Lower Complete Remission Rate Research Articles

Which Immunosuppressive Therapy should be used in Primary Membranous Glomerulonephritis?

Background: Different results have been reported on immunosuppressive treatments in patients with primary membranous nephropathy. In recent years, it has been determined that antiPLA2R antibodies can be used for the diagnosis of primary membranous glomerulonephritis. The aim of this study was to investigate the treatment responses of patients with primary membranous glomerulonephritis determined by the presence of PLA2-R antibody. Patients and Methods: Sixty patients (M:29, F:31) with membranous glomerulonephritis were retrospectively investigated. The presence of glomerular PLA2R antibodies were investigated by immunohistochemical method from the pathological specimen. Those patients were treated with immunosuppressants (methylprednisolon, cyclophosphamide, cyclosporine, azathioprine), and angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin II receptor blocker (ARB). The treatments were carried out with different combinations. The success of the treatment was defined as complete (<0.3g/day), partial (<3.5g/day or at least 50% reduction) or unresponsive (insufficient reduction) according to the reduction in proteinuria. In the patients, progression risks (low, moderate, high) were divided according to proteinuria and creatinine clearance. The results of immunosuppressive treatments were statistically analyzed, and p<0.05 was accepted significant. Results Glomerular PLA2R antibodies were positive in 50 cases (87.7%), negative in 7 cases (12.2%). The mean duration of treatment of the patients was 23 months (6-58 months). With the treatment of PLA2R antibody-positive patients, 29% developed complete remission, 56% partial remission, and 15% did not respond. Complete remission was achieved only by steroid plus cyclophosphamide or cyclosporine combinations. The overall response (complete plus partial) rates were similar (respectively, 91% and 89%) in cyclophosphamide or cyclosporine treatment with steroids. The reduction rates in proteinuria were 70.6% in patients using cyclophosphamide, steroid, and ARB, and 79.5% in patients using cyclosporine, steroid, and ARB; there was no difference between them (P=0.67). In patients with positive PLA2R antibodies, the risk of progression was low in 25%, moderate in 29%, and high in 46%. When the treatment responses were examined, a lower rate of complete remission and higher partial remission were found in the high-risk group than in the low-risk group. However, overall response rates were not different in risk groups. Conclusion In primary membranous glomerulonephritis, only cyclophosphamide or combinations of cyclosporine and steroids provided complete remission. The complete plus partial response rates were similar in all risk groups.

Ruxolitinib plus steroids for acute graft versus host disease: a multicenter, randomized, phase 3 trial

Newly diagnosed patients with high-risk acute graft-versus-host disease (aGVHD) often experience poor clinical outcomes and low complete remission rates. Ruxolitinib with corticosteroids showed promising efficacy in improving response and failure free survival in our phase I study. This study (ClinicalTrials.gov: NCT04061876) sought to evaluate the safety and effectiveness of combining ruxolitinib (RUX, 5 mg/day) with corticosteroids (1 mg/kg/day methylprednisolone, RUX/steroids combined group) versus using methylprednisolone alone (2 mg/kg/day, steroids-only group). Newly diagnosed patients with intermediate- or high-risk aGVHD were included, with risk levels classified by either the Minnesota aGVHD Risk Score or biomarker assessment. Patients were randomized in a ratio of 1:1 into 2 groups: 99 patients received RUX combined with methylprednisolone, while the other 99 received methylprednisolone alone as the initial treatment. The RUX/steroids group showed a significantly higher overall response rate (ORR) on day 28 (92.9%) compared to the steroids-only group (70.7%, Odds Ratio [OR] = 5.8; 95% Confidence Interval [CI], 2.4–14.0; P < 0.001). Similarly, the ORR on day 56 was higher in the RUX/steroids group (85.9% vs. 46.5%; OR = 7.07; 95% CI, 3.36–15.75; P < 0.001). Additionally, the 18-month failure-free survival was significantly better in the RUX/steroids group (57.2%) compared to the steroids-only group (33.3%; Hazard Ratio = 0.46; 95% CI, 0.31–0.68; P < 0.001). Adverse events (AEs) frequencies were comparable between both groups, with the exception of fewer grade 4 AEs in the RUX/steroids group (26.3% vs. 50.5% P = 0.005). To our knowledge, this study is the first prospective, randomized controlled trial to demonstrate that adding ruxolitinib to the standard methylprednisolone regimen provides an effective and safe first-line treatment for newly diagnosed high-risk acute GVHD.

Clinical relevance of long non-coding RNA in acute myeloid leukemia: A systematic review with meta-analysis

BackgroundLong noncoding RNAs (lncRNAs) may function as prognostic biomarkers in acute myeloid leukaemia (AML). However, it is still unknown exactly how significant lncRNAs are for the prognosis of AML. With a focus on their prognostic and therapeutic potential, the study aimed to provide a comprehensive review of the literature regarding the role of lncRNAs in AML. MethodPub Med, The Cochrane Library, Embase, Science Direct, Web of science, Scopus, and Google scholar were searched until November, 2023. Original publications of any type exploring the prognostic and therapeutic potential of lncRNAs in AML patients were included. Heterogeneity and publication bias were examined using the I2 test and a funnel plot, respectively. To quantify the relationship between various lncRNA expression in AML patient survival, odds ratios (ORs) or hazards ratios (HRs) with 95 % confidence intervals (CIs) were pooled. Quality of studies was assessed using the Critical Appraisal Checklists for Studies created by the Joanna Briggs Institute (JBI). ResultsTwenty-seven studies including 5665 subjects were selected for the final analysis. In patients with AML, abnormal lncRNA expression has been associated with significant worse overall survival (pooled HR = 2.05, 95 % CI = 1.79–2.30, P <0.001), shorter disease-free survival (pooled HR = 2.17, 95 % CI = 1.13–3.22, P< 0.001), and lower complete remission rate (pooled HR = 0.27, 95 % CI = 0.11–0.43, P< 0.001). Poor prognoses have been attributed to increased expression of HOX transcript antisense intergenic RNA (HOTAIR), Promoter Of CDKN1A Antisense DNA Damage Activated RNA (PANDAR), Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1), RP11–222K16.2, Taurine Upregulated Gene 1 (TUG1), Small Nucleolar RNA Host Gene 5 (SNHG5), Growth Arrest Specific 5 (GAS5), and H19 and decreased expression of IGF1R Antisense Imprinted Non-Protein Coding RNA (IRAIN). ConclusionThe prognoses of AML patients are significantly associated with abnormally expressed lncRNAs, which may be used as prognostic indicators for predicting the patient outcomes.

PTBP1 is a potential indicator of disease progression in acute myeloid leukemia.

