CR Patients Research Articles

Proteomic Profiling Identifies c-KIT and 53BP1 As Resistance Factors of AML Relapse Post Allogeneic Stem Cell Transplantation with G-CSF/Plerixafor/Busulfan-Fludarabine Conditioning

The CXCR4 inhibitor plerixafor in combination with G-CSF disrupts stroma-leukemia interactions, mobilizing leukemia cells from their niche microenvironment. This combination in conjunction with chemotherapy has been investigated in clinical trials in AML. We recently reported a phase 1/2 study of CXCR4 inhibition combined with chemotherapy prior to allogeneic stem cell transplantation (allo-SCT) (G-CSF-plerixafor (G+P) plus busulfan-fludarabine (Bu+Flu), Konopleva, et al. BMT 2015) and confirmed that patients who had not achieved remission at the time of transplant (“non-CR”) had poorer outcome than patients who were in remission at the time of allo-SCT (“CR”). Similar results have been reported in other clinical studies. Risk factors, such as the presence of circulating blasts and unfavorable cytogenetics are associated with poor outcome, but the molecular responses in patients treated with CXCR4 inhibitor and conditioning chemotherapy prior to allo-SCT are unknown. We investigated the hypothesis that the CXCR4 inhibition-driven preparative regimen modulates distinct signaling networks, which vary depending on disease status.Utilizing reverse phase protein array (RPPA), we profiled 157 proteins in 36 cellular signaling and functional groups in samples collected from ten AML patients who were studied in the phase 1/2 trial (Table1). Five CR patients had less than 1% blasts in bone marrow (BM) and no blasts in peripheral blood (PB) before conditioning regimen (baseline, day -9). Five non-CR patients had BM blasts ranging from 10-72% and PB blasts from 0-45%. Here we denote samples from “CR” patients as “normal” and from “non-CR” patient as “AML”. All “AML” patients with blasts had persistent blasts after G+P plus conditioning, ranging from 4-64%. However, four of five “AML” and five “normal” patients achieved complete response to allo-SCT. Engraftment was observed in all patients. Disease progression following allo-SCT was observed in four of five “AML” but not in “normal” patients. Overall survival in “AML” was significantly shorter than in “normal” patients (non-CR = 260 ± 55 days, CR = 2028 ± 103 days, P < 0.001).RPPA analysis of samples prior to conditioning (day -9) revealed that 9 proteins in 9 signaling pathways were expressed differently in “normal” and “AML” samples. Among them, c-KIT, 53BP1, a P53-binding DNA repair protein, and CIAP (a SMAC and IAP family member) had significantly higher expression in “AML”.G+P treatment significantly modulated 7 proteins in 4 pathways in “AML” samples, and 22 proteins in 13 signaling and functional groups in “normal” samples (Fig 1A). As a result, 22 proteins in 14 signaling and functional groups were differentially expressed in “AML” and “normal” samples post G+P treatment (day -7) (Fig 1B). Among the top 10 distinct proteins, PI3Kp110A, P53BP1, SMAD1 and p-C-JUN S73 had higher expression, and P38MAPK, p-HER2 Y1248, P-CADHERIN, SYK, P21 and TAU had lower expression in “AML” samples.Treatment with G+P plus Bu+Flu conditioning modulated 10 proteins in 7 signaling pathways in “AML” samples, and altered 40 proteins in 13 signaling pathways in “normal” samples (Fig 1C). As a result, G+P plus Bu+Flu conditioning caused significant differences in expression of 16 proteins in 14 signaling and functional groups in “AML” vs. “normal” samples (day -3) (Fig 1D). Among the top 10 distinct proteins, PI3Kp110A, XRCC1, p-ERA S118, 53BP1, and BCL2 had higher expression, and MIG6, SYK, TAU, p-AKT T308 and MEK1 had lower expression in “AML” samples. Notably, c-KIT and 53BP1 in “AML” baseline samples were persistently expressed at high levels in samples from G+P and G+P plus Bu+Flu treated patients, suggesting that c-KIT and 53BP1 mediated signaling might play a role in therapeutic resistance and disease relapse in patients with active disease at the time of transplant.In summary, CXCR4 inhibition combined with Bu+Flu conditioning triggered distinct molecular responses, resulting in differential signaling between “normal” and “AML” cells prior to allo-SCT. The persistence of c-KIT and 53BP1 might play a role in resistance and contribute to relapse in AML. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Prognostic Impact of Minimal Residual Disease on Risk of Progression and Progression Free Survival in Acute Myeloid Leukemia

Assessment of minimal residual disease (MRD) in patients with complete remission CR) defined as <5% bone marrow blast count at allogeneic stem cell transplantation (HSCT) provides powerful independent prognostic information in acute myeloid leukemia and defines risk groups for transplant outcomes. Previous studies showed that transplant outcomes for AML patients with morphologically detectable disease (active disease) are comparable to those for CR patients with MRD (CR-MRDpos).We aimed to compare the outcomes of 458 AML patients who underwent HSCT after 2012 at our institution based on the status of morphologically detectable disease and MRD by 8 color flow cytometry at HSCT in addition to cytogenetic and molecular risk classification by European LeukemiaNet. The primary outcomes were disease progression and progression free survival (PFS) and analyses were stratified by ELN risk classification as favorable and intermediate (n=295) and adverse (n=163).Patients were categorized as active disease (n=81) vs. CR-MRDneg (n=191) and CR-MRDpos (n=52) vs. primary induction failure with marrow aplasia (PIF)-MRD (n=25) and PIF-MRDpos (n=74) vs. relapsed refractory with marrow aplasia (RR)-MRDneg (n=19) and RR-MRDpos (n=16). Median age of cohort was 56 (range, 3-80). Conditioning intensity was either myeloablative (n=260) or reduced intensity (n=198).The median follow-up of survivors was 18 months. For disease progression in favorable/intermediate risk by ELN, the only prognostic factors were the morphological disease status and MRD as shown in Figure 1. Active disease patients had the highest incidence of progression at 2-year with 53% which was similar to 43% observed in RR patients (HR=0.6, p=0.3). In comparison to active disease, CR-MRDpos and PIF-MRDpos patients had lower incidence of progression with 29% and 32% at 2-yr (HR=0.5, p=0.08 and HR=0.5, p=0.06). Among adverse risk patients, CR patients had significantly lower risk of disease progression independent of their MRD status when compared with active disease patients (HR=0.4, p=0.002 for CR-MRDneg and HR=0.4, p=0.02 for CRMRDpos).For PFS at 2 year, not only morphological disease status and MRD but also older age and hematopoietic comorbidity index (HCT-CI) were prognostic. In patients with favorable/intermediate ELN risk, Classification and Regression Tree multivariate analysis revealed 3 potential PFS groups: high PFS group included CR-MRDneg patients aged <60 who had the best 2-yr PFS estimated at 81%, and CR-MRDneg but aged ≥60 who had an estimated 2-yr PFS of 61%. In contrast, low PFS group included not CR-MRDneg patients with HCT-CI ≥4 in combination with either RR-marrow aplasia (2-yr PFS 0%) or age >60 (2-yr PFS 10%). In the absence of RR-marrow aplasia and older age, not CR-MRDneg patients with HCT-CI ≥4 had an intermediate 2-yr PFS (30%) which was comparable to the PFS (43%) in not CR-MRDneg patient with HCT-CI <4, irrespective of age.For adverse ELN risk group, PFS was the best in patients with CR (independent of the MRD status) and HCT-CI <4 with 2 year PFS of 59%. All other adverse risk patients had similarly low PFS with estimates of 17%-23%.In conclusion, we observed a lower progression incidence in CRMRDpos patients compared with active disease in both intermediate and adverse risk ELN groups after HSCT. However, PFS is a more complex endpoint with not only morphological disease status and MRD but also ELN risk classification, older age and HCT-CI determining the outcome expectations. These factors need to be taken into account when planning treatment for HSCT and thereafter. [Display omitted] DisclosuresOran:Celgene: Research Funding; AROG: Research Funding; Astex: Research Funding.

