Publications by authors named "Haneen Shalabi"

20 Publications

  • Page 1 of 1

Case Report: Fatal Complications of BK Virus-Hemorrhagic Cystitis and Severe Cytokine Release Syndrome Following BK Virus-Specific T-Cells.

Front Immunol 2021 17;12:801281. Epub 2021 Dec 17.

Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, United States.

BK virus (BKV)-hemorrhagic cystitis (HC) is a well-known and rarely fatal complication of hematopoietic stem cell transplantation (HSCT). Treatment for BKV-HC is limited, but virus-specific T-cells (VST) represent a promising therapeutic option feasible for use posttransplant. We report on the case of a 16-year-old male with dedicator of cytokinesis 8 (DOCK8) deficiency who underwent haploidentical HSCT complicated by severe BKV-HC, catastrophic renal hemorrhage, and VST-associated cytokine release syndrome (CRS). Gross hematuria refractory to multiple interventions began with initiation of posttransplant cyclophosphamide (PT/Cy). Complete left renal arterial embolization (day +43) was ultimately indicated to control intractable renal hemorrhage. Subsequent infusion of anti-BK VSTs was complicated by CRS and progressive multiorgan failure, with postmortem analysis confirming diagnosis of hepatic sinusoidal obstruction syndrome (SOS). This case illustrates opportunities for improvement in the management of severe BKV-HC posttransplant while highlighting rare and potentially life-threatening complications of BKV-HC and VST therapy.
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http://dx.doi.org/10.3389/fimmu.2021.801281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8718506PMC
December 2021

Characterization of Extramedullary Disease in B-ALL and Response to CAR T-cell Therapy.

Blood Adv 2021 Dec 17. Epub 2021 Dec 17.

Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland, United States.

Chimeric antigen receptor (CAR) T-cells effectively eradicate medullary B-cell acute lymphoblastic leukemia (B-ALL) and can traffic to and clear central nervous system (CNS) involvement. CAR T-cell activity in non¬contral nervous system (CNS) extramedullary disease (EMD) has not been well-characterized. We systematically evaluated CAR T-cell kinetics, associated toxicities, and efficacy in B-ALL non-CNS EMD. We conducted a retrospective review of B-ALL patients with non-CNS EMD who were screened for/enrolled on one of three CAR trials at our institution (CD19, CD22, CD19/22). Non-CNS EMD was identified by histology or radiographic imaging at extramedullary sites excluding the cerebrospinal fluid and CNS parenchyma. Of approximately 180 patients with relapsed/refractory B-ALL screened across multiple early phase trials over an 8-year period, 38 (21.1%) presented with isolated non-CNS EMD (n=5) or combined medullary/non-CNS EMD (n=33) on FDG PET-CT imaging. A subset receiving CAR T-cells (18 infusions) obtained FDG PET-CT scans pre- and post-infusion to monitor response. At best response, 72.2% (13 of 18) of patients demonstrated a medullary MRD-negative complete remission and complete (CR, n=7) or partial (PR, n=6) non-CNS EMD response. Non-CNS EMD responses to CAR T-cells were delayed (n=3) and residual non-CNS EMD was substantial; rarely, discrepant responses (marrow without EMD response) were observed (n=2). Unique CAR-associated toxicities at non-CNS EMD sites were seen in select patients. CAR T-cells are active in B-ALL non-CNS EMD. Still, non-CNS EMD response to CAR T-cells may be delayed and sub-optimal, particularly with multifocal disease. Serial FDG PET-CT scans are necessary for identifying and monitoring non-CNS EMD.
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http://dx.doi.org/10.1182/bloodadvances.2021006035DOI Listing
December 2021

Factors Impacting Overall and Event-Free Survival following Post-Chimeric Antigen Receptor T Cell Consolidative Hematopoietic Stem Cell Transplantation.

Transplant Cell Ther 2021 Oct 20. Epub 2021 Oct 20.

Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address:

Hematopoietic stem cell transplantation (HSCT) may be used to consolidate chimeric antigen receptor (CAR) T cell therapy-induced remissions for patients with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL), but little is known about the factors impacting overall survival (OS) and event-free survival (EFS) for post-CAR hematopoietic stem cell transplantation (HSCT). The present study's primary objective was to identify factors associated with OS and EFS for consolidative HSCT following CAR-induced complete remission (CR) in transplantation-naïve patients. Secondary objectives included evaluation of OS/EFS, relapse-free survival and cumulative incidence of relapse for all patients who proceeded to HSCT, stratified by first and second HSCT, as well as the tolerability of HSCT following CAR-induced remission. This was a retrospective review of children and young adults enrolled on 1 of 3 CAR T cell trials at the National Cancer Institute targeting CD19, CD22, and CD19/22 (ClinicalTrials.gov identifiers NCT01593696, NCT02315612, and NCT03448393) who proceeded directly to HSCT following CAR T cell therapy. Between July 2012 and February 2021, 46 children and young adults with pre-B ALL went directly to HSCT following CAR therapy. Of these patients, 34 (74%) proceeded to a first HSCT, with a median follow-up of 50.8 months. Transplantation-naïve patients were heavily pretreated prior to CAR T cell therapy (median, 3.5 lines of therapy; range, 1 to 12) with significant prior immunotherapy exposure (blinatumomab, inotuzumab, and/or CAR T cell therapy in patients receiving CD22 or CD19/22 constructs (88%; 15 of /17)). Twelve patients (35%) had primary refractory disease, and the median time from CAR T cell infusion to HSCT Day 0 was 54.5 days (range, 42 to 127 days). The median OS following first HSCT was 72.2 months (95% confidence interval [CI], 16.9 months to not estimable [NE]), with a median EFS of 36.9 months (95% CI, 5.2 months to NE). At 12 and 24 months, the OS was 76.0% (95% CI, 57.6% to 87.2%) and 60.7% (95% CI, 40.8% to 75.8%), respectively, and EFS was 64.6% (95% CI, 46.1% to 78.1%) and 50.9% (95% CI, 32.6% to 66.6%), respectively. The individual factors associated with both decreased OS and EFS in univariate analyses for post-CAR consolidative HSCT in transplantation-naïve patients included ≥5 prior lines of therapy (not reached [NR] versus 12.4 months, P = .014; NR versus 4.8 months, P = .063), prior blinatumomab therapy (NR versus 16.9 months, P = .0038; NR versus 4.4 months, P = .0025), prior inotuzumab therapy (NR versus 11.5 months, P = .044; 36.9 months versus 2.7 months, P = .0054) and ≥5% blasts (M2/M3 marrow) pre-CAR T cell therapy (NR versus 17 months, P = .019; NR versus 12.2 months, P = .035). Primary refractory disease was associated with improved OS/EFS post-HSCT (NR versus 21.9 months, P = .075; NR versus 12.2 months, P = .024). Extensive prior therapy, particularly immunotherapy, and high disease burden each individually adversely impacted OS/EFS following post-CAR T cell consolidative HSCT in transplantation-naïve patients, owing primarily to relapse. Despite this, HSCT remains an important treatment modality in long-term cure. Earlier implementation of HSCT before multiply relapsed disease and incorporation of post-HSCT risk mitigation strategies in patients identified to be at high-risk of post-HSCT relapse may improve outcomes.
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http://dx.doi.org/10.1016/j.jtct.2021.10.011DOI Listing
October 2021

Characterization of HLH-like manifestations as a CRS variant in patients receiving CD22 CAR T cells.

Blood 2021 12;138(24):2469-2484

Center for Cellular Engineering, Department of Transfusion Medicine, NIH Clinical Center, Bethesda, MD.

Chimeric antigen receptor (CAR) T-cell toxicities resembling hemophagocytic lymphohistiocytosis (HLH) occur in a subset of patients with cytokine release syndrome (CRS). As a variant of conventional CRS, a comprehensive characterization of CAR T-cell-associated HLH (carHLH) and investigations into associated risk factors are lacking. In the context of 59 patients infused with CD22 CAR T cells where a substantial proportion developed carHLH, we comprehensively describe the manifestations and timing of carHLH as a CRS variant and explore factors associated with this clinical profile. Among 52 subjects with CRS, 21 (40.4%) developed carHLH. Clinical features of carHLH included hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, coagulopathy, hepatic transaminitis, hyperbilirubinemia, severe neutropenia, elevated lactate dehydrogenase, and occasionally hemophagocytosis. Development of carHLH was associated with preinfusion natural killer(NK) cell lymphopenia and higher bone marrow T-cell:NK cell ratio, which was further amplified with CAR T-cell expansion. Following CRS, more robust CAR T-cell and CD8 T-cell expansion in concert with pronounced NK cell lymphopenia amplified preinfusion differences in those with carHLH without evidence for defects in NK cell mediated cytotoxicity. CarHLH was further characterized by persistent elevation of HLH-associated inflammatory cytokines, which contrasted with declining levels in those without carHLH. In the setting of CAR T-cell mediated expansion, clinical manifestations and immunophenotypic profiling in those with carHLH overlap with features of secondary HLH, prompting consideration of an alternative framework for identification and management of this toxicity profile to optimize outcomes following CAR T-cell infusion.
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http://dx.doi.org/10.1182/blood.2021011898DOI Listing
December 2021

