CD19-specific CAR-T Cell Treatment of 115 Children and Young Adults with Acute B Lymphoblastic Leukemia: Long-Term Follow-up.

Purpose: Chemotherapy has been the primary treatment for patients with B-cell acute lymphoblastic leukemia (B-ALL). However, there are still patients who are not sensitive to chemotherapy, including those with refractory/relapse (R/R) disease and those experiencing minimal residual disease (MRD) re-emergence. Chimeric antigen receptor-T lymphocytes (CAR-T) therapy may provide a new treatment option for these patients. Materials and Methods: Oure institution conducted a single-arm prospective clinical trial (ChiCTR-OPN-17013507) using CAR-T-19 to treat R/R B-ALL and MRD re-emergent patients. One hundred and fifteen patients, aged 1-25 years (median age 8 years), were enrolled, including 67 R/R and 48 MRD re-emergent CD19-positive B-ALL patients. Results: All patients achieved morphologic CR, and within one month after infusion, 111 out of 115 (96.5%) patients achieved MRD-negative CR. With a median follow-up time of 48.4 months, the estimated 4-year leukemia-free survival (LFS) rate and overall survival (OS) rate were (68.7±4.5) % and (70.7±4.3) %, respectively. There were no significant differences in long-term efficacy observed among patients with different disease statuses before infusion (4-year OS: MRD re-emergence vs. R/R B-ALL, 70.6±6.6% vs. 66.5±6.1%, p=0.755; 4-year LFS: MRD re-emergence vs. R/R B-ALL, 67.3±7.0% vs. 63.8±6.2%, p=0.704). R/R B-ALL patients bridging to transplantation after CAR-T treatment had a superior OS and LFS compared to those who did not. However, for MRD re-emergent patients, there was no significant difference in OS and LFS, regardless of whether they underwent HSCT or not. Conclusion: CD19 CAR-T therapy effectively and safely cures both R/R B-ALL and MRD re-emergent patients.

[Clinical Significance of Minimal Residual Disease in Pediatric Patients with TCF3/PBX1+ B-cell Acute Lymphoblastic Leukemia].

OBJECTIVE: To explore the consistency of flow cytometry (FCM) method and polymerase chain reaction (PCR) technique in the detection of minimal residual disease (MRD) at different treatment stages in pediatric patients with TCF3/PBX1+ B-cell acute lymphoblastic leukemia (B-ALL) and the correlations between the detection results and prognosis. METHODS: The clinical data of 64 newly diagnosed pediatric patients with TCF3/PBX1+ B-ALL admitted to the Department of Pediatrics of Peking University People's Hospital from January 2005 to December 2017 were retrospectively analyzed. FCM and PCR methods were used to monitor the MRD level in bone marrow samples from 64 children during the same period of treatment on d33 and d90 respectively, and the detection results were analyzed. RESULTS: There were 37 males and 27 females in the 64 patients, with a median age of 8 years(range 0.8 to 16 years). The complete remission (CR) rate after the first cycle of induction chemotherapy was 98.4% (62/63), with overall CR rate of 100%. 12 patients experienced recurrence, with a median recurrence time of 16.9 (5.3-46.3) months. The median follow-up time of the 64 patients was 77.2 (1.0-184.8) months , and the 5-year overall survival (OS) rate and event-free survival (EFS) rate were 82.8%±4.7% and 75.0%±5.4%, respectively. On d90, the concordance rate of the MRD results from the two methods was 98.4%, and the related kappa value was 0.792 (P < 0.001), which were significantly higher than those on d33. After induction chemotherapy (d33), the 5-year EFS rate of MRD-FCM- group (79.3%±5.3%) was significantly better than that of MRD-FCM+ group (40.0%±21.9%) (P =0.028), there were no significant differences in the 5-year OS rate and EFS rate between MRD-PCR+ group and MRD-PCR- group, and the 5-year EFS rate of MRD-FCM-/PCR- group (85.4%±5.5%) was significantly better than that of MRD-FCM+/PCR+ group (40.0 %±21.9%) (P =0.026). CONCLUSION: In children with TCF3/PBX1+ B-ALL, the MRD results detected by FCM and PCR methods show good consistency, especially in consolidation therapy period (d90). The MRD level at the end of induction therapy (d33) is an important factor affecting the long-term prognosis, especially the MRD results detected by FCM method, which is significantly associated with prognosis.

