Difference In Complete Remission Rate Research Articles

Treatment of Patients with IgA Nephropathy: Evaluation of the Safety and Efficacy of Mycophenolate Mofetil.

Immunoglobulin A nephropathy (IgAN), characterized by aberrant IgA immune complex deposition, is the most prevalent primary glomerular disease and the main cause of end-stage renal disease, causing a significant physical and psychological burden on people worldwide. Conventional therapeutic approaches, such as renin-angiotensin-aldosterone system inhibitors and corticosteroids, may not achieve sufficient effectiveness and may produce major side events in the past. The previous data in Asian populations indicated that mycophenolate mofetil (MMF) might significantly advance the development of a new therapy strategy for IgAN. The effectiveness and safety of MMF in patients with IgAN will be investigated in this study. A literature search was conducted on June 30th, 2023, by searching the following databases: PubMed and the Cochrane Library according to predefined criteria. To investigate the renoprotective benefits and safety of MMF, statistical analyses were performed using Cochrane's Review Manager Version 5.3. The meta-analysis included nine randomized controlled studies that fulfilled the inclusion criterion. In the Asian population, the results revealed a substantial difference in remission rates between the MMF group and the control group (OR: 2.53, 95% CI: 1.02, 6.30, P = 0.05). MMF can increase the rate of decrease in proteinuria in IgAN patients when compared with controls in Asians (OR: 7.34, 95% CI: 2.69, 20.08, P = 0.0001), and MMF can reduce the urinary protein in patients with IgAN in Asians (WMD: -0.61, 95% CI: -1.15, -0.08, P = 0.02). Interestingly, these studies on Asians were conducted in China. However, the differences in remission rate, rate of decrease in proteinuria, and urinary protein reduction between the MMF group and control group were not found in overall populations and in the Caucasian population. The differences in complete remission rate, partial remission rate, serum creatinine (SCr) doubling rate, rate of 50% increase in SCr, and rate of need for renal replacement treatment between the MMF group and control group were not found in Asians, Caucasians, and overall populations. The difference in the rate of side effects between the MMF group and the control group was not found. MMF protects renal function and is a safe medication for treating Chinese IgAN patients. MMF might significantly advance the development of a new therapy strategy for IgAN in the Chinese population.

TP53-Mutated Acute Myeloid Leukemia Patients Treated with Intensive Therapies Have Superior Outcomes: A Single Institution, Retrospective Study

Background: Mutations in TP53, found in 5-20% of acute myeloid leukemia (AML), confer poor prognosis and are associated with high rates of therapy resistance, high relapse rates, and dismal overall survival (OS). Recent advances have provided a variety of options for up-front AML therapy including a liposomal preparation of standard-of-care chemotherapy (CPX-351) and venetoclax-based combinations. Due to known poor outcomes with intensive chemotherapy, many providers are favoring less intense strategies for patients with TP53 mutant AML, but these approaches have not been directly compared for this patient subgroup. Strategies for treating TP53 mutant AML are highly heterogeneous and optimal treatment strategies have not been defined in this setting. We performed a retrospective study to compare the clinical outcomes of TP53 mutant AML patients treated at our center. Methods: The study was a single-center, retrospective cohort analysis conducted at the University of Minnesota. Adult patients (age ≥18 years) with the diagnosis of AML or myeloid sarcoma between January 1, 2014 and July 31, 2022 who have next-generation sequencing panel confirming a pathogenic TP53 mutation and received front-line therapy for AML at our center were included in this study. Kaplan-Meier analysis was used to estimate the probabilities of OS, defined as the date of treatment initiation to the date of death from any cause or last follow-up. Results: Our study includes 88 patients with TP53 mutant AML with available clinical data in an AML registry at our institution. Baseline demographic and clinical characteristics are summarized in Table 1. The median age at diagnosis was 67 years (range 28-87) with male predominance (65.9%). Among this, 15/88 patients (17.1%) had therapy-related AML and 40/88 patients (45.5%) had secondary AML. The median bone marrow blast percentage at diagnosis was 31% and peripheral blast percentage was 9%. The majority of patients have high variant allelic frequency (VAF, 71.9% with VAF > 0.4 for patients with available VAF data) and ASXL1 was the most frequent co-mutation identified followed by KRAS and NRAS. Treatment regimens were classified as intensive or nonintensive. Intensive treatment regimens included infusional cytarabine with either daunorubicin or idarubicin (7+3), liposomal cytarabine and daunorubicin (CPX-351), and mitoxantrone, etoposide and cytarabine (MEC). Nonintensive regimens included hypomethylating agents (decitabine or azacitidine) with or without venetoclax and clofarabine with low-dose subcutaneous cytarabine. A total of 66 patients were included in the survival analysis. There was no significant difference in OS between patients aged < 65 years and ≥ 65 years at diagnosis (2-year OS, 11% versus 5%, P=0.76). Superior 2-year OS was observed in patients who received front-line intensive (n = 31) versus nonintensive (n = 35) induction chemotherapy (2-year OS, 13% versus 3%, P=0.01, Figure 1). Patients who received intensive therapy for any line of treatment also demonstrated superior OS compared to those who never received intensive therapy (2-year OS, 12% versus 3%, P=0.02). The rate of achieving complete remission (CR) was higher in patients who received intensive treatment compared to non-intensive therapy in the first-line (51.6% versus 25.7%, P=0.03). Rate of CR at any time was also higher for patients who received intensive treatment for any line of treatment (50% versus 18.2%, P<0.01). Among the intensive first-line treatment group, 7+3 (n = 18) showed superior OS relative to CPX-351 (n = 12) (2-year OS, 22% versus 0%, P=0.03) although there was no significant difference in CR rate (55.6% versus 50%, P=0.77). Furthermore, significant survival benefit was shown in patients who underwent allogeneic hematopoietic cell transplantation compared to patients who had not (2-year OS, 21% versus 4%, P<0.01]). Conclusions: In our cohort, TP53 mutant AML patients treated with intensive chemotherapy and transplant have superior outcomes to those who do not. Since this was a retrospective study, we cannot rule out the possibility that these results are confounded by providers favoring more intensive therapies for fitter patients. However, these data imply that TP53 mutant patients may benefit from more intensive therapy and suggests that future work to define optimal therapy regimens in this patient population may incorporate intensive strategies.

Individualized chemotherapy and efficacy analysis of hepatoblastoma in children.

