Acute leukaemias are the commonest cancers in children and young people (CYP). Off-treatment surveillance is assumed to improve relapse detection, but whether this affects subsequent survival and quality of life is unclear. This systematic review searched 13 databases and two trial registries in December 2022. Studies after 1990 investigating post-treatment surveillance in CYP ≤17 years old with acute leukaemias were included. Extracted outcomes included overall and event-free survivals, surveillance programme performance and cost-effectiveness. Screening, data extraction and quality assessment (using the Quality in Prognostic Studies tool) were conducted in duplicate. Data were narratively synthesised. Of 7899 records screened, 64 studies were included, of which 30 evaluated post-chemotherapy surveillance. 5672 CYP (5181 ALL, 491 AML) were included. 747 CYP experienced 800 relapses. Poor reporting hindered data extraction and quality assessment. Symptom-detected relapses were most common. Surveillance did not impact survival outcomes. Two studies demonstrated the high costs of surveillance programmes. No study reported on the experience or burdens of surveillance. The currently available evidence suggests that there is little support for the role of surveillance in detecting relapse in CYP with acute leukaemia. Prospective, longitudinal, randomised studies focused on key outcomes and high-quality reporting are needed. PROSPERO: CRD42023389281.

AbstractThe outcome for children with acute myeloid leukaemia (AML) continues to improve although not at the pace of acute lymphoblastic leukaemia (ALL). The current 3-year EFS and OS are 65–70% and 75–80%, respectively. The improved survival is attributed to better supportive care, refinement in risk stratification (particularly directing patients to allogeneic HCT in CR1), and improved salvage in relapsed/refractory AML (R/R AML). The enhanced understanding of the genomic landscape of paediatric AML has lead to the strategic use of novel treatments. The future of AML treatment lies in optimising the therapeutic potential of new treatments, including CAR T-cells, in combination with conventional chemotherapy and allogeneic HCT.

Introduction Adding one dose of 3mg/m2 of Gemtuzumab ozogamicin (GO), an anti CD33 antibody drug conjugate, showed an event-free survival (EFS) benefit in children with acute myeloid leukaemia (AML) in the AAML0531 trial (Gamis et al, JCO, 2014) whilst the adult ALFA-0701 trial reported a survival benefit of 3 fractionated doses with standard induction (Castaigne et al, Lancet, 2012). MyeChild 01, an international trial (UK, France, Australia, New Zealand, Ireland, Switzerland) for paediatric AML, high risk myelodysplastic syndrome (MDS > 10% blasts) or isolated myeloid sarcoma (IMS), embedded a GO dose finding study which established the safety of combining up to 3 doses of 3mg/m2 with intensive induction chemotherapy. 515 patients were randomised to 1 vs 3 doses of GO during course 1 (given on day 4 or days 4, 7, and 10 respectively), from Jan-2019 to Jun-2022. Due to regulatory commitments comparative results by randomisation are not available at the time of writing, but these data will be presented at the ASH annual meeting. Overall results are presented here. Methods Randomisation of GO doses was stratified by age; diagnosis (AML, MDS, IMS); disease type (de novo, secondary); white cell count (WCC) (<100, ≥100x109/L). Statistical analyses are by intention to treat with a primary outcome of EFS. All patients were allocated mitoxantrone and cytarabine (MA) with GO in course 1 and thereafter stratified by cyto/molecular genetics, remission status after course 1 and measurable residual disease (MRD). Patients with resistant disease post course 1 or poor risk (PR) cyto/molecular genetics were stratified high risk (HR) and received fludarabine, cytarabine and idarubicin (FLA-Ida) for course 2; all other patients received a second course of MA. Data is available on 472 patients; 142 received FLA-Ida and 330 MA. HR patients proceeded to allogeneic stem cell transplantation (HSCT). Non-HR patients were subsequently allocated treatment based on their cyto/molecular genetics and MRD response. Results Patient characteristics were: males 55%; median age 10yr; median WCC 14 x109/L; AML 96%, MDS 2.5%, isolated MS 1.9%; de novo 98%; CNS2 16%, CNS3 9%; non CNS extramedullary disease 16%. Of 515 patients randomised to 1 vs 3 doses, all but 16 received GO (6 ineligible, 5 prior toxicity, 5 other). 179 patients (35%) had a confirmed HSCT. Median follow-up is 3 years. The overall 2 yr EFS is 70% (95% CI: 66-74%) and overall survival (OS) 88% (85-91%). 94% achieved complete remission (CR) or CR with incomplete count recovery (CRi) post course 1 or 2; 6% failed to achieve CR/CRi (resistant disease 2.5%, non-evaluable 1%, unknown response 2.3%). 127 of 485 patients who achieved CR/CRi have relapsed giving a 2 yr cumulative incidence of relapse (CIR) of 25% (21-29%). Overall, there were 79 deaths but only 11 (2%) in first remission. 