This study aimed to verify a novel potential indicator of disease progression in acute myeloid leukemia (AML) patients. Bone marrow samples were collected from 27 AML patients and 27 controls without hematological malignancies. Polypyrimidine tract-binding protein 1 (PTBP1) expression in bone marrow samples was measured, and the association of PTBP1 with the French-American-British (FAB) classification, cytogenetics, risk stratification, and complete remission (CR) rate was analyzed. The correlation between PTBP1 and Ki-67/p53 expression in AML patients was ultimately evaluated. The results showed that PTBP1 mRNA and protein levels were greater in AML patients than in controls. PTBP1 expression was able to distinguish between AML patients and controls (area under the curve, 0.8601; 95% confidence interval, 0.7632-0.9570). Furthermore, PTBP1 expression was associated with an increased frequency of internal tandem duplication mutations within FMS-like tyrosine kinase-3 (FLT3) and a complex karyotype, while PTBP1 expression was not correlated with FAB classification, monosomal karyotype, isolated biallelic CCAAT/enhancer-binding protein α (CEBPA) mutation, or nucleophosmin 1 (NPM1) mutation in patients with AML. Moreover, PTBP1 expression was associated with a poorer prognosis according to risk stratification and a lower CR rate in AML patients. In addition, PTBP1 expression was positively correlated with the expression of the proliferation marker Ki-67 and negatively correlated with the expression of the apoptosis marker p53 in AML patients. Overall, PTBP1 is a viable biomarker that contributes to the risk prediction and the determination of potential drug targets for AML.

Rearrangements involving 11q23.3/KMT2A in adult AML: mutational landscape and prognostic implications – a HARMONY study

Balanced rearrangements involving the KMT2A gene (KMT2Ar) are recurrent genetic abnormalities in acute myeloid leukemia (AML), but there is lack of consensus regarding the prognostic impact of different fusion partners. Moreover, prognostic implications of gene mutations co-occurring with KMT2Ar are not established. From the HARMONY AML database 205 KMT2Ar adult patients were selected, 185 of whom had mutational information by a panel-based next-generation sequencing analysis. Overall survival (OS) was similar across the different translocations, including t(9;11)(p21.3;q23.3)/KMT2A::MLLT3 (p = 0.756). However, independent prognostic factors for OS in intensively treated patients were age >60 years (HR 2.1, p = 0.001), secondary AML (HR 2.2, p = 0.043), DNMT3A-mut (HR 2.1, p = 0.047) and KRAS-mut (HR 2.0, p = 0.005). In the subset of patients with de novo AML < 60 years, KRAS and TP53 were the prognostically most relevant mutated genes, as patients with a mutation of any of those two genes had a lower complete remission rate (50% vs 86%, p < 0.001) and inferior OS (median 7 vs 30 months, p < 0.001). Allogeneic hematopoietic stem cell transplantation in first complete remission was able to improve OS (p = 0.003). Our study highlights the importance of the mutational patterns in adult KMT2Ar AML and provides new insights into more accurate prognostic stratification of these patients.

Assessment of Complete Remission Rate in Patients with Acute Myeloid Leukemia Undergoing 7+3 Induction Chemotherapy

Acute leukemia is a fast-growing, overpopulated clone of immature proliferating cells that largely predominate in the bone marrow and have the capacity to prolong life indefinitely. Upon inspection and cytologic assessment of bone marrow or peripheral blood, the cells demonstrate quantified uncertainties. Objective: To determine the frequency of complete remission after induction 7+3 chemotherapy in patients with acute myeloid leukemia. Methods: The nature of this study was cross sectional study at Department of Oncology, Pakistan Institute of Medical Sciences, and Islamabad from 26 November, 2022 to 26 May, 2023. The hospital’s laboratory fulfilled the complete blood count and provided the confirmed baseline bone marrow biopsy reports. All patients who were admitted received treatment with a 7+3 regime, a standard treatment protocol for all the adolescents and adults admitted. Every patient was prescribed for 7+3 induction therapy regimen which consists of 200 mg/m2 cytarabine for seven days and idarubicin for three days, 12 mg/m2 on the 1st, 3rd and 5th day. Results: The complete remission estimated turns out to be 61.1% and rest need further treatment. The average age of the patients was 48.56 ± 6.91 years. The mean BMI stood at 24.46 ± 1.49 kg/m2. gender wise, 74 were male and 21 were female. Our mean CR was 61.1% that is 58 participants all the complete demographic is available. Conclusions: This study revealed a Complete Remission (CR) rate of 61.1% in patients with AML undergoing 7+3 induction chemotherapy. However, our findings suggest that older age is associated with lower CR rates, highlighting the need for tailored treatment strategies that balance efficacy with the potential risks of intensive therapies in this population.

#1162 Paraneoplastic podocytopathy in patients with solid cancer: clinical characteristics and new insights into pathophysiological processes about 21 cases

Abstract Background and Aims Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) may occur in patients with solid cancer but this rare association has never been extensively investigated. Here, we report the first series of patients presenting this association, also named paraneoplastic podocytopathy with nephrotic syndrome (PPNS) . Previous study has demonstrated the specific induction in both podocytes and Reed-Sternberg cells of C-Maf Inducing Protein (CMIP) in patients with MCD and Hodgkin lymphoma. Here, we examined whether this molecular relationship was also relevant in patients developing PPNS in the setting of solid cancer. We have investigated the potential CMIP expression in kidney biopsies and in tumor tissues. Method We collected data from patients who presented with histologically proven cancer and concomitantly developed a nephrotic syndrome (± 3 months) related to MCD or FSGS Follow-up data were collected after 3, 6, 12 months and at last visit. We identified a control group of idiopathic nephrotic syndromes (INS) matched on sex, age and histological type, in order to compare the characteristics of these controls with patients with PPNS. Expression of CMIP was studied by immunohistochemistry and by immunofluorescence confocal microscopy on kidney biopsy and tumor samples. We used kidney biopsies from INS and tumors from patients without associated nephrotic syndrome as controls. Results Twenty-one PPNS patients and 21 controls with INS without cancer were identified. The median age of PPNS patients was higher (68 years) than usually observed in INS. Most of them (76%) had a MCD. A broad spectrum of cancers was found (bronchopulmonary, prostatic, colorectal…) . Baseline characteristics were similar between PPNS patients and INS controls, with a median urinary protein creatinine ratio of 865 and 900 mg/mmol, blood albumin t 15 and 15.3 g/L. Estimated glomerular filtration rate were 48 and 60 ml/min/1.73 m² respectively (no significant difference) . At presentation, PPNS patients were more likely to have hematuria (p = 0.031) , a lower median hemoglobin level than controls (p = 0.039) . Moreover, PPNS patients were less often treated with immunosuppressive drugs (p = 0.004) . After 12 months of follow-up, PPNS patients had a less favorable outcome than INS controls, with a mortality rate three times higher (30% vs 9.5%, p = 0.098) and a much lower rate of complete remission of nephrotic syndrome (25% vs 73.7%, p = 0.008, Table 1). CMIP labeling was performed on 13 tumor samples and 16 kidney biopsies in PPNS patients, and on 5 kidney biopsies with INS, and on 5 control tumor samples. Podocyte labeling of CMIP is observed on all but one kidney biopsy. CMIP labeling was positive on all case tumors, but only a scarce staining was detected in control patients with solid cancer without nephrotic syndrome (Fig. 1). In PPNS patients, confocal microscopy analysis on tumoral tissue showed high expression of CMIP in some epithelial cells and in immune infiltrating cells.. In addition, we found that CMIP was specifically express in CD4 T lymphocyte subset (Fig. 2), but not in CD20, FOXP3 or PD1 lymphocytes, defining a novel FOXP3−/PD1− CMIP high CD4+T lymphocyte subpopulation, within immune cell infiltrates. Conclusion We report the first series of patients with PPNS, who have a more severe renal and overall prognosis than controls. We show that patients with PPNS display higher induction of CMIP, both in the tumor and in podocytes. Strikingly, we identified within immune infiltrates a new subset of T-cell harboring a particular phenotype (CD4+, CMIPhigh, FOXP3−, PD1−) , which is not detected in patients with solid tumor without nephrotic syndrome and which could play a key role in the pathophysiology of PPNS.