Consequences of hemophagocytic lymphohistiocytosis-like cytokine release syndrome toxicities and concurrent bacteremia.

Pediatr Blood Cancer 2021 10 26;68(10):e29247. Epub 2021 Jul 26.

Pediatric Oncology Branch, CCR, NCI, NIH, Bethesda, Maryland, USA.

Serious bacterial infections (SBI) can lead to devastating complications with CD19 CAR T cells and cytokine release syndrome (CRS). Little is known about consequences of and risk factors for SBI with novel CAR T-cell constructs or with CRS complicated by HLH-like toxicities. We report on three patients with B-cell acute lymphoblastic leukemia treated with CD22 CAR T cells who developed SBI and CRS-associated HLH. Serum cytokine profiling revealed sustained elevations well beyond CRS resolution, suggesting ongoing systemic inflammation. Heightened inflammatory states converging with SBI contribute to poor outcomes, and recognition and prevention of extended inflammation may be needed to improve outcomes.
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http://dx.doi.org/10.1002/pbc.29247DOI Listing
October 2021

Long-Term Follow-Up of CD19-CAR T-Cell Therapy in Children and Young Adults With B-ALL.

J Clin Oncol 2021 05 25;39(15):1650-1659. Epub 2021 Mar 25.

Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, MD.

Purpose: CD19 chimeric antigen receptor (CD19-CAR) T cells induce high response rates in children and young adults (CAYAs) with B-cell acute lymphoblastic leukemia (B-ALL), but relapse rates are high. The role for allogeneic hematopoietic stem-cell transplant (alloHSCT) following CD19-CAR T-cell therapy to improve long-term outcomes in CAYAs has not been examined.

Methods: We conducted a phase I trial of autologous CD19.28ζ-CAR T cells in CAYAs with relapsed or refractory B-ALL. Response and long-term clinical outcomes were assessed in relation to disease and treatment variables.

Results: Fifty CAYAs with B-ALL were treated (median age, 13.5 years; range, 4.3-30.4). Thirty-one (62.0%) patients achieved a complete remission (CR), 28 (90.3%) of whom were minimal residual disease-negative by flow cytometry. Utilization of fludarabine/cyclophosphamide-based lymphodepletion was associated with improved CR rates (29/42, 69%) compared with non-fludarabine/cyclophosphamide-based lymphodepletion (2/8, 25%; = .041). With median follow-up of 4.8 years, median overall survival was 10.5 months (95% CI, 6.3 to 29.2 months). Twenty-one of 28 (75.0%) patients achieving a minimal residual disease-negative CR proceeded to alloHSCT. For those proceeding to alloHSCT, median overall survival was 70.2 months (95% CI, 10.4 months to not estimable). The cumulative incidence of relapse after alloHSCT was 9.5% (95% CI, 1.5 to 26.8) at 24 months; 5-year EFS following alloHSCT was 61.9% (95% CI, 38.1 to 78.8).

Conclusion: We provide the longest follow-up in CAYAs with B-ALL after CD19-CAR T-cell therapy reported to date and demonstrate that sequential therapy with CD19.28ζ-CAR T cells followed by alloHSCT can mediate durable disease control in a sizable fraction of CAYAs with relapsed or refractory B-ALL (ClinicalTrials.gov identifier: NCT01593696).
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http://dx.doi.org/10.1200/JCO.20.02262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274806PMC
May 2021

Beyond the storm - subacute toxicities and late effects in children receiving CAR T cells.

Nat Rev Clin Oncol 2021 06 25;18(6):363-378. Epub 2021 Jan 25.

Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA.