63 deaths were disease-related, 12 transplant-related, 3 off-trial treatment related and 1 other non-cancer. A cyto/molecular risk group was available for 485 patients: 192 GR (40%), 162 IR (33%) and 131 PR (27%). GR patients had a CR/CRi of 100%, 2 yr EFS 81% (76-87%), CIR 18% (13-24%) and OS 96% (93-99%); IR patients had a CR/CRi of 97.5%, 2 yr EFS 64% (57-72%), CIR 33% (26-41%) and OS 87% (82-93%); PR patients had a CR/CRi of 93.9%, 2 yr EFS 68%(61-77%), CIR 24%(16-32%) and OS 78% (71- 85%). Time to count recovery was defined as time from day 1 of a course to date of neutrophils >0.75 x109/L and platelets >75 x 109/L. Median count recovery was 41days post course 1, 44 days post course 2 MA and 45 days post course 2 FLA-Ida. 59%of patients had at least one grade ≥3 adverse event or any grade serious adverse event, evaluated from the start of treatment until 30 days after end of induction. Most events were consistent with AML chemotherapy. Only 9 patients (1.7%) had grade ≥3 hyperbilirubinemia and 2 patients confirmed veno-occlusive disease (VOD) in induction. Conclusion At least one dose of GO in combination with mitoxantrone and cytarabine in induction followed by risk-adapted therapy has produced excellent results. Despite intensive treatment the death in first remission rate is remarkably low at 2% and VOD was rare. Although this abstract reports only pooled data, outcomes for the 1 vs 3 dose GO randomisation will be presented at the ASH annual meeting.

Introduction Approximately 80% of infants with B-cell acute lymphoblastic leukemia (B-ALL) harbor KMT2A rearrangements, defining a uniquely aggressive subtype of ALL with a poor outcome demonstrated by 5-year event free survival (EFS) < 40% in recent major international trials. Treatment is challenging due to the high rate of relapse, where intensification of chemotherapy has led to unacceptably high treatment-related mortality (TRM). Myeloid blocks in Interfant-06 did not reduce the risk of relapse but caused excess toxicity with a serious adverse event rate of 37% with the trial overall reporting a TRM of 7.1%. Relapse occurs early, often within the first year of treatment before a potential stem cell transplant (SCT) on traditional protocols. Early data from the blinatumomab pilot trial within the Interfant group has shown promise for the CD3/CD19 bi-specific T-cell engager. However, this pilot added blinatumomab to an intensive chemotherapy backbone with no reduction in chemotherapy, leading to caution in further reducing chemotherapy in the successor Interfant-21 trial. Within the United Kingdom (UK) Children's Cancer and Leukaemia Group (CCLG) we developed a treatment guideline to address the unacceptably high TRM and early relapse. All infants with KMT2A-rearranged B-ALL receive blinatumomab to replace toxic consolidation chemotherapy blocks (removal of myeloid blocks and protocol 1B) as a bridge to risk stratified allocation of further de-intensified chemotherapy or early SCT. Methods Patients were eligible if they had KMT2A-rearranged B-ALL, and aged < 365 days at diagnosis. All patients received a standard Interfant induction followed by a 28-day cycle of blinatumomab. High risk (HR) patients, were defined as infants who were <6 months at presentation with a white cell count >300 and/or a prednisolone poor response, or had minimal residual disease (MRD) > 1% at day 33 or MRD >0.01% at end of cycle one of blinatumomab. HR patients proceeded directly to SCT after one cycle of blinatumomab if MRD <0.01%. Medium risk (MR) patients were all other patients and proceeded to a second cycle of blinatumomab, followed by delayed intensification with OCTADAD (dexamethasone, vincristine, daunorubicin, pegylated asparaginase, cyclophosphamide and cytarabine) and oral maintenance with removal of MARMA block (high dose cytarabine, high dose methotrexate, pegylated asparaginase). For MR patients compared to the Interfant blinatumomab pilot this represents a 90% reduction in total cytarabine (from 28050 to 2850 mg/m2), 50% reduction in pegylated asparaginase (from 4000 to 2000 iu/m2), 66% reduction in cyclophosphamide (from 3000 to 1000 mg/m2), 45% reduction in 6-mercaptopurine (from 4575 to 2520 mg/m2) and removes high-dose methotrexate. For HR patients, there is a 96% reduction in cytarabine (from 26520 to 1050 mg/m2), a 66% reduction in pegylated asparaginase (from 3000 to 1000 iu/m2), and completely removes high dose methotrexate, cyclophosphamide and 6-mercaptopurine. Blinatumomab treatment failures and early relapses were brought to a national panel to be considered for chimeric antigen receptor T-cell (CART) therapy. Results We collected outcome data on 27 infants with KMT2A-rearranged B-ALL (17 MR, 10 HR) who presented since the 1st of January 2021, with a median follow-up of 15 months (mean 20 months). All infants received blinatumomab with 25/27 (93%) achieving a complete molecular remission (MRD <0.01%). There were 5 relapses (4 MR, 1 HR), with 1 death in the MR group due to disease, resulting in an overall survival at of 93%, and an EFS of 78% at 2 years. Four out of the 5 relapses were subsequently treated with CART therapy and remain in remission. There were no treatment-related deaths. Conclusions For infants with KMT2A-rerranged B-ALL, chemotherapy intensification has merely caused severe toxicity without improving outcomes. Overall, our data suggests the chemotherapy backbone can be radically de-escalated. Given most patients relapse within the first 18 months, our initial survival rates are encouraging. We plan to further reduce induction intensity by removing cytarabine and anthracycline for all patients and reducing induction to 15 days in patients who have achieved MRD <5% who are suitable to receive blinatumomab at this level of disease.