Adolescence-onset atypical hemolytic uremic syndrome: is it different from infant-onset?

Atypical hemolytic uremic syndrome (aHUS) is a rare, mostly complement-mediated thrombotic microangiopathy. The majority of patients are infants. In contrast to infantile-onset aHUS, the clinical and genetic characteristics of adolescence-onset aHUS have not been sufficiently addressed to date. A total of 28 patients (21 girls, 7 boys) who were diagnosed as aHUS between the ages of ≥10years and <18years were included in this study. All available data in the Turkish Pediatric aHUS registry were collected and analyzed. The mean age at diagnosis was 12.8±2.3years. Extra-renal involvement was noted in 13 patients (46.4%); neurological involvement was the most common (32%). A total of 21 patients (75%) required kidney replacement therapy. Five patients (17.8%) received only plasma therapy and 23 (82%) of the patients received eculizumab. Hematologic remission and renal remission were achieved in 25 (89.3%) and 17 (60.7%) of the patients, respectively. Compared with the infantile-onset aHUS patients, adolescent patients had a lower complete remission rate during the first episode (p=0.002). Genetic analyses were performed in all and a genetic variant was detected in 39.3% of the patients. The mean follow-up duration was 4.9±2.6years. At the last visit, adolescent patients had lower eGFR levels (p=0.03) and higher rates of chronic kidney disease stage 5 when compared to infantile-onset aHUS patients (p=0.04). Adolescence-onset aHUS is a rare disease but tends to cause more permanent renal dysfunction than infantile-onset aHUS. These results may modify the management approaches in these patients.

CD7-positive leukemic blasts with DNMT3A mutations predict poor prognosis in patients with acute myeloid leukemia.

DNMT3A mutations can be detected in premalignant hematopoietic stem cells and are primarily associated with clonal hematopoiesis of indeterminate potential; however, current evidence does not support assigning them to a distinct European Leukemia Net (ELN) prognostic risk stratification. CD7 is a lymphoid antigen expressed on blasts in approximately 30% of acute myeloid leukemia (AML), and its role in AML remains unclear and depends on subgroup evaluation. This study investigated the prognostic value of DNMT3A mutation combined with CD7 expression in AML. We retrospectively analyzed the clinical data of 297 newly diagnosed non-M3 AML patients. According to the DNMT3A mutation and CD7 expression in AML cells, patients were divided into the DNMT3A-mutated/CD7-positive (CD7+), DNMT3A-mutated/CD7-negative (CD7-), DNMT3A-wild-type/CD7+, and DNMT3A-wild-type/CD7- groups. The DNMT3A-mutated/CD7+ group had lower complete remission rates and higher relapse rates. Importantly, these patients had significantly shorter overall survival (OS) and relapse-free survival (RFS). Furthermore, multivariate analysis showed that CD7+ with DNMT3A mutation was an independent risk factor for OS and RFS. CD7+ with DNMT3A mutation predicts a poor prognosis in AML patients, and the immunophenotype combined with molecular genetic markers can help to further refine the current risk stratification of AML.

A critical evaluation of the EFS endpoint in AML: Does induction treatment failure timing have a profound impact on study design and results?

Despite emerging novel therapies, treating acute myeloid leukemia (AML) remains challenging. Complexities persist in designing pivotal clinical trials and establishing acceptable endpoints for AML. Recent FDA guidance for drug and biological products development for AML outlines considerations for trial design. The guidance defines overall survival (OS) and event-free survival (EFS) as endpoints representing clinical benefit for AML therapies without curative intent. We highlight the EFS definition, particularly the assignment of day 1 as the event date for patients with induction treatment failures (ITFs), as recommended in the guidance. Through a comprehensive simulation study, our results show that the guidance EFS definition performs adequately with high complete remission (CR) rates but may pose challenges for low CR rates. When the experimental arm CR rate is 5% or less over the control, the use of the ITF events at day 1 for EFS definition leads to a critical power decrease, hampering the ability to predict survival benefit for a moderate OS duration. We further expand upon the EFS definition with the event date at ITF period end. Our goal is to inform investigators and regulatory agencies about the implications and limitations of various EFS definitions for future pivotal trials in AML.

SPAG6 regulates cell proliferation and apoptosis via TGF-β/Smad signal pathway in adult B-cell acute lymphoblastic leukemia.

Adult B-cell acute lymphoblastic leukemia (B-ALL) prognosis remains unsatisfactory, and searching for new therapeutic targets is crucial for improving patient prognosis. Sperm-associated antigen 6 (SPAG6), a member of the cancer-testis antigen family, plays an important role in tumors, especially hematologic tumors; however, it is unknown whether SPAG6 plays a role in adult B-ALL. In this study, we demonstrated for the first time that SPAG6 expression was up-regulated in the bone marrow of adult B-ALL patients compared to healthy donors, and expression was significantly reduced in patients who achieved complete remission (CR) after treatment. In addition, patients with high SPAG6 expression were older (≥ 35years; P = 0.015), had elevated white blood cell counts (WBC > 30 × 109/L; P = 0.021), and a low rate of CR (P = 0.036). We explored the SPAG6 effect on cell function by lentiviral transfection of adult B-ALL cell lines BALL-1 and NALM-6, and discovered that knocking down SPAG6 significantly inhibited cell proliferation and promoted apoptosis. We identified that SPAG6 knockdown might regulate cell proliferation and apoptosis via the transforming growth factor-β (TGF-β)/Smad signaling pathway.

