High-risk Acute Lymphoblastic Leukemia Patients Research Articles

Efficacy and safety in early application of Ruxolitinib for high-risk acute lymphoblastic leukemia to prevent GVHD and recurrence after allogeneic hematopoietic stem cell transplantation

BackgroundAllogeneic hematopoietic stem cell transplantation (allo-HSCT) has been identified as the potentially curative treatment for high-risk acute lymphoblastic leukemia (ALL) in adult patients. However, relapse of the disease and/or development of graft-versus-host disease (GVHD) remain to be the most common barriers for successful allo-HSCT. Preclinical studies showed that ruxolitinib, a Janus tyrosine kinase (Jak)1 and Jak2 inhibitor, has a selective anti-GVHD effects while preserving a potent graft-versus-leukemia (GVL) effect. Our study aimed to investigate the efficacy and safety in early application of ruxolitinib for the high-risk ALL patients to prevent GVHD. MethodsThere were eight patients undergoing allo-HSCT at the Bone Marrow Transplantation Center of the Third Xiangya Hospital of Central South University between April 2020 and April 2021. Ruxolitinib (5–10 mg twice daily) was administered early (median time: 45 days) after stem cell infusion. ResultsAfter a median follow-up of 14 months (range from 8 to 18 months), the ALL disease relapse occurred in two cases. Among all eight patients, two of them developed grade I/II acute (a) GVHD, while no patient developed grade III/IV aGVHD, and one patient developed chronic (c) GVHD. As for the virus activation, no patient developed EBV activation or EBV related lymphoproliferative disease, and three patients developed CMV activation. Our results suggest that the early application of ruxolitinib could safely and effectively prevent the occurrence of GVHD after allo-HSCT for the high-risk ALL patients. However, it may have a limited effect on preventing the recurrence of high-risk ALL and thus may require additional therapy with other anti-relapse drugs. ConclusionsOur preliminary observations suggest that an early application of ruxolitinib can safely and effectively prevent the occurrence of GVHD after allo-HSCT for the high-risk ALL patients. However, ruxolitinib may have a limited effect on preventing the ALL recurrence of high-risk patients.

Intensified conditioning regimens with total marrow irradiation/etoposide/cyclophosphamide and busulfan/etoposide/cyclophosphamide overcome the impact of pre-transplant minimal residual disease on outcomes in high-risk acute lymphoblastic leukemia patients in complete remission.

Among high-risk acute lymphoblastic leukemia (ALL) patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), those with positive minimal residual disease (MRD) are susceptible to poor outcomes. Therefore, it is necessary to determine the most suitable preparatory regimen for these patients. Data were analyzed from 141 patients who received allo-HSCT and were diagnosed with high-risk ALL. These patients underwent intensified conditioning regimens, including either total marrow and lymphoid irradiation (TMLI)-etoposide (VP16)-cyclophosphamide (CY) or busulfan (BU)-VP16-CY between October 2016 and November 2022. A total of 141 individuals were in complete remission (CR) before transplantation and, among all patients, 90 individuals exhibited a negative MRD status and 51 patients had a positive MRD status. In patients who tested negative for MRD, the incidence of relapse within a 2-year timeframe was 25.0% (24.8%-25.5%), compared with 32.2% (31.2%-33.2%) in MRD-positive patients; however, this difference was not statistically significant. There were no significant differences in the 2-year disease-free survival (DFS) and 2-year overall survival (OS) rates between the MRD-negative and MRD-positive groups (DFS: 67.2% (57.9%-78.1%) vs. 55.5% (42.6%-72.3%); OS: 69.0% (61.9%-88.2%) vs. 66.7% (53.9%-82.5%)). Furthermore, no notable variations were observed in the occurrence of transplant-related mortality (TRM) and graft-versus-host disease (GVHD) across the two groups. This study reveals the benefits of TMLI-VP16-CY and BU-VP16-CY conditioning regimens in high-risk ALL patients with CR and MRD-positive status. A large-scale prospective clinical trial is warranted in the future.

Venetoclax+Azacytidine Followed By Modified BuCy Conditioning Regimen for High Risk or Refractory/Relapsed Acute Lymphoblastic Leukemia and High Risk Myelodysplastic Syndromes