A nomogram for predicting hospital mortality of critical ill patients with sepsis and cancer: a retrospective cohort study based on MIMIC-IV and eICU-CRD.

OBJECTIVE: Sepsis remains a high cause of death, particularly in immunocompromised patients with cancer. The study was to develop a model to predict hospital mortality of septic patients with cancer in intensive care unit (ICU). DESIGN: Retrospective observational study. SETTING: Medical Information Mart for Intensive Care IV (MIMIC IV) and eICU Collaborative Research Database (eICU-CRD). PARTICIPANTS: A total of 3796 patients in MIMIC IV and 549 patients in eICU-CRD were included. PRIMARY OUTCOME MEASURES: The model was developed based on MIMIC IV. The internal validation and external validation were based on MIMIC IV and eICU-CRD, respectively. Candidate factors were processed with the least absolute shrinkage and selection operator regression and cross-validation. Hospital mortality was predicted by the multivariable logistical regression and visualised by the nomogram. The model was assessed by the area under the curve (AUC), calibration curve and decision curve analysis curve. RESULTS: The model exhibited favourable discrimination (AUC: 0.726 (95% CI: 0.709 to 0.744) and 0.756 (95% CI: 0.712 to 0.801)) in the internal and external validation sets, respectively, and better calibration capacity than Acute Physiology and Chronic Health Evaluation IV in external validation. CONCLUSIONS: Despite that the predicted model was based on a retrospective study, it may also be helpful to predict the hospital morality of patients with solid cancer and sepsis.

Prognostic Significance of CD20 Expression in Children with Philadelphia Chromosome-Negative B-Cell Precursor Acute Lymphoblastic Leukemia.

INTRODUCTION: The prognostic significance of CD20 in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains unclear. Therefore, in this study, we evaluated the prognostic value of CD20 expression in leukemia blasts in pediatric BCP-ALL at our institute. METHODS: Between 2005 and 2017, 796 children with newly diagnosed Philadelphia-negative BCP-ALL were enrolled consecutively; clinical characteristics and treatment outcomes were analyzed and compared between CD20-positive and CD20-negative groups. RESULTS: CD20 positivity was observed in 22.7% of enrolled patients. The analysis of overall and event-free survival showed that white blood cell count ≥50 × 109/L, no ETV6-RUNX1, day 33 minimal residual disease (MRD) ≥0.1%, and week 12 MRD ≥0.01% were independent risk factors. Meanwhile, in the CD20-positive group, week 12 MRD ≥0.01% was the only factor associated with long-term survival. Moreover, subgroup analysis revealed that in patients with extramedullary involvement (p = 0.047), MRD ≥0.1% on day 33 (p = 0.032), or MRD ≥0.01% at week 12 (p = 0.004), CD20 expression led to a poorer outcome compared to those without CD20 expression. CONCLUSIONS: Pediatric BCP-ALL with CD20 expression had unique clinicopathological characteristics, and MRD remained the major prognostic factor. CD20 expression had no prognostic value in pediatric BCP-ALL.

Clinical Analysis of Pediatric T-Cell Acute Lymphoblastic Leukemia Using the MRD-Oriented Strategy System.

Pediatric T-cell acute lymphoblastic leukemia (T-ALL) has historically been associated with a poor prognosis. However, prognostic indicators and methods of treatment used for T-ALL remain controversial. A total of 136 children newly diagnosed with T-ALL between 2005 and 2018 were consecutively enrolled in this study. We assessed the effect of different prognostic factors, such as clinical characteristics, minimal residual disease (MRD), and the role of transplantation in postremission treatment, as the outcomes. Compared with B-ALL patients, patients with T-ALL are generally older, more likely to be male and have a higher white blood cell count. The complete remission (CR) rate was 95.6%, while the 5-year overall survival (OS), event-free survival (EFS), and cumulative incidence of relapse (CIR) were 74.3 ± 3.7%, 71.3 ± 3.9%, and 24.4 ± 3.8%, respectively. In the multivariate analysis, day 33 MRD ≥0.1% and hyperleukocytosis were associated with a significantly worse prognosis in the whole group. Transplantation resulted in a significant survival advantage, compared with chemotherapy, for high-risk (HR) patients (5-year CIR: 15.6 ± 10.2% vs. 55.6 ± 11.7%, P = .029). The prognosis of children with T-ALL was poor, and the MRD on day 33 was found to be an important predictive factor of clinical outcome at our center.