Children diagnosed with acute myeloid leukaemia (paediatric AML [pAML]) have limited treatment options and relapse rates due to chemoresistance and refractory disease are over 30%. Current treatment is cytotoxic and in itself has long-lasting harsh side effects. New, less toxic treatments are needed. The bone marrow microenvironment provides chemoprotection to leukaemic cells through cell communication and interaction with mesenchymal stem cells (MSCs), but this is not well defined in pAML. Using primary patient material, we identify a cell contact-independent mechanism of MSC-mediated chemoprotection involving extrinsic soluble factors that is abrogated through inhibition of the JAK/STAT and ERK pathways.

Early-phase trials of venetoclax in children and teenagers/young adults with leukaemia have yielded promising results, but there remains a paucity of real-world data. To address this, we report a cohort of 41 children treated with venetoclax for a range of haematological malignancies, demonstrating complete remission in 43.6%, with most achieving minimal residual disease (MRD) negativity. Venetoclax was particularly effective as a bridge to transplant, with bridging successful in 75% of patients. Patients with MRD <1% at initiation of venetoclax were more likely to achieve MRD negativity (81.8% vs. 34.5%, p = 0.007) and had improved overall survival (54.5% vs. 17.9%, p = 0.004).

Introduction: Allogeneic hematopoietic stem cell transplantation (HSCT) is the standard of care for pediatric acute lymphoblastic leukemia (pALL) patients with inadequate response to therapy or relapse. Children older than 4 years (yrs) of age, are conditioned with total body irradiation (TBI) and etoposide according to the results of the Forum trial, which demonstrated superior overall survival compared to chemotherapeutic conditioning regimens (CTx) in this age group. Due to several side effects of TBI, children under the age of 2 yrs usually receive CTx conditioning resulting in higher post-HSCT relapse. The optimal conditioning regimen for children between 2 and 4 yrs of age remains controversial. Patients and methods: In this retrospective analysis, we investigated the outcomes of TBI- vs. CTx-based conditioning in children of 2 to 4 yrs, undergoing alloHSCT for pALL in first (CR1) or second complete remission (CR2), transplanted between 2000 and 2012. The primary objective was the incidence of subsequent malignant neoplasms (SMN); secondary objectives included key alloHSCT outcome parameters. Results: Overall, 282 patients were included and the median follow-up (FU) was 13.2 yrs [CI95%: (12.8-13.8)]. Patients who received CTx-based conditioning (n=119) were younger [median age: 2.8 yrs (Q1 2.3; Q3 3.3) vs. 3.3 yrs (Q1 2.8; Q3 3.6); p<0.001] than patients receiving TBI (n=163). Additionally, the CTx group received more frequently peripheral blood stem cells (PBSC; 26.1% vs 10.4%), and cord blood (CB; 21.0% vs 17.2%) and less frequently bone marrow (BM; 52.9% vs. 72.4%) as stem cells source compared to the TBI cohort. Descriptive characteristics, including gender, Lansky score prior to HSCT, yr of transplant, disease remission status at HSCT, and donor type, were not significantly different. Within the TBI group the majority received a radiation dosage of 10-12 Gy (79.7%). CTx-conditioning was either based on busulfan (86.4%), treosulfan (10.1%) or fludarabine/melphalan (3.3%). A total of 20 SMNs (7%) were seen in the study population; 5 SMNs were identified in the CTx group: 1 osteosarcoma, 2 post-transplant lymphoproliferative disorders (PTLDs), 1 Non-Hodgkin lymphoma (NHL) and 1 thyroid carcinoma. One patient succumbed to his PTLD and the NHL patient had a fatal ALL relapse. In the TBI group 15 SMNs were identified: 2 glioblastomas, 1 neurinoma, 1 malignant melanoma, 1 osteosarcoma, 1 intestinal polyposis with signs of malignant transformation and 9 thyroid carcinomas. All, but the 2 glioblastoma patients, are still alive. The cumulative incidence of SMNs (with CI95%) was 2.5% (1.1-4.9) at 5 yrs, 5.3% (3.0-8.5) at 10 yrs, and 7.3% (4.5-11.1) at 15 yrs. Overall survival (OS) was