Background:Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only potential curable treatment for myelodysplastic syndromes (MDS) and acute lymphoblastic leukemia (ALL). However, for patients with high-risk or refractory relapsed (R/R) B-ALL with allo-HSCT, the three-year overall survival (OS) rate is only 5-10%, more worse in T-ALL. It is widely known that MDS patients in the high-risk group do not benefit from induction chemotherapy, the five-year OS rate is 23-39% when they received allo-HSCT. Nevertheless, relapse remains a significant cause of treatment failure after allo-HSCT, highlighting the urgent need for improved conditioning regimens that can improve prognosis and reduce relapse rates. Azacytidine (AZA) combined with Venetoclax (VEN), showed a synergistic anti-tumor activity against several hematological malignancies, Therefore, we explored AZA+VEN (VA) combined with modified BuCy(mBuCy) (semustine, cytarabine, busulfan, and cyclophosphamide) conditioning regimen and assessed the safety and effectiveness. Aims ：The aim of this study is to assess the safety, and effectiveness of the VA treatment regimen followed by mBuCy as conditioning regimen for high-risk or R/R ALL(NCT05809167) and high-risk MDS(NCT03256071) . Methods:Patients diagnosed with high-risk or R/R ALL or high-risk MDS (IPSS-R score), undergoing VA+mBuCy as conditioning regimen, and consolidation treatment with demethylating drugs every three months after transplantation, for a total of 8-12 cycles. Results:Patients diagnosed with high-risk or R/R ALL(n=11) or high-risk MDS (IPSS-R score)(n=8) were enrolled between January 13, 2022, and June 9, 2023. The ALL cohort comprised of 5 Ph-negative B-ALL, 2 Ph-positive B-ALL, 3 mixed phenotype leukemias (MPAL), and one T-lymphoblastic lymphoma/leukemia (T-ALL/LBL). There were 7 males and 4 females, with a median age of 33 years (17-54 years) (Table 1). Out of the eleven patients, four had previously undergone Chimeric Antigen Receptor T-Cell Immunotherapy (CAR-T) therapy, and one patient had received Blinatumomab. One patient experienced relapse, another patient was refractory, and 3 patients had extramedullary infiltration. All patients achieved morphological complete remission prior to transplantation, and 10 patients (90.9%) achieved a MRD negative remission. Additionally, all the transplantations successfully completed, with a median time to absolute neutrophil counts (ANC) recovery of 12 days (11-15 days) and platelet (PLT) recovery of 16 days (15-21 days). The median follow-up time was 6.4 months (2.4 -13.6 months), no patient experienced relapse or death, the OS and DFS are both 100%. There were no grade 3 or higher adverse events (AEs), hepatic veno-occlusive disease (VOD),and the transplant-related mortality (TRM). Four patients who developed acute graft-versus-host disease (aGVHD) post-transplantation, all cases involved grade I/II skin aGVHD, and one of them involved grade III GI aGVHD, and no chronic graft-versus-host disease (cGVHD) were observed during the follow-up period. By the endpoint of follow-up, Cytomegalovirus (CMV) activation was 45.4% (5/11) and Epstein-Barr virus (EBV) activation was 27.3% (3/11). The MDS cohort consisted of 7 cases of MDS-EB-I, 1 case of MDS-EB-II. There were 5 males and 3 females, with a median age of 42 years (23-57 years)(Table 2). Two patients received chemotherapy before transplantation, and the other six patients directly received allo-HSCT. In MDS cohort, the median recovery time for ANC was 12 days (11-13 days) and PLT was 17.5 days (16-20 days). The median follow-up was 14.3 months (1.2-18.3 months), no patient had relapsed or died, both OS and DFS are 100%. There were no grade 3 or higher AEs, and TRM. One patient developed VOD. Three patients developed aGVHD after transplantation, all involving degree I/II skin aGVHD, and there was one case of cGVHD during the follow-up period, where the patient developed a mild pulmonary cGVHD. By the endpoint of the follow-up, the rate of CMV activation was 37.5% (3/8) and EBV activation was 25% (2/8). Conclusion:The VA combined with the mBuCy proves to be a effective and safe conditioning regimen for high-risk ALL and MDS patients. However, more patients are needed for follow-up and validation.

Spectrum and clinical features of gene mutations in Chinese pediatric acute lymphoblastic leukemia

PurposeThe 5-year survival rate of children with acute lymphoblastic leukemia (ALL) is 85–90%, with a 10–15% rate of treatment failure. Next-generation sequencing (NGS) identified recurrent mutated genes in ALL that might alter the diagnosis, classification, prognostic stratification, treatment, and response to ALL. Few studies on gene mutations in Chinese pediatric ALL have been identified. Thus, an in-depth understanding of the biological characteristics of these patients is essential. The present study aimed to characterize the spectrum and clinical features of recurrent driver gene mutations in a single-center cohort of Chinese pediatric ALL.MethodsWe enrolled 219 patients with pediatric ALL in our single center. Targeted sequencing based on NGS was used to detect gene mutations in patients. The correlation was analyzed between gene mutation and clinical features, including patient characteristics, cytogenetics, genetic subtypes, risk stratification and treatment outcomes using χ2-square test or Fisher’s exact test for categorical variables.ResultsA total of 381 gene mutations were identified in 66 different genes in 152/219 patients. PIK3R1 mutation was more common in infants (P = 0.021). KRAS and FLT3 mutations were both more enriched in patients with hyperdiploidy (both P < 0.001). NRAS, PTPN11, FLT3, and KMT2D mutations were more common in patients who did not carry the fusion genes (all P < 0.050). PTEN mutation was significantly associated with high-risk ALL patients (P = 0.011), while NOTCH1 mutation was common in middle-risk ALL patients (P = 0.039). Patients with ETV6 or PHF6 mutations were less sensitive to steroid treatment (P = 0.033, P = 0.048, respectively).ConclusionThis study depicted the specific genomic landscape of Chinese pediatric ALL and revealed the relevance between mutational spectrum and clinical features of Chinese pediatric ALL, which highlights the need for molecular classification, risk stratification, and prognosis evaluation.

TBI-Based Myeloablative Conditioning Prior to Haploidentical Versus Matched Donor Transplantation for Acute Lymphoblastic Leukemia

Data from the CIMBTR has previously demonstrated the non-inferiority of transplantation from a haploidentical donor (HAPLO) using post-transplant cyclophosphamide (PTCy) vs. matched related (MRD) or unrelated donors (MUD) for acute lymphoblastic leukemia (ALL) (Wieduwilt et al. Blood Advances 2022). However, total body irradiation (TBI)-containing myeloablative conditioning (MAC) was used in less than 60% of MRD/MUD patients and in approximately 40% of HAPLO patients. We aimed to better define the role of donor type (HAPLO vs. MRD/MUD) following TBI-MAC-based allogenic transplant for ALL. To this end, we analyzed 105 consecutive ALL patients receiving a first allogeneic transplant at our institution following TBI-MAC from an MRD [30], MUD [24] or HAPLO [51] donor between Jan 2011 to Sept 2021. HAPLO patients received a preparative regimen of fludarabine (90mg/m2) and TBI 1200 cGy, followed by post-transplant cyclophosphamide (PTCy), tacrolimus and mycophenolate mofetil. MRD/MUD patients received TBI 1200 cGy with either Cy (120mg/kg, n= 33) or etoposide (60mg/kg, n=21), followed by tacrolimus and methotrexate for GVHD prophylaxis. Baseline characteristics include a median age of 40 (range, 29-51) years, HCT-CI ≥3 in 53%, poor risk cytogenetics in 60% (Ph+ [37%], Ph-like [11%], complex karyotype [7%] and 11q23 translocation [5%]). PBSC was the graft source in 94%. Pre-transplant status was CR1, CR2/3, or PIF/relapse in 75%, 12% and 13% respectively. Pre-transplant measurable residual disease (MRD) was seen in 28%). Baseline demographics of HAPLO and MRD/MUD recipients were similar with the exception of race/ethnicity, where HAPLO recipients (vs. MRD/MUD) were significantly less likely to be non-Hispanic White (29% vs. 67%). Comparison of baseline disease characteristics revealed more T-cell lineage disease (27% vs. 4%) and less poor risk cytogenetics (47% vs. 72%) in HAPLO vs. MRD/MUD recipients, respectively. After a median follow-up of 70 months (range, 8-134), 5-yr overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) for the whole cohort was 62%, 54%, 29% and 18% respectively, with no significant differences between HAPLO and MRD/MUD transplants (see figure). In multivariable analysis, controlling for other significant covariates (race, pre-transplant disease status and pre-transplant MRD), donor type (HAPLO vs. MRD/MUD) did not have a significant impact on OS (HR 1.04, p=0.91)) or DFS (HR 0.99, p=0.97)). TBI-MAC-based HAPLO represents a favorable alternative donor source with comparable long-term DFS and OS. This is of particular importance to patients of racial/ethnic minorities, whereby rapid and practically universal access to a HAPLO donor allows for curative-intent therapy in the vast majority of high-risk ALL patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Predictive Factors and Outcomes after Allogeneic Stem Cell Transplantation for Adults with Acute Lymphoblastic Leukemia in Brazil