Prognostic significance of Wilms' tumor gene 1 expression in children with B-cell precursor acute lymphoblastic leukemia.

Introduction: The prognostic role of Wilms' tumor 1 (WT1) gene expression at diagnosis in children with B cell precursor acute lymphoblastic leukemia (BCP-ALL) is still controversial. Methods: We detected the WT1 transcript levels of 533 de novo pediatric BCP-ALL patients using TaqMan-based real-time quantitative PCR and analyzed their clinical features. Results: The WT1 transcript levels differed among the distinct molecularly defined groups, with the highest levels in the KMT2A rearrangements (KMT2A-r) group. According to the results of the X-tile software, all patients were divided into two groups: WT1/ABL ≥ 0.24% (group A) and <0.24% (group B). The proportions of patients whose age was ≥10 years old, with immunophenotype of Pro-B, belonging in high-risk group, or with minimal residual disease (MRD) ≥ 0.01% at week 12 were significantly higher in group A than in group B. In the B-other group, WT1 overexpression was an independent risk factor of overall survival (OS) rate (P = 0.042), and higher MRD ≥ 0.01% at week 12 was associated with lower OS rate (P<0.001) and event-free survival rate (P<0.001). Moreover, the subgroup analysis revealed that, in patients with initial WBC<50 × 109/L or MRD<0.1% at day 33 or MRD<0.01% at week 12 or in the standard-risk group, WT1 overexpression led to a poorer outcome in comparison with those with WT1 downexpression (P<0.05). Discussion: Therefore, pediatric BCP-ALL with WT1 overexpression had unique clinico-pathological characteristics and poor treatment response. In B-other patients, WT1 overexpression at diagnosis predicted an inferior prognosis. The WT1 gene may serve as a biomarker for monitoring residual disease in the B-other population, especially in children in the standard-risk group.

Outcomes of Adolescent Patients with Acute Lymphoblastic Leukemia: Long-term Follow-up of 335 Patients.

BACKGROUND: Adolescents (aged 10-17 years) with acute lymphoblastic leukemia (ALL) represent a unique patient population, with a disproportionate survival disadvantage compared with younger patients. We aimed to determine the outcomes and prognostic factors of adolescent patients treated at our institution. PATIENTS AND METHODS: Between 2005 and 2017, 335 adolescents with ALL were enrolled; clinical characteristics and treatment outcomes were analyzed and compared between adolescents and younger children (1-9 years old, n = 704). RESULTS: Adolescents were more likely to have high-risk factors such as hyperleukocytosis, a T-cell immunophenotype, BCR-ABL1, and/or poor early treatment responses. Compared with younger children, adolescents had significantly worse 5-year event-free survival (EFS) (73.0% ± 2.5% vs. 82.6% ± 1.5%; P < .001) and overall survival (OS) (77.1% ± 2.3% vs. 87.7% ± 1.3%; P < .001). Furthermore, younger adolescents (10-14 years) tended to have better outcomes compared with those older than 15 years (5-year OS: 79.3% ± 2.5% vs. 68.4% ± 5.7%; P = .042), mainly because of the lower frequencies of toxicities. On multivariate analysis, white blood count ≥ 50 × 109/L and extramedullary involvement at diagnosis were the most powerful prognostic factors for both OS and EFS. CONCLUSION: The outcomes among adolescent patients were not as good as that of younger children. Further studies are required to define optimal treatment strategies for adolescents, particularly those aged 15 to 17 years.

