Susan R. Rheingold

Summary: Inotuzumab ozogamicin (InO) is approved by the U.S. Food and Drug Administration (FDA) for relapsed/refractory (R/R) B‐cell acute lymphoblastic leukaemia (B‐ALL), with a standard schedule of 1.8 mg/m ² fractionated into three doses for cycle 1. Alternative dosing with fewer doses or lower cumulative doses may be considered to minimize toxicity or expedite transition to consolidative therapy, though data on the efficacy and toxicity of this approach are limited. We conducted a multi‐institutional retrospective analysis of 72 paediatric, adolescent and young adult (AYA) patients receiving at least one InO dose; 41 with standard dosing and 31 with alternative dosing. Between the two approaches, standard dosing was associated with improved composite complete response (CRc); however, there was no difference in ability to proceed to consolidative cellular therapy, nor differences in 2‐year event‐free or overall survival. Ten per cent of patients experienced sinusoidal obstruction syndrome (SOS), all following haematopoietic stem cell transplant. Most cases occurred in patients receiving standard InO dosing; however, given the overall few cases, it is unclear if this is due to a difference in dosing regimen. In conclusion, this large real‐world study of InO use in the paediatric/AYA R/R B‐ALL population suggests using alternate InO dosing strategies can successfully bridge patients to consolidative therapy with no difference in outcomes compared with standard dosing.

Relapsed acute leukemia can be difficult to salvage. An uncommon but increasingly recognized and aggressive mechanism of relapse involves lineage switch. In lineage switch, the immunophenotype of the leukemia at relapse differs from the immunophenotype at initial diagnosis, with the underlying genetic driver(s) conserved, confirming a clonal relationship. Lineage switch is most common-and was first recognized-in B-cell acute lymphoblastic leukemia with KMT2A rearrangement, which often relapses as acute myeloid leukemia. In an era where antigen-targeted therapies, including chimeric antigen receptor T-cells and bispecific T-cell engagers, are increasingly utilized and thus apply selective antigen pressure, this may increase the incidence of lineage switch across different leukemia subtypes. Patients with lineage switch have dismal outcomes and optimal therapies remain unknown, thus there is a large unmet need to better understand the biology, define the diagnosis, and determine the therapeutic approaches to lineage switch. Here, we address these needs providing a review of the current biology of lineage switch, the relationship to different genetic subtypes and present definitions and recommendations for immunophenotypic and molecular monitoring.

CD19 chimeric antigen receptor T cells (CD19-CAR) are effective at eradicating bone marrow (BM) B-cell acute lymphoblastic leukemia (B-ALL), but efficacy data for the treatment of extramedullary leukemia are lacking. We conducted a multisite, retrospective review of 308 children and young adults who received CD19-CAR and report efficacy in patients with active central nervous system (CNS) disease (CNS cohort, n = 36), active non-CNS extramedullary disease (EMD; n = 21), or isolated BM disease (iBM; n = 251) at infusion. The overall survival (OS) at 24 months in the iBM, EMD, and CNS cohorts was 71.5% (95% confidence interval [CI], 66.0-77.6), 66.7% (95% CI, 49.3-90.2), and 57.0% (95% CI, 42.6-76.3), respectively (P = .032); the corresponding event-free survival (EFS) was 51.8% (95% CI, 45.8-58.6), 45.8% (95% CI, 28.2-74.4), and 35.2% (95% CI, 22.4-55.3) (P = .035). All patients with isolated EMD (n = 5) achieved complete response and did not relapse. Eight patients (80%) with isolated CNS disease (n = 10) had clearing of the CNS, and 3 (37.5%) subsequently relapsed. Concurrent EMD or CNS disease with high BM disease burden (HD) was associated with inferior outcomes when compared with low BM disease burden (LD) in terms of OS (EMD-HD, 41.7% vs EMD-LD, 100%; P = .005; CNS-HD, 33.3% vs CNS-LD, 92.3%; P = .001) and EFS (EMD-HD, 8.3% vs EMD-LD, 100%; P< .001; CNS-HD, 14.3% vs CNS-LD, 63.6%; P< .001). In summary, CD19-CAR may be an effective option for relapsed/refractory B-ALL with active EMD or CNS disease, but concurrent HD predicts inferior outcomes, prompting consideration of enhanced preinfusion evaluation and treatment.

Pediatric Hispanic and Black patients with newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL) experience worse overall survival (OS). We hypothesized that differential outcomes by race and ethnicity following relapse may contribute to disparities. We examined 2053 patients with ALL enrolled in frontline Children’s Oncology Group trials from 1996 to 2014 who relapsed. We assessed the association of race and ethnicity, disease characteristics, and socioeconomic status with relapse survival predictors and postrelapse OS. For noninfant B-ALL, postrelapse OS (P = .002) and disease-related prognosticators such as time to relapse (P = .0002) differed by race and ethnicity. After adjusting for disease and patient characteristics, the OS association with overall race and ethnicity was attenuated, and lost statistical significance; Hispanic ethnicity specifically remained associated with worse OS (hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.01-1.41). Patients from highest annual median household income ZIP codes (>$85 000, approximately the highest quartile of patients) had better 5-year OS than those from the lowest (<$50 000; HR, 0.79; 95% CI, 0.63-0.99). Non-Hispanic Black and Hispanic patients more commonly lived in lower-income ZIP codes. For T-cell ALL, race, ethnicity, and socioeconomic status were not associated with OS. Worse postrelapse outcomes among racial and ethnic minority patients are largely driven by the prevalence of adverse disease-related factors at time of relapse, with a persistent disparity observed in Hispanic patients. The greatest impact in decreasing racial and ethnic B-ALL outcome disparities may be achieved by targeting frontline treatment interventions to address increased relapse among Black and Hispanic patients, and by developing and enabling equitable access to effective relapse treatments such as novel immunotherapies.