Allogeneic stem cell transplantation (HSCT) remains a potentially curative approach for acute lymphoblastic leukemia (ALL), especially for high-risk patients and those with relapsed/refractory disease, although its efficacy is offset by a not-negligible toxicity. Adult patients with ALL fare worse in developing countries, with little data about the HSCT in this setting. In this study, we aimed to describe outcomes and examine risk factors for overall survival (OS), leukemia-free survival (LFS), cumulative incidence of relapse (CIR), nonrelapse mortality (NRM), and graft-versus-host disease (GVHD) after HSCT for ALL in Brazilian centers. This retrospective registry study included patients with ALL or ambiguous lineage leukemia age >16 years who underwent a first HSCT at 5 Brazilian centers between January 2007 and December 2017. A total of 275 patients were included, with a median age of 31 years (range, 16 to 65 years). Thirty-five percent were Philadelphia chromosome-positive. A matched sibling donor was used in 53%, a matched unrelated donor (MUD) in 19%, a mismatched unrelated donor in 9%, a haploidentical donor in 19%, and umbilical cord blood in 5%. The engraftment failure rate was 1.5%. The 5-year cumulative incidence of acute grade II-IV was 54.2%, and that of chronic GVHD was 26.2%. Five-year CIR and NRM were 28.1% and 34.1%, respectively. Central nervous system involvement at diagnosis (hazard ratio [HR], 2.2) and disease status (HR, 1.8 for second or later complete response and 7.9 for refractory) were associated with increased relapse incidence, whereas the use of peripheral blood graft (HR, .51) and a haploidentical donor (HR, .4) significantly decreased relapse incidence. Five-year OS and LFS were 40.7% (95% confidence interval [CI], 35.1-47.1) and 37.8% (95% CI, 32.3-44.1), respectively. Patient age, donor age, and disease status were independently associated with OS and LFS. Pre-HSCT positivity of minimal residual disease (>.01%) was associated with worse LFS (HR, 1.47) in available cases. This is the largest series of adults with ALL undergoing HSCT from Brazil reported to date. Although OS and LFS were similar to data reported in the literature, NRM was higher. Patient age and donor age outweighed donor type or graft source in our analysis. Interestingly, haploidentical HSCT was associated with lower CIR, whereas the use of MUDs was associated with higher NRM and GVHD rates. These results impact donor selection strategy in Brazil with the aim of offering timely HSCT for high-risk ALL patients in our setting.

Evaluation of Interleukin-6 Level Before Chemotherapy in Acute Lymphoblastic Leukemia L1 Standard-Risk and High-risk Patients

BACKGROUND: Acute lymphoblastic leukemia (ALL) is a malignancy originating from the clonal expansion of lymphoid progenitors that have undergone neoplastic transformation at various stages of differentiation. Interleukin-6 (IL-6) is a pleiotropic inflammatory cytokine produced by various cell types, including T-cells, macrophages, and stromal cells in response to tumor necrosis factor-alpha and interleukin-1. AIM: This study aims to evaluate serum levels of IL-6 before chemotherapy in standard-risk (SR) and high-risk (HR) ALL patients. METHODS: The research method was a cross-sectional study conducted on ALL patients who were treated at Dr. Wahidin Sudirohusodo hospital from April 2021 to June 2021. A total of 60 ALL patients were included in the study. Serum IL-6 specimens were examined before the patient received chemotherapy. RESULTS: The results showed that from 60 samples of ALL patients, 30 were SR and 30 were HR. Elevated levels of IL-6 before chemotherapy were found in both SR and HR ALL but were significantly higher in the HR group compared to the SR group with p value = 0.022. The cutoff point of 64.23 ng/mL for HRALL patients was obtained through ROC with a sensitivity of 63.3%, specificity of 63.3%, a positive predictive value of 63.3%, and a negative predictive value of 63.3%. Adjusted odds ratio are 2,983 with 95% confidence interval of 1.044–8.527. CONCLUSION: IL-6 levels among HR ALL were higher than SR. Elevated levels of IL-6 were found in both SR and HR ALL.