Prolonged Progression Free Survival and Time to Next Treatment Are Achievable Outcomes in Patients with Systemic AL Amyloidosis Treated with Novel Agent Chemotherapy: Analysis of the Alchemy Study

BackgroundSystemic AL amyloidosis (AL) is associated with an underlying plasma cell dyscrasia and caused by deposition of abnormally folded monoclonal immunoglobulin light chains. Novel chemotherapy has improved overall survival (OS) and haematological responses in recent years but little is known about durability of treatment response in this disease. In multiple myeloma, progression free survival (PFS) without ASCT is short. We report data on PFS and time to next treatment (TNT) in a predominantly non-ASCT population from the ALChemy study, a large prospective study of patients with AL.MethodsAll patients with newly diagnosed AL amyloidosis from January 2009 to March 2016 were included. All underwent serial organ function assessment, imaging and biomarkers. Organ involvement and responses were defined by international amyloidosis consensus criteria. Survival was calculated by Kaplan-Meier analysis. All outcomes are reported on an intention-to-treat (ITT) basis (patients who died before response assessment were assessed as non-responders). Progression free survival (PFS) was defined as time to death or progression to next line of chemotherapy. Time to next treatment (TNT) was defined as time from the beginning of first line therapy to the next line.Results1203 patients were recruited. Median age was 66.3 years (29.5-89.4), M:F 58%:42%, median NT-proBNP was 1974ng/L and median dFLC was 181.7mg/L. 62 patients (5.2%) died before treatment initiation. Treatments were: bortezomib-based regimen (mainly CyBorD) - 57.6%, immunomodulatory (IMID)-based (mainly CTD) - 32.4%, oral melphalan-dexamethasone - 5%, rituximab-based regimen - 3.2%, upfront ASCT - 1.3%, other - 0.5%. Median number of chemotherapy cycles was 5. Overall haematological response (FLC and M-protein response) at 6 months on an ITT basis (n=1037) was: CR 17.6%, VGPR 15.3%, PR 17.7% and non-response 49.4%. On an evaluable basis, overall haematological response at 6 months (n=723) was: CR 25.3%, VGPR 22%, PR 27.1% and non-response 25.6%.260 patients (21.6%) died within 6 months of diagnosis. Median OS was 47 months. Median PFS and TNT of the whole cohort was 17 months and 54 months respectively (Fig 1a and 1b). Median TNT in Mayo Stage 1, 2, 3A and 3B was 44, 46, 48 months and not reached (no second line treatment by 5 years = 54%), (p=0.63). Median PFS in Mayo Stage 1, 2, 3A and 3B was 34, 26, 14 and 4 months respectively (p<0.001).Median OS was not reached in patients who achieved an overall PR, VGPR or CR at 6 months, compared to median OS of 8 months in non-responders (p<0.001). Median PFS in patients who achieved an overall CR, VGPR, PR or non response at 6 months was: not reached (5 year PFS = 77%), 54 months, 20 months and 5 months respectively (p<0.001) (Fig. 1c). Median TNT in patients in overall CR, VGPR, PR or non response at 6 months was as follows: not reached (66% at 5 yrs), not reached (55% at 5 yrs), 26 months and 15 months (p<0.001) (Fig. 1d).Median OS in patients treated with bortezomib, IMID and melphalan was: 83 months, 55 months and 42 months respectively (p=0.11). Median OS in Stage 3 patients treated with bortezomib and IMID was 38 and 12 months respectively (p=0.001). Median PFS in patients treated with bortezomib, IMID and melphalan was: 21, 15 and 14 months (p=0.04). Among patients with stage 3 disease, median PFS in patients treated with bortezomib and IMID was 15 and 7 months respectively (p<0.001). Median TNT in patients treated with bortezomib, IMID and melphalan was: not reached (no second line by 5 years = 57%), 32 and 26 months (p=0.001). Among Stage 3 patients, median TNT in patients treated with bortezomib and IMID therapy was not reached (no second line by 5 years = 63%) and 28 months respectively (p<0.001).ConclusionThese prospectively collected data from a real world setting report on progression free survival and time to next treatment in AL with predominant non-transplant novel agent based regimens, which has thus far been lacking. Patients treated with bortezomib based therapy had superior PFS, TNT and OS. Median TNT was 4.5 years. Strikingly, PFS and TNT were remarkably long in patients achieving a complete haematological response (PFS 77% at 5 years) - akin to those previously reported in patients treated with upfront ASCT and perhaps raising questions about the role of upfront ASCT. These data confirm the efficacy of bortezomib based regimens in AL amyloidosis and the value of CR as the goal of induction therapy in this disease. [Display omitted] DisclosuresWechalekar:Celgene: Honoraria; Janssen: Honoraria.

Bone Marrow Infiltrating T-Cell Signatures Following Allo-HCT for Adult Acute Lymphoblastic Leukaemia Differentiate between Patients in Continuous CR and Those with Persistent Minimal Residual Disease or Relapse

Allogeneic stem cell transplantation (allo-HCT) has a proven survival benefit in adult acute lymphoblastic leukaemia (ALL) and remains the most commonly applied immunotherapy. The mechanism of graft-versus-leukaemia (GVL) in allo-HCT relies upon donor T cell immunity. After contributing to initial control of ALL, allo-reactive anti-tumour T cells may either persist, thus providing continuing immune surveillance, or undergo deletion/loss of function as a result of both extrinsic regulation and/or exhaustion. Therefore, there is a clear need to identify and track T cells with potential anti-ALL reactivity. UKALL14 (ISRCTN66541317) is an ongoing clinical trial for adults with de novo ALL in the UK in which all patients over 40 years are regarded as ‘high risk’ and are assigned to reduced intensity-conditioned allo-HCT. Minimal residual disease (MRD) monitoring - by immunoglobulin heavy chain/ T cell receptor quantification - of bone marrow and peripheral blood multilineage chimerism are assessed at regular intervals for 2 years post allo-HCT.We hypothesised that it would be possible to differentiate bone marrow infiltrating T-cell (BiL-T) signatures in patients in complete molecular remission versus those with MRD or frank clinical relapse. We have evaluated the feasibility of performing gene expression profiling on BiL-T cells from cryopreserved bone marrow samples of patients following allo-HCT and correlated this information with clinical outcome data.BiL-T were flow-sorted using the BD FACSAria ™ Fusion into CD3+,TCRab+, CD4+ and CD3+,TCRab+, CD8+. After extraction of total mRNA, samples with an RNA integrity index (RIN) >7 were subjected to RNA sequencing using the Illumina Hiseq. Data were analysed using differential expression gene analysis (DeSeq 2) and gene set enrichment analysis (GSEA). The Human Immunology V2 panel on the NanoString nCounter® SPRINT Profiler was used for gene expression profiling of samples with adequate RNA but a RIN <7. Gene expression data was correlated with molecular MRD data and other clinical parameters, including T cell chimerism where available.Both CD4+ and CD8+ subsets of BiL-T were successfully sorted from all 15 cryopreserved samples. DeSeq2 and GSEA of the RNAseq data was performed for CD4+TCRab+ BiL (n=5; 3 MRD- and 2 MRD+/relapse) (Figure 1) and CD8+TCRab+ (n=6; 4 MRD- and 2 MRD+/relapse). Despite the modest number of samples in this feasibility study, CD4+ T cells from patients with relapsing or MRD+ ALL showed significantly increased expression of genes associated with terminal differentiation (e.g. LAG3, GZMK); by contrast, there was lower expression of genes associated with memory differentiation and proliferative fitness (e.g. MYC, CCR7), a finding linked to increased pathway enrichment for PD-1 and telomere maintenance. CD8+ T cells from patients with relapsing or MRD+ ALL also demonstrated a terminally differentiated signature (e.g. increased expression of KLRC1 encoding NKG2A and lower expression of CCR7). GSEA showed enrichment for pathways linked to oxidative phosphorylation and interaction with non-haematopoetic stroma). We also analysed n=9 CD8+TCRab+ samples (n=4 MRD- and n=5 MRD+ or relapse) by Nanostring. These groups could also be segregated on the basis of genes representing pathways related to T cell survival, death receptor signalling and TCR signalling; in each case, CD8+ T cells from MRD+ or relapsing patients were characterised by a hypo-functional and apoptosis-prone signature.Our data show features suggestive of T cell exhaustion and altered metabolomes in patients with residual ALL post-allo-HCT, whether they are MRD+ or in frank clinical relapse; these features were not present in patients in continuous remission. To further test the hypothesis that T cell dysfunction significantly compromises GVL efficacy, we intend to perform transcriptional profiling of BiL-T in a wider cohort of UKALL14 patients who underwent allo-HCT. Since clinical strategies for reversal of T cell exhaustion including donor lymphocyte infusion (DLI) and potential PD-1 blockade already exist, we hope the impact of this project will be to determine precisely when and in whom to use these strategies during therapy for adult ALL. We expect that our findings will have relevance to the wider field of immunotherapy for ALL including blinatumomab and CAR-T approaches. [Display omitted] DisclosuresFielding:Baxalta: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