significantly higher in the TBI group (10-yr OS: 68.4% vs 50.7%; HR: 1.79, p=0.004), with an increased relapse incidence (RI) in the CTx group (10-yr RI: 41.5% vs 22.1%; HR: 2.34, p<0.001). In line with these results, leukemia-free survival (LFS) was higher for TBI (64.8% vs. 44.0%; HR: 1.94, p<0.001). Graft-versus-host-disease (GvHD) related outcomes did not differ significantly between the two groups. However, recent transplants have been associated with a lower risk for chronic GvHD (HR {per 3-yr increment} 0.55 (CI95%: 0.41-0.74), p<0.001). Conclusions: Based on these results, TBI should be offered to very high-risk ALL patients above the age of 2 years due to its efficacy and the relatively low rate of SMNs. Despite the higher incidence of SMNs in the TBI group, the incidence remained within the expected range and is acceptable when considering the excellent outcomes regarding relapse and leukemia-free survival.

Poor-risk (PR) cytogenetic/molecular abnormalities generally direct pediatric patients with acute myeloid leukemia (AML) to allogeneic hematopoietic stem cell transplant (HSCT). We assessed the predictive value of cytogenetic risk classification at diagnosis with respect to post-HSCT outcomes in pediatric patients. Patients younger than 18 years at the time of their first allogeneic HSCT for AML in CR1 between 2005 and 2022 who were reported to the European Society for Blood and Marrow Transplantation registry were subgrouped into four categories. Of the 845 pediatric patients included in this study, 36% had an 11q23 abnormality, 24% had monosomy 7/del7q or monosomy 5/del5q, 24% had a complex or monosomal karyotype, and 16% had other PR cytogenetic abnormalities. In a multivariable model, 11q23 (hazard ratio [HR] = 0.66, P = 0.03) and other PR cytogenetic abnormalities (HR = 0.55, P = 0.02) were associated with significantly better overall survival when compared with monosomy 7/del7q or monosomy 5/del5q. Patients with other PR cytogenetic abnormalities had a lower risk of disease relapse after HSCT (HR = 0.49, P = 0.01) and, hence, better leukemia-free survival (HR = 0.55, P = 0.01). Therefore, we conclude that PR cytogenetic abnormalities at diagnosis predict overall survival after HSCT for AML in pediatric patients.

Data comparing hematopoietic stem cell transplantation (HSCT) using bone marrow (BM) or peripheral blood stem cell (PBSC) grafts in children after alemtuzumab-based conditioning are lacking. We investigated whether in vivo T cell depletion using alemtuzumab could reduce the risk of severe acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD) after HSCT with matched unrelated donor (MUD) BM or PBSCs. This retrospective multicenter study included 397 children (BM group, n = 202; PBSC group, n = 195) who underwent first MUD HSCT at 9 pediatric centers in the United Kingdom between 2015 and 2019. The median age at transplantation was 7.0 years (range, .1 to 19.3 years), and the median duration of follow-up was 3.1 years (range, .3 to 7.5 years). The 3-year overall survival was 81% for the entire cohort (BM group, 80%; PBSC group, 81%). The incidence of grade II-IV aGVHD was significantly higher in the PBSC group (31%) compared to the BM group (31% versus 19%; P = .003), with no difference in the incidence of grade III-IV aGVHD (BM, 7%; PBSC, 12%; P = .17). CD3+ T cell dose >5 × 108/kg and the use of PBSCs were independent predictors of grade II-IV aGVHD. When considering CD3+ T cell dose and GVHD prophylaxis, PBSC transplantation with a calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF) and a CD3+ T cell dose ≤5 × 108/kg had a comparable grade II-IV aGVHD to BM transplantation plus a CNI (20% versus 18%; P = .52). PBSC transplantation was associated with a lower incidence of cGVHD compared to BM transplantation (6% versus 11%; P = .03). Within the limits of this study, we identified a potential strategy to reduce the risk of severe GVHD in pediatric PBSC recipients that includes a combination of in vivo T cell depletion using alemtuzumab and dual GVHD prophylaxis (with a CNI and MMF) and limiting the CD3+ T cell dose to ≤5 × 108/kg.