ESTRO ACROP and SIOPE recommendations for myeloablative Total Body Irradiation in children

Background and purposeMyeloablative Total Body Irradiation (TBI) is an important modality in conditioning for allogeneic hematopoietic stem cell transplantation (HSCT), especially in children with high-risk acute lymphoblastic leukemia (ALL). TBI practices are heterogeneous and institution-specific. Since TBI is associated with multiple late adverse effects, recommendations may help to standardize practices and improve the outcome versus toxicity ratio for children. Material and methodsThe European Society for Paediatric Oncology (SIOPE) Radiotherapy TBI Working Group together with ESTRO experts conducted a literature search and evaluation regarding myeloablative TBI techniques and toxicities in children. Findings were discussed in bimonthly virtual meetings and consensus recommendations were established. ResultsMyeloablative TBI in HSCT conditioning is mostly performed for high-risk ALL patients or patients with recurring hematologic malignancies. TBI is discouraged in children <3–4 years old because of increased toxicity risk. Publications regarding TBI are mostly retrospective studies with level III–IV evidence. Preferential TBI dose in children is 12–14.4 Gy in 1.6–2 Gy fractions b.i.d. Dose reduction should be considered for the lungs to <8 Gy, for the kidneys to ≤10 Gy, and for the lenses to <12 Gy, for dose rates ≥6 cGy/min. Highly conformal techniques i.e. TomoTherapy and VMAT TBI or Total Marrow (and/or Lymphoid) Irradiation as implemented in several centers, improve dose homogeneity and organ sparing, and should be evaluated in studies. ConclusionsThese ESTRO ACROP SIOPE recommendations provide expert consensus for conventional and highly conformal myeloablative TBI in children, as well as a supporting literature overview of TBI techniques and toxicities.

Blinatumomab maintenance after allogeneic hematopoietic cell transplantation for B-lineage acute lymphoblastic leukemia

Patients with B-lineage acute lymphoblastic leukemia (ALL) are at high-risk for relapse after allogeneic hematopoietic cell transplantation (HCT). We conducted a single-center phase 2 study evaluating the feasibility of 4 cycles of blinatumomab administered every 3 months during the first year after HCT in an effort to mitigate relapse in high-risk ALL patients. Twenty-one of 23 enrolled patients received at least 1 cycle of blinatumomab and were included in the analysis. The median time from HCT to the first cycle of blinatumomab was 78 days (range, 44 to 105). Twelve patients (57%) completed all 4 treatment cycles. Neutropenia was the only grade 4 adverse event (19%). Rates of cytokine release (5% G1) and neurotoxicity (5% G2) were minimal. The cumulative incidence of acute graft-versus-host disease (GVHD) grades 2 to 4 and 3 to 4 were 33% and 5%, respectively; 2 cases of mild (10%) and 1 case of moderate (5%) chronic GVHD were noted. With a median follow-up of 14.3 months, the 1-year overall survival (OS), progression-free survival (PFS), and nonrelapse mortality (NRM) rates were 85%, 71%, and 0%, respectively. In a matched analysis with a contemporary cohort of 57 patients, we found no significant difference between groups regarding blinatumomab's efficacy. Correlative studies of baseline and posttreatment samples identified patients with specific T-cell profiles as “responders” or “nonresponders” to therapy. Responders had higher proportions of effector memory CD8 T-cell subsets. Nonresponders were T-cell deficient and expressed more inhibitory checkpoint molecules, including T-cell immunoglobulin and mucin domain 3 (TIM3). We found that blinatumomab postallogeneic HCT is feasible, and its benefit is dependent on the immune milieu at time of treatment. This paper is posted on ClinicalTrials.gov, study ID: NCT02807883.

Predictive Factors and Outcomes after Allogeneic Stem-Cell Transplantation for Adults with Acute Lymphoblastic Leukemia in Brazil

Introduction: Allogeneic stem-cell transplantation (HSCT) remains a potentially curative approach for acute lymphoblastic leukemia (ALL), especially for high-risk patients and those with relapsed/refractory disease, although its efficacy is offset by a not negligible toxicity. Adult patients with ALL fare worse in developing countries with low data about the HSCT in this setting. In this study, we aim to describe outcomes and examine risk factors for overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse (CIR), non-relapse mortality (NRM) and graft-versus-host disease (GVHD) after HSCT for ALL in Brazilian centers.Methods: This is a retrospective registry study. Patients with ALL or ambiguous lineage leukemia above 16 years who underwent a first HSCT in 5 Brazilian centers between January 2007 and December 2017 were included. Kaplan-Meier method and competing risk analysis were used. Multivariable analysis (MVA) was performed using Cox regression and the Akaike's information criteria was used for model selection. Cut-offs for continuous variables were calculated through “findcut” R function. Center effect was evaluated by using frailty model.Results: Overall, 275 patients were included with a median age of 31y (range, 16-65). Philadelphia chromosome was found in 35%. Baseline characteristics are summarized in Table 1. Matched sibling donor (MSD), matched unrelated donor (MUD), mismatched unrelated donor (MMUD), haploidentical donor and umbilical cord were reported in 53%, 19%, 9%, 19%, and 5%, respectively. Total body irradiation (TBI) was used in 67% of myeloablative HSCT. Median time to HSCT in CR1 was 7.8 months. Engraftment failure rate was 1.5%. Median follow-up time was 6.4 y. Cumulative incidence of acute grade II-IV and chronic GVHD were 54.2% and 26.2%, respectively. In MVA, the use of MUD (HR=2.3) and increased donor age (HR=1.02) were associated with GVHD. Five-year CIR was 28.1% (95% CI 22.9-33.6) and 5-y NRM was 34.1% (95% CI 28.4-39.8). At D+100, NRM incidence was 22.6%. Central nervous system involvement at the diagnosis (HR=2.2), and disease status (HR 1.8 for CR2+, and HR 7.9 for refractory) increased relapse incidence, whereas the use of peripheral blood graft (HR=0.51) and haploidentical donor (HR=0.4) significantly decreased relapse incidence. In MVA, NRM was increased by patient's age (HR=1.04), refractory status (HR=4.2), MUD (HR=3.8) and donor age (HR=1.02). Center effect was significantly associated with relapse and NRM. Five-year OS and DFS were 40.7% (95% CI 35.1-47.1) and 37.8% (95% CI-32.3-44.1), respectively (Figure 1). Patient's age, donor age and disease status were independently associated with OS and DFS (Table 2). When GVHD (as a time-dependent variable) was introduced in the MVA for OS and DFS, it was associated with decreased OS (HR 4.2, p<0.001) but not with DFS. Pre-HSCT positivity of minimal residual disease (>0.01%) was associated with worse DFS in univariate analysis (HR=1.47) in available cases.Conclusions: This is the largest series of ALL adults receiving HSCT from Brazil. While OS and DFS were similar to published data, NRM was higher. Patient's age and donor age outweighed donor type or graft source in our analysis. Interestingly, haploidentical HSCT related to lower CIR, whereas the use of MUD was associated with higher NRM and GVHD rates. These results impact on donor selection strategy in our country, aiming to timely offer HSCT for high-risk ALL patients in our setting. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Donor-Derived Adoptive T-Cell Therapy Targeting Multiple Tumor Associated Antigens to Prevent Post-Transplant Relapse in Patients with ALL