As clinical advances with chimeric antigen receptor (CAR) T cells are increasingly described and the potential for extending their therapeutic benefit grows, optimizing the implementation of this therapeutic modality is imperative. The recognition and management of cytokine release syndrome (CRS) marked a milestone in this field; however, beyond the understanding gained in treating CRS, a host of additional toxicities and/or potential late effects of CAR T cell therapy warrant further investigation. A multicentre initiative involving experts in paediatric cell therapy, supportive care and/or study of late effects from cancer and haematopoietic stem cell transplantation was convened to facilitate the comprehensive study of extended CAR T cell-mediated toxicities and establish a framework for new systematic investigations of CAR T cell-related adverse events. Together, this group identified six key focus areas: extended monitoring of neurotoxicity and neurocognitive function, psychosocial considerations, infection and immune reconstitution, other end organ toxicities, evaluation of subsequent neoplasms, and strategies to optimize remission durability. Herein, we present the current understanding, gaps in knowledge and future directions of research addressing these CAR T cell-related outcomes. This systematic framework to study extended toxicities and optimization strategies will facilitate the translation of acquired experience and knowledge for optimal application of CAR T cell therapies.
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http://dx.doi.org/10.1038/s41571-020-00456-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335746PMC
June 2021

Diagnostic approach to the evaluation of myeloid malignancies following CAR T-cell therapy in B-cell acute lymphoblastic leukemia.

J Immunother Cancer 2020 11;8(2)

Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA

Immunotherapeutic strategies targeting B-cell acute lymphoblastic leukemia (B-ALL) effectively induce remission; however, disease recurrence remains a challenge. Due to the potential for antigen loss, antigen diminution, lineage switch or development of a secondary or treatment-related malignancy, the phenotype and manifestation of subsequent leukemia may be elusive. We report on two patients with multiply relapsed/refractory B-ALL who, following chimeric antigen receptor T-cell therapy, developed myeloid malignancies. In the first case, a myeloid sarcoma developed in a patient with a history of myelodysplastic syndrome. In the second case, two distinct events occurred. The first event represented a donor-derived myelodysplastic syndrome with monosomy 7 in a patient with a prior hematopoietic stem cell transplantation. This patient went on to present with lineage switch of her original B-ALL to ambiguous lineage T/myeloid acute leukemia. With the rapidly evolving field of novel immunotherapeutic strategies, evaluation of relapse and/or subsequent neoplasms is becoming increasingly more complex. By virtue of these uniquely complex cases, we provide a framework for the evaluation of relapse or evolution of a subsequent malignancy following antigen-targeted immunotherapy.
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http://dx.doi.org/10.1136/jitc-2020-001563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703409PMC
November 2020

Perforin-deficient CAR T cells recapitulate late-onset inflammatory toxicities observed in patients.

J Clin Invest 2020 10;130(10):5425-5443

Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute (NCI), NIH.

Late-onset inflammatory toxicities resembling hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) occur after chimeric antigen receptor T cell (CAR T cell) infusion and represent a therapeutic challenge. Given the established link between perforin deficiency and primary HLH, we investigated the role of perforin in anti-CD19 CAR T cell efficacy and HLH-like toxicities in a syngeneic murine model. Perforin contributed to both CD8+ and CD4+ CAR T cell cytotoxicity but was not required for in vitro or in vivo leukemia clearance. Upon CAR-mediated in vitro activation, perforin-deficient CAR T cells produced higher amounts of proinflammatory cytokines compared with WT CAR T cells. Following in vivo clearance of leukemia, perforin-deficient CAR T cells reexpanded, resulting in splenomegaly with disruption of normal splenic architecture and the presence of hemophagocytes, which are findings reminiscent of HLH. Notably, a substantial fraction of patients who received anti-CD22 CAR T cells also experienced biphasic inflammation, with the second phase occurring after the resolution of cytokine release syndrome, resembling clinical manifestations of HLH. Elevated inflammatory cytokines such as IL-1β and IL-18 and concurrent late CAR T cell expansion characterized the HLH-like syndromes occurring in the murine model and in humans. Thus, a murine model of perforin-deficient CAR T cells recapitulated late-onset inflammatory toxicities occurring in human CAR T cell recipients, providing therapeutically relevant mechanistic insights.
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http://dx.doi.org/10.1172/JCI130059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524496PMC
October 2020

Impact of cytokine release syndrome on cardiac function following CD19 CAR-T cell therapy in children and young adults with hematological malignancies.

J Immunother Cancer 2020 09;8(2)

National Cancer Institute/Pediatric Oncology Branch, National Institutes of Health, Bethesda, Maryland, USA.