The role of minimal residual disease in specific subtypes of pediatric acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is a heterogeneous disease whose prognostic factors include minimal residual disease (MRD) and cytogenetic abnormalities. To explore the significance of MRD in ALL subtypes, we analyzed the outcomes of 1126 children treated with risk-stratified therapy based on sequential MRD monitoring. MRD distributions and treatment outcomes differed between distinct leukemia subtypes. Patients with ETV6-RUNX1 or hyperdiploidy had the best prognosis (5-year OS: 97 ± 1.5% and 89.2 ± 2.7%). However, hyperdiploidy patients with MRD ≥ 10% on day 15 had a higher risk of relapse (36.4%) than those with ETV6-RUNX1. TCF3-PBX1 patients had the fastest disease clearance (negative MRD rate on day 33: 92.1%), but the overall prognosis was intermediate (5-year OS: 82.5%). Patients with high-risk characteristics and ALL-T had inferior outcomes: even with undetectable MRD on day 33, cumulative incidence of relapse was 19.9% and 23.4%, respectively. Moreover, those with poor early-treatment response and detectable week-12 MRD had a worse prognosis. After adjusting for other risk factors, re-emergent MRD was the most significant adverse prognostic indicator overall. Sequential MRD measurement is important for MRD-guided therapy, and integration of MRD values at different timepoints based on leukemia subtype could allow for more refined risk stratification.

Long-Term Results of the Risk-Stratified Treatment of TCF3-PBX1-Positive Pediatric Acute Lymphoblastic Leukemia in China.

BACKGROUND: Acute lymphoblastic leukemia (ALL) with t(1;19)/TCF3-PBX1 is a common genotype, and its prognosis has significantly improved owing to risk stratification and intensive treatment. This study aimed to determine the outcomes and prognostic factors of patients with TCF3-PBX1 treated with the modified Berlin-Frankfurt-Münster protocol. PATIENTS AND METHODS: Between 2005 and 2017, a total of 1051 pediatric patients with ALL were enrolled. TCF3-PBX1 was detected by reverse-transcriptase PCR and/or cytogenetic analysis. Clinical characteristics and treatment outcomes were analyzed and compared in patients with TCF3-PBX1 and with other B-precursor ALL (B-ALL). RESULTS: TCF3-PBX1 was detected in 64 patients with ALL (6.1%), and all were of B-cell lineage. These patients were more likely to express the pre-B-ALL immunophenotype (P < .001), be in the National Cancer Institute high-risk group (P = .030), and exhibit more rapid disease clearance during induction therapy (P < .001) compared to patients with other B-ALL. However, the outcomes of this genotype were not better than those of other patients with intermediate risk. At a median (range) follow-up of 60.6 (0.8-184.5) months, the estimated 5-year overall survival was 85.2 ± 4.6% versus 88.2 ± 1.8% (P = .500) and 5-year event-free survival was 76.8 ± 5.5% versus 83.0 ± 2.0% (P = .210) for patients with TCF3-PBX1 and those with other B-ALL. After adjusting for other risk factors, reemergent minimal residual disease (MRD) was the most significant poor prognostic indicator for patients with TCF3-PBX1. CONCLUSION: The overall outcome of patients with TCF3-PBX1 was intermediate at our institution. Sequential MRD measurement is important for this genotype. Thus, more efforts should be made to eradicate reemergent MRD to improve prognosis.

Efficacy of Haploidentical Hematopoietic Stem Cell Transplantation Compared With Chemotherapy as Postremission Treatment of Children With Intermediate-risk Acute Myeloid Leukemia in First Complete Remission.

BACKGROUND: The role of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) for children with intermediate-risk acute myeloid leukemia (IR-AML) in first complete remission has been controversial. The present study compared the effect of chemotherapy with unmanipulated haplo-HSCT as treatment of patients with IR-AML in first complete remission (CR1). PATIENTS AND METHODS: We retrospectively analyzed the outcomes of 80 children with IR-AML and compared the effects of chemotherapy (n = 47) with those of haplo-HSCT (n = 33) as treatment in CR1. RESULTS: The 3-year overall survival, event-free survival (EFS), and cumulative incidence of relapse (CIR) was 85.4% ± 4.1%, 73.2% ± 5.0%, and 25.4% ± 4.5%, respectively. Compared with the chemotherapy group, the patients in the haplo-HSCT group had a lower CIR (P = .059) and better EFS (P = .108), but roughly equivalent overall survival (P = .841). Multivariate analysis revealed chemotherapy and minimal residual disease (MRD) of ≥ 10-3 after induction therapy as independent risk factors affecting CIR and EFS. EFS (P = .045) and CIR (P = .045) differed significantly between the 2 treatment groups in patients with MRD of ≥ 10-3 after induction therapy. CONCLUSION: Haplo-HSCT might be a feasible option for children with IR-AML in CR1, especially for patients with MRD of ≥ 10-3 after induction therapy.