Donor-Derived Adoptive T-Cell Therapy Targeting Multiple Tumor Associated Antigens to Prevent Post-Transplant Relapse in Patients with ALL

Impact of Donor Type on Long-Term Outcomes of Hematopoietic Cell Transplantation for Adult Acute Lymphoblastic Leukemia during First Remission

Background: Standard therapy for adult patients with high-risk acute lymphoblastic leukemia (ALL) consists of hematopoietic cell transplantation (HCT) including autologous-HCT (AUTO) and allogeneic-HCT from a matched-sibling donor (MSD) or matched unrelated donor (MUD). When a conventional donor is not available, HCT from a partially-mismatched unrelated donor (MMUD), cord blood transplantation (CBT) or a familial haploidentical donor (HID) is considered.Aim: Although HCT outcomes of those alternative strategies are advancing with optimization of pre-conditioning regimens with immunosuppressive agents, there are still subjects to debate. We tried to analyze the long-term HCT outcomes according to the donor types including MMUD, double CBT (DCBT) and AUTO as an alternative choice compared to the conventional donors.Methods: We enrolled 661 adult ALL patients who underwent transplantation from 1995 to 2015 in their first remission (CR1). Patients with acute undifferentiated leukemia (AUL, n=5) and mixed phenotype acute leukemia (MPAL, n=52) in the same department were also enrolled and median age was 33 years old (range, 15-65). Before 2010, our treatment strategy for ALL patients in CR1 was to offer allogeneic or autologous HCT according to the donor availability and the presence of high-risk features. After 2010, DCBT was mainly used for patients who were not available with conventional donors. For myeloablative regimen, we administered cyclophosphamide (120 mg/kg) combined with TBI (1320 cGy), and reduced intensity regimen was applied for elderly or patients with comorbid conditions which consisted of fludarabine (150 mg/m2 in total) and melphalan (140 mg/m2 in total). Conditioning regimen for AUTO was TBI (1200 cGy), ARA-C (9g/m2 in total) and melphalan (100mg/m2 in total), and fludarabine (150mg/m2 in total) was used for DCBT instead of melphalan. Graft-versus-host disease (GVHD) prophylaxis was attempted by administering calcineurin inhibitors (cyclosporine for MSD, tacrolimus for others) plus methotrexate or mycophnolate mofetil (for DCBT). Antithymocyte globulin (ATG) was administered to the patients who received grafts from MMUD.Results: Engraftment was successful in all donor types, but neutrophil and platelet recovery was significantly delayed only after DCBT (median recovery for neutrophil and platelet was 25 and 33.5 days respectively). After median follow-up of 80.4 months (range, 6.5-259.1), 7-year OS for the entire 661 patients was 57.0%. In detail, 7-year OS for MSD, MUD, MMUD, DCBT, and AUTO was 56.9%, 56.8%, 62.6%, 65.1% and 48.6% (p=0.423). MSD, MUD and MMUD showed similar relapse rate (27.5%) and non-relapse mortality (NRM) rate (20.6%), but DCBT showed significantly higher NRM rate (29.6%) and AUTO showed significantly higher relapse rate (41.6%). In contrast, DCBT showed lower relapse rate (7.2%) and AUTO showed lower NRM rate (9.7%). Interestingly, 7-year GVHD and relapse-free survival (GRFS) for MSD, MUD, MMUD, and DCBT was 34.1%, 15.0%, 40.9%, and 50.3%, respectively, which was related with higher incidence of severe chronic GVHD in MUD (27.6%) and MSD (14.1%) compared to DCBT (4.2%, p < 0.001). In high-risk subgroup (n=517) including 233 Philadelphia chromosome (Ph)-positive ALL, 7-year OS for MSD, MUD, MMUD, DCBT, and AUTO was 54.9%, 58.1%, 57.8%, 60.7%, and 33.3%, respectively. But the 7-year GRFS for MSD, MUD, MMUD, and DCBT was 30.7%, 14.5%, 35.3%, and 47.7%, respectively, which revealed lower relapse rate (8.7%) and low severe chronic GVHD (2.6%) of DCBT. Multivariate analysis showed that old age and AUTO was related with poor OS in high-risk ALL patients group, and old age and poor-risk karyotype and MUD transplant without ATG were related with poor GRFS.Conclusion: Our data showed similar transplant outcomes of alternative donors such as DCBT and ATG-applied MMUD compared to conventional donor transplants in ALL patients in CR1. In addition, GRFS was rather superior in patients treated with DCBT. Our long-term transplantation outcome results revealed that DCBT might be a good alternative choice for patients who are not available with conventional allogeneic donors, and AUTO may be considered for selected standard-risk patients with low NRM rate without a risk of GVHD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Implications of ACMG guidelines to identify high-risk acute lymphoblastic leukemia patients with hereditary cancer susceptibility syndromes (HCSS) in a highly consanguineous population