We aimed to assess the clinical utility of the mini patient-derived xenograft (MiniPDX) model in screening individualized chemotherapy regimens for pediatric hepatoblastoma. We included 31 children with hepatoblastoma who had unsatisfactory decreases in alpha-fetoprotein levels during neoadjuvant chemotherapy or poor clinical control of recurrence with or without metastasis. We established a MiniPDX model using surgically resected tumor tissue specimens. The sensitivities of five chemotherapeutic regimens were tested to determine the one with the lowest tumor proliferation rate, which was then set as the experimental group. We compared the clinical characteristics and efficacy with those of conventional chemotherapy regimens. The median follow-up period for the experimental group was 27months, with a complete remission (CR) rate of 80.64%. Among stage IV cases, there was a significant between-group difference in CR rate (experimental [73.68%] vs. control [37.5%]) and 3-year event-free survival rate (79.3% vs. 26.7%). The most effective individualized chemotherapy regimens were ifosfamide + pirarubicin + etoposide + carboplatin (54.84%), followed by pirubicin + cyclophosphamide + cisplatin (16.13%), ifosfamide + carboplatin + etoposide (12.90%), cisplatin + 5-fluorouracil + vincristine + adriamycin (12.90%), and vincristine + irinotecan + cyclophosphamide + cisplatin (3.23%). Using the MiniPDX model to screen individualized chemotherapy regimens for pediatric hepatoblastoma can significantly improve the CR rate.

Secondary-Type Mutations Do Not Impact the Favorable Outcome of NPM1-Mutated Acute Myeloid Leukemia Patients - Results from a Large Cohort of Intensively Treated Patients

Introduction: In 2022, the ELN risk classification for AML was updated for the second time. One of the major novelties of the ELN2022 is that all secondary-type mutations (STMs, i.e., mutations in the genes SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG2) were now added to the adverse risk characteristics. However, a pertinent question also raised by the ELN expert panel is whether STMs abrogate the positive prognostic value of co-occurring, favorable NPM1 mutations. Aim: The aim of this study was to analyze the prognostic value of STMs in AML patients (pts) who also harbor an NPM1 mutation. Methods: We investigated a pooled cohort of 936 NPM1-mutated AML pts who were treated in previously reported multicenter trials of the Study Alliance Leukemia or the AML Cooperative Group. Eligibility was determined based on diagnosis of non-APL, age ≥ 18 years, NPM1 mutation detected in targeted sequencing, curative treatment intent, and available biomaterial at diagnosis. Standard techniques for chromosome banding and fluorescence-in-situ-hybridization (FISH) were used for karyotyping. Next-generation panel sequencing was performed to detect genetic alterations that are recurrently found in myeloid neoplasms. Results: In our multicenter cohort of 936 NPM1-mutated AML pts, median follow-up for the entire cohort was 8.0 years. We found 125 patients (13.4%) harboring at least one STM ( SRSF2 [n=48; 5.1%], STAG2 [n=32; 3.2%], EZH2 [n=22, 2.4%], BCOR [n=16; 1.7%], SF3B1 [n=13; 1.4%], ASXL1 [n=12; 1.3%], ZRSR2 [n=5; 0.5%], and U2AF1 [n=4; 0,4%]). A comparison of pretreatment clinical and genetic features revealed that pts with a STM were significantly older ( p=.003, median 59 vs. 55 years), had lower white blood cell counts ( p<.001, 22.2*10 9/L vs. 39.7*10 9/L,) and platelet counts ( p<.001, 46.5*10 9/L vs. 65.0 10 9/L). The strongest pair-wise associations between gene mutations were observed between U2AF1 and RUNX1 ( p<.001) as well as SRSF2 and IDH2 ( p<.001). With respect to outcome, complete remission (CR) rate did not differ significantly between NPM1-mutated patients with or without additional STMs ( p=.41, 74.4% vs. 77.7%, OR 0.83 [95%-CI 0.54-1.29]). Median RFS for NPM1-mutated pts with STMs was 32.9 months (95%-CI: 13.0-46.0) while patients without STMs had a median RFS of 24.3 months (95%-CI: 18.7-33.3) corresponding to a HR of 1.04 ( p=0.80, 95%-CI 0.79-1.37; Figure A). Median OS for NPM1-mutated pts with or without STMs was 27.2 months (95%-CI: 14.2-49.0) and 29.1 months (95%-CI: 23.5-41.4), respectively, corresponding to a HR of 1.11 ( p=.37, 95%-CI 0.88-1.41; Figure B). To focus solely on the impact of STMs, we subsequently excluded patients with co-occurring mutations in TP53 or myelodysplasia-related cytogenetics, which all define an ELN adverse risk. Again, we observed no differences in CR rate ( p=.54, 78% vs. 75.4%), RFS ( p=.59, median 33.2 months vs. 26.6 months), or OS ( p=.33, median 27.4 month vs. 32.6 month) between NPM1-mutated patients with or without STMs. Next, we restricted our analysis to pts who are classified favorable risk according to ELN2022. Again, we found no significant outcome differences based on the STM status (unmutated vs. mutated: CR rate, 80% vs. 70.7% [ p=.072]; RFS, median 49.7 months vs. 46.0 months [ p=.702]; OS, median 45.3 months vs. 59.8 months [ p=.092]). Conclusion: NPM1 mutations rank as the second most frequent mutations in AMLand the most common in patients with a normal karyotype and serve as an established favorable prognostic marker. Our data from a large cohort demonstrate that additional STMs have no adverse effect on the clinical outcome of NPM1-mutated patients. As a result, these patients should still be considered ELN favorable risk.