[Clinical characteristics and prognostic analysis of pediatric pro-B cell acute lymphoblastic leukemia].

OBJECTIVE: To explore the clinical-biological characteristics and prognosis of pediatric pro-B cell acute lymphoblastic leukemia (pro-B-ALL). METHODS: A total of 64 patients aged less than 18 years old with pro-BALL were enrolled. Clinical characteristics, therapeutic effect and prognostic factors were retrospectively analyzed. RESULTS: Pro-B-ALL occurred in 6.23% (64/1 028) of pediatric ALL. Among the 64 patients, 35 were male and 29 were female. The median age was 7.0 years (range 0.4-16.0 years) at diagnosis, of which 39% and 6% were ≥ 10 years old and < 1 year old respectively. The median WBC count was 25.5×109/L[range (0.4-831.9)×109/L], of which 35.9% were ≥ 50×109/L. MLL-r positivity was the most frequent genetic alteration in pro-B ALL, occurring in 34% of patients, with lower frequency of CD22 and CD13 expression and higher frequency of CD7 expression, while lower frequency of CD33 expression was found in patients with MLL-AF4 positivity. At a median follow-up of 60.0 months (range 4.9-165.3 months), the estimated 5-year overall survival (OS) and event-free survival (EFS) in the 64 patients were (85±5)% and (78±5)% respectively. Cox proportional hazards regression analysis identified MRD ≥ 0.1% at 3 months after chemotherapy as an independent adverse prognostic factor for both 5-year OS and EFS. CONCLUSIONS: Pediatric pro-B ALL is a heterogeneous disease with clinical and biological diversity. Biological characteristics, such as immunological markers, genetic alterations, and MRD at 3 months after chemotherapy may be important factors for the long-term prognosis.

Re-Emergence of Minimal Residual Disease Detected by Flow Cytometry Predicts an Adverse Outcome in Pediatric Acute Lymphoblastic Leukemia.

PURPOSE: While the role of minimal residual disease (MRD) assessment and the significance of achieving an MRD-negative status during treatment have been evaluated in previous studies, there is limited evidence on the significance of MRD re-emergence without morphological relapse in acute lymphoblastic leukemia (ALL). We sought to determine the clinical significance of MRD re-emergence in pediatric ALL patients. METHODS: Between 2005 and 2017, this study recruited 1126 consecutive patients newly diagnosed with ALL. Flow cytometry was performed to monitor MRD occurrence during treatment. RESULTS: Of 1030 patients with MRD-negative results, 150 (14.6%) showed MRD re-emergence while still on morphological complete remission (CR). Patients with white blood cell counts of ≥50 × 109/L (p = 0.033) and MRD levels of ≥0.1% on day 33 (p = 0.012) tended to experience MRD re-emergence. The median re-emergent MRD level was 0.12% (range, 0.01-10.00%), and the median time to MRD re-emergence was 11 months (range, <1-52 months). Eighty-five (56.6%) patients subsequently developed relapse after a median of 4.1 months from detection of MRD re-emergence. The median re-emergent MRD level was significantly higher in the relapsed cohort than in the cohort with persistent CR (1.05% vs. 0.48%, p = 0.005). Of the 150 patients, 113 continued to receive chemotherapy and 37 underwent transplantation. The transplantation group demonstrated a significantly higher 2-year overall survival (88.7 ± 5.3% vs. 46.3 ± 4.8%, p < 0.001) and cumulative incidence of relapse (23.3 ± 7.4% vs. 64.0 ± 4.6%, p < 0.001) than the chemotherapy group. CONCLUSIONS: MRD re-emergence during treatment was associated with an adverse outcome in pediatric ALL patients. Transplantation could result in a significant survival advantage for these patients.