BackgroundHereditary cancer susceptibility syndrome (HCSS) contributes to the cancer predisposition at an early age, therefore, identification of HCSS has found to be crucial for surveillance, managing therapeutic interventions and refer the patients and their families for genetic counselling. The study aimed to identify ALL patients who meet the American College of Medical Genetics (ACMG) criteria and refer them for the genetic testing for HCSS as hereditary leukemia and hematologic malignancy syndrome, and to elucidate the significance of high consanguinity with the prevalence of inherited leukemia in Pakistani population.MethodsA total of 300 acute lymphoblastic leukemia patients were recruited from the Children’s Hospital, Lahore, Pakistan from December 2018 to September 2019. A structured self-reporting questionnaire based on family and medical history of the disease was utilized for the data collection.ResultsIn our cohort, 60.40% of ALL patients were identified to meet ACMG criteria. Among them, a large number of patients (40.65%) solely fulfil the criteria due to the presence of parental consanguinity. However, parental consanguinity showed protective impact on the onset at early age of disease [OD = 0.44 (0.25–0.77), p-value = 0.00] while, a family history of cancer increased the risk of cardiotoxicity [OD = 2.46 (1.15–5.24), p-value = 0.02]. Parental consanguinity shows no significant impact on the family history of cancer and the number of relatives with cancer.ConclusionsMore than 50% of the ALL patients were considered the strong candidates’ for genetic testing of HCSS in the Pakistani population, and parental consanguinity was the leading criteria fulfilled by the individuals when assessed through ACMG guidelines. Our study suggests revisiting ACMG guidelines, especially for the criterion of parental consanguinity, and formulating the score based criteria based on; genetic research, the toxicology profile, physical features, personal and family history of cancer for the identification of patients for the genetic testing.

Comparing the outcomes between TMLI and non-TMLI conditioning regimens for adult high-risk acute lymphoblastic leukemia patients undergoing allogeneic hematopoietic stem cell transplantation: a single-center experience

This study aimed to retrospectively evaluate the outcomes of adult patients with high-risk acute lymphoblastic leukemia (ALL) who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) with either total marrow and lymphoid irradiation (TMLI)-containing or non-TMLI conditioning regimen. Seventy adult patients with high-risk ALL who received allo-HSCT were enrolled in this study and divided into two groups based on the conditioning regimen type (TMLI group: n = 29 and non-TMLI group: n = 41). We noted significant statistical differences in the 1-year estimated cumulative incidence of relapse (25% vs. 46.5%, p = 0.018), the 1-year estimated overall survival (73.1% vs. 52.6%, p = 0.033) and disease-free survival (65.2% vs. 48.2%, p = 0.026) but found no considerable difference in transplant-related mortality (12% vs. 13.4%, p = 0.619) between patients in the TMLI and non-TMLI groups. The TMLI-containing regimen is safe and alternative for patients with high-risk ALL undergoing allo-HSCT.

Clinical impact of early minimal residual disease detection at day 15 in precursor B-childhood acute lymphoblastic leukemia: an Egyptian experience

BackgroundChromosomal abnormalities in childhood acute lymphoblastic leukemia (ALL) are well-established prognostic markers and useful tools for minimal residual disease (MRD) assessment. This study aimed to stratify high-risk precursor B-childhood ALL (pre-B-ALL) patients according to standard prognostic factors (age and total leucocytic count), fluorescence in situ hybridization (FISH) analysis for these cytogenetic abnormalities [t (9;22) BCR/ABL, t(1;19)TCF3/PBX1, and 11q23 MLL gene rearrangement], and MRD status at day 15. Besides, we aimed to demonstrate the relation of these prognostic factors (standard and cytogenetic risk groups) to patients’ outcome at day 15 of induction therapy as well as exploring the impact of early MRD assessment during remission induction compared to other prognostic factors together with the ability to tailor investigations as needed especially in places with limited health resources without compromising the outcome. Seventy-two newly-diagnosed Egyptian children with pre-B-ALL, aged 6 months to 15.5 years, registered from February 2016 to February 2018 were included. They were treated according to the modified Children’s Oncology Group (COG) protocol. Patients were classified into (a) standard and high-risk groups according to standard prognostic factors. (b) Patients with the studied cytogenetic abnormalities and patients without the studied cytogenetic abnormalities. (c) Good outcome (negative MRD) and bad outcome (positive MRD) groups according to day 15 MRD status.ResultsThe studied cytogenetic abnormalities were identified in 22.2% of patients, all of them were in the high-risk group, and 75% of them had a bad outcome (positive MRD) at day 15 of induction therapy.ConclusionPatients with favorable presenting features (standard risk) and undetectable MRD after 2 weeks remission induction therapy would not be in need to advanced molecular studies, while these studies should be considered for patients with high-risk presenting features and high levels of MRD after 2 weeks remission induction therapy. Therefore, this could provide a cost-effective guideline in countries suffering from financial challenges without affecting the outcome