Impact of Residence in an Agricultural Zone on AML Characteristics

Background: Acute Myeloid Leukemia (AML) is associated with several well-established risk factors. These include cigarette smoking, exposure to benzene, to ionizing radiation, and previous exposure to chemotherapy. Interestingly, studies have observed higher incidence rates of AML in farming regions, suggesting that farming activities and related exposures, such as pesticides, may increase the risk. However, data regarding the potential variations in clinical, cytogenetic, and molecular profiles between individuals living in rural and urban areas are lacking. Therefore, we aim to specifically examine the characteristics and the outcomes of AML patients living in agricultural areas. Patients and methods: We performed a retrospective analysis including 315 patients newly diagnosed with AML from two French institutions, namely Amiens University Hospital and Lille University Hospital, from 2008 to 2013. We collected patient demographics, along with comprehensive data encompassing clinical and biological information, including cytogenetics and molecular data. The data was obtained from the Observatoire des Hauts-de-France, enabling a comprehensive and exhaustive review of the AML cases in this specific region. We geocoded the patients' residential addresses. This process involved linking the patient's location to the corresponding agricultural areas per municipality, by using geographical information from the French Ministry of Agriculture's statistics department (AGRESTE, https://www.agreste.agriculture.gouv.fr). This enabled us to establish a connection between the patients' locations and the specific agricultural regions they resided in. We categorized the population into terciles based on the proportion of local companies engaged in farming activities. Results: Approximately one-third (n=108) of patients were living in areas with less than 1.3% of farm companies, one-third (n=102) lived in regions with a percentage ranging from 1.3% to 6.9%, while the remaining third (n=105) lived in areas where the proportion of farm companies exceeded 6.9%. Sex ratio (p=0.7) and median age at diagnosis (60 vs 60.5 vs 58 years, p=0.5) were similar between the 3 groups. There was no difference in body mass index (BMI), smoking activity, alcohol consumption and performance status score between the three groups. At baseline, there was no difference in blood counts (hemoglobin, platelets, leukocytes, and circulating blasts levels), bone marrow blasts percentage, AML type (de novo vs. post MDS or MPN), or WHO classification between the 3 groups. Regarding cytogenetic abnormalities, people living on agricultural lands had fewer normal karyotypes (27% vs 33% and 43%, p=0.045) and more MLL rearrangement (20% vs 8% and 5%, p=0.013). However, there was no difference in the SWOG and ELN 2017 classifications. Regarding molecular characteristics, NPM1 mutations were found less frequently in people living in agricultural regions (13% vs 30% and 29%, p=0.021). There was no difference for FLT3-ITD positivity and CEBPA mutation. There was no difference in complete remission rate and hematopoietic stem cell transplantation treatment though we could underline an especially low rate of HSCT in the < 1.3% group. OS was also similar between the three groups (Table 1.). Conclusions: Our study showed a correlation between living in agricultural areas and a higher prevalence of unfavorable cytogenetic and molecular features in AML patients, although clinical outcomes remain unchanged. These findings suggest that the proximity to agricultural activities could have an impact on leukemogenesis, by increasing the rate of MLL rearrangements and chromosomic abnormalities.

Efficacy and Safety of Decitabine Combined with Modified CAG Regimen in Patients Aged ≥ 70 Years with Newly Diagnosed Acute Myeloid Leukemia

To evaluate the clinical efficacy and safety of decitabine combined with modified CAG regimen (D-CAG regimen) in patients aged ≥70 years with newly diagnosed acute myeloid leukemia (AML). The clinical data of 59 AML patients (≥70 years old) who were newly diagnosed and treated in the Hematology Department of the First Affiliated Hospital of Nanjing Medical University from November 2010 to June 2021 were retrospectively analyzed. Among the 59 AML patients, 28 were males and 31 were females, with a median age of 74 (70-86) years. The complete remission (CR) rate was 69.4% (34/49), and the median duration of CR was 10.7 (0.6-125.4) months after 2 courses of D-CAG treatment. According to the British Medical Research Council (MRC) classification, there was only one patient in the favorable-risk group, and the CR rate was 71.8% (28/39) in the intermediate-risk group, and 55.6% (5/9) in the adverse-risk group, respectively. There was no statistical difference in the CR rate between the intermediate-risk and adverse-risk group. Referring to ELN 2017 genetic risk classification, CR rate was 88.2% (15/17) in the favorable-risk group, 45.5% (5/11) in the intermediate-risk group, and 66.7% (14/21) in the adverse-risk group. There was no significant difference in CR rate between the favorable-risk and adverse-risk categories, but both were significantly higher than that in the intermediate-risk group (P <0.05). Next-generation sequencing (NGS) analysis showed that 11 gene mutations with a frequency of more than 10%, including TET2 mutation (35.6%), ASXL1 mutation (30.5%), NPM1 mutation (28.8%), FLT3-ITD mutation (27.1%), DNMT3A mutation (22.0%), IDH1 mutation (15.3%), CEBPA single mutation (13.6%), TP53 mutation (13.6%), IDH2 mutation (11.9%), RUNX1 mutation (11.9%), and NRAS mutation (10.2%). There were no statistical differences in mutation frequency of these 11 genes between CR group and non-CR group. Compared with normal karyotypes, patients with complex karyotypes were more likely to develop TP53 mutations (P <0.001), while FLT3-ITD and DNMT3A mutations were more likely to occur in patients with normal karyotypes (P =0.04, P =0.047). The median follow-up, overall survival (OS), and event-free survival (EFS) of all the patients was 11.7 (1.5-128.2) months, 12.3 (1.5-128.2) months, and 8.5 (1.5-128.2) months, respectively. The median OS and EFS of CR patients were 19.8 and 13.3 months, respectively, which were significantly longer than 6.4 and 5.7 months in patients experiencing treatment failure (P < 0.001, P =0.009). In regard to genes with mutation frequency >10%, there were no statistical differences in CR rate, median OS, and median EFS between mutated and wild-type patients by Chi-square test and survival analysis. Univariate analysis showed that age, hemoglobin, lactate dehydrogenase, cytogenetics and CR were factors affecting prognosis, while multivariate analysis showed that only CR failure was an independent adverse prognostic factor for OS. The major adverse reactions to D-CAG regimen were grade 3-4 myelosuppression, pulmonary infection, and fever (infection focus was not identified). D-CAG regimen is safe and effective in the treatment of AML patients ≥70 years old, and can partially improve the prognosis of elderly and high-risk patients.