Superior survival of unmanipulated haploidentical haematopoietic stem cell transplantation compared with intensive chemotherapy as post-remission treatment for children with very high-risk philadelphia chromosome negative B-cell acute lymphoblastic leukaemia in first complete remission.

We explored the prognostic factors for children with very high-risk (VHR) Philadelphia chromosome (Ph) negative B-cell acute lymphoblastic leukaemia (B-ALL) and compared the therapeutic effects of intensive chemotherapy and unmanipulated haploidentical haematopoietic stem cell transplantation (haplo-HSCT) as post-remission treatment in these patients undergoing first complete remission (CR1). A total of 104 paediatric patients with VHR B-ALL in CR1 were retrospectively enrolled in this study, including 42 receiving unmanipulated haplo-HSCT (Group A) and 62 receiving ongoing chemotherapy (Group B). Estimated 3-year overall survival (OS), disease-free survival (DFS) and cumulative incidence of relapse (CIR) at 36·2 months median follow-up were 69·5 ± 4·7%, 63·5 ± 4·8% and 32·4 ± 4·7%, respectively. Maintenance of persistent positive or conversion from negative to positive of measurable residual disease (MRD) and chemotherapy were independent risk factors associated with inferior long-term survival and higher CIR. OS, DFS, and CIR differed significantly between the groups in patients with persistent positive or negative-to-positive MRD. Haplo-HSCT may be an option for children with VHR Ph-negative B-ALL in CR1, especially for patients with persistent positive or negative-to-positive MRD, and could achieve better survival than intensive chemotherapy as post-remission treatment.

Allogeneic Hematopoietic Stem Cell Transplantation, Especially Haploidentical, May Improve Long-Term Survival for High-Risk Pediatric Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in the Tyrosine Kinase Inhibitor Era.

The role of allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly haploidentical (haplo)-HSCT, in pediatric patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in the tyrosine kinase inhibitor (TKI) era is unclear. This study aimed to identify prognostic factors and explore the role of haplo-HSCT in the treatment of Ph+ ALL in the TKI era. We analyzed clinical data of Ph+ ALL patients aged 1 to 18 years who received imatinib added to intensive chemotherapy at the start of induction therapy. Among the 68 patients who completed at least 2 consolidation cycles, 44 underwent transplantation (transplant arm) and 24 received continuous TKI with chemotherapy (nontransplant arm). At the 3-year follow-up the cumulative incidence of relapse (CIR), event-free survival (EFS), and overall survival (OS) were 23.5%, 73.4%, and 80.3%, respectively. Multivariate analysis showed that hematologic response (whether complete remission [CR] was achieved) at the induction end, BCR-ABL levels (whether major molecular response [MMR] was achieved) at 3 months, and transplantation were independent affecting factors for CIR, EFS, and OS. In the risk stratification analysis based on the first 2 prognostic factors mentioned above, no significant difference existed between the transplant and nontransplant arms for the probabilities of 3-year OS, EFS, and CIR in the standard-risk group (no poor prognostic factors). Meanwhile, OS, EFS, and CIR rates were significantly better in the transplant arm in the high-risk group (≥1 poor prognostic factor). Among the 44 patients in the transplant arm, 37 underwent haplo-HSCT. Achieving CR at the induction end, MMR at 3 months, and haplo-transplant were also independent favorable factors of CIR, EFS, and OS in the nontransplant and haplo-HSCT arms. Haplo-HSCT showed a significant survival advantage in the high-risk group only. Hematologic response at the induction end and BCR-ABL levels at 3 months are likely to be useful for identifying pediatric Ph+ ALL patients at a high risk of relapse in the TKI era. Children with Ph+ ALL in first CR may benefit from allo-HSCT, particularly those at high risk. Haplo-HSCT could achieve good long-term survival for pediatric Ph+ ALL. Thus, haplo-HSCT can be an alternative approach for high-risk Ph+ ALL patients.