Background: Chimeric antigen receptor (CAR) T-cell-associated cytokine release syndrome (CRS) may present with tachycardia, hemodynamic instability and reduced cardiac function. Pediatric CAR studies examining cardiac toxicity are limited.

Methods: We report on cardiac toxicity observed in children and young adults with hematologic malignancies enrolled in a CD19-28ζ CAR T-cell phase I trial (NCT01593696). All patients had a formal baseline echocardiogram. Real-time studies included echocardiograms on intensive care unit (ICU) transfer, and serial troponin and pro-B-type natriuretic peptide (pro-BNP) in the select patients.

Results: From July 2012 to March 2016, 52 patients, with a median age of 13.4 years (range 4.2-30.3) were treated. CRS developed in 37/52 (71%), which was grade 3-4 CRS in nine patients (17%). The median prior anthracycline exposure was 205 mg/m (range 70-620 mg/m) in doxorubicin equivalents. The median baseline left ventricle ejection fraction (LVEF) and baseline LV global longitudinal strain (GLS) were 60% (range 50%-70%) and 16.8% (range 14.1%-23.5%, n=37) respectively. The majority, 78% (29/37), of patients had a reduced GLS <19% at baseline, and 6% (3/52) of patients had baseline LVEF <53%. ICU transfers occurred in 21 patients, with nine requiring vasoactive hemodynamic support and three necessitating >1 vasopressor. Six (12%) patients developed cardiac dysfunction (defined by >10% absolute decrease in LVEF or new-onset grade 2 or higher LV dysfunction, per CTCAE v4), among whom 4 had grade 3-4 CRS. Troponin elevations were seen in 4 of 13 patients, all of whom had low LVEF. Pro-BNP was elevated from baseline in 6/7 patients at the onset of CRS, with higher levels correlating with more severe CRS. Cardiac dysfunction fully resolved in all but two patients by day 28 post-CAR.

Conclusion: Cardiac toxicity related to CD19-28ζ CAR T-cell-associated CRS was generally reversible by day 28 postinfusion. Implementation of more frequent monitoring with formal echocardiograms incorporating systemic analysis of changes in GLS, and cardiac biomarkers (troponin and proBNP) may help to earlier identify those patients at highest risk of severe cardiac systolic dysfunction, facilitating earlier interventions for CRS to potentially mitigate acute cardiac toxicity.
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http://dx.doi.org/10.1136/jitc-2020-001159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473612PMC
September 2020

CD4/CD8 T-Cell Selection Affects Chimeric Antigen Receptor (CAR) T-Cell Potency and Toxicity: Updated Results From a Phase I Anti-CD22 CAR T-Cell Trial.

J Clin Oncol 2020 06 14;38(17):1938-1950. Epub 2020 Apr 14.

Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Purpose: Patients with B-cell acute lymphoblastic leukemia who experience relapse after or are resistant to CD19-targeted immunotherapies have limited treatment options. Targeting CD22, an alternative B-cell antigen, represents an alternate strategy. We report outcomes on the largest patient cohort treated with CD22 chimeric antigen receptor (CAR) T cells.

Patients And Methods: We conducted a single-center, phase I, 3 + 3 dose-escalation trial with a large expansion cohort that tested CD22-targeted CAR T cells for children and young adults with relapsed/refractory CD22 malignancies. Primary objectives were to assess the safety, toxicity, and feasibility. Secondary objectives included efficacy, CD22 CAR T-cell persistence, and cytokine profiling.

Results: Fifty-eight participants were infused; 51 (87.9%) after prior CD19-targeted therapy. Cytokine release syndrome occurred in 50 participants (86.2%) and was grade 1-2 in 45 (90%). Symptoms of neurotoxicity were minimal and transient. Hemophagocytic lymphohistiocytosis-like manifestations were seen in 19/58 (32.8%) of subjects, prompting utilization of anakinra. CD4/CD8 T-cell selection of the apheresis product improved CAR T-cell manufacturing feasibility as well as heightened inflammatory toxicities, leading to dose de-escalation. The complete remission rate was 70%. The median overall survival was 13.4 months (95% CI, 7.7 to 20.3 months). Among those who achieved a complete response, the median relapse-free survival was 6.0 months (95% CI, 4.1 to 6.5 months). Thirteen participants proceeded to stem-cell transplantation.