Background: Outcomes for pediatric acute myeloid leukemia (AML) remain disappointing, particularly for patients with poor risk cytogenetic/molecular genetic abnormalities and those who fail to achieve complete remission following course 1 of induction chemotherapy. Despite upfront allogeneic hematopoietic stem cell transplantation (HSCT) for these patients, high rates of relapse persist. The optimal approach to chemotherapy intensification and timing of HSCT for high risk (HR) patients remains unknown, with variable approaches employed by cooperative trial groups. Methods: The MyeChild 01 international phase III trial (NCT02724163) in children with de novo AML allocated patients up to 3 doses of gemtuzumab ozogamicin (GO 3mg/m 2/dose) during the first course of induction chemotherapy (mitoxantrone 12 mg/m2/dose x4; cytarabine 100 mg/m2/dose x20). Patients classified as HR after course 1 received FLA-Ida for course 2 followed by allogeneic HSCT. If required, a third course of bridging therapy (FLA) was given prior to HSCT. HR patients in MyeChild 01 included those with NUP98 fusions, selected KMT2A fusions ( KMT2A::MLLT10, KMT2A::MLLT4, KMT2A::AFF1, KMT2A::ABI1), CBFA2T3::GLIS2, DEK::NUP214, MECOM ( EVI1) rearrangements and all 12p abnormalities including MNX1::ETV6, in addition to the traditional HR abnormalities -7, -5/del(5q) and FLT3-ITD (without concurrent good risk abnormalities, including NPM1 mutations). Patients with induction failure after course 1 (≥ 5% blasts confirmed by flow) and those with non-HR cytogenetics/molecular genetics who remained MRD positive after course 2 (intermediate risk cytogenetics) or 3 (good risk cytogenetics) were also classified as HR. Here, we report the estimated 2-year outcomes for patients assigned HR post course 1 who received mitoxantrone and cytarabine and at least 1 dose of GO during course 1 (MA-GO). Outcomes of trial randomisations (1 vs 2 or 3 GO doses; consolidation for standard risk patients; HSCT conditioning) will be reported separately. Results: Of 749 patients enrolled at initial diagnosis, 183 received MA-GO during course 1 and were assigned HR post course 1. Of these, 172 (94%) patients had poor risk cytogenetic/molecular genetics, of which 32 also failed to achieve CR. Additionally, 11 (6%) patients did not have poor risk cytogenetic/molecular genetics but failed to achieve CR with MA-GO and thus were assigned to the HR group. Post course 1, 140 (77%) of these HR patients achieved CR/CRi, with 102/155 (66%) patients with evaluable samples achieving MRD negativity post course 1. Following course 1, 174 (95%) remained on trial and received FLA-Ida as course 2 and 163 patients (89%) proceeded to HSCT, 55 on trial and 108 following discontinuation from the trial. Estimated event-free survival (EFS) and overall survival (OS) at 2 years was 62% (95% CI: 56-70%) and 71% (64-78%) respectively (Figure 1 & 2). Estimated cumulative incidence of relapse (CIR) and death in remission at 2 years was 26% (19-33%) and 7% (3-11%) respectively. For HR patients who received MA-GO in course 1, on trial FLA-Ida as course 2 and on or off trial HSCT (n = 156), 2 year estimated outcomes were EFS 69% (62-77%), OS 77% (70-85%) and CIR 24% (17-32%). The most common cytogenetic/molecular genetic abnormalities were rearrangements of KMT2A (50/183, 27%), with KMT2A::MLLT10 predominating (70%). FLT3-ITD (19%), NUP98 fusions (14%), -7 (13%), abn(12p) (11%), del(5q) (8%) and CBFA2T3::GLIS2 (6%) accounted for the majority of other abnormalities with outcomes varying by subtype. Collectively, KMT2A-rearranged patients had EFS and OS of 68% (55-83%) and 71% (59-86%) respectively and CIR of 26% (12-40%). For FLT3-ITD, the EFS and OS was 75% (62-92%) and 83% (69-99%) respectively with a CIR of 14% (1-26%). Of the 25 patients with a NUP98 fusion, 17 (68%) were NUP98::NSD1. The EFS and OS for patients with NUP98 fusions was 71% (55-92%) and 96% (88-100%) respectively with CIR 25% (1-48%). Conclusions: Two intensive courses of induction chemotherapy, including GO and mitoxantrone in course 1 and FLA-Ida in course 2, consolidated with allogeneic HSCT, appears to be an effective approach for most HR patients. 2 year estimated outcomes for HR patients compare favourably to recent trials of GO in pediatric AML, with particularly encouraging data for patients with KMT2A-r and FLT3-ITD.

