Blinatumomab Added to Chemotherapy in Infant Lymphoblastic Leukemia.

BACKGROUND: KMT2A-rearranged acute lymphoblastic leukemia (ALL) in infants is an aggressive disease with 3-year event-free survival below 40%. Most relapses occur during treatment, with two thirds occurring within 1 year and 90% within 2 years after diagnosis. Outcomes have not improved in recent decades despite intensification of chemotherapy. METHODS: We studied the safety and efficacy of blinatumomab, a bispecific T-cell engager molecule targeting CD19, in infants with KMT2A-rearranged ALL. Thirty patients younger than 1 year of age with newly diagnosed KMT2A-rearranged ALL were given the chemotherapy used in the Interfant-06 trial with the addition of one postinduction course of blinatumomab (15 µg per square meter of body-surface area per day; 28-day continuous infusion). The primary end point was clinically relevant toxic effects, defined as any toxic effect that was possibly or definitely attributable to blinatumomab and resulted in permanent discontinuation of blinatumomab or death. Minimal residual disease (MRD) was measured by polymerase chain reaction. Data on adverse events were collected. Outcome data were compared with historical control data from the Interfant-06 trial. RESULTS: The median follow-up was 26.3 months (range, 3.9 to 48.2). All 30 patients received the full course of blinatumomab. No toxic effects meeting the definition of the primary end point occurred. Ten serious adverse events were reported (fever [4 events], infection [4], hypertension [1], and vomiting [1]). The toxic-effects profile was consistent with that reported in older patients. A total of 28 patients (93%) either were MRD-negative (16 patients) or had low levels of MRD (<5×10-4 [i.e., <5 leukemic cells per 10,000 normal cells], 12 patients) after the blinatumomab infusion. All the patients who continued chemotherapy became MRD-negative during further treatment. Two-year disease-free survival was 81.6% in our study (95% confidence interval [CI], 60.8 to 92.0), as compared with 49.4% (95% CI, 42.5 to 56.0) in the Interfant-06 trial; the corresponding values for overall survival were 93.3% (95% CI, 75.9 to 98.3) and 65.8% (95% CI, 58.9 to 71.8). CONCLUSIONS: Blinatumomab added to Interfant-06 chemotherapy appeared to be safe and had a high level of efficacy in infants with newly diagnosed KMT2A-rearranged ALL as compared with historical controls from the Interfant-06 trial. (Funded by the Princess Máxima Center Foundation and others; EudraCT number, 2016-004674-17.).

Monocentric experience of venetoclax-based regimen in paediatric refractory and relapsed AML/MDS.

BCL-2 inhibitor venetoclax demonstrates promising efficacy in paediatric relapsed/refractory acute myeloid leukaemia (r/r AML). This retrospective analysis evaluated 12 patients treated with venetoclax-based regimens under compassionate use for r/r myeloid malignancies. The overall response rate (ORR) was 41.6%, with complete response (CR) achieved in 33% of patients. Three patients successfully underwent allogeneic haematopoietic scell transplantation (HSCT) after venetoclax bridging therapy. Venetoclax demonstrated a favourable safety profile with manageable side effects. These findings suggest venetoclax's potential as a valuable therapeutic option for paediatric r/r AML, particularly for heavily pretreated patients. Further investigation in larger multicentre trials is warranted to refine treatment strategy.

Inotuzumab ozogamicin combined with chemotherapy in pediatric B-cell precursor CD22+ acute lymphoblastic leukemia: results of the phase IB ITCC-059 trial.

Inotuzumab ozogamicin (InO) is a CD22-directed antibody conjugated with calicheamicin. The phase IB of the ITCC-059 trial tested InO combined with chemotherapy in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Relapsed /refractory CD22+ BCP-ALL pediatric patients were enrolled. The primary objective was to establish the recommended phase II dose (RP2D). Secondary objectives included preliminary efficacy and tolerability. InO was combined with 1.5 mg/m2 of vincristine (days 3, 10, 17, 24), 20 mg/m2 of dexamethasone (2 5-day blocks, then amended), and intrathecal therapy. A rolling-6 design was used testing InO from 0.8 to 1.8 mg/m2/cycle. Between May 2020 and April 2022, 30 patients were treated, and 29 were evaluable for dose limiting toxicities (DLT). At 1.1 mg/m2/cycle, two of four patients had DLT (liver toxicity). InO was de-escalated to 0.8 mg/m2/cycle (N=6) without DLT while awaiting a protocol amendment to reduce dexamethasone dose to 10 mg/m2. Post amendment, InO was re-escalated to 1.1 mg/m2/cycle (N=6, 1 DLT), then to 1.4 mg/m2/ cycle (N=3, no DLT), and finally to 1.8 mg/m2/cycle (N=7, 1 DLT). Three additional patients were treated in an expansion cohort. The pooled response rate was 80% (24/30; 95% confidence interval [CI]: 61.4-92.3) and, among responders, 66.7% achieved minimal residual disease negativity. The RP2D of InO combined with vincristine, dexamethasone and intrathecal therapy was declared at 1.8 mg/m2/cycle (1.5 mg/m2/cycle after remission) in a fractioned schedule. This combination showed a response rate similar to the single agent cohorts of this trial, with liver toxicity issues at the initial higher dexamethasone dose (clinicaltrials gov. Identifier: NTR5736).