Analysis of the characteristics of primary acute myeloid leukemia with 11q23/KMT2A rearrangements in ninety patients

To investigate the clinical and prognostic characteristics of primary acute myeloid leukemia (AML) with 11q23/KMT2A rearrangements. Clinical data of 90 patients with primary AML and 11q23/KMT2A rearrangements were analyzed retrospectively. By karyotyping analysis, 80 of the 90 patients had translocations involving 11q23/KMT2A, with t(9;11)(p22;q23), t(6;11)(q27;q23), t(10;11)(p12;q23) and t(11;19)(q23;p13) being the most common ones, while 10 cases were found to have non-translocation abnormalities. The overall complete remission (CR) rate was 75.6%, and patients with t(6;11) had lower CR rate compared with non-t(6;11) patients (47.1% vs. 82.2%, P = 0.005). After a median follow-up of 24.5 months, the patients receiving allo-hematopoietic stem cell transplantation (allo-HSCT) had significantly higher 3-year overall survival (OS) (80.3% vs. 16.6%, P < 0.001) and 3-year event-free survival (EFS) (73.5% vs. 16.3%, P < 0.001) compared with non-transplant patients. Patients with t(6;11) had the lowest 3-year OS (11.8% vs. 56.0%, P < 0.001) and 3-year EFS (5.9% vs. 53.8%, P < 0.001) compared with other type of abnormalities. No significant difference was noted in the survival between patients with t(9;11) and non-t(9;11) regardless whether they had received HSCT. The clinical characteristics of primary AML with 11q23/KMT2A rearrangements are heterogeneous. Patients did not receive HSCT had poorer survival, particularly with the presence of t(6;11). Allo-HSCT could significantly improve the survival of such patients.

Ratio of Circulating CD8 + T Lymphocytes to M-MDSCs (CD8MMR): A Novel Prognostic Predictor for Treatment-Naïve DLBCL Patients

Introduction: CD8 + T lymphocytes are crucial in contemporary cell-and-immunotherapies as they can be functionally enhanced or manipulated. Monocytic myeloid-derived suppressor cells (M-MDSCs) are known for their intense immunosuppressive ability, and higher percentages of circulating M-MDSCs among peripheral-blood monocytes or white cells are associated with a worse prognosis. Recently, a low lymphocyte-to-monocyte ratio (LMR) has been linked to a poor prognosis in lymphoma patients. Consequently, we hypothesized that the ratio of circulating CD8 + T lymphocytes to M-MDSCs (CD8MMR) could be a novel and more precise predictor for the clinical outcomes of DLBCL patients before initiating treatment. Methods: This prospective, observational study enrolled 136 adults with treatment-naïve DLBCL from May 2019 to March 2023 in a tertiary medical center in Taiwan. Patients with primary CNS lymphoma or primary mediastinal B-cell lymphoma were excluded. Fresh peripheral blood samples were obtained to calculate the absolute counts of CD8 + T lymphocytes and M-MDSCs, defined as alive singlets with CD45 + CD3 + CD8 + and CD45 + CD15 - CD14 + CD11b + CD33 + HLA-DR low/- by flow cytometry, respectively. ROC analysis and AUC determined the cut-off values for LMR and CD8MMR. Results: For 136 treatment-naïve DLBCL patients, the median age was 70, with 61.8% being male. Among them, 37.5% were in stage IV, and 27.9% were classified as the germinal-center B-cell (GCB) subtype by IHC staining according to the Hans algorithm. Additionally, 43.4% were diagnosed with double expressor lymphoma (DEL). The IPI risk score distribution was as follows: 7.4%, 18.4%, 17.6%, 24.3%, 19.9%, and 12.5% were in scores 0, 1, 2, 3, 4, and 5, respectively. Of note, the median level of LMR was 2.17, the median level of absolute counts of circulating CD8 + T lymphocytes was 385/µL, the median level of absolute counts of circulating M-MDSCs was 102/µL, and the median level of CD8MMR was 3.56. DLBCL patients with high-risk IPI had a significantly lower CD8MMR than patients with intermediate or low-risk IPI (1.34 vs. 4.51 vs. 7.82, PH vs. L = 0.001, PH vs. I = 0.060, PI vs. L = 0.082). DLBCL patients with the non-GCB subtype (2.75 vs. 5.63, P = 0.031) also demonstrated a significantly lower CD8MMR. Additionally, there were trends of lower CD8MMR in elderly patients &amp;gt; 70 (2.74 vs. 3.91, P = 0.209) and patients with DEL (3.33 vs. 4.65, P = 0.101). After a median follow-up of 22.6 months for the 136 DLBCL patients, LMR was at first tested, and patients with LMR &amp;lt; 1.19 had significantly worse PFS (13.8 months vs. non-reach, Log Rank P = 0.004) and OS (non-reach vs. non-reach, Log Rank P = 0.019) than those with LMR ≥ 1.19. Next, we examined the CD8MMR, and patients with CD8MMR &amp;lt; 4.40 experienced significantly worse PFS (21.3 months vs. non-reach, Log Rank P &amp;lt; 0.001) and OS (non-reach vs. non-reach, Log Rank P &amp;lt; 0.001) compared to those with CD8MMR ≥ 4.40 [Figure]. We subsequently conducted a multivariate Cox regression analysis to validate whether CD8MMR &amp;lt; 4.40 could serve as an independent predictor of poor prognosis [Table]. The results showed that “CD8MMR &amp;lt; 4.40” was confirmed as an independent prognostic factor for both PFS (HR = 2.747; 95% CI = 1.275 to 5.918; P = 0.010) and OS (HR = 3.669; 95% CI = 1.462 to 9.211; P = 0.006) after adjusting for confounding factors, including age, sex, IPI risk scores, bulky mass &amp;gt; 10 cm, non-GCB type, DEL, and LMR &amp;lt; 1.19. In this study cohort, 106 (77.9%) patients received R-CHOP-like regimens as induction therapies, 25 (18.4%) patients received an R-EPOCH regimen, two (1.5%) patients received an R-HyperCVAD regimen, and three (2.2%) patients died before completing the first cycle of chemoimmunotherapy. Among the 106 DLBCL patients receiving R-CHOP-like regimens, 57 patients showed CD8MMR &amp;lt; 4.40 and reported a significantly lower rate of complete remission (73.7% vs. 95.9%, P = 0.006) at the end of induction therapy compared to the 49 patients with CD8MMR ≥ 4.40. Furthermore, patients with CD8MMR &amp;lt; 4.40 had significantly worse PFS (17.4 months vs. non-reach, P &amp;lt; 0.001) and OS (non-reach vs. non-reach, P &amp;lt; 0.001) compared to those with CD8MMR ≥ 4.40. Conclusion: A low ratio of circulating CD8 + T lymphocytes to M-MDSCs (CD8MMR) serves as a poor prognostic factor for both PFS and OS in treatment-naïve DLBCL patients. This finding warrants further investigation and highlights the possibility of risk-adapted strategies when treating DLBCL patients.