Clinical Observation on 98 Cases of Hematological Malignancies Treated with Autologous Hematopoietic Stem Cell Transplantation Cryopreserved By Ladder-Style Freezing from Low Temperature Refrigerator to Liquid Nitrogen

Background: Programmed cooling - 196℃ liquid nitrogen preservation and non- programmed cooling - 80℃ low temperature refrigerator preservation have been widely used in Auto- HSCT. Programmed cooling and - 196℃ liquid nitrogen preservation can set the rate of temperature fall in advance and standardize the cooling process, reducing the damage to hematopoietic stem cells caused by temperature fall. But programmed cooling is a time-consuming process and it needs to purchase expensive control rate freezer. Non- programmed cooling - 80℃ low temperature refrigerator preservation is easy to operate, but it cannot keep a long preservation period. Since 2002, we tried combining two preservation methods into one: first we placed freezer bags in - 80℃ low temperature refrigerator and then placed them in -196℃ liquid nitrogen tank for long-term preservation, with the purpose of prolonging the cryopreservation of stem cells.Method:We observed the influence of cryopreservation of hematopoietic stem cells with ladder-style freezing from low temperature refrigerator to liquid nitrogen in transplantation treatment of hematological malignancies, and analyzed the survival condition of patients after hematopoietic stem cell transplantation.We retrospectively analyzed the clinical datas of 98 patients with hematological malignancies treated by hematopoietic stem cell transplantation from 2002-01 to 2016-12 in our center.Results: 98 patients, 56 males and 42 females, aged 14-69 years (avenge age36.46±14.19 years). Disease subtypes: 10 cases of acute lymphoblastic leukemia(ALL), 24 cases of acute non- lymphoblastic leukemia(ANLL) , 11 cases of multiple myeloma(MM), 53 cases of malignant lymphoma(ML). One case failed in implantation due to intracranial hemorrhage and the other 97 cases all succeeded in hematopoietic reconstitution. The median survival time was 47 months and the average follow-up time was 50.11 months. The average time needed to neutrophil count ≥0.5×109/L was 9.24±1.89d, and the average time needed to platelet count≥20×109/L without platelet transfusion for 3 days was 11.04±1.84d. The median survival time was 47.6 months (1~80 months). The overall survival rates of 1 year, 3-year and 5-year were (97.2±1.9) %, (84.2±4.6) % and (77.8±5.6) %, respectively. PFS (progression-free survival) of patients in 3 years and 5 years were (74.4±5.1)% and (61.2±6.2)% (Figure1), which is consistent with data reported by other transplantation centers. In this study, it is found that the application of auto-HSCT has significantly improved OS and PFS of patients with acute leukemia, malignant lymphoma and multiple myeloma, but there is no significant difference in OS and PFS among three groups(Figure2)(P=0.537). The survival condition of CR1 patients was better than no-CR1 patients(Figure3). The complication about transplantation mainly were digestive tract symptoms. 9.18% patients complicated with liver function injury and 58.16% patients got infection.We continuously improved cryophylactic agent and obtained cryoprotectant formed by 3%hydroxyethyl starch, 4% albumin and 5% DMSO to replace the traditional 10% DMSO cryoprotectant used in programmed cooling. During stem cell infusion, the occurrence rate of complication was 8.16%, significant lower than the occurrence rate of adverse events occurring in the usage of 10% DMSO cryoprotectant.Conclusions: ladder-style freezing from low temperature refrigerator to liquid nitrogen with cryoprotectant that is formed by 3% hydroxyethyl starch, 4% albumin and 5% dimethyl sulfoxide (DMSO) for cryopreservation of hematopoietic stem cells. It can reach the same clinical transplantation effect with traditional programmed cooling freezing method in autologous hematopoietic stem cells transplantation (auto-HSCT) and can effectively improve OS, PFS of hematological malignancies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Complete Remissions Post Infusion of Multiple Tumor Antigen Specific T Cells for the Treatment of High Risk Leukemia and Lymphoma Patients after HCT

Background/Objectives: Relapse of hematologic malignancies after hematopoietic cell transplantation (HCT) confers high mortality because of progressive disease and graft-vs.-host disease (GVHD). Hence, we hypothesized that tumor-associated antigen-specific lymphocytes (TAA-L) would be specific, diminish immune escape, and could safely decrease cancer burden.Design/Methods: We expanded lymphocytes reactive to TAA: WT1, PRAME, Survivin, which are over-expressed and immunogenic in hematologic malignancies. On a prospective study: NCT002203902, eligible patients received TAA-L infusions at 4 sequential dose levels: 0.5 to 4.0e7/m2 per dose.Results: Thirty-two donor-derived TAA-L products were generated and lacked alloreactivity in vitro. TAA-L products comprised predominantly effector memory T-cells, with <15% of T-cells expressing exhaustion markers (PD1, TIM3, LAG3). Specificity of TAA-L showed greatest response to PRAME by ELIspot. Eleven HCT recipients (aged 9-70 years) with relapsed: Hodgkin's lymphoma (n=2), B-ALL (n=3), or AML (n=5), or high risk for relapse: AML post 2nd HCT (n=1)) received 1-3 doses of TAA-L. Patients had relapsed 2-12 months after HCT (9 allo, 1 auto) and all received therapy pre-TAA-L. Post infusion, there was only one adverse event possibly attributed to TAA-L (GVHD post viral infection on vidaza). One patient withdrew prior to study completion due to progressive disease with steroids for sepsis. Responses of evaluable patients (n=10) were: PD (n=2), PR (n=3), CR (n=5), with only 1 patient receiving adjunct therapy. Of the CR patients: AML (n=4); one patient who relapsed 10 months post HSCT is in a continuous CR for 314+ days after 3 doses of TAA-L only, one patient cleared peripheral blasts with TAA-L; one patient with Ph+-ALL achieved bcr-abl negativity post TAA-L only for the first time post-HSCT and has a continuous CR with 2 doses of TAA-L for 261 days. Immunosequencing of T-cell receptors showed expansion of TAA-L clones derived from the TAA-L product 4-5 weeks after infusion.Conclusion: This unique immunotherapeutic has been well tolerated without causing life-threatening cytokine release syndrome. Despite aggressive and multiply relapsed disease, 8/10 evaluable patients have demonstrated evidence of disease control after TAA-L, with 50% complete response, suggesting that TAA-L may have efficacy in relapsed high-risk hematological malignancies after HCT. DisclosuresBollard:Torque: Membership on an entity's Board of Directors or advisory committees; Cellectis: Membership on an entity's Board of Directors or advisory committees; Neximmune: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Objective Responses Achieved in Patients with MYC-Altered Relapsed/Refractory Diffuse Large B-Cell Lymphoma Treated with the Dual PI3K and HDAC Inhibitor CUDC-907