Pathogenic TP53 mutations Are Associated with a Poor Prognosis in De Novo AML

Introduction: Mutations in TP53 are the most common mutations in human cancer and occur in almost every cancer subtype. In adult acute myeloid leukemia (AML), TP53 mutations, especially those associated with complex cytogenetics, are associated with a poor prognosis. However, given the rarity of TP53 mutations in pediatric AML, less is known about its prognostic significance. Methods:TP53 variant status was determined in patients with AML enrolled on 4 successive COG trials for de novo pediatric AML (NCT00002798, NCT00070174, NCT01407757, NCT01371981). Next generation sequencing was retrospectively employed on diagnostic specimens to screen for variants including single nucleotide variants (SNVs) and insertions and deletions (indels). Variants were classified as benign, likely benign, unknown significance, likely pathogenic, and pathogenic using ClinVar and ACMG/AMP guidelines. Results: Of 1790 patients (age: median 10.48 years, range 0.01-29.84 years), 68 (3.8%) had TP53 variants. Sixty-four (94.1%) of these were SNVs, 2 (2.9%) were in-frame indels, and 2 (2.9%) were frameshifts leading to early protein truncation. Twenty-six (38.2%) were considered likely pathogenic or pathogenic (TP53mut) (age: median 8.38 years, range 0.31-17.97 years), 33 (48.5%) considered likely benign or benign, and the remaining 9 (13.2%) were of unknown significance. Thirty-four (53.1%) TP53 SNVs fell within the DNA binding domain, including 100% of TP53mut SNVs (including many occurring at DNA binding sites). We compared disease characteristics and clinical outcomes between patients with TP53mut and patients without any TP53 variant (TP53wt). Patients with non-pathogenic variants were excluded from the analysis. There was a higher prevalence of complex cytogenetics (defined as 3 or more chromosomal aberrations, including at least one structural aberration on karyotype) in TP53mut patients compared to TP53wt patients (55% vs. 18%; p=<.0001). There was no difference in the prevalence of co-occurring contemporarily defined high-risk alterations (TP53mut 30.8% vs. TP53wt 32.1%; p=0.879) but TP53mut patients were less likely to have co-occurring low-risk alterations compared to TP53wt patients (15.4% vs. 41.1%; p=0.008). While there were no differences in complete remission rates (TP53mut 85% vs. TP53wt 77.6%; p=0.426) or their ability to clear minimal residual disease (TP53mut 55% vs. TP53wt 71.6%; p=0.132), TP53mut patients had a lower event-free survival (EFS) compared to TP53wt patients (5yr: 13.3% vs. 46.3%; p <.0001), which was largely driven by a higher relapse risk (RR) (5yr: 76.5% vs. 42.1%; p <.0001). Salvageability following an event was largely unsuccessful for TP53mut patients, including only 1 long-term survivor following an event, which contributed to a lower overall survival (OS) compared to TP53wt patients (5yr: 15.9% vs. 64.7%; p < .0001). Further, EFS (13.3% vs. 26.3%; p <.0001; Figure 1a), RR (5yr: 76.5% vs. 60.9%; p <.0001; Figure 1b) and OS (5yr: 15.9% vs. 42.1%; p <.0001; Figure 1a) were significantly inferior compared to contemporarily defined high-risk patients. When patients with co-occurring high-risk alterations were excluded from analysis, TP53mut patients maintained their poor 5-yr EFS (13.3%), RR (76.5%) and OS (15.9%). Conclusions: In the largest study of TP53 mutations in pediatric patients with de novo AML, we show that pathogenic TP53variants are rare but prognostically significant. TP53mut patients were more likely to have complex cytogenetics and less likely to have co-occurring low-risk alterations. Outcomes for TP53mut patients were significantly inferior compared to contemporarily defined high-risk patients. Finally, these poor outcomes were maintained even when TP53mut patients with co-occurring high-risk lesions were excluded from analysis. Taken together, these data would suggest TP53 pathogenic mutations should be considered high-risk defining lesions in pediatric AML. Since HSCT is the standard of care for relapsed disease, the lack of salvageability following an event may suggest this disease is less alloreactive than other subtypes of AML, but further investigation is needed. Given the dismal outcomes after an event, clinical trials and novel targeted agents should be prioritized for relapsed patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Polish Acute Leukemia Group Prospective Multicenter Clinical Trial to Compare the Efficacy of Two Standard Induction Therapies (DA-90 vs DAC) and Two Standard Salvage Regimens (FLAG-IDA vs CLAG-M) in Acute Myeloid Leukemia (AML) Patients ≤ 60 Years Old (PALG-AML1/2016)

Background: AML is the most common acute leukemia in adults. While most adults < 60 years achieve complete remission (CR) with intensive induction chemotherapy, approximately one third have primary refractory disease and, overall, the majority of AML patients still relapse despite having attained initial remission (Dohner et al, 2017). The combination of an anthracycline and cytarabine has been the mainstay of intensive AML induction for more than 50 years. Combined with cytarabine (AraC), high-dose daunorubicin (90 mg/m2) in induction (DA-90) resulted in a higher rate of CR (70.6% vs. 57.3%, P<0.001) and improved overall survival (OS) (median 23.7 vs. 15.7 months; P = 0.003), without increased serious adverse events compared with DA-45 (Fernandez et al, 2009). In two PALG randomized trials, the combination of cladribine with DA (DAC regimen) also resulted in significantly increased CR after a single induction course, compared with the standard two-drug induction (DA-60) (Holowiecki et al, 2012). Both regimens have a recommendation from the National Cancer Comprehensive Network (NCCN) for routine use. For patients with primary refractory disease, the commonly used FLAG-IDA (fludarabine, cytarabine, idarubicin, GCSF) regimen results in a CR rate of 52% (Pastore et al, 2003). Two previous PALG studies confirmed that another standard regimen, CLAG-M (a combination of cladribine, Ara-C, G-CSF and mitoxantrone) is also effective with tolerable toxicity in refractory/relapsed AML patients (Wierzbowska et al, 2008; Jaglal et al, 2014). PALG-AML1/2016 aims to compare the safety and efficacy of two commonly used induction and salvage regimens in AML. This trial is also the first international randomized trial in AML induction to prospectively evaluate the impact of measurable residual disease (MRD) on overall survival, using multi-modality testing (flow-cytometry, next-generation sequencing, and PCR) of serial samples. The study is conducted in accordance with the principles of the "Declaration of Helsinki". Study Design and Methods: PALG-AML1/2016 is a multicenter, randomized, Phase III study which will include 582 patients with newly-diagnosed AML treated at multiple centers across Poland and at Weill Cornell Medicine and The New York Presbyterian Hospital in New York City. This will allow a 10% difference in CR rate between the DAC and DA-90 induction regimens to be confirmed with a power of 80% and level of significance 0.05. Eligible patients must be 18 to 60 years of age with untreated AML, Eastern Cooperative Oncology Group performance status 0-2 and HCT-CI Index of comorbidities, ≤ 3. The trial schema is shown in Figure 1. The trial was initiated in July 2017; 408 patients have been enrolled to date and accrual is ongoing. Preliminary safety and efficacy data were reviewed by the data safety monitoring committee after 194 patients and the recommendation was to proceed without changes. The CR, CRi, CRh after single or double induction were achieved in 63.4%, 16.5% and 0.6% patients, respectively leading to an overall composite CR (cCR) rate 80.5%. Thirty-day mortality, mainly due to infectious complications in aplasia, were observed in 5% and 14.5% did not achieved cCR. Serial samples for MRD are being collected from all patients at multiple time points and analysis is ongoing. ClinicalTrials.gov Identifier: NCT03257241 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical characteristics and prognosis of 16 relapsed/refractory B-cell malignancy patients with CAR T-cell-related hyperferritinaemia.