Olverembatinib (HQP1351) Combined with Chemotherapy Is an Effective and Safe Treatment in Patients with Philadelphia Chromosome-Positive (Ph +) Acute Lymphoblastic Leukemia (ALL) and Chronic Myeloid Leukemia in Lymphoid Blast Phase (CML-LBP) That Failed TKI-Based Regimens

Background The prognosis of relapsed or refractory (R/R) Philadelphia Chromosome-Positive (Ph+) acute lymphoblastic leukemia (ALL) and TKI-resistant chronic myeloid leukemia in lymphoid blast phase (CML-LBP) remains poor, with lower rates of complete remission (CR) and shorter durations of response. Olverembatinib is a novel third-generation tyrosine kinase inhibitor (TKI) that has been demonstrated to effectively target a wide range of BCR::ABL1 kinase mutations, especially T315I, in patients with CML in the chronic or accelerated phase resistant to either imatinib or second-generation TKIs. However, data on olverembatinib-based regimens in R/R Ph+ ALL and CML-LBP are limited. Here, we report the efficacy and safety of olverembatinib, combined with chemotherapy, in patients with Ph+ ALL or CML-LBP that failed prior TKI-based therapies. Methods A retrospective study was conducted in adults with Ph + ALL or CML-LBP who failed imatinib- or second-generation TKI-based chemotherapy and subsequently received olverembatinib-based chemotherapy. Per NCCN 2023 guidelines: refractory disease was defined as CR not achieved at the end of induction; relapsed disease, reappearance of blasts in the blood or bone marrow (&amp;gt; 5%) or any extramedullary site after CR; molecular resistance, persistent or rising BCR::ABL1 transcript (&amp;gt; 1-log) by real-time quantitative polymerase chain reaction (RT-qPCR); and complete molecular response (CMR), BCR::ABL1 transcript &amp;lt; 0.01% by RT-qPCR. The primary endpoints of this study were CR rates in R/R patients and CMR rates in molecular-resistant patients. Results From February 2022 to May 2023, 31 patients were included in this study, including 24 (77%) with TKI-based chemotherapy-failed Ph + ALL; 7 (23%) with TKI-resistant CML-LBP; 15 (48%) with R/R disease; and 16 (52%) with molecular-resistant disease. A total of 17 (57%) patients were male, and the median (range; IQR) age was 46 (20-72; 30-64) years. Among 30 patients screened for BCR::ABL1 kinase domain mutations before administration of olverembatinib, 6 (19%) had no mutations; 15 (48%) had T315I; and 9 (29%) had other mutations, including E255K (n = 2), G250E(n = 2), D241E (n = 1), Y253H (n = 1), F317L (n = 1), F359C(n = 1), and Y253Fplus M351T (n = 1). The 15 R/R patients (11, Ph + ALL; 4, CML-BP) received olverembatinib 30 or 40 mg on alternate days combined with VP (vindesine 4 mg once per week for 4 weeks and prednisone 1 mg/kg for 3 weeks and tapered at the fourth). A total of 13 (86%) patients achieved CR after 4-week induction therapy. At a median (IQR) follow-up of 8 (4-13) months, 5 patients received allogeneic transplantation in CR, and were alive in CMR. A total of 8 patients received olverembatinib-based consolidation chemotherapy of either VP (n = 4) or hyper-CVAD (n = 4) after achieving CR. Six patients relapsed, of whom 4 died, and 1 remained in CMR. The 1-year relapse-free survival (RFS) and 1-year survival rates were 52% (95% CI, 21-83) and 68% (95% CI, 37-98), respectively. Among the 16 patients with molecular resistance to TKI-based chemotherapy (imatinib [n = 4]; dasatinib [n = 9]; flumatinib [n = 3]), 2 received olverembatinib monotherapy, 7 olverembatinib plus VP, and 7 hyper-CVAD, of whom 8 received subsequent allogeneic transplantation. At a median (IQR) follow-up of 9 (5-11) months, 1 of the patients receiving olverembatinib monotherapy progressed to hematologic relapse and was switched to CAR T-cell therapy; the other patient did not achieve CMR and underwent transplantation. Of the 14 patients receiving olverembatinib plus chemotherapy, 7 (50%) achieved CMR and 3 (21.4%) progressed to relapse, of whom 1 had hematological relapse and 2 developed central nervous system leukemia (CNSL) with bone marrow remission. A total of 7 patients received allogeneic transplantation, of whom 3 achieved and 4 did not achieve CMR before transplantation. After transplantation, all the 7 patients were in CMR except one who developed CNSL. The 1-year RFS and survival rates were 67% (95% CI, 42-91) and 93% (95% CI, 79-100), respectively. Among all patients, hematologic adverse events were readily manageable. Treatment-related nonhematologic severe adverse events were observed in 3 patients, including (each) stable angina pectoris, severe pneumonia, and fatal Klebsiella sepsis. Conclusions Olverembatinib-based chemotherapy is effective and safe in patients with R/R and molecular resistant Ph + ALL or CML-LBP.

The Relapse-to-Therapy Interval in Relapsed or Refractory Diffuse Large B Cell Lymphoma Is Associated with Clinical Outcomes

Introduction In newly diagnosed diffuse large B cell lymphoma (DLBCL), the diagnosis-to-treatment (DTI) interval is associated with clinical outcomes: patients who initiated therapy early after DLBCL diagnosis have significantly worse event free survival (EFS) (Maurer JM et al. J Clin Oncol 2018;36:1603-1610). In relapsed or refractory (R/R) DLBCL, the relapse-to-treatment interval (RTI) has gained more relevance with the recent approvals of several novel therapies including chimeric antigen receptor (CAR) T-cell therapies, which require several weeks of manufacturing time, and bispecific antibody therapies that require several weeks of desensitization through dose ramp-up to achieve therapeutic levels. The association between RTI and patient outcomes in R/R DLBCL has not yet been reported. Methods We conducted an IRB-approved retrospective review of r/r DLBCL patients treated with rituximab, ifosfamide, carboplatin, etoposide (R-ICE) as second line treatment at three academic medical centers between 2010-2020. Characteristics at the time of relapse, including RTI and treatment outcomes were collected from the electronic medical record. Outcomes evaluated included disease response to R-ICE, subsequent autologous stem cell transplant (ASCT) and CAR T cell therapy, progression free survival (PFS) and OS. All analyses were done using R and its packages. The optimal cutoff values for RTI were determined using maximally selected rank test from MaxStat and survminer packages. The association between RTI and clinical outcomes was evaluated using Fisher test and Wilcoxon rank-sum test. Survival was calculated using the Kaplan Meier method, comparisons done using log-rank. Results We identified 249 patients treated with second line R-ICE for r/r DLBCL with available RTI data. The median RTI was 18 days (IQR 9-31). The optimal RTI cutoffs calculated with maximally selected rank test were 7 days for PFS and 11 days for OS. An intermediate value of 10 days was chosen. At the time of relapse, age, gender, cell of origin and double expressor / double hit features were comparable among groups, but patients with an RTI of ≤ 10 days were more likely to have B symptoms, elevated lactate dehydrogenase, and intermediate or high IPI scores compared to those with longer RTI (table 1). The RTI had a strong association with patient outcomes. Patients with RTI of 10 days or less had a lower rate of complete remission (20% vs. 45%, p = 0.003). After a median follow up of 53 months (IQR 36-73), median PFS for patients with RTI ≤ 10 days was 5.1 vs. 12.7 months for patients with RTI &amp;gt; 10 days (p &amp;lt;0.001). Four-year PFS estimates were 17.3% for patients with RTI ≤ 10 days vs. 35.3% for patients with RTI &amp;gt; 10 days. Median OS was 26 months for patients with RTI 10 days vs. 85 months for patients with RTI &amp;gt; 10 days (figure 1). Among patients with RTI of ≤ 10 days, 46% went on to receive ASCT, whereas 64% of patients with RTI &amp;gt; 10days had ASCT (p = 0.048). On multivariate Cox proportional hazards analysis including RTI ≤10 days, age &amp;gt; 60 years at time of relapse, elevated LDH, and ECOG ≥ 2, the proportional hazards condition was met for both PFS and OS. Shorter RTI had a statistically significant association with PFS and OS, with hazard ratios (HR) of 1.80 (95% CI 1.27-2.56, p = 0.001) and 1.97 (95% CI 1.29-3.03, p = 0.002), respectively. Conclusions There is a strong association between RTI and the outcomes of R/R DLBCL patients treated with second line R-ICE chemotherapy. Our findings highlight the worse outcomes of patients with rapidly progressive, symptomatic R/R DLBCL and are particularly impactful in the era of CAR T-cells and novel immunotherapies, which can take many weeks to become available or effective. As with the DTI, clinical trials of DLBCL therapies should report RTI whenever possible. More effective and rapidly available treatment approaches should be designed to improve the outcomes of this high-risk patient population.