IntroductionPatients with relapsed/refractory (RR) diffuse large B-cell lymphoma (DLBCL) characterized by translocation or amplification of MYC or increased expression of MYC protein (MYC-altered) are reported to have a dismal prognosis (Blood. 2012 May 17;119(20):4619-24. and Haematologica. 2013 Oct;98(10):1554-62.). CUDC-907, a first-in-class oral dual inhibitor of HDAC and PI3K enzymes, has demonstrated downregulation of MYC mRNA and protein levels in MYC-altered DLBCL cell lines, as well as anti-tumor activity in multiple MYC-driven animal cancer models. In a Phase 1 study, objective responses were reported in a number of patients with MYC-altered RR DLBCL treated with CUDC-907. This Phase 2 study is designed to further explore the efficacy of CUDC-907 in this population. Clinical trial information: NCT02674750.Patients and MethodsUp to 200 RR DLBCL patients may be enrolled to enrich for a total of 100 patients with confirmed MYC-altered disease by central immunohistochemistry (IHC) testing. Following central testing, patients are placed into one of three groups; Group A consists of patients with MYC translocation and/or amplification by fluorescent in situ hybridization (FISH) without MYC protein expression ≥40% by IHC, Group B (n = 100) of patients with MYC protein expression ≥40% by IHC (regardless of FISH results), and Group C of patients that do not qualify for Group A or B. Central testing of BCL2 and BCL6 gene and protein expression status are also being performed. Key eligibility criteria include confirmed availability of viable biopsy tissue (fresh or archival) for central testing, ECOG score ≤1, 2-4 prior lines of therapy for DLBCL, and ineligible for/failed prior autologous stem cell transplantation. Transformed follicular lymphoma patients are also eligible. All patients receive 60 mg of CUDC-907 orally once a day on a 5 days on/2 days off schedule in 21-day cycles. The primary endpoint is to assess the objective response rate (ORR) in Group B. The evaluable population in this analysis are defined as any patient who received at least one dose of CUDC-907 and had a post-baseline disease assessment.ResultsAs of 29 June 2017, 68 patients received CUDC-907; 5 in Group A, 44 in Group B, and 19 in Group C. All patients with MYC translocations also had MYC protein expression ≥40% by IHC (n = 16). There were 17 patients with MYC amplifications, 12 of which also had MYC protein expression ≥40% by IHC, making all 5 Group A patients MYC amplifications only.The most frequently reported adverse events were diarrhea (64.1%), nausea (42.2%), thrombocytopenia (35.9%), fatigue (31.3%), hypokalemia (29.7%), and vomiting (25%). The most frequently reported Grade ≥3 treatment-related adverse events were thrombocytopenia (18.8%), neutropenia (14.1%), diarrhea (14.1%), anemia (6.3%), and hypokalemia (6.3%).Seven objective responses (3 CR and 4 PR) were reported in Group B and none in Groups A or C. The ORR in evaluable Group B patients was 19.4% (7/36). One of the PRs was reported in a double-hit lymphoma patient (both MYC and BCL2 translocations present). Responses showed encouraging durability considering the follow-up time with a range of 0.8 to 6.9+ months. Four of the responses were ongoing as of the data-cut, including 2 CRs. One of the CR patients discontinued study treatment early to pursue a stem cell transplant. The median duration of treatment for responders was not reached (95% confidence interval, 4.7 months to not reached).ConclusionsThe biologic rationale, tolerable safety profile, and evidence of anti-tumor activity in MYC-altered RR DLBCL support the continued development of CUDC-907 in this poor-prognosis patient population. DisclosuresLandsburg:Takeda: Research Funding; Curis: Consultancy, Research Funding. Ramchandren:Seattle Genetics: Consultancy; Janssen: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding. Pagel:Pharmacyclics: Consultancy; Gilead: Consultancy. Lugtenburg:Roche: Research Funding; Takeda: Research Funding; Roche: Honoraria; Takeda: Honoraria; Celgene: Honoraria; BMS: Honoraria; Servier: Honoraria; Sandoz: Honoraria.

Detection of miR3151 Gene Expression in De Novo Adult Acute Myeloid Leukemia and Its Clinical Implication

OBJECTIVE: Acute myeloid leukemia (AML) is a heterogeneous disease, in terms of genetic/molecular abnormalities resulting into marked differences in outcome. We had demonstrated that BAALC expression was of prognostic significance in intermediate-risk AML in the prophase study. MiR-3151 was discovered in intron 1 of BAALC. However, miR-3151 prognostic value has not been examined in Chinese adult de novo AML patients. METHODS: Pretreatment bone marrow samples from 209 adult de novo AML patients were analyzed for miR-3151mRNA expression by real-time reverse transcriptase polymerase chain reaction. Patients were divided into different groups according to miR-3151 level and were compared for clinical outcome. RESULTS: 73 cases of 92 intermediated cytogenetically AML patients got CR after the first block with a CR rate being 79.3% and the CR rate of total group is 72.7%(152/209). However , 29 cases of the CR patients with intermediated cytogenetically AML relapsed with the relapsed rate being 39.7%. Results showed no statistical difference in CR rate (74.0 %vs 71.4 %, P=0. 672),relapse rate (36.4 % vs. 48 . 0 %, P=0.14 6) and OS (35.4 % vs 40 . 0 %,P=0. 919) for 209 AML patients with low miR3151 comparing to those with high miR3151 expression. Patients with low miR3151 had a superior CR rate (88 . 6 %vs 70 . 8 %, P=0.0 35), OS (69.9% vs 11.5% P=0.00 0) and lower relapse rate(28.2 % vs. 5 2. 9 %, P=0.000) than low miR3151 expression in 92 intermediated cytogenetically AML. Conclusion: High expression of miR3151 identifies intermediated cytogenetically AML patients with a unfavorable long-term outcome. DisclosuresNo relevant conflicts of interest to declare.

Repetitively Administered Low-Dose Donor Lymphocyte Infusion for Prevention of Relapse after Allogeneic Stem Cell Transplantation in Patients with High-Risk Acute Leukemia.