With the success of chimeric antigen receptor-modified (CAR) T-cell therapy for relapsed/refractory (r/r) B-cell malignancies, severe complications after CAR T-cell infusion have emerged as nonnegligible prognosis-related factors. However, the prognosis of patients with CAR T-cell-related hyperferritinaemia (HFA) is unclear. We report the efficacy and safety of CAR T-cell therapy in 16 r/r B-cell malignancy patients with CAR T-cell-related HFA. The rates of serum ferritin levels above 10,000 ng/ml during CAR T-cell therapy were 6.2% and 14.3% in B-cell non-Hodgkin’s lymphoma (B-NHL) and acute B lymphocyte leukemia (B-ALL), respectively. These patients were characterized by an extremely high tumor burden and a high rate of extranodal involvement. In lymphoma, the complete remission (CR) rate was 37.5% (3/8), which was lower than that in the control group with the lowest value of ferritin (CR was 87.5% (7/8), P=0.0406), and it could also be seen that the OS of the control group (1-year OS rate 100%) had a better trend than HFA group (1-year OS rate 50%). In the B-ALL patients, the OS of the control group (1-year OS rate 100%) was higher than HFA group (1-year OS rate 45%, P=0.0189), although there was no significant difference in CR rate. High-grade CRS (≥3) occurred in 56.25% of the patients, and the mortality rate was 56.25%, which was significantly higher than control group (12.5% and 12.5%, P=0.009). The peak serum ferritin level in the patients who died of CRS was significantly higher than others (P=0.0168). Regardless of whether the CAR T-related MAS diagnostic criteria were met, there was no significant difference in ORR and OS in HFA group, however patients with MAS showed a higher rate of high-grade CRS. Interestingly, in our study, glucocorticoid intervention in HFA group showed little impact on expansion of CAR-T cells, whether compared with control group or compared within HFA group by dividing patients into high and low dosage subgroups based on the median dose of glucocorticoid. High mortality was observed in patients with CAR T-cell-related HFA. Early glucocorticoid intervention might be worth trying to improve the safety of CAR T therapy in these patients.

Analysis of Coexisting Gene with NRAS in Acute Myeloid Leukemia

To investigate the coexisting mutations and clinical significance of Homo sapiens neuroblastoma RAS viral oncogene homolog (NRAS) gene in acute myeloid leukemia (AML) patients. High-throughput DNA sequencing and Sanger sequencing were used to detect 51 gene mutations. The occurrence, clinical characteristics and treatment efficacy of coexisting genes with NRAS were investigated. A total of 57 NRAS mutations (17.5%) were detected in 326 patients with AML. Compared with the patients in NRAS non-mutation group, patients in the mutant group were younger (P=0.018) and showed lower platelet count (P=0.033), but there was no significant difference in peripheral leukocyte count, hemoglobin, and sex. For FAB classification, NRAS mutation and M2 subtype showed mutually exclusive (P=0.038). Among 57 patients carried with NRAS mutation, 51 (89.5%) patients carried with other gene mutations, 25 (43.9%) carried with double gene mutations, 10 (17.5%) carried with 3 gene mutations, and 16 (28.1%) corried with ≥ 4 gene mutations. The most common coexisting gene mutation was KRAS (24.6%, 14/57), followed by FLT3-ITD (14.0%, 8/57), RUNX1 (12.3%, 7/57), NPM1 (10.5%, 6/57), PTPN11 (10.5%, 6/57), DNMT3A (10.5%, 6/57) and so on. The age (P=0.013, P=0.005) and peripheral platelet count (P=0.007, P=0.021) of patients with NPM1 or DNMT3A mutations were higher than those of the patients with wild type, but there was no significant difference in peripheral leukocyte count and hemoglobin. Also, there was no significant difference in age, peripheral leukocyte count, hemoglobin, and peripheral platelet count between the patients in KRAS, FLT3-ITD, RUNX1 or PTPN11 mutant group and the wild group. Patients with FLT3-ITD mutations showed a lower complete remission (CR) rate (P=0.044). However, there was no significant difference in CR rate between the patients with KRAS, NPM1, RUNX1, PTPN11 or DNMT3A mutations and the wild group. The CR rate of the patents with single gene mutation, double gene mutations, 3 gene mutations, and≥ 4 gene mutations were decreased gradually, and there was no significant difference in CR rate between pairwise comparisons. The mutation rate of NRAS mutation is 17.5%, 89.5% of AML patients with NRAS mutation coexist with additional gene mutations. The type of coexisting mutations has a certain impact on clinical characteristics and CR rate of patients with AML.

Toxic Nephropathy Secondary to Chronic Mercury Poisoning: Clinical Characteristics and Outcomes

IntroductionKidney disease secondary to mercury poisoning has not been well documented and is often misdiagnosed and mistreated.MethodsWe performed a retrospective analysis of patients diagnosed with having mercury poisoning over a 6-year period between July 2013 and June 2019. Demographics, clinical measures, renal pathologic examinations, treatments, and outcomes were compared between patients with kidney disease and those without kidney disease.ResultsOf the 172 patients with mercury poisoning, 46 (26.74%) had renal damage. Among the 46 patients, 41 (89.13%) presented nephrotic syndrome, and 5 (10.87%) showed proteinuria alone. The pathologic abnormality associated with kidney disease caused by mercury poisoning was mainly membranous nephropathy (18 of 35 patients, 51.43%). Among 41 patients with nephrotic syndrome, 25 were treated with chelation therapy alone and 12 with mercury chelation therapy and glucocorticoids. The remaining 4 patients were treated with chelation therapy, glucocorticoids, and immunosuppressive therapies. The overall effective rate was 97.5% (40 patients). There was no significant difference in complete remission rate among the 3 treatment methods (P < 0.05).ConclusionThe main clinical manifestation of kidney disease secondary to chronic mercury poisoning was nephrotic syndrome, which was reflected in pathologic examinations as membranous nephropathy. Kidney disease to chronic mercury poisoning is prone to misdiagnosis and missed diagnosis. Chelation therapy is the main treatment, and the prognosis is good. Patients with severe condition can be supplemented with glucocorticoid.

Analysis and Study on Epidemiological Features and Prognosis of Nephrotic Syndrome in Xinjiang and Heilongjiang.