Clinical Features and Treatment in Patients Diagnosed with Blastic Plasmacytoid Dendritic Cell Neoplasm: Interim Analysis from the Pethema Epidemiologic Registry (EPI-BLAS study)

Background BPDCN (Blastic Plasmacytoid Dendritic Cell Neoplasm) is a rare and aggressive hematological neoplasm, and due to its rarity there are scarce registry studies analyzing the disease in real-world. The proposed study seeks to fill this knowledge gap and gain insights into various aspects of the disease, including demographics, presentation features, biological data, treatment patterns, and individual patient outcomes. Ultimately, the study aims to shed light on how to best manage BPDCN and identify patients who could benefit from curative treatments, including front-line agents followed by allogeneic stem cell transplant (allo-HSCT) and novel therapies, like IL3R-diphteric toxin compound (SL-140; Tagraxofusp) which showed remarkable activity in front-line therapy. Methods The EPI-BLAS is a retrospective, multicenter, non-interventional chart review study of patients diagnosed with BPDCN. Approximately 150 patients treated at PETHEMA participating sites in Spain will be included in final analyses. The review will focus on medical records of patients diagnosed with BPDCN, and the data will be entered into an electronic case report form (eCRF) for all patients who meet the inclusion and exclusion criteria. For this analysis, we included a first cohort of 68 adult patients (≥18 years old) who were diagnosed BPDCN between January 2010 and January 2022. Results The median age at diagnosis was 66 years (range 18-87 years). The majority of the patients (74%) was de novo, while 26% of them had a prior history of neoplastic disease [43% of them had prior solid neoplasm (thyroid cancer, prostate adenocarcinoma, melanoma and breast ductal carcinoma) and 57% suffered from hematological neoplasms as large granular lymphocytic leukemia, myelodysplastic syndromes, non-Hodgkin T-cell lymphoma and chronic myelomonocytic leukemia]. Previous anti-cancer therapy was received by 36 patients. Table 1 shows main baseline characteristics of BPDCN patients. Regarding first-line treatment, 34 patients (50%) received AML-like regimens [19 underwent anthracycline and cytarabine (3+7 regimen), 4 FLAGIDA, 4 received FLUGA (fludarabine plus low-dose cytarabine), 1 cytarabine alone, and 1 azacitidine alone]; 9 (13%) acute lymphoblastic leukemia-like regimens; 8 patients (12%) were treated with lymphoma-like regimens; 6 (9%) received medication within clinical trial; 2 (3%) compassionate use of Tagraxofusp, and 9 (13%) supportive care only. Among 59 treated patients, front-line treatment resulted in 27 (47%) complete remission, 1 (2%) morphologic leukemia-free state (MLFS), 6 (10%) partial remission, 14 (24%) showed resistance, 7 (12%) died during induction (causes of death were cerebral bleeding [3] and multiorgan failure [4]), and 4 (7%) had not available response. Of among 42 treated patients with available post-remission treatment, 9 (21%) received an allogeneic hematopoietic stem cell transplant in first CR. With a median follow-up of 9.6 months, the median overall survival of the cohort was 8.58 months. Median OS was 6 months in patients not transplanted and not reached among those transplanted in first CR (p=0.000695) (Figure 1). Conclusions Our preliminary analysis confirms the dismal prognosis of this rare entity (median OS of 8.6 months). We found large heterogeneity of therapeutic approaches, low complete remission rates and scarce rates of allogeneic transplant in the front-line. Improvement of outcomes through well-defined treatment protocols and innovative agents are needed for this high unmet need disease.

Impact of Cytarabine Pharmacogenomics on Survival of Adolescent and Young Adults with AML and Its Clinical Relevance in Black Patients

