agents and broader use of stem cell transplant has led to significant improvement in survival of patients (pts) with Multiple Myeloma (MM). However, there are well-described issues with affordability of novel drugs and rapidly escalating price of these agents (Shih et al. JCO 2017), leading to significant disparity among different sociodemographic groups. Hereby, we interrogated the National Cancer Database (NCDB) (which covers 70% of MM patient diagnosed nationwide) to assess impact of insurance type on survival. We also sought to investigate if autologous transplant may overcome socioeconomic effects on survival, by potentially minimizing the need for chronic use of expensive drugs. Methods: Data from 117,926 MM pts diagnosed with MM (ICD-O 9732) between year 2005 and 2014 were analyzed.. The comparison of patient characteristics among insurance types was done using ANOVA for continuous measurements and Chi-square test for categorical factors. OS was measured from the date of diagnosis to the date of death, censored at the date of last follow-up for survivors. Survivor distribution was estimated using Kaplan-Meier methods and difference of OS between groups was examined by log-rank test. The effect of continuous measurements including age, distance to medical facility and facility volume on OS was estimated using Cox proportional hazard model. The effect of insurance type on OS was estimated using multivariable Cox proportional hazard regression after adjusting the effects of confounding factors. Results: Median age at diagnosis was 67 years (19-90); 55% were males. 57% of pts lived in areas where the median income was &amp;lt; $46k/year (individual income data was not available); Primary insurance was Medicare (52%), private insurance (35%) or Medicaid (5%), and 3% were uninsured. 40% were treated in academic institutions. Median follow up was 30.2 (range, 0-145.2) months. By univariate analysis, better OS was observed in pts with primary MM, lower Charlson Comorbidity Index (CCI), treatment in academic institutions, higher median regional income, or private insurance (p&amp;lt;0.001 for all) (Table-1). Ninety six percent of patients were treated in facilities located ≤ 120 miles from area of residence. More patients with private insurance (5.7%) travelled &amp;gt; 120 miles to the treatment facility than patients with Medicare (3%).Amongst patients younger than 65 years, 33% of patients with private insurance received transplant compared to 20% of those on Medicare (p&amp;lt;0.001). For those 65 years and older, 11% of privately insured patients were transplanted compared to only 6 % for those on Medicare (p&amp;lt;0.001). Median age of pts on Medicare and private insurance, was 74 and 57 years old, respectively. When restricting the analysis to pts ≥ 65 years old, pts with private insurance had longer OS compared to Medicare pts (p&amp;lt;0.0001). Table-2 shows the results of multivariate analysis. There was a statistically significant difference in survival between patients with private insurance and those with Medicare in favor of the private insurance among patients older than 65 years old (41.9 vs. 30.8 months, p&amp;lt;0.001 (Figure-1)). Similarly insurance type was a significant predictor of survival among patients who received therapies other than transplant among pts younger or older than 65 years old (Figure-2), however when considering patients who received transplant, there was no difference in survival between privately insured patients and Medicare in both age group (Figure-3). Conclusions: Although insurance type and regional income are associated with MM survival among patients who relied on non-transplant modalities, there was no significant impact of these socioeconomic factors on survival of patients that received an autologous transplant in this large database. This finding merits further investigation. Disclosures Malek: Janssen: Speakers Bureau; Amgen: Speakers Bureau; Adaptive: Consultancy; Celgene: Consultancy; Medpacto: Research Funding; Takeda: Consultancy; Sanofi: Consultancy.