Simple SummaryPatients with high-risk acute leukemia (AL) have a high risk of relapse after allogeneic stem cell transplantation (allo-SCT). Prophylactic donor lymphocyte infusion (pro-DLI) has shown significant efficacy in reducing relapse rate but its widespread application has been limited due to concerns of graft versus host disease (GVHD) development. In the present study, we tested the safety and efficacy of a novel method of pro-DLI based on repetitive administration of low lymphocyte doses. Low-dose pro-DLI was administered every two months for at least 3-years. Forty-four high-risk AL patients with a median age of 53-years who underwent allo-SCT from a matched-sibling (38pts) or a matched-unrelated donor (6pts) received pro-DLI. Acute and chronic-GVHD developed in 14% and 12% of patients. With a median follow-up of 44-months, the cumulative incidence of relapse and non-relapse mortality was 12% and 13%, while the overall survival was 78%. Prolonged up to 3-years low-dose pro-DLI administered every two months is safe and effective in reducing relapse rate in patients with high-risk AL. The low-dose repetitive administration DLI strategy reduced the risk of DLI-mediated GVHD, while the prolonged repeated administration helped in preventing relapse, possibly by inducing a sustained and prolonged immunological pressure on residual leukemic cells. Background: Patients with high-risk acute leukemia have a high risk of relapse after allogeneic stem cell transplantation (allo-SCT). In an effort to reduce the relapse rate, various therapeutic methods have been implemented into clinical practice. Among them, prophylactic donor lymphocyte infusion (pro-DLI) has shown significant efficacy. However, the widespread application of pro-DLI has been restricted mostly due to concerns regarding the development of graft versus host disease (GVHD). In the present study, we tested the safety and efficacy of a novel method of prophylactic-DLI based by repetitive administration of low lymphocyte doses. Methods: DLI was administered to patients with high-risk acute leukemia at a dose of 2 × 106/kg CD3-positive cells. DLI at the same dose was repeated every two months for at least 36 months post-allo-SCT, or until relapse or any clinical or laboratory feature suggested GVHD, whichever occurred first. Forty-four patients with a median age of 53 years (range 20–67) who underwent allo-SCT between 2011 and 2020 were included in our study. Thirty-three patients with high-risk acute myeloid leukemia (AML) and 11 with high-risk acute lymphoblastic leukemia (ALL) after allo-SCT from a matched sibling (MSD, no = 38 pts) or a matched-unrelated donor (MUD, no = 6 pts) received pro-DLI. Twenty-three patients were in CR1, all with unfavorable genetic features; 12 patients were in CR2 or beyond; and 9 patients had refractory disease at the time of transplant. Ten out of 23 patients in CR1 had detectable minimal residual disease (MRD) at the time of allo-SCT. Disease risk index (DRI) was high and intermediate in 21 and 23 patients, respectively. Conditioning was myeloablative (MAC) in 36 and reduced intensity (RIC) in 8 patients, while GVHD prophylaxis consisted of cyclosporine-A in combination with low-dose alemtuzumab in 39 patients or with low-dose MTX in 5 patients, respectively. Results: Thirty-five patients completed the scheduled treatment and received a median of 8 DLI doses (range 1–35). Fifteen out of 35 patients received all planned doses, while DLI was discontinued in 20 patients. Reasons for discontinuation included GVHD development in nine, donor unavailability in seven, disease relapse in three, and secondary malignancy in one patient, respectively. Nine patients were still on treatment with DLI, and they received a median of four (range 2–12) doses. Fourteen percent of patients developed transient grade-II acute GVHD while 12% developed chronic GVHD post-DLI administration. Acute GVHD was managed successfully with short course steroids, and four out of five patients with cGVHD were disease-free and off immunosuppression. With a median follow-up of 44 months (range 8–120), relapse-free (RFS) and overall survival (OS) were 74%, (95% CI, 54–87%) and 78%, (95% CI, 58–89%) respectively, while the cumulative incidence of non-relapse mortality (NRM) was 13% (95% CI, 4–28%). The cumulative incidence of relapse in patients with intermediate and high DRI is 7% and 15%, respectively. Conclusion: Prolonged—up to three years—low-dose pro-DLI administered every two months is safe and effective in reducing relapse rate in patients with high-risk acute leukemia. The low-dose repetitive administration DLI strategy reduced the risk of DLI-mediated GVHD, while the prolonged repeated administration helped in preventing relapse, possibly by inducing a sustained and prolonged immunological pressure on residual leukemic cells. This novel strategy deserves testing in larger cohort of patients with high-risk acute leukemia.

MO128RETINOL BINDING PROTEIN (RBP) - NEW BIOMARKER OF KIDNEY INJURY IN MULTIPLE MYELOMA PATIENTS*

Abstract Background and Aims The aim of the study was to analyse the utility of retinol binding protein (RBP) in case of renal impairment in MM patients and investigate its relationship with acclaimed parameters of renal failure and markers of MM stages. Method We recruited 73 patients (35 women, 38 men, in age range of 29-90 years, mean 70 ± 10 years) with multiple myeloma (MM), including 6 (8%) with smoldering MM, 40 (55%) with International Staging System (ISS) stage I, 15 (21%) with ISS II and 12 (16%) with ISS III. The majority of patients (65, 89%) received at least one treatment scheme. Thirty patients (41%) received maintenance treatment at recruitment. Median eGFR based on serum creatinine (CKD-EPICr) equaled 67 (range 9 – 117) ml/min/1.73 m2. Results Significant correlation was observed between RBP and the ordered variable describing MM stage from smoldering myeloma to ISS III (R=0.36; p=0.002). There were no differences between patients in CR, PR, SD and PD at the time of samples’ collection. Patients who were on maintenance treatment at recruitment tended to have higher serum RBP (median 42.6 versus 37.7 mg/l), however, the difference was not statistically significant (p=0.068). The patients who received steroid treatment had significantly higher RBP concentrations. There were no such association with other medications. There was no association between RBP and the number of previous treatment lines (p=0.8). Serum RBP did not differ between men and women (p=0.7) and did not correlate with age (p=0.6). Significant correlations were found between RBP and serum creatinine, cystatin C and eGFR values calculated based on creatinine and/or cystatin C (Table 1). In multiple regression, serum creatinine or cystatin C and the treatment with steroids were associated with RBP independently of ISS stage (Table 2). Moreover, RBP correlated with β2-microglobulin, LDH, leukocyte count, α-klotho, FGF-23, GDF-15, uNGAL and uIGFBP-7, however, only the associations with β2-microglobulin and sTfR were independent of serum creatinine in multiple regression (Table 1). Baseline serum RBP concentration was significantly correlated with eGFR after a median of 19 months follow-up (range 1-24 months) (R=-0.35; p=0.003), however, the correlation was not independent of baseline serum creatinine ((beta ± SE: 0.06 ± 0.10; p=0.5). To the contrary, baseline serum cystatin C (beta ± SE: -0.36 ± 0.13; p=0.009) predicted final eGFR independently of baseline serum creatinine. Conclusion RBP may be useful marker in renal damage in patients with chronic kidney injury among patients with MM. This can lead to noninvasive biomarker-targeted diagnostic interventions and contribute to early beginning of treatment that may improve life expectancy quality of life in MM.

Real-world evidence of axicabtagene ciloleucel (Axi-cel) for the treatment of large B-cell lymphoma (LBCL) in the United States (US).

7552 Background: Axi-cel is approved in the US for the treatment of adult patients with relapsed or refractory LBCL after 2 or more lines of systemic therapy. Post-market long term follow up study of commercial Axi-cel recipients using the Center for International Blood and Marrow Transplant Research was recently completed. Methods: From October 2017 to August 2020, 1,500 Axi-cel recipients from 79 centers were enrolled. Of these, 1001 patients with at least 6 months of follow-up were included in this analysis. Outcomes include complete and overall responses rates (CR and ORR), duration of response (DOR), progression-free and overall survival (PFS and OS), cytokine release syndrome (CRS) (Lee D 2014 and American Society for Transplantation and Cellular Therapy [ASTCT]), immune effector cell associated neurotoxicity syndrome (ICANS), hematologic recovery and subsequent neoplasm (SN). Subgroup analysis by sensitivity to therapy, defined as responsive to the last line of therapy prior to Axi-cel. Median follow-up was 12 months (range, 6-28 months). Results: The median age overall was 62 years, 37% were ≥ 65 years, 83% with Eastern Cooperative Oncology Group (ECOG) performance score 0-1, 28% with transformed lymphoma, 14% with high grade lymphoma, 29% with prior autologous transplant, and 66% with chemotherapy-resistant disease prior to Axi-cel. The median time from diagnosis to Axi-cel infusion was 15 months. Best ORR was 70% (CR 53%). Landmark analysis of patients in CR at 6 months post Axi-cel demonstrates a low number of subsequent progression/death events. With respect to outcomes for chemotherapy-sensitive disease versus resistant disease, the ORR, CR, 12-month PFS and OS were 78% vs. 66%, 60% vs. 48%, 55% (95% CI, 48-62%) vs. 40% (95% CI, 37-44%), and 70% (95% CI, 63-76%) vs. 54% (95% CI, 50-58%), respectively. CRS of any grade was reported in 83% of patients. Incidence of Grades ≥ 3 CRS was 10% according to Lee et al 2014, and 13% according to ASTCT Consensus Grading. Median time to any grade CRS was 4 days (range, 1-28 days), and 93% of CRS cases resolved with a median duration of 7 days (range, 1-121 days). ICANS were reported in 576 (57%) patients, grade &gt;3 was 26%. The median time to onset of ICANS was 7 days (range, 1-82 days), and 86% resolved with a median duration of 9 days (range, 1 to 115 days). Twenty-nine patients (2.9%) reported SN: hematologic (N = 17), solid tumors (N = 12). Conclusions: This is the largest report on Axi-cel in the real-world setting and demonstrates consistent efficacy outcomes and further characterizes safety outcomes. Patients in CR at 6 months have sustained disease control with low number of relapse events. Although patients with therapy-sensitive disease experience better outcomes than patients with therapy-resistant, the overall outcomes on both groups of patients are favorable.