Cytarabine (also known as ara-C) has been the mainstay of AML chemotherapy for both pediatric and adult patients (pts) since 1970s, and when given in combination with anthracycline it induces remission in ~60% of adult and 80% of pediatric pts. However, almost ~40% of pts relapse. Cytarabine is a prodrug requiring activation to ara-CTP for its antileukemic effect. Our group has been investigating the relevance of cytarabine pharmacogenomics and recently reported a pharmacogenomics-based polygenic score (ACS10) that includes 10 SNPs spanning 9 genes within metabolic pathway of cytarabine. ACS10 is predictive of intracellular levels of ara-CTP as well as outcome in pediatric AML pts enrolled in multiple clinical trials led by St Jude Children's Research Hospital and Children's Oncology Group (Elsayed et al, JCO 2022;40:772-3). Overall, pediatric AML pts with ACS10 low (≤0), had inferior outcomes compared with ACS10 high pts. Thus far, the ACS10 score has not been tested for its performance in adult AML, especially adolescent and young adult (AYA) AML pts. We hypothesized that ACS10 might be predictive of chemotherapy resistance in this defined pt population that is commonly treated with intensive induction therapy. Moreover, as several SNPs included in ACS10 show ancestry-enrichments, we speculated whether this might help explain the high resistance to treatment recently observed in Black AYA AML pts. A total of 406 newly diagnosed AYA AML pts (age 17-39y, median: 30y), similarly treated in 8 Alliance for Clinical Trials in Oncology frontline protocols were included in the study. All pts had centrally reviewed cytogenetics, targeted gene mutation profiling and SNP data (Illumina 2.5 omni array, see Walker et al, Leukemia 2019;33:771-5). ACS10 score was calculated for each pt using the equation defined by Elsayed et al (&amp;gt;0, ACS10 high; ≤0, ACS10 low) and Kaplan-Meier method and the log-rank test was used for survival analysis and Fisher's exact test was used for frequency comparison. Two hundred eighty-three pts were ACS10 high and 123 pts were ACS10 low. Though not statistically significant, ACS10 low pts tended to have a shorter overall survival (OS) compared with ACS10 high pts (p=.11). Restricting the analysis to those who received chemotherapy only (excluding allogeneic transplant recipients), showed that ACS10 low group had significantly shorter OS compared with ACS10 high group (p=.03). Further, event-free survival (EFS) was shorter (3y rates, 32% vs. 42%, p=0.09) and number of early deaths (death within 30 days of treatment initiation) was higher (5% vs 1%, p=.07) in ACS10 low pts. Given that the majority of patients received etoposide as part of the induction regimen, analysis within this subset showed ACS10 high pts having higher complete remission (CR) rates (85% vs 72%, p=.05) and longer EFS and OS compared with ACS10 low pts (EFS, 3y rates, 41% vs 28%, p=.02; OS, 3y rates, 54% vs 32%, p=.007). We have previously shown significant difference in abundance of ACS10 low by race/ethnicity in pediatric AML, 70% of Black pts being ACS10 low as compared with only 30% of White pts. Similarly, the current cohort showed significant differences in ACS10 score groups by race/ethnicity: of 32 Black pts included in the analysis, 27 (84%) were ACS10 low and only 5 (16%) were ACS10 high. Given the enrichment of the racial-ethnic survival disparity in AYA pts (Larkin et al, Blood Adv 2022;6:5570-81), we further investigated the impact of ACS10 on survival of Black AYA pts. Though limited by numbers, we observed worse OS (p=0.05) of ACS10 low group, which comprised 80% of Black pts. We show the impact of cytarabine pharmacogenomics and its relevance in AYA AML pts. Consistent with the results in pediatric AML, pts with low ACS10 score, which is reflective of lower cytarabine activation and intracellular ara-CTP accumulation, had worse outcome than pts with high ACS10 score. Further, low ACS10 score was highly abundant in Black compared to White AYA AML pts. Given the low CR rates, high relapse rates and inferior survival of Black pts, our results imply cytarabine pharmacogenomics as a possible crucial contributor. In conclusion, given that cytarabine is the backbone of AML chemotherapy and is used as a frontline agent in essentially all induction regimens, our results highlight the need for in-depth evaluation of ACS10 score in AML that may open opportunities to improve treatment response in AYA AML.

RUNX1 Mutation Does Not Significantly Impact the Outcome of Newly Diagnosedadult AML: A Retrospective Study of Chinese AML Patients

Background RUNX1 is one of the recurrent mutated genes in newly diagnosed acute myeloid leukemia (AML) with a frequency of 6%~15%. Although historically recognized as a provisional distinct entity, the AML subtype with RUNX1 mutations (AML- RUNX1mut) was eliminated from the 2022 WHO classification system. With the update of AML diagnosis and treatment protocol, different outcomes of AML- RUNX1muthave been reported. However, an in-depth study about the prognostic value of RUNX1 mutations, epecifically the classification change related to AML- RUNX1mut in a large well-annotated cohort is lacking. Methods The clinical data of 1065 AML (excluding acute promyelocytic leukemia and RUNX1 germline mutations) patients according to WHO 2016 and treated from January 2017 to December 2021 at Jiangsu Institute of Hematology were retrospectively collected and analyzed after informed consent. All AML diagnosis samples were analyzed by targeted Next Generation Sequencing (NGS) panel covering 172 frequently mutated genes in hematological malignancies. Demographic and clinical data, disease characteristics at diagnosis, first-line treatment and clinical outcome data were available for all patients. The survival time of allogeneic hematopoietic stem cell transplantation patients was censored at the time of stem cell transfusion. Cytogenetic and molecular characteristics were used to classify patients into ELN2017 and ELN2022 risk groups (excluding the effect of RUNX1 mutation). Results RUNX1 mutations were detected in 112 (10.5%) patients, namely, 66 (58.9%) male and 46 (41.1%) female. A total of 132 RUNX1 alterations were detected with a medianvariant allelic frequency of 40% (3%~93%). RUNX1 mutations were associated with older age (48.5 vs. 46.0 years old, P=0.087) and antecedent myeloid disorders (6.3% vs. 1.0%, P&amp;lt;0.001). One or more comutations were detected in 106 (94.7%) AML- RUNX1mut patients. The most frequent co-gene abnormalities were FLT3-ITD and DNMT3A mutations which represented the 23.2% and 18.7%. Mutations of CEBPA bZIP, NPM1 and translocations of t(8;21), t(16;16)/inv(16) were uncommon in AML- RUNX1mut with a frequency of 6.3%, 1.8%, 2.7%, 0%, respectively (Table 1). Compared with AML with wild-type RUNX1 (AML- RUNX1wt), AML- RUNX1mut patients had a lower complete remission rate (19.6% vs. 29.7%, P=0.034), lower overall response rate (ORR) (73.5% vs. 84.3%, P=0.006) and higher no response rate (26.5% vs. 15.5%, P=0.021) in the first induction chemotherapy. When comparing groups based on the ELN2017 risk stratification criteria, no significant difference in ORR was observed between RUNX1mut and RUNX1wt patients in the favorable (91.2% vs. 94.0%, P=0.572), intermediate (75.0% vs. 78.4%, P=0.570) and adverse (63.3% vs. 71.4%, P=0.370 ) subgroups (Table 2). The median duration of follow-up of the entire cohort was 8.7 months ( RUNX1wt: 8.4 months; RUNX1mut: 10.0 months). Comparing the two groups, patients with RUNX1 mutations had a lower 5-year overall survival (OS) rate (35.4% vs. 42.3%; HR=1.563; 95% CI: 1.091~2.237, P=0.026), but no significant difference was observed in the 5-year event-free survival (EFS) rate (40.8% vs. 35.4%; HR=1.084; 95% CI: 0.750~1.570, P=0.098) (Table 2). However, when patients were stratified according to the ELN2017 guidelines (excluding the effect of RUNX1 mutation), outcomes did not differ between patients withor without RUNX1 mutation in the favorable (OS: P=0.629, EFS: P=0.137), intermediate (OS: P=0.629, EFS: P=0.114) and adverse (OS: P=0.544; EFS: P=0.714) subgroups. Similar results were obtained according to the ELN2022 guidelines. In multivariate analysis, RUNX1 was not an independent prognostic factor for OS (HR=1.353, 95% CI: 0.922~1.985, P=0.122) and EFS (HR=1.422, 95% CI: 0.975~2.075, P=0.068), while significantly worse OS and EFS were observed in patients with mutated FLT3-ITD, TP53, and DNMT3A ( P-values were all less than 0.05). Conclusion RUNX1 mutations were rarely isolated genetic abnormities that conferred inferior outcomes. However, on the basis of ELN prognosis risk stratification, RUNX1mutation had no impact on the clinical outcomes of AML patients in stratified subgroups. RUNX1 was not an independent prognostic factor for survival. Overall, our findings agree with the updated WHO classification system for AML that AML- RUNX1mut should not be recognized as a distinct AML entity.