The prognostic impact of PICALM::MLLT10 status in childhood leukaemia is not well described. Ten International Berlin Frankfurt Münster-affiliated study groups and the Children's Oncology Group collaborated in this multicentre retrospective study. The presence of the PICALM::MLLT10 fusion gene was confirmed by fluorescence in situ hybridization and/or RNA sequencing at participating sites. Ninety-eight children met the study criteria. T-cell acute lymphoblastic leukaemia (T-ALL) and acute myeloid leukaemia (AML) predominated 55 (56%) and 39 (40%) patients, respectively. Most patients received a chemotherapy regimen per their disease phenotype: 58% received an ALL regimen, 40% an AML regimen and 1% a hybrid regimen. Outcomes for children with PICALM::MLLT10 ALL were reasonable: 5-year event-free survival (EFS) 67% and 5-year overall survival (OS) 76%, but children with PICALM::MLLT10 AML had poor outcomes: 5-year EFS 22% and 5-year OS 26%. Haematopoietic stem cell transplant (HSCT) did not result in a significant improvement in outcomes for PICALM::MLLT10 AML: 5-year EFS 20% for those who received HSCT versus 23% for those who did not (p = 0.6) and 5-year OS 37% versus 36% (p = 0.7). In summary, this study confirms that PICALM::MLLT10 AML is associated with a dismal prognosis and patients cannot be salvaged with HSCT; exploration of novel therapeutic options is warranted.

Risk factors for severe SARS-Cov-2 infection course are poorly described in children following hematopoietic cell transplantation (HCT). In this international study, we analyzed factors associated with a severe course (intensive care unit (ICU) admission and/or mortality) in post-HCT children. Eighty-nine children (58% male; median age 9 years (min-max 1-18)) who received an allogeneic (85; 96%) or an autologous (4; 4%) HCT were reported from 28 centers (18 countries). Median time from HCT to SARS-Cov-2 infection was 7 months (min-max 0-181). The most common clinical manifestations included fever (37; 42%) and cough (26; 29%); 37 (42%) were asymptomatic. Nine (10%) children following allo-HCT required ICU care. Seven children (8%) following allo-HCT, died at a median of 22 days after SARS-Cov-2 diagnosis. In a univariate analysis, the probability of a severe disease course was higher in allo-HCT children with chronic GVHD, non-malignant disease, immune suppressive treatment (specifically, mycophenolate), moderate immunodeficiency score, low Lansky score, fever, cough, coinfection, pulmonary radiological findings, and high C-reactive protein. In conclusion, SARS-Cov-2 infection in children following HCT was frequently asymptomatic. Despite this, 10% needed ICU admission and 8% died in our cohort. Certain HCT, underlying disease, and SARS-Cov-2 related factors were associated with a severe disease course.

Survival after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for severe idiopathic aplastic anemia (SAA) has improved in recent years, approaching 75% at 5 years. However, an SAA-adapted composite endpoint, graft-versus-host disease (GvHD) and relapse/rejection-free survival (GRFS), may more accurately assess patient outcomes beyond survival. We analyzed GRFS to identify risk factors and specific causes of GRFS failure. Our retrospective analysis from the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation included 479 patients with idiopathic SAA who underwent allo-HSCT in two conventional situations: i) upfront allo-HSCT from a matched related donor (MRD) (upfront cohort), and ii) allo-HSCT for relapsed or refractory SAA (rel/ref cohort). Relevant events for GRFS calculation included graft failure, grade 3-4 acute GvHD, extensive chronic GvHD, and death. In the upfront cohort (n=209), 5-year GRFS was 77%. Late allo-HSCT (i.e., >6 months after SAA diagnosis) was the main poor prognostic factor, specifically increasing the risk of death as the cause of GRFS failure (hazard ratio [HR]=4.08; 95% confidence interval [CI]: 1.41-11.83; P=0.010). In the rel/ref cohort (n=270), 5-year GRFS was 61%. Age was the main factor significantly increasing the risk of death (HR=1.04; 95% CI: 1.02-1.06; P<0.001), acute GvHD (HR=1.03; 95% CI: 1.00-1.07; P=0.041), and chronic GvHD (HR=1.04; 95% CI: 1.01-1.08; P=0.032) as the cause of GRFS failure. GRFS after upfront MRD allo-HSCT was very good, notably with early allo-HSCT, confirming that younger patients with an MRD should be transplanted immediately. GRFS was worse in cases of salvage allo-HSCT, most notably in older patients, questioning the utility of allo-HSCT earlier in the disease course.