A phase 1 study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study).

This phase 1 study investigated the recommended phase 2 dose (RP2D) of inotuzumab ozogamicin (InO), a CD22-directed antibody-drug conjugate, in pediatric patients with multiple relapsed/refractory (R/R) CD22+ acute lymphoblastic leukemia (ALL). Patients (age ≥1 year or <18 years) received 3 doses of InO (days 1, 8, and 15) per course. Dose escalation was based on dose-limiting toxicities (DLTs) during course 1. Dose level 1 (DL1) was 1.4 mg/m2 (0.6, 0.4, 0.4 mg/m2) and DL2 was 1.8 mg/m2 (0.8, 0.5, 0.5 mg/m2). Secondary end points included safety, antileukemic activity, and pharmacokinetics. Twenty-five patients (23 evaluable for DLTs) were enrolled. In course 1, the first cohort had 1 of 6 (DL1) and 2 of 5 (DL2) patients who experienced DLTs; subsequent review considered DL2 DLTs to be non-dose-limiting. Dose was de-escalated to DL1 while awaiting protocol amendment to re-evaluate DL2 in a second cohort, in which 0 of 6 (DL1) and 1 of 6 (DL2) patients had a DLT. Twenty-three patients experienced grade 3 to 4 adverse events; hepatic sinusoidal obstruction syndrome was reported in 2 patients after subsequent chemotherapy. Overall response rate after course 1 was 80% (95% confidence interval [CI], 59% to 93%) (20 of 25 patients; DL1: 75% [95% CI, 43% to 95%], DL2: 85% [95% CI, 55% to 98%]). Of the responders, 84% (95% CI, 60% to 97%) achieved minimal residual disease (MRD)-negative complete response, and 12-month overall survival was 40% (95% CI, 25% to 66%). Nine patients received hematopoietic stem cell transplantation or chimeric antigen receptor T cells after InO. InO median maximum concentrations were comparable to simulated adult concentrations. InO was well tolerated, demonstrating antileukemic activity in heavily pretreated children with CD22+ R/R ALL. RP2D was established as 1.8 mg/m2 per course, as in adults. This trial was registered at https://www.clinicaltrialsregister.eu as EUDRA-CT 2016-000227-71.

Invasive Fungal Infections in Immunocompromised Children: Novel Insight Following a National Study.

OBJECTIVE: To obtain a national overview of the epidemiology and management of invasive fungal infections (IFIs) in France for severely immunocompromised children who were treated for acute leukemia or had undergone allogeneic hematopoietic stem cell transplantation (a-HSCT). STUDY DESIGN: We performed a national multicenter retrospective study to collect epidemiologic data for proven and probable IFIs in children with acute leukemia under first- line or relapse treatment or who had undergone a-HSCT. We also conducted a prospective practice survey to provide a national overview of IFI management in pediatric hematology units. RESULTS: From January 2014 to December 2017, 144 cases of IFI were diagnosed (5.3%) in 2721 patients, including 61 cases of candidiasis, 60 cases of aspergillosis, and 23 cases of infection with "emergent" fungi, including 10 cases of mucormycosis and 6 cases of fusariosis. The IFI rate was higher in patients with acute myelogenous leukemia (12.9%) (OR, 3.24; 95% CI, 2.15-4.81; P < .0001) compared with the rest of the cohort. Patients undergoing a-HSCT had an IFI rate of only 4.3%. In these patients, the use of primary antifungal prophylaxis (principally fluconazole) was associated with a lower IFI rate (OR, 0.28; 95% CI, 0.14-0.60; P = 4.90 ×10-4) compared with a-HSCT recipients who did not receive antifungal prophylaxis. The main cause of IFI in children receiving prophylaxis was emergent pathogens (41%), such as mucormycosis and fusariosis, which were resistant to the prophylactic agents. CONCLUSIONS: The emerging fungi and new antifungal resistance profiles uncovered in this study should be considered in IFI management in immunocompromised children.