CoupledCAR technology for treating thyroid cancer.

e14507 Background: Chimeric antigen receptor modified T-cells (CAR-T) have demonstrated remarkable clinical efficacy in the treatment of B-cell malignancies. Significant challenges restrict their application across solid tumors due to multiple obstacles, including the lack of robust in vivo CAR-T cell expansion and persistence in the immunosuppressive tumor microenvironment. Methods: To address these difficulties, we generated CAR-T cells using a novel CoupledCAR technology. Specifically, we engineered CoupledCAR-T cells with lentiviral vectors encoding an anti-thyroid stimulating hormone receptor (TSHR) CAR molecule. In vitro co-culture experiments showed that TSHR CAR-T cells specifically recognized and subsequently killed TSHR-positive tumor cells. Animal model experiments showed that TSHR CAR-T cells inhibited the proliferation of TSHR-positive tumor cells. Results: Patient 1: Male, 64Y, Papillary Thyroid Carcinoma. In May 2017, his Thyroid cancer was diagnosed, bilateral total thyroidectomy, and right cervical lymph node functional dissection were performed in Jun 2018, followed by iodine 131 isotope therapy. In December 2018, bilateral multiple cervical lymph nodes were enlarged, especially on the right side. In February 2019, right neck lymphadenectomy was performed. One month after infusion (M1) of the anti-TSHR CoupledCAR-T cells, the patient was evaluated as PR. Three months after infusion (M3), the patient was evaluated as CR, and the patient's CR lasted from M3 to M12 after infusion of the CoupledCAR-T cells. We are still following the patient for long-term clinical effects. Patient 2: Female, 60Y, Thyroid Carcinoma: In Aug 2013, a "double lobectomy of the thyroid gland” was performed. From Oct 2013 to Jan 2014, she received iodine 131 isotope therapy. In Sep 2014, she was diagnosed with iodine-resistant thyroid cancer. From Sep to Jan 2016, 5 cycles of chemotherapy were performed. In Jun 2016, she enrolled in the Anlotinib experimental group. In Mar 2019, multiple metastases in both lungs and multiple enlarged lymph nodes in the mediastinum were observed. At month 1 (M1) post cell infusion, the patient was evaluated as PR (Partial Response): the tumor volume in the right lower lobe of the lung was reduced by approximately 67.51% (decreased from 65*55mm to 42*39mm). Three months after infusion (M3), the tumor volume was reduced by approximately 73.54% and SUV max value decreased from 14.9 to 2.8. Therefore, the patient was evaluated as nCR (near complete remission). Conclusions: In summary, we showed that TSHR is an attractive and specific target for treating thyroid cancer and our anti-TSHR CoupledCAR-T cells are safe and effective for treating thyroid cancer. Recruitment is ongoing to evaluate the safety and efficacy of our CoupledCAR-T cells. Further, since our CoupledCAR technology is a platform technology, we are developing additional CoulpledCAR-T cells to treat other solid tumors using different target tumor markers.

Multicenter phase II study of romidepsin plus lenalidomide for patients with previously untreated peripheral T-cell lymphoma (PTCL).

7514 Background: PTCL are aggressive malignancies associated with poor prognosis when treated with cytotoxic chemotherapy. Novel agents, such as HDAC inhibitor romidepsin and immunomodulatory agent lenalidomide, have shown clinical activities as single agents and in combination in R/R PTCL. We hypothesize that upfront treatment with these agents is an effective and well-tolerated option to defer chemotherapy, particularly in patients who are not candidates for intensive approach. We report the findings of the first chemo-free combination of romidepsin plus lenalidomide as initial treatment for PTCL (ClinicalTrials.gov-NCT02232516). Methods: Patients with untreated PTCL who were over 60 or noncandidates for chemotherapy based on comorbidity CIRS score were eligible. Treatment was initiated with romidepsin 10 mg/m2 IV on d 1, 8, 15, and lenalidomide 25 mg PO on d 1-21 of 28-day cycle for up to 1 year, unless discontinued prior due to POD, toxicities, or withdrawal of consent. The primary objective was to evaluate ORR per Cheson criteria. Secondary objectives included safety, PFS, OS, DOR, and delay to chemotherapy. The sample size was 20 evaluable patients, which allows to estimate the underlying true response rate with the margin of error of an approximate 95% confidence interval equal to 0.22, assuming the true ORR = 0.5. Results: The study enrolled 29 subjects at 3 US centers, including 16 (55%) AITL, 11 (38%) PTCL-NOS, 1 ATLL and 1 EATCL. The median age was 75 (range 49-84), and M:F ratio was 1:1. Nineteen (66%) had stage III/IV disease, 23 (79%) had elevated LDH, and 9 (31%) had IPI 3-5. Treatment was well tolerated with expected side effects. Grade 3-4 hematologic toxicities included neutropenia (45%), thrombocytopenia (34%) and anemia (28%). Grade 3-4 non-hematologic toxicities included hyponatremia (45%), hypertension (38%), hypoalbuminemia (24%), fatigue (17%), hyperglycemia (14%), hypokalemia (14%), dehydration (10%), lung infection (10%) and sepsis (10%). At a median follow-up of 8 months, 20 subjects were evaluable with at least one response assessment, and received a median treatment of 6 cycles. The ORR was 75% (95%CI: 50.9%, 91.3%) with CR at 30% (11.9%, 54.3%). For AITL, the ORR was 85% (54.6%, 98.1%) with CR at 38% (13.9%, 68.4%). Median DOR was 4.2 months for all responders, and 14.3 months for CR patients. The estimated 1-yr PFS was 54.3% with 3-yr PFS at 36.2%, and the estimated 1-yr OS was 76.0% with 3-yr OS at 51.3%. Two subjects moved onto consolidative ASCT in remission, and 4 received additional cytotoxic chemotherapy after progression. Conclusions: This study provides the first demonstration that chemo-free biologic combination of romidepsin and lenalidomide is feasible and effective as initial therapy for PTCL patients who are not candidates for cytotoxic chemotherapy. These data justify further evaluation of such novel agents as a frontline strategy. Clinical trial information: NCT02232516.