Conclusion: In the largest experience of CD22 CAR T-cells to our knowledge, we provide novel information on the impact of manufacturing changes on clinical outcomes and report on unique CD22 CAR T-cell toxicities and toxicity mitigation strategies. The remission induction rate supports further development of CD22 CAR T cells as a therapeutic option in patients resistant to CD19-targeted immunotherapy.
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http://dx.doi.org/10.1200/JCO.19.03279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280047PMC
June 2020

Serial evaluation of CD19 surface expression in pediatric B-cell malignancies following CD19-targeted therapy.

Leukemia 2020 11 26;34(11):3064-3069. Epub 2020 Feb 26.

Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, MD, USA.

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http://dx.doi.org/10.1038/s41375-020-0760-xDOI Listing
November 2020

Disease detection methodologies in relapsed B-cell acute lymphoblastic leukemia: Opportunities for improvement.

Pediatr Blood Cancer 2020 04 25;67(4):e28149. Epub 2020 Jan 25.

Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), NIH, Bethesda, Maryland.

Background: Accurate disease detection is integral to risk stratification in B-cell acute lymphoblastic leukemia (ALL). The gold standard used to evaluate response in the United States includes morphologic evaluation and minimal residual disease (MRD) testing of aspirated bone marrow (BM) by flow cytometry (FC). This MRD assessment is usually made on a single aspirate sample that is subject to variability in collection techniques and sampling error. Additionally, central nervous system (CNS) assessments for ALL include evaluations of cytopathology and cell counts, which can miss subclinical involvement.

Procedure: We retrospectively compared BM biopsy, aspirate, and FC samples obtained from children and young adults with relapsed/refractory ALL to identify the frequency and degree of disease discrepancies in this population. We also compared CNS FC and cytopathology techniques.

Results: Sixty of 410 (14.6%) BM samples had discrepant results, 41 (10%) of which were clinically relevant as they resulted in a change in the assignment of marrow status. Discrepant BM results were found in 28 of 89 (31.5%) patients evaluated. Additionally, cerebrospinal fluid (CSF) FC identified disease in 9.7% of cases where cytopathology was negative.

Conclusions: These results support further investigation of the role of concurrent BM biopsy, with aspirate and FC evaluations, and the addition of FC to CSF evaluations, to fully assess disease status and response, particularly in patients with relapsed/refractory ALL. Prospective studies incorporating more comprehensive analysis to evaluate the impact on clinical outcomes are warranted.
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http://dx.doi.org/10.1002/pbc.28149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036332PMC
April 2020

Invasive fusariosis masquerading as extramedullary disease in rapidly progressive acute lymphoblastic leukemia.

Pediatr Blood Cancer 2019 07 22;66(7):e27732. Epub 2019 Mar 22.

Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Invasive fusariosis (IF) most commonly occurs in patients with hematologic malignancies and severe neutropenia, particularly during concomitant corticosteroid use. Breakthrough infections can occur in high-risk patients despite Aspergillus-active antifungal prophylaxis. We describe a patient with rapid acute lymphoblastic leukemia (ALL) progression who presented with multifocal skin nodules thought to be choloromatous disease. These lesions were ultimately diagnosed as IF and the patient had two simultaneously active disease processes. This case highlights the importance of pathologic diagnosis of new skin lesions in ALL patients, even during leukemia progression, and demonstrates that IF can occur despite normal neutrophil counts and Aspergillus-active prophylaxis.
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http://dx.doi.org/10.1002/pbc.27732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237328PMC
July 2019

Systematic Evaluation of Neurotoxicity in Children and Young Adults Undergoing CD22 Chimeric Antigen Receptor T-Cell Therapy.

J Immunother 2018 Sep;41(7):350-358

Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda.