Backgrounds The pathogenesis of nephrotic syndrome (NS) is complex, and there are differences between regions. This study attempted to collect clinicopathological data of patients diagnosed with NS in Xinjiang and Heilongjiang in the past 2 years, so as to explore the onset features of NS and treatment and prognosis of patients in the two regions. Methods Clinical data of 375 patients diagnosed with NS using renal biopsy in Xinjiang and Heilongjiang from March 2019 to March 2021 were collected. Clinical data of patients before treatment were collected, and the chi-square test was utilized to compare the differences in the sex distribution of two groups. The U test was utilized to compare abnormal distribution continuous data between two groups, such as age, hemoglobin, plasma albumin, proteinuria, and triglycerides. Independent sample t-test was utilized to compare normal distribution continuous data between two groups, such as serum total protein, serum creatinine, blood urea nitrogen, glomerular filtration rate, and total cholesterol. The independent sample t-test was also used to compare the immunoglobulin levels and complement levels between the two groups after treatment, including IgA, IgG, IgM, C3, and C4. Kaplan-Meier method was used to analyze and plot the cumulative curves of complete remission rate and partial remission rate. Results For 275 NS patients from Xinjiang, the male-to-female ratio was 0.81 : 1. For 84 patients from Heilongjiang, the male-to-female ratio was 1.05 : 1. The onset ages of patients in Xinjiang and Heilongjiang were 22-45 years old and 22-47 years old, respectively. Respectively, there were 221 cases (80.36%) and 66 cases (78.57%) of primary NS in Xinjiang and Heilongjiang. There were 54 cases (19.64%) and 18 cases (21.43%) of secondary NS in Xinjiang and Heilongjiang, respectively. There was no statistically significant difference in cause distribution between the two regions (p = 0.756). After treatment, immunoglobulin levels (IgA (p = 0.009), IgG (p = 0.002), IgM (p < 0.001)) and complement C3 (p < 0.001) and C4 (p < 0.001) levels in Xinjiang and Heilongjiang were statistically significant. 129 cases in Xinjiang (46.91%) and 55 cases in Heilongjiang (65.48%) were treated with glucocorticoid (GC) combined with immunosuppressive therapy, respectively. After receiving treatment, 67 (24.36%) of 275 patients in Xinjiang achieved complete remission, 166 (60.36%) achieved partial remission, 22 (26.19%) of 84 patients in Heilongjiang achieved complete remission, and 56 (66.67%) achieved partial remission, and there was no statistically significant difference in remission rate between the two regions (p = 0.159). Patients in Xinjiang and Heilongjiang achieved complete remission at an average of 10.34 weeks (9.98-10.70) and 9.95 weeks (9.26-10.65), respectively. There was no significant difference in complete remission rates between the two regions (p = 0.663). Patients in Xinjiang and Heilongjiang achieved partial remission at an average of 8.76 weeks (8.38-9.14) and 7.99 weeks (7.33-8.65), respectively. There was no significant difference in the partial remission rate between the two regions (p = 0.065). Conclusion The causes of NS in Xinjiang and Heilongjiang were similar. After treatment, there were differences in immunoglobulin levels (IgA, IgG, IgM) and complement levels (C3, C4) in the two regions. The main treatment methods used in the two regions were GC combined with immunosuppressive therapy. The prognosis of patients in the two regions was similar. The complete remission rate and partial remission rate after treatment in the two regions were similar, and the average time required to achieve complete remission and partial remission was also similar.

Clinicopathological characteristics and prognosis of hepatitis B associated membranous nephropathy and idiopathic membranous nephropathy complicated with hepatitis B virus infection

The main objective of this study is to analyze the clinical and pathological features and prognosis of patients with Hepatitis B associated membranous nephropathy (HBV-MN) and idiopathic membranous nephropathy (IMN) complicated with hepatitis B virus (HBV) infection. This study will provide more basis for diagnosis and prognosis evaluation. A total of 50 patients with HBV-MN were included in this study. 56 IMN patients complicated with HBV infection diagnosed during the same period formed the control group. Parameters including blood routine, urine routine and plasma levels of albumin (ALB), serum creatinine (SCR), blood urea nitrogen (BUN), urea acid (UA), total cholesterol (T-CHO), triglycerides (TG), complement C3 and C4, glutamic pyruvic transaminase (ALT), glutamic pyruvic transaminase (AST), 24-h urinary protein quantification (24 h-TP), renal phospholipase A2 receptor (PLA2R) and HBV related markers during the hospitalization and outpatient follow-up study period were collected for all the patients. The proportion of male patients was high in both groups. The average age of the HBV-MN group was 37.2 ± 14.187 years old, it was younger compared with the IMN group (P = 0.003). Nephrotic syndrome was the major clinical manifestation among patients. There was no significant difference between the two groups in the levels of anemia, microscopic hematuria, renal dysfunction, liver dysfunction, liver cirrhosis. The level of serum C3 and C4 in the HBV-MN group was lower compared with the IMN group (P = 0.002, P = 0.014). In the HBV-MN group, serum HBV markers were negative in 6 (12%) patients, 4 patients (8%) were positive for PLA2R in serum, and 5 patients (10%) were positive for PLA2R in renal tissue. Stronger IgG1 and C1q and weaker IgG4 staining were found in HBV-MN group renal tissues (P = 0.003, P = 0.025, and P = 0.001, respectively). There were no statistical differences compared with serum and renal PLA2R between HBV-MN and IMN groups (P = 0.098, P = 0.109). During the 1-year follow-up, there was no significant difference in complete remission rate between the two groups (P = 0.7739). Renal biopsy is crucial to diagnose HBV-MN. IgG subtypes in the HBV-MN group were mainly IgG1 deposition, while those in IMN complicated with HBV infection group were mainly IgG4 deposition. When HBV-associated antigen and PLA2R are present in renal tissue, lower level of serum C3 and C4, high intensity of renal C1q and IgG1 is more supportive of HBV-MN. The positive of PLA2R in serum and renal tissue in differentiating HBV from IMN complicated with HBV infection remains to be discussed.

Expanding the immune armoury against myelodysplastic syndrome.

Expanding the immune armoury against myelodysplastic syndrome.