Improved Treatment of Childhood ALL in Malaysia

The survival rate of childhood acute lymphoblastic leukemia (ALL) has reached &gt;80-90% in developed countries, which is a triumph of modern medicine. This success is due to implementation of contemporary treatment protocols, optimal application of risk stratification, risk-directed multi-agent chemotherapy regimens, and improved supportive care. Unfortunately, such improvements have not translated to Low Middle Income Countries (LMICs), where 90% of the world's children live. The estimated 5 year survival rates in Asia range widely between 44.3% and 80%. The Intercontinental-BFM2002 study, conducted in 15 upper-middle and high-income countries reported a 5 year event-free survival (EFS) and overall survival (OS) rates of 74% and 82%, respectively. Factors that may contribute to the lower survival in LMICs are highly complex, including delays in presentation, diagnostic inaccuracy, restricted budget for risk-stratification and appropriate treatment, treatment abandonment and socio economic status. In Malaysia, different protocols are used by different leukemia treatment centers for treating children with ALL. In UKM Medical Centre (UKMMC), the UKALL protocols (modified UK X, XI, XII, 97(99) and 2003) have been used in the Pediatric Hemato-Oncology Unit since the 1990s. Herein, we report the adopted protocol, the stratification profile and outcome of children with ALL, treated with modified UKALL 97(99) and UKALL 2003 in our institution from 2006 to 2014. Clinical data from children with ALL, who received these modified therapies, were retrospectively reviewed. Prednisolone was used in modified UKALL97(99) and Dexamethasone in modified UKALL 2003, while 6-mercaptopurine was used in both modified protocols. Otherwise, chemotherapy and duration of treatment were identical to the original protocols of Regimens A, B and C. ALL was diagnosed based on standard morphology and immunophenotyping criteria. At diagnosis, patients were stratified according to the National Cancer Institute (NCI) risk criteria and using FISH for detection of cytogenetic abnormalities. EFS and OS were determined using the Kaplan-Meier methods. Newly diagnosed ALL in 156 children were included in the study; 103 (66.0%) were standard risk, 49 (31.4%) were high risk and 4 (2.5%) were infants. There were 2 children with Down syndrome. The success rate of FISH was 76.4% (94/123). Patients were stratified as standard risk, based on ETV6-RUNX1, and high risk based on unfavorable cytogenetics, BCR-ABL and MLL rearrangements. Half of the patients with unfavorable cytogenetics were classified in the NCI high risk group, with WCC &gt;100x109/L. A total of 151 patients were treated as per risk stratification, 2 patients transferred care, while 3 patients refused treatment. Mortality from sepsis during treatment was approximately 10%, including 2 deaths during induction remission and induction at relapse. The majority of disease progression was relapse-related, however, treatment abandonment also contributed to relapse. Approximately 5% of patients abandoned their treatment (3 patients abandoned and 3 patients refused treatment). The 5-year OS for the standard risk group was 86.6%, with 3-year and 5-year EFS of 88.1% and 83.4%, respectively. The 5-year OS for the high risk group was 65.7%, while 3-year and 5-year EFS were 64.7% and 58.2%, respectively (Figure 1). The MRC UKALL97 stratification by NCI risk reported a 5-year EFS of 83.1% for the standard risk group and 66.9% for the high risk group, while the UKALL2003 interim analysis reported a 5-year EFS of 87.7%. The MRC UKALL97/99 reported a 5-year OS of 88%. The cure rate of children with standard risk ALL at UKMMC, using modified UKALL 97(99) and UKALL 2003 protocols, was comparable to MRC UKALL97. However, the cure rate for high risk ALL was comparatively lower. This single center study from UKMMC has highlighted some critical factors that improved the outcome of children with ALL and suggests further improvements that are necessary to reduce the relapse rate, especially in the high risk ALL patients. Disclosures No relevant conflicts of interest to declare.

Germline Gene Aberrations Are Common in High-Risk Adult and Pediatric Acute Lymphoblastic Leukemia Patients

Personalized medicine involves a comprehensive analysis of factors affecting a disease. Family history is an important but not a definitive indicator of inherited predisposition to malignancy and thus studying the germline gene aberrations alongside somatic variants is warranted. The significance of germline predisposition has been increasingly recognized in acute myeloid leukemia and is noted in the latest WHO classification.1,2,3Despite the recent progress in acute lymphoblastic leukemia (ALL) therapies, many adult patients with ALL still do poorly and there is a need for new biomarkers and therapy targets. The aim of our study was to identify and determine the frequency of germline mutations in known ALL genes, to discover new genes associated with ALL predisposition, and to compare the germline genetic background and respective consequences of pediatric and adult high-risk ALL. We examined exome sequencing data from biobanked samples of adult (50) and pediatric (68) patients with high-risk ALL (Finnish Hematological Registry and Biobank - FHRB, and clinical repositories). First, a candidate-gene analysis consisted of 92 genes previously associated with germline predisposition to ALL or syndromes predisposing to ALL. Variants with minor allele frequency of &amp;lt;0.01 in the Genome Aggregation Database were considered. Missense variants were considered significant if ≥2/3 algorithms (CADD, DANN, Revel) classified it as pathogenic. We also reviewed literature, public databases and the American College of Medical Genetics classification (ACMG) in filtering the variants. Clinical characteristics of the patients were retrieved from hospital records and the Finnish Hematological Registry. Second, an unbiased approach was applied to find novel genes predisposing to ALL by checking pathogenic variants in the same gene in at least two (adult/pediatric) patients and filtering by gene ontologies DNA repair, cell cycle, and lymphocyte differentiation; and by COSMIC cancer census genes. In both analyses, only statistically significantly more common variants in our series compared to normal population were included. We also conducted a mutational signature analysis on the samples. Our analysis (Table 1) demonstrates that 8% of adult and 10% pediatric study patients carried a pathogenic or likely pathogenic mutation in their germline in known ALL predisposing genes. All these mutations were at least 30-fold more frequent in our study series compared with allele frequencies in the normal population (p&amp;lt;0.05). Four pediatric patients were identified to suffer from undiagnosed syndromes, which predispose to ALL (Li-Fraumeni and Noonan syndromes). We also found recurring aberrations in new genes with biological relevance to ALL, such as MUTYH and IL21R, potentially associating with ALL predisposition. Final results of the mutational signature analyses are pending. In conclusion, our results emphasize that germline predisposition is not rare among high-risk ALL patients. In addition to pediatric ALL patients, we show contributing germline variants also in adult patients. At least 20% of the adult ALL patients are transplanted and a potential germline basis of the disease should be considered when choosing the donor. Our analysis also reveals new information on the biology of high-risk ALL and may contribute to the future studies seeking for therapy options in this challenging patient category. Despite the anxiety that acknowledging inheritable factors may cause in patients, families, and caretakers, we encourage clinicians to integrate carefully interpreted germline data into patient care.

Blinatumomab Is Well Tolerated Maintenance Therapy Following Allogeneic Hematopoietic Cell Transplantation for Acute Lymphoblastic Leukemia