Obese patients' characteristics and weight loss outcomes in cardiac rehabilitation: An observational study of registry data

AimCardiac rehabilitation (CR) guidelines advocate weight loss for obese patients but mean weight loss is small. We sought to determine the extent to which obese patients' characteristics prior to CR predict weight loss. MethodsAn observational, pre- and post CR study of routine practice using the UK National Audit of Cardiac Rehabilitation dataset was undertaken. Backward, stepwise, multiple linear regression analysis was used to identify characteristics prior to CR that predicted weight change in obese patients. ResultsIn 29,601 obese patients undertaking CR, mean weight loss was 0.9 kg (SD 4.3; p < 0.001) in men (74% of sample) and 0.5 kg (SD 3.9; p < 0.001) in women. Smoking cessation since the cardiac event independently predicted less weight loss by 1.2 kg (95% CI; 0.9, 1.5 kg; p < 0.001). Diabetes, cardiac surgery, living in a deprived area, being female, low fitness levels and pain independently predicted less weight loss during CR. Higher initial weight, greater age and being employed predicted increased weight loss. ConclusionThis is the first study to identify how the characteristics of obese patients independently predict different amounts of weight loss during CR in free-living individuals. It is also the largest, registry-based study to investigate predictors of weight loss in obese patients in CR. Knowledge of the extent to which obese patients' characteristics predict more or less weight loss can aid: the generation of guidelines; agreement of realistic goals with patients; and tailoring of weight management support.

Effect of a Virtual Reality-Enhanced Exercise and Education Intervention on Patient Engagement and Learning in Cardiac Rehabilitation: Randomized Controlled Trial.

BackgroundCardiac rehabilitation (CR) is clinically proven to reduce morbidity and mortality; however, many eligible patients do not enroll in treatment. Furthermore, many enrolled patients do not complete their full course of treatment. This is greatly influenced by socioeconomic factors but is also because of patients’ lack of understanding of the importance of their care and a lack of motivation to maintain attendance.ObjectiveThis study aims to explore the potential benefits of virtual reality (VR) walking trails within CR treatment, specifically with regard to patient knowledge retention, satisfaction with treatment, and the overall attendance of treatment sessions.MethodsNew CR patients were enrolled and randomized on a rolling basis to either the control group or intervention group. Intervention patients completed their time on the treadmill with VR walking trails, which included audio-recorded education, whereas control patients completed the standard of care therapy. Both groups were assisted by nursing staff for all treatment sessions. Primary outcomes were determined by assessing 6-minute walk test improvement. In addition, secondary outcomes of patients’ cardiac knowledge and satisfaction were assessed via a computer-based questionnaire; patient adherence to the recommended number of sessions was also monitored. Cardiac knowledge assessment included a prerehabilitation education quiz, and the same quiz was repeated at patients’ final visit and again at the 2-month follow-up. The satisfaction questionnaire was completed at the final visit.ResultsBetween January 2018 and May 2019, 72 patients were enrolled—41 in the intervention group and 31 in the control group. On the basis of the results of the prerehabilitation and postrehabilitation 6-minute walk test, no significant differences were observed between the intervention and control groups (P=.64). No statistical differences were observed between groups in terms of education (P=.86) or satisfaction (P=.32) at any time point. The control group had statistically more favorable rates of attendance, as determined by the risk group comparison (P=.02) and the comparison of the rates for completing the minimum number of sessions (P=.046), but no correlation was observed between the study group and reasons for ending treatment.ConclusionsAlthough no improvements were seen in the VR intervention group over the control group, it is worth noting that limitations in the study design may have influenced these outcomes, not the medium itself. Furthermore, the qualitative information suggests that patients may have indeed enjoyed their experience with VR, even though quantitative satisfaction data did not capture this. Further considerations for how and when VR should be applied to CR are suggested in this paper.Trial RegistrationClinicalTrials.gov NCT03945201; https://clinicaltrials.gov/ct2/show/NCT03945201

Regulation Effect of Myeloid Leukemia No.1 Chinese Herb Medicine Prescription Combined with Chemotherapy on Th17 Cells in Bone Marrow of Patients with Acute Myeloid Leukemia

To explore the regulation effect of myeloid leukemia No.1 Chinese herb medicine prescription combined with chemotherapy on Th17 cells in bone marrow fluid of AML patients, so as to provide guidance for improving AML treatment effect and patients' long-term survival. Seventy patients with AML who were hospitalized in Department of Hematology, Wuwei People's Hospital from April 2017 to August 2019 were selected and enrolled in AML group, 25 healthy volunteers were selected and enrolled in control group; then according to therapeutic regimen, AML patients were divided into 2 groups: combined therapy group (myeloid leukemia NO.1 Chinese herb medicine prescription combined with chemotherapy) and non-combined therapy group (chemotherapy alone). Flow cytometry was used to detect the ratio of CD3+ CD161+ IL-17+ IFN-γ+ T cells in bone marrow fluid, and ELISA was used to detect the vascular endothelial growth factor (VEGF) and interleukin-17 (IL-17) concentrations in bone marrow fluid. Statistical analysis was performed on the data with SPSS 22.0. The ratio of CD3+ CD161+ IL-17+ IFN-γ+ T cells, VEGF and IL-17 concentration in newly diagnosed and relapsed AML patients were significantly higher than those in the normal control group (P<0.001); while those in CR and DFS stage patients were significantly lower than those in newly diagnosed and relapsed patients (P<0.001), and the ratio of CD3+ CD161+ IL-17+ IFN-γ+ T cells, VEGF and IL-17 concentration in DFS patients with AML were not significantly different from those in the control group (P>0.05). The ratio of CD3+ CD161+ IL-17+ IFN-γ+ T cells, VEGF and IL-17 concentration in CR stage of AML patients treated with chemotherapy alone were significantly higher than those in the control group (P<0.05), but there was no difference between combined therapy group and the control group; the ratio of CD3+ CD161+ IL-17+ IFN-γ+ T cells, the concentration of VEGF and IL-17 in CR stage of AML patients treated with chemotherapy alone were higher than those of patients treated with combined therapy regimen (P<0.05). AML patients treated with combined therapy regimen had a significantly higher complete remission rate compared with patients received chemotherapy alone (P<0.05), but the recurrence rate was significantly lower (P<0.05). Th17 cells expression in bone marrow of newly diagnoses and relapsed AML patients significantly increase, and decrease significantly after treatment. Myeloid leukemia No.1 Chinese herb prescription combined with chemotherapy can significantly increase the CR rate and reduce the RL rate for AML.

Superior survival with pediatric-style chemotherapy compared to myeloablative allogeneic hematopoietic cell transplantation in older adolescents and young adults with Ph-negative acute lymphoblastic leukemia in first complete remission: analysis from CALGB 10403 and the CIBMTR

Optimal post-remission therapy for adolescents and young adults (AYAs) with Ph-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1) is not established. We compared overall survival (OS), disease-free survival (DFS), relapse, and non-relapse mortality (NRM) for patients receiving post-remission therapy on CALGB 10403 to a cohort undergoing myeloablative (MA) allogeneic hematopoietic cell transplantation (HCT) in CR1. In univariate analysis, OS was superior with chemotherapy compared to MA allogeneic HCT (3-year OS 77% vs. 53%, P < 0.001). In multivariate analysis, allogeneic HCT showed inferior OS (HR 2.00, 95% CI 1.5–2.66, P < 0.001), inferior DFS (HR 1.62, 95% CI 1.25–2.12, P < 0.001), and increased NRM (HR 5.41, 95% CI 3.23–9.06, P < 0.001) compared to chemotherapy. A higher 5-year relapse incidence was seen with chemotherapy compared to allogeneic HCT (34% vs. 23%, P = 0.011). Obesity was independently associated with inferior OS (HR 2.17, 95% CI 1.63–2.89, P < 0.001), inferior DFS (HR 1.97, 95% CI 1.51–2.57, P < 0.001), increased relapse (1.84, 95% CI 1.31–2.59, P < 0.001), and increased NRM (HR 2.10, 95% CI 1.37–3.23, P < 0.001). For AYA ALL patients in CR1, post-remission therapy with pediatric-style chemotherapy is superior to MA allogeneic HCT for OS, DFS, and NRM.