PURPOSE We tested whether blinatumomab (Blina) is effective as a toxicity-sparing alternative to first-line intensive chemotherapy in children and young persons (CYP) with B-ALL who were chemotherapy-intolerant or chemotherapy-resistant. METHODS Data were collected for consecutive CYP (age 1-24 years) with Philadelphia chromosome–positive or Philadelphia chromosome–negative B-ALL who received Blina as first-line therapy. Blina was given as replacement for postremission intensive chemotherapy to patients with chemotherapy intolerance or resistance. Blina responders received further chemotherapy (Blin-CT) or first remission hematopoietic stem-cell transplant (Blin-HSCT) if indicated. Event-free survival (EFS) and overall survival (OS) of the Blin-CT group were compared with those of matched controls treated with standard chemotherapy in the UKALL 2003 trial. Events were defined as death, relapse, or secondary cancer. RESULTS From February 2018 to February 2023, 105 patients were treated, of whom 85 were in the Blin-CT group and 20 were in the Blin-HSCT group. A majority of Blin-CT patients received Blina for chemotherapy intolerance (70 of 85, 82%), and the group had a higher-risk profile than unselected patients with B-ALL. Blina was well tolerated with only one patient having a grade 3/4–related toxicity event, and of the 60 patients who were minimal residual disease–positive pre-Blina, 58 of 60 (97%) responded. At a median follow-up of 22 months, the 2-year outcomes of the 80 matched Blin-CT group patients were similar to those of 192 controls (EFS, 95% [95% CI, 85 to 98] v 90% [95% CI, 65 to 93] and OS, 97% [95% CI, 86 to 99] v 94% [95% CI, 89 to 96]). Of the 20 in the HSCT group, three died because of transplant complications and two relapsed. CONCLUSION Blina is safe and effective in first-line treatment of chemotherapy-intolerant CYP with ALL.

Introduction Recent studies have demonstrated that Blinatumomab is more effective and less toxic than intensive chemotherapy in children and young persons (CYP) with relapsed B-ALL. Although Blinatumomab is standard of care in adults with persistent MRD during first line therapy based on the BLAST study, there is no published evidence in CYP of its efficacy and toxicity in this setting. We report our experience of Blinatumomab as a toxicity sparing alternative to chemotherapy in first line treatment of CYP with B-ALL. Patients and Methods We audited the outcome of patients treated according to a consensus UK guideline for first line treatment with Blinatumomab of CYP patients with B-ALL who were considered unfit for post-remission intensive chemotherapy or CR1 HSCT because of toxicity to previous chemotherapy or significant co-morbidities. Treating clinicians obtained consent for treatment with Blinatumomab as standard of care after counselling patients and carers about the risk and benefits of this approach. The guideline mandated discussion of all such patients at national tumour board meetings and data was captured through a referral proforma and follow-up questionnaire. It recommended replacing consolidation and/or interim maintenance phases with 2 cycles of blinatumomab as a single agent with a 1-2 week break between cycles. Patients who obtained an MRD response (defined as MRD <0.01%) received delayed intensification (DI) followed by maintenance, or maintenance therapy alone if they were unfit for DI. Patients who had persistent MRD >0.01% were categorised as Blinatumomab failures and received either further chemotherapy, HSCT or CART depending on performance status. Events were defined as death, relapse, or secondary cancer. Results Sixty patients were eligible for analysis, including 4 cases of Ph+ ALL and 8 with Down syndrome. Compared to the B-ALL cohort in a previous trial, UKALL 2003, there was a higher proportion of NCI high risk, cytogenetic high risk, end of induction MRD positive and Down Syndrome patients (Table 1). All patients were in morphological complete remission prior to receiving Blinatumomab. Blinatumomab was administered for toxicity (47/60 (78%), including G3/4 pancreatitis, typhlitis, severe infections often requiring intensive care or surgery, disseminated fungal infections, CNS haemorrhage or liver failure) or co-morbidities (Down syndrome, Li-Fraumeni syndrome (n=2), Schimke immune-osseous dysplasia and 7q11.21-23 duplication) or in one case to minimise transfusion requirements (Jehovah's witness.) In the remaining 13 cases, blinatumomab was either administered for end of consolidation MRD of ≥0.05% (n=10) in patients unfit for intensive chemotherapy/HSCT, or positive end of induction MRD in patients with HR cytogenetics (n=3). Blinatumomab replaced consolidation and interim maintenance therapy in 32/60 (53%) cases, and interim maintenance in the remaining 28/60 (47%) cases. Blinatumomab was well tolerated with 1 G3 neurotoxicity (seizure in a Down syndrome patient who had not received prophylactic anti-convulsants) and no grade 2-4 CRS. Of the 50/60 patients with positive MRD pre-Blinatumomab (median = 0.1%, range = 0.01%-8%), 48 (96%) had a reduction in level to <0.01% (45 after cycle 1, 3 after cycle 2), and 10 patients maintained MRD negativity