Acquired Hemophilia a: A Single-Center Study of 165 Patients

Introduction and aim: Acquired hemophilia A (AHA) is a rare hemorrhagic disorder caused by the existence of factor VIII (FVIII) inhibitors with an estimated annual incidence of 1.5 per million people. AHA patients are characterized by exceeding bleeding of varying severity, while approximately 10% of AHA patients have no bleeding symptoms. It's a challenge to diagnose and manage AHA due to its rarity and heterogeneity. We conducted a retrospective study to report the characteristics and outcomes of AHA and enhance its recognition and management. Methods: Patients diagnosed and treated with AHA at the Blood Disease Hospital, Chinese Academy of Medical Sciences between July 1997 to December 2021 were retrospectively enrolled. Demographics, clinical characteristics, treatments, and outcomes were collected. All Patients were followed immediately from admission to our center and ended in March 2022. Bleeding severity was assessed retrospectively in March 2022 by bleeding score (BS), a summary score aggregated by the International Society on Thrombosis and Hemostasis/ Scientific and Standardization Committee (ISTH/SSC) bleeding assessment tool (BAT) (2010 edition). Results: A total of 165 AHA patients admitted to our center were enrolled. The median age at diagnosis was 45 (10-90) years. Overall, a female preponderance (106/165, 64.2%) was observed in this cohort. Notable, the proportion of male patients increased with age. Most patients (126/165, 76.4%) were idiopathic with no underlying diseases discovered. Of the 39 (23.6%) patients with associated diseases, 12 patients had autoimmune diseases, 16 patients had infections, eight patients had malignancies (all solid tumors) and three patients were secondary to pregnancy. All patients presented at least one bleeding episode. Subcutaneous bleeding was most common affecting 84.8% (140/165) of patients, while hemarthrosis was infrequent (n=11, 6.7%). The median time from bleeding to be diagnosed as AHA was delayed (30, 2-5650 days). Anti-FVIII antibody titer and FVIII level showed no correlation. A significant difference in FVIII activity was observed between patients with anti-FVIII antibody titer &amp;lt; 20 BU/ml and ≥ 20 BU/ml. The BS varied among all patients ranging from 2 to 12 with a median of 4. A significant difference in BS was observed among the mild (FVIII: C &amp;gt; 5 IU/dl), moderate (1 IU/dl &amp;lt; FVIII: C ≤ 5 IU/dl), and severe (FVIII: C ≤ 1 IU/dl) AHA patients (p &amp;lt; 0.05). The same conclusion was also drawn between patients with low anti-FVIII antibody titer (&amp;lt; 20 BU/ml) and high antibody titer (≥ 20 BU/ml). BS was not correlated with APTT (r=0.-0.04, 95% CI (-0.19-0.12), p &amp;gt; 0.05). Hemostatic treatment was applied to 129 (78.2%) AHA patients. Of the 163 patients who received immunosuppressive therapy (IST), 22 (13.5%) received steroids alone, with an 82.4% complete remission (CR) rate, 50 (30.7%) received steroids plus cyclophosphamide (CTX), with an 85.0% CR rate, 80 (49.1%) received rituximab-based therapy, which includes rituximab plus steroids, rituximab plus steroids and CTX, and rituximab plus steroids and other immunosuppressants, with a 93.3% CR rate (Figure 1A). There were seven deaths. Causes of death were bleeding (n=3), underlying disease (n=1), pulmonary infection (m=1), and unknown (n=2). FVIII inhibitor titer ≥ 20 BU/ml was the only significant poor prognostic factor for CR (HR 0.56; 95% CI, 0.37-0.85; p &amp;lt; 0.01). In addition, patients with FVIII inhibitor titers ≥ 20 BU/ml needed more time to achieve CR (130 days vs. 35 days; p &amp;lt; 0.01) and showed a lower CR rate (77.6% vs. 94.9%, p &amp;lt; 0.01) than those with FVIII inhibitor titers &amp;lt; 20 BU/ml (Figure 1B). Conclusions: Delayed diagnosis of AHA patients is a severe issue. The rituximab-based regimen is more likely to achieve a CR in AHA patients. The only poor predictor of CR for AHA patients was FVIII inhibitor titer ≥ 20 BU/ml.

Interim results of a multicenter cohort study for Chinese Children Leukemia Group-acute lymphoblastic leukemia 2018 regimen

Objective: To summarize the therapeutic effects of Chinese Children Leukemia Group-acute lymphoblastic leukemia (CCLG-ALL) 2018 regimen in children with T cell acute lymphoblastic leukemia (T-ALL) and to find out risk indicators for prognosis. Methods: This study was a prospective multicenter cohort study involving 299 newly diagnosed T-ALL children in 21 Grade A tertiary hospitals nationwide. All patients received CCLG-ALL 2018 regimen and clinical data for treatment efficacy evaluating was collected. Variables associated with event free survival (EFS) rate, overall survival (OS) rate and cumulative recurrence rate were evaluated by Lasso regression analysis (including variables selection, model construction and hazard ratio calculating). Results: A total of 299 newly diagnosed T-ALL children were included, accounting for 9.9% (299/3 026) of all ALL patients. Among these patients, there were 224 males and 75 females, and the age of onset was 7.0 (4.7, 10.6) years. All patients received CCLG-ALL 2018 regimen treatment. After 31.1 (17.3, 43.8) months follow-up, 3-year EFS, 3-year OS and cumulative recurrence rate of them were (83.2±2.7)%, (91.3±1.8)%, and (7.9±1.7)%, respectively. Minimal residual disease (MRD) greater than 10.00% on day 15 of induction therapy was a risk factor for EFS (HR=1.89, 95%CI 1.04-3.44), OS (HR=2.82, 95%CI 1.35-5.92), and cumulative recurrence rate (HR=3.05, 95%CI 1.46-6.34). Compared with the medium-risk group, the high-risk group had higher induction failure rate (5.2% (7/134) vs. 0 (0/145), P=0.016) and lower complete remission rate (88.8% (119/134) vs.97.9% (142/145),P=0.004). Most complications happened during induction therapy (95 cases), and the most common complication was serious infection (158 cases). Conclusions: CCLG-ALL 2018 regimen shows good prognosis. MRD greater than 10.00% on day 15 of induction therapy is a strong risk factor, which can indicate the prognosis in the early stage of the disease and guide the appropriate treatment.