Background: Patients with high-risk or multiply relapsed B-lineage acute lymphoblastic leukemia (ALL) have a very high rate of relapse, even after allogeneic hematopoietic cell transplantation (HCT). In an effort to reduce the risk for relapse, we investigated the role of blinatumomab (Blin), a bi-specific T cell immunotherapy targeting CD19, as maintenance therapy following allogeneic HCT for adult patients with advanced B ALL. We rationalized that this is an ideal agent with little cytotoxicity, and the potential to provide immune protection against disease relapse during the first year post HCT when graft versus leukemia (GVL) is still maturing. Methods: Adult patients with B-ALL deemed high risk for relapse defined as disease stage beyond CR1, any active disease including MRD, or presence of high risk molecular mutations or karyotype at time of HCT, or patients with evidence of MRD immediately following HCT, were eligible for study enrollment; prior Blin treatment was allowed. Patients with active disease defined as &gt;5% malignant blasts or active GVHD requiring steroid therapy post HCT were excluded. Patients were scheduled to receive 4 cycles of Blin as a continuous intravenous infusion at the dose of 28 microgram/24 hours over 4 weeks, with the first cycle to be administered within the first 3 months post HCT after count recovery; the subsequent cycles were administered at 6, 9, and 12 months following HCT (day of hematopoietic progenitor cell infusion). Dose escalation for cycle 1 and hospitalization for observation during cycles 1 and 2 followed standard FDA issued guidelines. Results: 14 patients enrolled to date with 12 patients treated with median age 30 years (range, 21-65 years); two patients did not proceed with treatment due to graft versus host disease (GVHD). Patient characteristics and outcomes are listed in Table 1. The median days to start of therapy post HCT was 84 (range, 38-105 days). The treatment was well tolerated with no reported cytokine release syndrome, GVHD, graft failure, or grade 5 adverse events (AE). A cumulative 26 cycles of Blin were administered with 7 Blin-related grade 3 or 4 AEs reported (leukopenia n=4, transaminitis n=2, rash n=1). Grade 2 neurotoxicity manifesting as confusion and dysphagia requiring temporary suspension of therapy and short course steroids noted in 1 patient. Median follow up was 8.5 months post HCT (range 2-35 months). All 4 patients who were MRD positive prior to start of Blin have progressed and 2 have died. None of the 8 patients who were MRD negative post transplant has relapsed. We performed multiparametric flow cytometry studies on serial peripheral blood patient samples collected prospectively at multiple time points to measure T cell subsets, T-cell function and cell surface expression of various checkpoint inhibitors including PD1, TIGIT, Tim3, 2B4 and CD160. Samples were studied on an X-20 Fortessa, and the data analyzed using Kaluza software. Interestingly, the 4 patients who progressed on Blin maintenance had lower CD8 to CD4 ratio compared to non-progressors (17:60 vs. 46:42) (Figure 1). Furthermore, compared to healthy controls, we observed higher levels of checkpoint molecules as multiple checkpoints per cell. PD1 and TIGIT upregulation and co-expression were more common in progressing patients compared to non-progressors (Figure 2). Conclusion: We observed that Blin maintenance following allogeneic HCT for B ALL is well tolerated. More patients need to be treated to confirm the efficacy of this approach. This approach is encouraging for high risk ALL patients who are MRD negative post transplant. Strategies to increase CD8 levels and blockade against checkpoint inhibitors may overcome resistance to therapy. Disclosures Kebriaei: Amgen: Research Funding; Jazz: Consultancy; Pfizer: Honoraria; Kite: Honoraria. Ravandi:Xencor: Consultancy, Research Funding; Selvita: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding. Jabbour:Adaptive: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding. Kantarjian:AbbVie: Honoraria, Research Funding; Novartis: Research Funding; Jazz Pharma: Research Funding; Agios: Honoraria, Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Astex: Research Funding; Ariad: Research Funding. Champlin:Sanofi-Genzyme: Research Funding; Johnson and Johnson: Consultancy; Actinium: Consultancy.

Demographics and Outcome of Philadelphia-positive ALL in a Pediatric Population in North India: a Single-center Experience.

Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) in children had a worse outcome before the use of tyrosine kinase inhibitors. We have evaluated the demographics and outcome of Ph+ ALL patients treated with imatinib without blood marrow transplantation. Of the 206 children with ALL registered for treatment, the demographic data of 15 Ph+ ALL patients were compared with the remaining Ph- patients. Imatinib (340 mg/m) was started on day 5 (D5) of induction in Ph+ patients, and their overall survival was compared with Ph- high-risk patients treated on similar protocols. Statistical analysis was carried out by the Fisher exact test and the t test. The Kaplan-Meier test was used for survival analysis. Philadelphia positivity noted in 15/206 (7.28%) ALL patients was higher than reported earlier. Median initial total leukocyte count and central nervous system positivity were significantly higher in Ph+ patients. Myeloid markers, CD13 and CD33, were also positive in 33.3% Ph+ patients. D15 and D35 marrow showed remissions in a larger proportion of Ph+ ALL, as compared with Ph- patients, but chemotherapy interruptions and neutropenic deaths were significantly higher after starting imatinib, as compared with Philadelphia high-risk patients. Overall survival was similar in Ph+ and Ph- high-risk ALL patients. Ph+ ALL, noted in 7.28%, presented with high initial white blood cell counts, high central nervous system positivity, poor steroid response, and higher induction deaths, as compared with high-risk Ph- ALL, and raised the question about the appropriate dose and time of introduction of imatinib to prevent toxicity.

Improved Outcome of a Pediatric-Inspired Protocol for High-Risk Adolescent and Young Adult Acute Lymphoblastic Leukemia Patients Using Peg-Asparaginase and Escalating Dose of Methotrexate: Tolerability and Outcome

BackgroundTreatment of acute lymphoblastic leukemia (ALL) in adolescent and young adult (AYA) patients using traditional adult chemotherapy protocols give low overall survival (OS) rates. Data are growing regarding the use of pediatric-inspired chemotherapy protocols in AYA patients with improvement in OS. Patients and MethodsTo assess efficacy and tolerability of using a pediatric-inspired protocol in AYA patients, we initiated our local prospective trial using a modified version of the Children’s Cancer Group 1900 protocol for newly diagnosed high-risk Philadelphia chromosome-negative ALL patients. ResultsA total of 40 patients were enrolled in the study (from 2015 to 2018). The median age was 18 years (range, 14-34 years). The complete remission rate after induction was 37 patients [93%] and after a median follow-up of 5 years, OS, disease-free survival (DFS), and event-free survival were 75%, 72%, and 60%, respectively. Use of this protocol was well tolerated with manageable toxicities. Pegylated asparaginase was given to all patients during the induction phase and was well tolerated. ConclusionThe use of a pediatric-inspired protocol for high-risk AYA ALL patients was effective and well tolerated with improvement in OS and DFS compared with historical data using adult protocols in such populations.