Neurotoxicity associated with CAR-T cell therapy can be life-threatening. With rapid development of CAR-T therapies, a systematic method is needed to identify and monitor symptoms of neurotoxicity, elucidate potential etiologies, and compare toxicity across trials. This paper presents a systematic evaluation developed and used to prospectively assess neurotoxicity in our phase I anti-CD22 CAR-T-cell trial and describes the symptoms of neurotoxicity identified using this methodology. Central nervous system (CNS) studies included routine lumbar punctures performed for disease evaluation pretherapy and posttherapy and a baseline brain MRI. Brief cognitive evaluations, assessing 4 domains (attention, working memory, cognitive flexibility, and processing speed), were administered preinfusion and postinfusion. A newly developed CAR-T-specific neurological symptom checklist (NSC) was completed by caregivers at 3 designated time-points. Serial serum cytokine levels were compared with neurotoxicity symptoms and severity. The majority of the first 22 consecutively treated subjects (ages, 7-30) demonstrated stable or improved cognitive test scores following therapy and no irreversible neurotoxicity, despite CAR-T-related antileukemic response, cytokine release syndrome, and trafficking of CAR-T cells to the CSF. The NSC allowed us to document the type and timing of symptoms and explore the etiology of neurotoxicity associated with CD22 CAR-T therapy. Cytokine profiling demonstrated that more concerning symptoms of neurotoxicity, such as hallucination and disorientation, were significantly associated with higher serum cytokine levels, supporting the hypothesis of inflammation-driven neurotoxicity. Systematic assessments of neurotoxicity were feasible in acutely ill children and young adults and served to characterize and monitor the symptoms associated with CAR-T therapy. We recommend these evaluations be incorporated into future immunotherapy protocols.
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http://dx.doi.org/10.1097/CJI.0000000000000241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086728PMC
September 2018

CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy.

Nat Med 2018 01 20;24(1):20-28. Epub 2017 Nov 20.

Department of Pediatrics and Standford Cancer Center, Stanford University, Stanford, California, USA.

Chimeric antigen receptor (CAR) T cells targeting CD19 mediate potent effects in relapsed and/or refractory pre-B cell acute lymphoblastic leukemia (B-ALL), but antigen loss is a frequent cause of resistance to CD19-targeted immunotherapy. CD22 is also expressed in most cases of B-ALL and is usually retained following CD19 loss. We report results from a phase 1 trial testing a new CD22-targeted CAR (CD22-CAR) in 21 children and adults, including 17 who were previously treated with CD19-directed immunotherapy. Dose-dependent antileukemic activity was observed, with complete remission obtained in 73% (11/15) of patients receiving ≥1 × 10 CD22-CAR T cells per kg body weight, including 5 of 5 patients with CD19 or CD19 B-ALL. Median remission duration was 6 months. Relapses were associated with diminished CD22 site density that likely permitted CD22 cell escape from killing by CD22-CAR T cells. These results are the first to establish the clinical activity of a CD22-CAR in B-ALL, including leukemia resistant to anti-CD19 immunotherapy, demonstrating potency against B-ALL comparable to that of CD19-CAR at biologically active doses. Our results also highlight the critical role played by antigen density in regulating CAR function.
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http://dx.doi.org/10.1038/nm.4441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5774642PMC
January 2018

Beyond CD19: Opportunities for Future Development of Targeted Immunotherapy in Pediatric Relapsed-Refractory Acute Leukemia.

Front Pediatr 2015 1;3:80. Epub 2015 Oct 1.

Hematologic Malignancies Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, MD , USA.

Chimeric antigen receptor (CAR) T cell therapy has been used as a targeted approach in cancer therapy. Relapsed and refractory acute leukemia in pediatrics has been difficult to treat with conventional therapy due to dose-limiting toxicities. With the recent success of CD 19 CAR in pediatric patients with B cell acute lymphoblastic leukemia (ALL), this mode of therapy has become a very attractive option for these patients with high-risk disease. In this review, we will discuss current treatment paradigms of pediatric acute leukemia and potential therapeutic targets for additional high-risk populations, including T cell ALL, AML, and infant ALL.
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http://dx.doi.org/10.3389/fped.2015.00080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589648PMC
October 2015

Prolonged Complete Response in a Pediatric Patient With Primary Peripheral T-Cell Lymphoma of the Central Nervous System.

Pediatr Hematol Oncol 2015 18;32(8):529-34. Epub 2015 Sep 18.

e Food and Drug Administration , Silver Spring , Maryland , USA.

We describe a child with a 2-week history of progressive headaches, blurry vision, and intermittent vomiting. Magnetic resonance imaging (MRI) of the brain showed a deep left hemispheric lesion with extension into the corpus callosum. Histology and immunophenotyping of the lesion was consistent with peripheral T-cell lymphoma, not otherwise specified. Chemotherapy was initiated and a complete remission was achieved. This case illustrates that a chemotherapeutic regimen used in adults with central nervous system (CNS) lymphoma can achieve durable remissions in pediatric patients with peripheral T-cell lymphoma, not otherwise specified of the CNS.
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http://dx.doi.org/10.3109/08880018.2015.1074325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942274PMC
September 2016
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