Acute Myeloid Leukemia (AML) Patients with an Isolated Trisomy Display Increased Frequency of Spliceosome Mutations

Abstract Introduction: The molecular landscape of patients (pts) with cytogenetically normal (CN) AML has been extensively evaluated; however, there are limited data providing comprehensive mutation analysis of AML pts with sole somatic trisomy. A few analyses with small numbers of pts found frequent mutations of spliceosome encoding genes (Eisfeld et al, Leukemia 2016, Herold et al, Blood 2014). Methods: Review of the Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology cytogenetics database found 138 de novo adult AML pts with isolated trisomy of chromosomes 4, 8, 11, 13 or 21. We compared clinical and molecular data between pts within each isolated trisomy group as well as with 131 pts who had ≥1 chromosome abnormality in addition to a trisomy (non-sole trisomy) and with 716 pts with CN-AML. Results: Spliceosome encoding genes, mainly SRSF2 and U2AF1, were often mutated in pts with isolated trisomy (Figure 1). SRSF2 was mutated in 28% of +8 pts and 35% of +21 pts. SRSF2 mutations were the most common mutation in +13 pts, seen in 48% of +13 pts. U2AF1 was mutated in 15% of +8 pts and in 43% of +11 pts. Other genes commonly mutated in each trisomy group included DNMT3A, FLT3 -ITD, IDH2, NRAS, RUNX1 and TET2. Notably, pts with +4 lacked mutations in ASXL1, BCOR, STAG2 and WT1 genes, all of which were mutated in pts in the other sole trisomy groups. NPM1 mutations, often seen in the +4, +8, +13 and +21 groups, were not seen in +11 pts. There were no differences in complete remission rates, relapse rates, disease-free or overall survival among trisomy groups. For pre-treatment clinical features of the 138 de novo isolated trisomy AML pts see Table 1. The median age was 61 years (range, 19-84 years). We saw several differences in the mutation spectrum between older (aged ≥60 years) and younger (aged We next studied molecular differences between the 138 sole trisomy pts and 131 pts with non-sole trisomy. We saw more mutations in SRSF2 (29% vs 14%, P=.003) and U2AF1 (14% vs 14%, P=.003) in sole trisomy versus non-sole trisomy pts. Several genes were often mutated (≥5%) in both sole and non-sole trisomy groups; most common were spliceosome genes SRSF2 , U2AF1, ZRSR2, and others were ASXL1, BCOR, DNMT3A, FLT3 -ITD, FLT3 -TKD, IDH1, IDH2, NPM1, NRAS, RUNX1, STAG2, TET2. TP53 mutations were often seen in non-sole trisomy pts, but were rare in sole trisomy pts (17% vs 1%, P Comparing sole trisomy pts to 716 CN-AML pts, we found spliceosome encoding genes more often mutated (48% vs 19%, P Conclusions: This is the largest series of de novo AML pts with isolated trisomy that provides comprehensive mutation analysis. These pts display a distinct molecular landscape from AML pts with non-sole trisomy and from CN-AML pts. Mutations affecting spliceosome encoding genes were seen in almost 50% of pts with isolated trisomy suggesting that aberrant RNA splicing may be implicated in the pathogenesis of these pts. Support: U10CA180821, U10CA180850, U10CA180882, U24CA196171; ClinicalTrials.gov Ids: NCT00048958, NCT00900224 Download : Download high-res image (236KB) Download : Download full-size image Disclosures Kolitz: Gilead, Magellan, Novartis, Pharmacyclics, and Seattle Genetics: Consultancy; Boehringer Ingelheim, Cantex, Erytech, and Millennium: Research Funding; Gilead, Novartis, and Seattle Genetics: Other: Travel Support; Celgene, Jazz: Equity Ownership; Gilead, Magellan, and Novartis: Honoraria. Powell: Rafael Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Byrd: Acerta Pharma: Research Funding; Genentech: Research Funding; The Ohio State University: Patents & Royalties: OSU-2S; Janssen: Research Funding; Pharmacyclics: Research Funding.

Poor Treatment Outcomes of Young (

Poor Treatment Outcomes of Young (<60 Years) African American Patients (Pts) Diagnosed with Acute Myeloid Leukemia (AML) (Alliance)

A Polish Acute Leukemia Group Prospective Multicenter Clinical Trial to Compare the Efficacy of Two Standard Induction Therapies (DA-90 vs DAC) and Two Standard Salvage Regimens (FLAG-IDA vs CLAG-M) in Acute Myeloid Leukemia (AML) Patients ≤ 60 Years Old (PALG-AML1/2016)

Background: AML is the most common acute leukemia in adults. While most adults &amp;lt; 60 years achieve complete remission (CR) with intensive induction chemotherapy, approximately one third have primary refractory disease and, overall, the majority of AML patients still relapse despite having attained initial remission (Dohner et al, Blood 2017). The combination of an anthracycline and cytarabine has been the mainstay of intensive AML induction for more than 50 years. Combined with cytarabine (AraC), high-dose daunorubicin (90 mg/m2) in induction (DA-90) resulted in a higher rate of CR (70.6% vs. 57.3%, P&amp;lt;0.001) and improved overall survival (OS) (median 23.7 vs. 15.7 months; P = 0.003), without increased serious adverse events compared with DA-45 (Fernandez et al, NEJM, 2009). In two PALG randomized trials, the combination of cladribine with DA (DAC regimen) also resulted in significantly increased CR after a single induction course, compared with the standard two-drug induction (DA-60) (Holowiecki et al, Leukemia, 2004 and JCO 2012). Both regimens have a recommendation from the National Cancer Comprehensive Network (NCCN) for routine use. For patients with primary refractory disease, the commonly used FLAG-IDA (fludarabine, cytarabine, idarubicin, GCSF) regimen results in a CR rate of 52% (Pastore et al, Ann Hem, 2003). Two previous PALG studies confirmed that another standard regimen, CLAG-M (a combination of cladribine, Ara-C, G-CSF and mitoxantrone) is also effective with tolerable toxicity in refractory/relapsed AML patients (Robak et al Leuk Lymph, 2000; Wrzesień-Kuś et al, Eur J Haematol 2003; Wrzesień-Kuś et al, Ann Hematol, 2005; Wierzbowska et al, Eur J Haematol ,2008; Jaglal et al, Leuk Res, 2014). PALG-AML1/2016 aims to compare the safety and efficacy of two commonly used induction and salvage regimens in AML. This trial is also the first international randomized trial in AML induction to prospectively evaluate the impact of measurable residual disease (MRD) on overall survival, using multi-modality testing (flow-cytometry, next-generation sequencing, and PCR) of serial samples. The study is conducted in accordance with the principles of the "Declaration of Helsinki". Study Design and Methods: PALG-AML1/2016 is a multicenter, randomized, Phase III study which will include 582 patients with newly-diagnosed AML treated at multiple centers across Poland and at Weill Cornell Medicine and The New York Presbyterian Hospital in New York City. This will allow a 10% difference in CR rate between the DAC and DA-90 induction regimens to be confirmed with a power of 80% and level of significance 0.05. Eligible patients must be 18 to 60 years of age with untreated AML, Eastern Cooperative Oncology Group performance status 0-2 and HCT-CI Index of comorbidities, ≤ 3. As midostaurin treatment has become approved and available the study was amended with an exclusion of FLT3-mutated patients. The trial schema is shown in Figure 1. The trial was initiated in July 2017 and 279 patients have been enrolled to date and accrual is ongoing. Preliminary safety and efficacy data were reviewed by the data safety monitoring committee after 194 patients and the recommendation was to proceed without changes. Serial samples for MRD are being collected from all patients at multiple time points and analysis is ongoing. ClinicalTrials.gov Identifier: NCT03257241 Figure 1 Disclosures Wierzbowska: Janssen: Honoraria; Celgen/BMS: Honoraria; Novartis: Honoraria; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Research Funding. Pluta:Angelini: Research Funding; Celgene/BMS: Honoraria. Libura:Novartis: Honoraria. Wrobel:Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau. Zaucha:Abbvie: Honoraria; Sandoz: Consultancy, Honoraria; Cellgene: Other: travel, accomodations, expenses; Novartis: Consultancy; BMS: Consultancy; Takeda: Consultancy, Honoraria, Other: travel, accomodations, expenses; Roche: Consultancy, Honoraria, Other: travel, accomodations, expenses. Robak:AstraZeneca: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; GSK: Research Funding; Bristol Meyers Squibb: Research Funding; Novartis: Honoraria, Research Funding; Morphosys: Research Funding; UCB: Honoraria, Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; UTX-TGR: Research Funding; BioGene: Honoraria, Research Funding; Acerta: Research Funding; Momenta: Consultancy; Pfizer: Research Funding; Sandoz: Consultancy, Honoraria; Octapharma: Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Medical University of Lodz: Current Employment; Takeda: Consultancy. Lee:BMS: Consultancy; Helsinn: Other: Member -DSMB; AstraZeneca: Consultancy; Jazz: Consultancy; Roche Molecular Systems: Consultancy. Ritchie:Novartis: Honoraria; Incyte: Speakers Bureau; Sierra Oncology: Honoraria; Abbvie: Honoraria; Pfizer: Honoraria, Research Funding; Jazz pharmaceuticals: Honoraria, Research Funding. Guzman:Cellectis: Research Funding; SeqRx: Honoraria. Roboz:Agios: Consultancy; Amphivena: Consultancy; Astex: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Array BioPharma: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Eisai: Consultancy; Jazz: Consultancy; Roche/Genentech: Consultancy; Sandoz: Consultancy; Actinium: Consultancy; Argenx: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; AstraZeneca: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Takeda: Consultancy; Trovagene: Consultancy; Cellectis: Research Funding; Jasper Therapeutics: Consultancy; Epizyme: Consultancy; Helsinn: Consultancy; MEI Pharma: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy. OffLabel Disclosure: cladribine - in induction regimen in AML

Clinical and Prognostic Implications of PTPN11 Mutations in Acute Myeloid Leukemia (Alliance)

Clinical and Prognostic Implications of PTPN11 Mutations in Acute Myeloid Leukemia (Alliance)

Integrated transcriptomic and genomic analysis improves prediction of complete remission and survival in elderly patients with acute myeloid leukemia

Relevant molecular tools for treatment stratification of patients ≥65 years with acute myeloid leukemia (AML) are lacking. We combined clinical data with targeted DNA- and full RNA-sequencing of 182 intensively and palliatively treated patients to predict complete remission (CR) and survival in AML patients ≥65 years. Intensively treated patients with NPM1 and IDH2R172 mutations had longer overall survival (OS), whereas mutated TP53 conferred lower CR rates and shorter OS. FLT3-ITD and TP53 mutations predicted worse OS in palliatively treated patients. Gene expression levels most predictive of CR were combined with somatic mutations for an integrated risk stratification that we externally validated using the beatAML cohort. We defined a high-risk group with a CR rate of 20% in patients with mutated TP53, compared to 97% CR in low-risk patients defined by high expression of ZBTB7A and EEPD1 without TP53 mutations. Patients without these criteria had a CR rate of 54% (intermediate risk). The difference in CR rates translated into significant OS differences that outperformed ELN stratification for OS prediction. The results suggest that an integrated molecular risk stratification can improve prediction of CR and OS and could be used to guide treatment in elderly AML patients.

Efficacy and safety of anti-CD19 CAR T-cell therapy in 110 patients with B-cell acute lymphoblastic leukemia with high-risk features

AbstractAnti-CD19 chimeric antigen receptor (CAR) T-cell therapy is effective in patients with advanced B-cell acute lymphoblastic leukemia (B-ALL). However, efficacy data is sparse in subgroups of patients with high-risk features such as BCR-ABL+, TP53 mutation, extramedullary disease (including central nervous system leukemia) or posttransplant relapse. It is also uncertain whether there is an added benefit of transplantation after anti-CD19 CAR T-cell therapy. We conducted a phase 1/2 study of 115 enrolled patients with CD19+ B-ALL. A total of 110 patients were successfully infused with anti-CD19 CAR T cells. In all, 93% of patients achieved a morphologic complete remission, and 87% became negative for minimal residual disease. Efficacy was seen across all subgroups. One-year leukemia-free survival (LFS) was 58%, and 1-year overall survival (OS) was 64% for the 110 patients. Seventy-five nonrandomly selected patients (73.5%) subsequently received an allogeneic hematopoietic stem cell transplant (allo-HSCT). LFS (76.9% vs 11.6%; P < .0001; 95% confidence interval [CI], 11.6-108.4) and OS (79.1% vs 32.0%; P < .0001; 95% CI, 0.02-0.22) were significantly better among patients who subsequently received allo-HSCT compared with those receiving CAR T-cell therapy alone. This was confirmed in multivariable analyses (hazard ratio, 16.546; 95% CI, 5.499-49.786). Another variate that correlated with worse outcomes was TP53 mutation (hazard ratio, 0.235; 95% CI, 0.089-0.619). There were no differences in complete remission rate, OS, or LFS between groups of patients age 2 to 14 years or age older than 14 years. Most patients had only mild cytokine release syndrome and neurotoxicity. Our data indicate that anti-CD19 CAR T-cell therapy is safe and effective in all B-ALL subgroups that have high-risk features. The benefit of a subsequent allo-HSCT requires confirmation because of nonrandom allocation. This trial was registered at www.clinicaltrials.gov as #NCT03173417.