CardioMEMS Pulmonary Artery Pressure Guided Management of Advanced HF Patients Supported with a HeartMate LVAD: INTELLECT 2-HF Study

PurposeHemodynamic-guided management with a pulmonary artery pressure (PAP) sensor (CardioMEMS) is effective in reducing HF hospitalization (HFH) in chronic HF patients. We sought to determine the utility of managing patients on continuous-flow LVAD support using the CardioMEMSTM HF system.MethodsIn this multi-center observational study, we enrolled patients with a HeartMate 2 (HM2) (n=52) or HM3 (n=49) LVAD who either already had a CardioMEMS sensor (n=53) or were clinically implanted after enrollment for residual HF (n=48). Patients underwent assessments at baseline, 1, 3 and 6 months for endpoints: 6-minute walk distance (6MWD), change in PAP, quality of life score (EQ-5D-5L scores), and HFH rates. Patients were stratified post-hoc as clinical responders (cR) if there was a reduction in PA diastolic pressure (PAD) of at least 1 mmHg at 6 months, and the remainder were deemed non-responders (cNR).ResultsOf 101 patients enrolled, 88 patients completed 6-month follow-up. PAP measurement was feasible with excellent weekly patient compliance (91.1% ± 19.8%). There were no clinically relevant differences between cR (n=37) and cNR (n=46) patients at baseline (data not shown). PAD at 6 months was 3.5 ± 4.6 mmHg lower than baseline within the cR group (20.8 to 17.3 mmHg, p=0.0002) (Figure-panel A). While there were no observed differences in QoL or HFH between cR and cNR, significant increases in 6MWD occurred among cR (286 vs 332 meters, p=0.03, Figure-panel B). Those individuals who maintained a PAD < 20mmHg had significantly reduced HFH (Figure-panel C).ConclusionThe use of CardioMEMS system in HeartMate LVAD patients is feasible. Significant reduction in PAD at 6 months was associated with improvements in 6MWD and achieving a PAD < 20 mmHg was associated with lower HFH events. These findings provide justification and guidance for prospective investigations utilizing the CardioMEMS system to improve the management and outcomes of LVAD patients. Hemodynamic-guided management with a pulmonary artery pressure (PAP) sensor (CardioMEMS) is effective in reducing HF hospitalization (HFH) in chronic HF patients. We sought to determine the utility of managing patients on continuous-flow LVAD support using the CardioMEMSTM HF system. In this multi-center observational study, we enrolled patients with a HeartMate 2 (HM2) (n=52) or HM3 (n=49) LVAD who either already had a CardioMEMS sensor (n=53) or were clinically implanted after enrollment for residual HF (n=48). Patients underwent assessments at baseline, 1, 3 and 6 months for endpoints: 6-minute walk distance (6MWD), change in PAP, quality of life score (EQ-5D-5L scores), and HFH rates. Patients were stratified post-hoc as clinical responders (cR) if there was a reduction in PA diastolic pressure (PAD) of at least 1 mmHg at 6 months, and the remainder were deemed non-responders (cNR). Of 101 patients enrolled, 88 patients completed 6-month follow-up. PAP measurement was feasible with excellent weekly patient compliance (91.1% ± 19.8%). There were no clinically relevant differences between cR (n=37) and cNR (n=46) patients at baseline (data not shown). PAD at 6 months was 3.5 ± 4.6 mmHg lower than baseline within the cR group (20.8 to 17.3 mmHg, p=0.0002) (Figure-panel A). While there were no observed differences in QoL or HFH between cR and cNR, significant increases in 6MWD occurred among cR (286 vs 332 meters, p=0.03, Figure-panel B). Those individuals who maintained a PAD < 20mmHg had significantly reduced HFH (Figure-panel C). The use of CardioMEMS system in HeartMate LVAD patients is feasible. Significant reduction in PAD at 6 months was associated with improvements in 6MWD and achieving a PAD < 20 mmHg was associated with lower HFH events. These findings provide justification and guidance for prospective investigations utilizing the CardioMEMS system to improve the management and outcomes of LVAD patients.

Role of Hematopoietic Stem Cell Transplantation in Acute Promyelocytic Leukemia.

The indication of hematopoietic stem cell transplantation (HSCT) in acute promyelocytic leukemia (APL) has evolved historically from a widespread use in front-line therapy during the pre-ATRA era to a virtual rejection of this indication for patients treated with modern treatments. HSCT in first complete remission could only be considered for an extremely small fraction of patients with persistent MRD at the end of consolidation or for those who relapse. In the pre-ATO era, relapsed patients were usually treated with readministration of ATRA and chemotherapy as salvage therapy, generally containing high-dose cytarabine and an anthracycline, followed by further post-remission chemotherapy and/or HSCT. ATO-based regimens are presently regarded as the first option for relapsed APL. The selection of the most appropriate post-remission treatment option for patients in second CR (CR2), as well as the modality of HSCT when indicated, depends on several variables, such as pre-transplant molecular status, duration of first remission, age, and donor availability. Although with a moderate level of evidence, based on recent retrospective studies, autologous HSCT would be at present the preferred option for consolidation for patients in molecular CR2. Allogeneic HSCT could be considered in patients with a very early relapse or those beyond CR2. Nevertheless, the superiority of HSCT as consolidation over other alternatives without transplantation has recently been questioned in some studies, which justify a prospective controlled study to resolve this still controversial issue.

G-CSF-Primed Peripheral Blood Stem Cell Haploidentical Transplantation Could Achieve Satisfactory Clinical Outcomes for Acute Leukemia Patients in the First Complete Remission: A Registered Study.

G-CSF-mobilized peripheral blood (G-PB) harvest is the predominant graft for identical sibling donor and unrelated donor allogeneic hematopoietic stem cell transplantation (HSCT) recipients, but it was controversial in haploidentical related donor (HID) HSCT. In this registry study, we aimed to identify the efficacy of HID G-PB HSCT (HID-PBSCT) for acute leukemia (AL) patients in first complete remission (CR1). Also, we reported the outcomes for the use of G-PB grafts in comparison with the combination of G-BM and G-PB grafts in HID HSCT recipients. Sixty-seven AL patients in CR1 who received HID-PBSCT were recruited at Institute of Hematology, Peking University. Patients who received haploidentical HSCT using the combination of G-BM and G-PB harvests in the same period were enrolled as controls (n=392). The median time from HSCT to neutrophil and platelet engraftment was 12 days (range, 9–19 days) and 12 days (range, 8–171 days), respectively. The 28-day cumulative incidence of neutrophil and platelet engraftment after HSCT was 98.5% and 95.5%, respectively. The cumulative incidences of grade II–IV and grade III–IV acute graft-versus-host disease (GVHD) were 29.9% (95%CI 18.8–40.9%) and 7.5% (95%CI 1.1–13.8%), respectively. The cumulative incidences of total and moderate-severe chronic GVHD were 54.9% (95%CI 40.9–68.8%) and 17.4% (95%CI 6.7–28.0%), respectively. The cumulative incidences of relapse and non-relapse mortality were 13.9% (95%CI 5.4–22.5%) and 3.4% (95%CI 0–8.1%), respectively. The probabilities of overall survival (OS) and leukemia-free survival (LFS) were 84.7% (95%CI 74.7–94.7%) and 82.7% (95%CI 73.3–92.1%) respectively. Compared with the HID HSCT recipients using the combination of G-BM and G-PB grafts, the engraftments of neutrophil and platelet were both significantly faster for the G-PB group, and the other clinical outcomes were all comparable between the groups. In multivariate analysis, graft types did not influence the clinical outcomes. Overall, for the patients with AL CR1, G-PB graft could be considered an acceptable graft for HID HSCT recipients. This study was registered at https://clinicaltrials.gov as NCT03756675.