PURPOSE: Current care guidelines for children with AML recommend hospitalization during severe neutropenia. However, selected patients discharged before neutrophil recovery have similar chemotherapy course–specific bacteremia and mortality rates to those who remain hospitalized. On the basis of published literature, we developed a toolkit to guide outpatient care after myelosuppressive AML chemotherapy and piloted its implementation at a single institution. We present the pilot clinical and implementation outcomes. METHODS: The AML Care at Home toolkit includes a discharge eligibility assessment tool and outpatient management guidelines for pediatric patients with AML and was implemented on November 15, 2022. Toolkit reach, defined as the proportion of postinduction 1 courses with toolkit use (target: 60%), was the coprimary implementation outcome, and total inpatient days per course was the coprimary clinical outcome. Chart abstractions were used to ascertain total inpatient days per course and other clinical outcome designations. RESULTS: During this pilot implementation program, 22 patients underwent 48 postinduction 1 chemotherapy courses. The toolkit was used in 33 (68.8%) courses. Appropriate toolkit use allowed for early discharge in 21 (43.8%) courses and directed inpatient recovery in 11 (22.9%). Median total inpatient days were markedly fewer for toolkit-guided early-discharge courses (8 days, IQR, 5.5-14.5) than toolkit-guided inpatient-only courses (26 days, IQR, 22-39) or when the toolkit was not used as intended (31 days, IQR, 25.3-34.8). CONCLUSION: Pilot implementation of the AML Care at Home toolkit exceeded our target reach goal and led to fewer inpatient days per course than expected on the basis of previous studies of outpatient neutropenia management. These data reflect the utility of a toolkit created on the basis of published data to identify and support appropriate patients for early hospital discharge and safe outpatient monitoring.

Lineage switch (LS), defined as the immunophenotypic transformation of acute leukemia, has emerged as a mechanism of relapse after antigen-targeted immunotherapy, which is associated with dismal outcomes. Through an international collaborative effort, we identified cases of LS after a host of antigen-targeted therapies (eg, CD19, CD22, CD38, and CD7), described how LS was diagnosed, reviewed treatment approaches, and analyzed overall outcomes for this form of postimmunotherapy relapse. Collectively, 75 cases of LS were evaluated, including 53 (70.7%) cases of B-cell acute lymphoblastic leukemia (B-ALL) transforming to acute myeloid leukemia (AML), 17 (22.7%) cases of B-ALL transforming to mixed phenotypic acute leukemia (MPAL)/acute leukemias of ambiguous lineage (ALAL), and 5 (6.7%) cases of rare LS presentation (ie, T-cell ALL to AML). An additional 10 cases with incomplete changes in immunophenotype, referred to as “lineage drift” were also described. With a primary focus on the 70 cases of LS from B-ALL to AML or MPAL/ALAL, LS emerged at a median of 1.5 months (range, 0-36.5) after immunotherapy, with 81.4% presenting with LS within the first 6 months from the most proximal immunotherapy. Although most involved KMT2A rearrangements (n = 45, 64.3%), other rare cytogenetic and/or molecular alterations were uniquely observed. Treatment outcomes were generally poor, with remission rates of <40%. The median overall survival after LS diagnosis was 4.8 months. Outcomes were similarly poor for those with rare immunophenotypes of LS or lineage drift. This global initiative robustly categorizes lineage changes after immunotherapy and, through enhanced understanding, establishes a foundation for improving outcomes of LS.

Immune effector cell–associated neurotoxicity syndrome (ICANS) is a common but potentially severe adverse event associated with chimeric antigen receptor T-cell (CART) therapy, characterized by the development of acute neurologic symptoms following CART infusion. ICANS encompasses a wide clinical spectrum typified by mild to severe encephalopathy, seizures, and/or cerebral edema. As more patients have been treated with CART, new ICANS phenomenology has emerged. We present the clinical course of 5 children who developed acute onset of quadriparesis or paraparesis associated with abnormal brain and/or spine neuroimaging after infusion of CD19- or CD22-directed CART, adverse events not previously reported in children. Orthogonal data from autopsy studies, cerebrospinal fluid (CSF) flow cytometry, and CSF proteomics/cytokine profiling demonstrated chronic white matter destruction, but a notable lack of inflammatory pathologic changes and cell populations. Instead, children with quadriparesis or paraparesis post-CART therapy had lower levels of proinflammatory cytokines, such as interferon gamma, CCL17, CCL23, and CXCL10, than those who did not develop quadriparesis or paraparesis. Taken together, these findings imply a noninflammatory source of this newly described ICANS phenomenon in children. The pathophysiology of some neurologic symptoms following CART may therefore have a more complex etiology than exclusive T-cell activation and excessive cytokine production.