Oncogenetic mutations combined with MRD improve outcome prediction in pediatric T-cell acute lymphoblastic leukemia.

Risk stratification in childhood T-cell acute lymphoblastic leukemia (T-ALL) is mainly based on minimal residual disease (MRD) quantification. Whether oncogenetic mutation profiles can improve the discrimination of MRD-defined risk categories was unknown. Two hundred and twenty FRALLE2000T-treated patients were tested retrospectively for NOTCH1/FBXW7/RAS and PTEN alterations. Patients with NOTCH1/FBXW7 (N/F) mutations and RAS/PTEN (R/P) germ line (GL) were classified as oncogenetic low risk (gLoR; n = 111), whereas those with N/F GL and R/P GL mutations or N/F and R/P mutations were classified as high risk (gHiR; n = 109). Day 35 MRD status was available for 191 patients. Five-year cumulative incidence of relapse (CIR) and disease-free survival were 36% and 60% for gHiR patients and 11% and 89% for gLoR patients, respectively. Importantly, among the 60% of patients with MRD <10-4, 5-year CIR was 29% for gHiR patients and 4% for gLoR patients. Based on multivariable Cox models and stepwise selection, the 3 most discriminating variables were the oncogenetic classifier, MRD, and white blood cell (WBC) count. Patients harboring a WBC count ≥200 × 109/L, gHiR classifier, and MRD ≥10-4 demonstrated a 5-year CIR of 46%, whereas the 58 patients (30%) with a WBC count <200 × 109/L, gLoR classifier, and MRD <10-4 had a very low risk of relapse, with a 5-year CIR of only 2%. In childhood T-ALL, the N/F/R/P mutation profile is an independent predictor of relapse. When combined with MRD and a WBC count ≥200 × 109/L, it identifies a significant subgroup of patients with a low risk of relapse.

Clofarabine, high-dose cytarabine and liposomal daunorubicin in pediatric relapsed/refractory acute myeloid leukemia: a phase IB study.

Survival in children with relapsed/refractory acute myeloid leukemia is unsatisfactory. Treatment consists of one course of fludarabine, cytarabine and liposomal daunorubicin, followed by fludarabine and cytarabine and stem-cell transplantation. Study ITCC 020/I-BFM 2009-02 aimed to identify the recommended phase II dose of clofarabine replacing fludarabine in the abovementioned combination regimen (3+3 design). Escalating dose levels of clofarabine (20-40 mg/m2/day × 5 days) and liposomal daunorubicin (40-80 mg/m2/day) were administered with cytarabine (2 g/m2/day × 5 days). Liposomal DNR was given on day 1, 3 and 5 only. The cohort at the recommended phase II dose was expanded to make a preliminary assessment of anti-leukemic activity. Thirty-four children were enrolled: refractory 1st (n=11), early 1st (n=15), ≥2nd relapse (n=8). Dose level 3 (30 mg/m2clofarabine; 60 mg/m2liposomal daunorubicin) appeared to be safe only in patients without subclinical fungal infections. Infectious complications were dose-limiting. The recommended phase II dose was 40 mg/m2 clofarabine with 60 mg/m2 liposomal daunorubicin. Side-effects mainly consisted of infections. The overall response rate was 68% in 31 response evaluable patients, and 80% at the recommended phase II dose (n=10); 22 patients proceeded to stem cell transplantation. The 2-year probability of event-free survival (pEFS) was 26.5±7.6 and probability of survival (pOS) 32.4±8.0%. In the 21 responding patients, the 2-year pEFS was 42.9±10.8 and pOS 47.6±10.9%. Clofarabine exposure in plasma was not significantly different from that in single-agent studies. In conclusion, clofarabine was well tolerated and showed high response rates in relapsed/refractory pediatric acute myeloid leukemia. Patients with (sub) clinical fungal infections should be treated with caution. Clofarabine has been taken forward in the Berlin-Frankfurt-Münster study for newly diagnosed acute myeloid leukemia. The Study ITCC-020 was registered as EUDRA-CT 2009-009457-13; Dutch Trial Registry number 1880.

Appendicitis in a Neutropenic Patient: A Multicentric Retrospective Study.

To study the management of acute appendicitis in neutropenic patients, we retrospectively reviewed cases of acute appendicitis in neutropenic children treated for cancer. The patients' demographics, medical records, and outcomes were tracked. We compared nonoperative treatment versus emergency or delayed surgery. The cases of 30 patients with a mean age of 8.8 years in 12 French departments of Pediatric Hematology/Oncology between 1995 and 2013 were studied. Most patients (90%) were treated for hematological malignancies. Seven of the 30 children were successfully treated with exclusive medical treatment. Early surgery was performed in 6 patients, and the remaining 17 underwent combined management with a first-line antibiotic treatment and delayed appendectomy. Treatments were successful in all cases with transitory complications in only 3 patients. No death linked to infection was reported. Surgery was well tolerated even in the neutropenic period. Appendix perforation was a major risk factor of prolonged hospitalization. Histologic as well as bacteriologic and mycologic/parasitologic analyses were required in case of surgery. Analysis of diagnostic assessments showed the major importance of imaging (ultrasonography and tomography) on diagnosis confirmation. We could not come to a conclusion in the few numbers of reviewed cases because of a significant difference in management strategies, but we can conclude that early surgery after adequate supportive care is an acceptable modality of treatment and must be chosen in the face of life-threatening conditions.

Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis.

RASopathies, a family of disorders characterized by cardiac defects, defective growth, facial dysmorphism, variable cognitive deficits and predisposition to certain malignancies, are caused by constitutional dysregulation of RAS signalling predominantly through the RAF/MEK/ERK (MAPK) cascade. We report on two germline mutations (p.Gly39dup and p.Val55Met) in RRAS, a gene encoding a small monomeric GTPase controlling cell adhesion, spreading and migration, underlying a rare (2 subjects among 504 individuals analysed) and variable phenotype with features partially overlapping Noonan syndrome, the most common RASopathy. We also identified somatic RRAS mutations (p.Gly39dup and p.Gln87Leu) in 2 of 110 cases of non-syndromic juvenile myelomonocytic leukaemia, a childhood myeloproliferative/myelodysplastic disease caused by upregulated RAS signalling, defining an atypical form of this haematological disorder rapidly progressing to acute myeloid leukaemia. Two of the three identified mutations affected known oncogenic hotspots of RAS genes and conferred variably enhanced RRAS function and stimulus-dependent MAPK activation. Expression of an RRAS mutant homolog in Caenorhabditis elegans enhanced RAS signalling and engendered protruding vulva, a phenotype previously linked to the RASopathy-causing SHOC2(S2G) mutant. Overall, these findings provide evidence of a functional link between RRAS and MAPK signalling and reveal an unpredicted role of enhanced RRAS function in human disease.

A Phase I Study of Clofarabine With Multiagent Chemotherapy in Childhood High Risk Relapse of Acute Lymphoblastic Leukemia (VANDEVOL Study of the French SFCE Acute Leukemia Committee).

BACKGROUND: Current outcome of very early relapse of acute lymphoblastic leukemia (ALL) in children remains poor. As a single agent, clofarabine provided a response rate of 26% in childhood ALL second relapse and, in combination with cyclophosphamide and etoposide, a 44% complete remission and complete remission without platelet recovery (CR+CRp) rate. Further multi-drug combinations need to be investigated. We used the VANDA regimen as a template, cytarabine being replaced by clofarabine. PATIENTS AND METHODS: A phase I study combining escalating doses of clofarabine (25% increments from 20 to 40 mg/m(2)/d) with fixed doses of mitoxantrone, etoposide, asparaginase, and dexamethasone was undertaken in children presenting with very early or second or post-transplant ALL relapse. RESULTS: Twenty patients were enrolled, 19 were evaluable. Four patients had previously been allografted. Dose-limiting toxicity (DLT) appeared at dose level 3 (32 mg/m(2)), one out of six patients experienced a liver DLT. At dose level 4 (40 mg/m(2)), four DLT occurred (two fungal infection and two liver DLT). The maximum tolerated dose (MTD) of clofarabine was thus determined to be 32 mg/m(2). There was no toxic death. Eleven (57.9%) patients achieved a CR. Six patients proceeded to allogeneic stem cell transplantation. CONCLUSION: Clofarabine MTD was 32 mg/m(2)/d in this combination which appeared feasible and effective in this population.

The strategy for the diagnosis of invasive pulmonary aspergillosis should depend on both the underlying condition and the leukocyte count of patients with hematologic malignancies.

The identification of the causative organism in invasive pulmonary aspergillosis (IPA) is recommended. We investigated whether a mycologic diagnostic strategy could be optimized based on patient characteristics. Fifty-five patients were enrolled in a prospective study. The presence of Aspergillus in respiratory samples occurred more frequently in non-acute leukemia (AL) patients than in AL patients (P = .0003), and in patients with leukocyte counts more than 100/mm(3) (P = .002). In a logistic regression model, these 2 factors appeared to be independent, with an adjusted odds ratio of 7.14 (95% confidence interval, 1.40-36.5) for non-AL patients and an adjusted odds ratio of 6.97 (95% confidence interval, 1.33-36.5) for patients with leukocyte counts more than 100/mm(3). A positive mycologic result was also more frequent among patients with lung CT scan signs of airway-invasive disease than among other patients (P = .043). Airway-invasive signs were more frequent among non-AL patients (P = .049), whereas angioinvasive disease was more frequent among both AL patients (P = .01) and patients with leukocyte counts less than 100/mm(3) (P = .001). A concomitant pulmonary infection was identified more frequently among non-AL patients (P = .005 vs allogeneic hematopoietic stem cell transplant and P = .048 vs others). Our results suggest that different strategies for diagnosing IPA should be considered based on the underlying condition.

[SFCE harmonization workshops: Neonatal acute myeloid leukemia]. / Orientation et prise en charge de la leucémie aiguë myéloïde néonatale : recommandations du comité leucémies de la SFCE.

Neonatal acute myeloid leukemias (AML) occurred within the first 28 days of life and constitute only a small proportion of all AL. They are distinguished from leukemias of older children by their clinical presentation, which frequently includes cutaneous localizations ("blueberry muffin rash syndrome") and a leukocytosis above 50 ×109/L. This proliferation may be transient, causing a transient leukemoid reaction in a background of constitutional trisomy 21 ("Transient Abnormal Myelopoieseis" or TAM) or Infantile Myeloproliferative Disease in the absence of constitutional trisomy 21 ("Infantile Myeloproliferative Disease" or IMD). In cases of true neonatal AML, the prognosis of patients is poor. Overall survival is around 35 % in the largest historical series. This poor prognosis is mainly due to the period of onset of this pathology making the use of chemotherapy more limited and involving many considerations, both ethical and therapeutic. The objective of this work is to review this rare pathology by addressing the clinical, biological, therapeutic and ethical particularities of patients with true neonatal AML or transient leukemoid reactions occurring in a constitutional trisomy 21 (true TAM) or somatic background (IMD).

Population Pharmacokinetics of Inotuzumab Ozogamicin in Pediatric Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: Results of Study ITCC-059.

BACKGROUND AND OBJECTIVE: Inotuzumab ozogamicin is an antibody-drug conjugate approved for treating relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults. Pediatric pharmacokinetic data of inotuzumab ozogamicin are lacking. This study is the first to examine the population pharmacokinetics of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL. METHODS: From 531 adult patients with B-cell non-Hodgkin's lymphoma, 234 adult patients with BCP-ALL, and 53 pediatric patients with BCP-ALL, 8924 inotuzumab ozogamicin serum concentrations were analyzed using non-linear mixed-effects modeling. A published adult inotuzumab ozogamicin population-pharmacokinetic model, a two-compartment model with linear and time-dependent clearance, was adapted to describe the pediatric data. RESULTS: Modifications in this analysis, compared to the published adult model, included: (i) re-estimating pharmacokinetic parameters and covariate effects; (ii) modifying covariate representation; and (iii) introducing relevant pediatric covariate effects (age on the decay coefficient of time-dependent clearance and ALL effect (disease type and/or different bioanalytical analysis methods) on initial values of time-dependent clearance). For patients with relapsed/refractory BCP-ALL, increasing age was associated with a decreasing decay coefficient of time-dependent clearance, reflecting that the target-mediated drug clearance declines more rapidly in children. In pediatric BCP-ALL, the median [interquartile range] cumulative area under the concentration-time curve was significantly higher among responders (n = 42) versus non-responders (n = 10) at the end of the first cycle (26.1 [18.9-35.0] vs 10.1 [9.19-16.1], × 103 ng*h/mL, p < 0.001). From simulations performed at the recommended pediatric phase II dose, inotuzumab ozogamicin exposure reached a similar level as observed in responding pediatric trial participants. CONCLUSIONS: The pharmacokinetic profile of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL was well described in this study. No dose adjustment is required clinically for pediatric patients with BCP-ALL based on the simulated inotuzumab ozogamicin exposure at the recommended pediatric phase II dose, promising efficacy and acceptable tolerability.