before and after 2 cycles of Blinatumomab. In the two patients who did not respond (3%), 1 received CART followed by transplant for persistent MRD, the other is receiving intensive chemotherapy. Of the responders, 47 (80%) received DI and maintenance and 10 maintenance alone. With a median follow up of 16 months (range 2-44 months), 2 patients have relapsed (1 at 2 years, the other at 9 months) but remain alive. The 4 patients with Ph+ ALL and the 8 with Down syndrome are alive and in remission, with a median follow up of 12.5 months (range 7-22 months). Conclusion In this large case series, we found Blinatumomab is safe and highly active with promising short-term efficacy in a higher risk cohort of CYP patients with B-ALL in first remission. Our results support its use in place of intensive chemotherapy for patients with relative chemo-intolerance. Furthermore, if the efficacy is sustained on longer follow-up, the results argue for replacing parts of post-remission intensive chemotherapy with Blinatumomab to reduce attendant morbidity and mortality. SS and AV are joint senior authors, AH and AM joint first authorsFigure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Introduction Despite the emergence of effective novel immunotherapies, the outcome of relapsed pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains poor due to treatment-related mortality (TRM) and resistant disease. In response to accumulating evidence on the efficacy and low toxicity of blinatumomab in relapsed B-ALL and the availability of highly active CD19-targeted chimeric antigen receptor T-cell therapy (CART), we redesigned the United Kingdom (UK) relapse treatment pathway, based on two key guiding principles: 1) to reduce chemotherapy burden and associated toxicity through a move away from the highly intensive ALL R3 backbone towards increased reliance on blinatumomab to clear disease, and 2) to identify treatment failures early and direct them to CART, given the poor responses reported with hematopoietic stem cell transplant (HSCT) in this context. Methods Patients were treated with UKALL induction chemotherapy (<16yr: 3-drugs; >16yr: 4-drugs) until adequate blast clearance. Patients with blasts <5% at Day 15 progressed directly to blinatumomab; remaining patients continued to Day 28. Following reinduction, patients received up to 2 cycles of blinatumomab as a single agent. HR patients (early/very early relapses and/or HR cytogenetics) proceeded to HSCT once minimal residual disease (MRD) <0.01%. Those with high-risk (HR) isolated central nervous system (CNS) disease had the option to proceed directly to HSCT following CSF blast clearance without blinatumomab. All Standard risk (SR) patients continued on chemotherapy alone. Patients who were refractory after re-induction (>25% disease), blinatumomab (MRD >0.01%), or for whom there was no available donor were considered for CART. All patients were required to be discussed at a national tumour board, and data were subsequently collected every 3 months for analysis. Events were defined as death, relapse, and secondary cancer. Results Between September 2018 and July 2022, 111 patients were treated on the pathway; 63 (56.8%) were HR and 48 (43.2%) were SR. There were 26 patients >15yr, 3 Infant ALL, 2 Ph+ ALL and 4 with Down Syndrome. Induction therapy achieved disease reduction to <5% and CNS clearance in 98 patients (88%). Of the 90 patients with BM involvement, 52.2% required only 15 days of induction therapy. Induction failure (>25% blasts) occurred in 6.3%, comparable to the 7.1% using the R3 induction in the COG AALL1331 trial (p=1.00); 6/7 patients with induction failure successfully underwent CART infusion. The rate of end of induction MRD <0.01% in the HR group was also similar to COG AALL1331 (30% vs. 27.4%, p=0.669). Importantly, there were no cases of TRM with the reduced intensity induction, compared to 2.4-4% reported with the ALL R3 induction (p=0.06). Ninety patients received blinatumomab, of whom 87% achieved a complete MRD response, with grade 3 or 4 treatment-related toxicity in 11 patients (12.2%). Amongst HR patients, 86.8% underwent HSCT, significantly more than in the blinatumomab-treated IR/HR arm of COG AALL1331 (66%, p=0.02). With a median follow-up of 12 months (range 2-49), 19% of HR patients and 8.3% of SR patients have relapsed, comparable to results achieved in the blinatumomab-treated arm of the COG AALL1331 trial. There were no deaths in the SR group, and 12 deaths in the HR group (6 due to relapse/refractory disease, 6 due to post-HSCT TRM). Conclusions Our findings demonstrate that a reduced intensity reinduction can achieve equivalent disease control to the more intensive ALL R3 induction, with a substantial reduction in TRM. Although follow-up is short, consolidative blinatumomab achieved very high rates of MRD clearance, allowing a greater number of HR patients to reach potentially curative therapy with HSCT, the key predictor of outcome in the COG AALL1331 trial. We propose that our strategy represents a new standard of care for reinduction therapy in relapsed childhood B-ALL. DO and AV are joint senior authors Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal