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NEW TARGETED THERAPIES FOR RELAPSED PEDIATRIC LYMPHOBLASTIC LEUKEMIA

Pierro, Joanna; Hogan, Laura E; Bhatla, Teena; Carroll, William L
INTRODUCTION: The improvement in outcomes for children with acute lymphoblastic leukemia (ALL) is one of the greatest success stories of modern oncology however the prognosis for patients who relapse remains dismal. Recent discoveries by high resolution genomic technologies have characterized the biology of relapsed leukemia, most notably pathways leading to the drug resistant phenotype. These observations open the possibility of targeting such pathways to prevent and/or treat relapse. Likewise, early experiences with new immunotherapeutic approaches have shown great promise. Areas Covered: We performed a literature search on PubMed and recent meeting abstracts using the keywords below. We focus on the biology and clonal evolution of relapsed disease and highlight potential new targets of therapy. We further summarize the results of early trials of the three most prominent immunotherapy agents currently under investigation. Expert Commentary: Discovery of targetable pathways that lead to drug resistance and recent breakthroughs in immunotherapy show great promise towards treating this aggressive disease. The best way to treat relapse, however, is to prevent it which makes incorporation of these new approaches into frontline therapy the best approach. Challenges remain to balance efficacy with toxicity and to prevent the emergence of resistant subclones which is why combining these newer agents with conventional chemotherapy will likely become standard of care.
PMCID:6028000
PMID: 28649891
ISSN: 1744-8328
CID: 2614552

Primary Ewing Sarcoma of the Mastoid: A Novel Case Mimicking Acute Mastoiditis

Egan, Grace; Pierro, Joanna; Madhusoodhan, Pillai Pallavi; Ilyas, Ghulam; Cohen, Benjamin; Bhatla, Teena
Ewing sarcoma (EWS) is a primitive neuroectodermal tumor arising in bone or soft tissue. It is the second most common primary bone malignancy of children and adolescents, with a peak incidence in the second decade of life. It most often arises in the long bones of the extremities and pelvis. Here, we present a novel case of EWS arising from the mastoid bone in a 5-year-old African American male who presented with symptoms of acute mastoiditis. This unique presentation highlights the importance of considering EWS in a patient who presents with atypical mastoiditis or a rapidly growing mass in the postauricular region.
PMID: 29176463
ISSN: 1536-3678
CID: 2798222

Adult Langerhans Cell Histiocytosis As a Diagnostic Pitfall [Case Report]

Pierro, Joanna; Vaiselbuh, Sarah R
PMID: 24958830
ISSN: 1527-7755
CID: 3225802

NSD2 E1099K drives relapse in pediatric acute lymphoblastic leukemia by disrupting 3D chromatin organization

Narang, Sonali; Evensen, Nikki A; Saliba, Jason; Pierro, Joanna; Loh, Mignon L; Brown, Patrick A; Kolekar, Pandurang; Mulder, Heather; Shao, Ying; Easton, John; Ma, Xiaotu; Tsirigos, Aristotelis; Carroll, William L
BACKGROUND:The NSD2 p.E1099K (EK) mutation is shown to be enriched in patients with relapsed acute lymphoblastic leukemia (ALL), indicating a role in clonal evolution and drug resistance. RESULTS:To uncover 3D chromatin architecture-related mechanisms underlying drug resistance, we perform Hi-C on three B-ALL cell lines heterozygous for NSD2 EK. The NSD2 mutation leads to widespread remodeling of the 3D genome, most dramatically in terms of compartment changes with a strong bias towards A compartment shifts. Systematic integration of the Hi-C data with previously published ATAC-seq, RNA-seq, and ChIP-seq data show an expansion in H3K36me2 and a shrinkage in H3K27me3 within A compartments as well as increased gene expression and chromatin accessibility. These results suggest that NSD2 EK plays a prominent role in chromatin decompaction through enrichment of H3K36me2. In contrast, we identify few changes in intra-topologically associating domain activity. While compartment changes vary across cell lines, a common core of decompacting loci are shared, driving the expression of genes/pathways previously implicated in drug resistance. We further perform RNA sequencing on a cohort of matched diagnosis/relapse ALL patients harboring the relapse-specific NSD2 EK mutation. Changes in patient gene expression upon relapse significantly correlate with core compartment changes, further implicating the role of NSD2 EK in genome decompaction. CONCLUSIONS:In spite of cell-context-dependent changes mediated by EK, there appears to be a shared transcriptional program dependent on compartment shifts which could explain phenotypic differences across EK cell lines. This core program is an attractive target for therapeutic intervention.
PMCID:10071675
PMID: 37016431
ISSN: 1474-760x
CID: 5463712

v-SYMPHONY career development series: A collaboration to enhance professional awareness for pediatric hematology oncology trainees

Tal, Adit L; Bailey, Kayleen A; Chou, Alexander; Offer, Katharine; Rosenblum, Jeremy; Moerdler, Scott; Askew, Megan; Roberts, Stephen; Vagrecha, Anshul; Orsey, Andrea; Robbins, Gabriel; Satwani, Prakash; Pierro, Joanna; Levine, Jennifer
BACKGROUND:A recent survey of pediatric hematology oncology (PHO) physicians identified that a majority believe fellows are struggling to find jobs that align with their goals. Career development for trainees has historically been home institution-specific, limiting fellows' exposures to career path possibilities. The "virtual-Symposium of Pediatric Hematology/Oncology of New York (v-SYMPHONY)" instituted a tristate Career Development Series for PHO trainees to better address their needs and increase awareness of the variety of PHO career opportunities. PROCEDURE/METHODS:The v-SYMPHONY Career Development Series incorporated three sessions: (a) institutional perspective, (b) individual perspectives, and (c) nuts and bolts of job search. Pre- and post-series surveys were administered to participants to measure impact. RESULTS:Forty-one fellows registered for the series and completed a pre-survey. Over half (54%) were in their third or later year of fellowship. Careers with a clinical focus were the most commonly desired career path (59%). Most had received career development advice only from faculty within their institutions (90%). Post-surveys were completed by 11 PHO fellows. Overall, 100% of respondents reported benefiting from the career sessions and recommended the series should be repeated annually. Over 90% learned new information to prepare for the job search. CONCLUSIONS:The v-SYMPHONY Career Development Series for PHO fellows across multiple institutions was established and was extremely well received by its participants. PHO fellows agreed that these sessions were beneficial in helping prepare them for the job search process. An annual regional Career Development Series is feasible and is strongly suggested to support PHO fellows.
PMID: 36573297
ISSN: 1545-5017
CID: 5409552

Do Not Forget About the Ticks: An Unusual Cause of Fever, GI Distress, and Cytopenias in a Child With ALL

Ungar, Stephanie P; Varkey, Joyce; Pierro, Joanna; Raetz, Elizabeth; Ratner, Adam J
We report the case of a 5-year-old male with B-cell acute lymphoblastic leukemia in remission, receiving maintenance chemotherapy, who presented with fever, emesis, diarrhea, headache, and lethargy. He developed rapidly progressive cytopenias and was found to have acute human granulocytic anaplasmosis as well as evidence of past infection with Babesia microti. The case highlights the need to maintain a broad differential for infection in children undergoing chemotherapy or other immunosuppressive therapies with possible or known tick exposure.
PMID: 34935737
ISSN: 1536-3678
CID: 5108892

Activation of the mitogen-activated protein kinase-extracellular signal-regulated kinase pathway in childhood B-cell acute lymphoblastic leukemia

Pillai, Pallavi M; Mallory, Nicole; Pierro, Joanna; Saliba, Jason; Newman, Daniel; Hu, Jiyuan; Bhatla, Teena; Raetz, Elizabeth; Carroll, William L; Evensen, Nikki A
RAS mutations are frequently observed in childhood B-cell acute lymphoblastic leukemia (B-ALL) and previous studies have yielded conflicting results as to whether they are associated with a poor outcome. We and others have demonstrated that the mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK) pathway can be activated through epigenetic mechanisms in the absence of RAS pathway mutations. Herein, we examined whether MAPK activation, as determined by measuring phosphorylated extracellular signal-regulated kinase (pERK) levels in 80 diagnostic patient samples using phosphoflow cytometry, could be used as a prognostic biomarker for pediatric B-ALL. The mean fluorescence intensity of pERK (MFI) was measured at baseline and after exogenous stimulation with or without pretreatment with the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib. Activation levels (MFI stimulated/MFI baseline) ranged from 0.76 to 4.40 (median = 1.26), and inhibition indexes (MFI stimulated/MFI trametinib stimulated) ranged from 0.439 to 5.640 (median = 1.30), with no significant difference between patients with wildtype versus mutant RAS for either. Logistic regression demonstrated that neither MAPK activation levels nor RAS mutation status at diagnosis alone or in combination was prognostic of outcome. However, 35% of RAS wildtype samples showed MAPK inhibition indexes greater than the median, thus raising the possibility that therapeutic strategies to inhibit MAPK activation may not be restricted to patients whose blasts display Ras pathway defects.
PMID: 35593589
ISSN: 1545-5017
CID: 5247702

Levocarnitine for pegaspargase-induced hepatotoxicity in older children and young adults with acute lymphoblastic leukemia

Schulte, Rachael; Hinson, Ashley; Huynh, Van; Breese, Erin H; Pierro, Joanna; Rotz, Seth; Mixon, Benjamin A; McNeer, Jennifer L; Burke, Michael J; Orgel, Etan
BACKGROUND:Pegaspargase (PEG-ASP) is an integral component of therapy for acute lymphoblastic leukemia (ALL) but is associated with hepatotoxicity that may delay or limit future therapy. Obese and adolescent and young adult (AYA) patients are at high risk. Levocarnitine has been described as potentially beneficial for the treatment or prevention of PEG-ASP-associated hepatotoxicity. METHODS:We collected data for patients age ≥10 years who received levocarnitine during induction therapy for ALL, compared to a similar patient cohort who did not receive levocarnitine. The primary endpoint was conjugated bilirubin (c.bili) >3 mg/dl. Secondary endpoints were transaminases >10× the upper limit of normal and any Grade ≥3 hepatotoxicity. RESULTS:Fifty-two patients received levocarnitine for prophylaxis (n = 29) or rescue (n = 32) of hepatotoxicity. Compared to 109 patients without levocarnitine, more patients receiving levocarnitine were obese and/or older and had significantly higher values for some hepatotoxicity markers at diagnosis and after PEG-ASP. Levocarnitine regimens varied widely; no adverse effects of levocarnitine were identified. Obesity and AYA status were associated with an increased risk of conjugated hyperbilirubinemia and severe transaminitis. Multivariable analysis identified a protective effect of levocarnitine on the development of c.bili >3 mg/dl (OR 0.12, p = 0.029). There was no difference between groups in CTCAE Grade ≥3 hepatotoxicity. C.bili >3 mg/dl during induction was associated with lower event-free survival. CONCLUSIONS:This real-world data on levocarnitine supplementation during ALL induction highlights the risk of PEG-ASP-associated hepatotoxicity in obese and AYA patients, and hepatotoxicity's potential impact on survival. Levocarnitine supplementation may be protective, but prospective studies are needed to confirm these findings.
PMCID:8559504
PMID: 34528411
ISSN: 2045-7634
CID: 5067262

Characterization of COVID-19 disease in pediatric oncology patients: The New York-New Jersey regional experience

Madhusoodhan, P Pallavi; Pierro, Joanna; Musante, Jordan; Kothari, Prachi; Gampel, Bradley; Appel, Burton; Levy, Adam; Tal, Adit; Hogan, Laura; Sharma, Archana; Feinberg, Shari; Kahn, Alissa; Pinchinat, Ashley; Bhatla, Teena; Glasser, Chana L; Satwani, Prakash; Raetz, Elizabeth A; Onel, Kenan; Carroll, William L
PURPOSE/OBJECTIVE:Pediatric oncology patients undergoing active chemotherapy are suspected to be at a high risk for severe disease secondary to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection; however, data to support this are lacking. We aim to describe the characteristics of coronavirus disease 2019 (COVID-19) in this population and also its impact on pediatric cancer care in the New York region during the peak of the pandemic. PATIENTS AND METHODS/METHODS:This multicenter, retrospective study included 13 institutions. Clinical and laboratory information on 98 patients ≤21 years of age receiving active anticancer therapy, who tested positive for SARS-CoV-2 by nasopharyngeal swab polymerase chain reaction (PCR), was collected. RESULTS:Of the 578 pediatric oncology patients tested for COVID-19, 98 were positive, of whom 73 were symptomatic. Most experienced mild disease, 28 required inpatient management, 25 needed oxygen support, and seven required mechanical ventilation. There is a slightly higher risk of severe disease in males and obese patients, though not statistically significant. Persistent lymphopenia was noted in severe cases. Delays in cancer therapy occurred in 67% of SARS-CoV-2-positive patients. Of four deaths, none were solely attributable to COVID-19. The impact of the pandemic on pediatric oncology care was significant, with 54% of institutions reporting delays in chemotherapy, 46% delays in surgery, and 30% delays in transplant. CONCLUSION/CONCLUSIONS:In this large multi-institutional cohort, we observed that mortality and morbidity from COVID-19 amongst pediatric oncology patients were low overall, but higher than reported in general pediatrics. Certain subgroups might be at higher risk of severe disease. Delays in cancer care due to SARS-CoV-2 remain a concern.
PMID: 33338306
ISSN: 1545-5017
CID: 4718302

Immunotherapy in Pediatric B-Cell Acute Lymphoblastic Leukemia: Advances and Ongoing Challenges

Jasinski, Sylwia; De Los Reyes, Francis Andrew; Yametti, Gloria Contreras; Pierro, Joanna; Raetz, Elizabeth; Carroll, William L
Leukemia, most commonly B-cell acute lymphoblastic leukemia (B-ALL), accounts for about 30% of childhood cancer diagnoses. While there have been dramatic improvements in childhood ALL outcomes, certain subgroups-particularly those who relapse-fare poorly. In addition, cure is associated with significant short- and long-term side effects. Given these challenges, there is great interest in novel, targeted approaches to therapy. A number of new immunotherapeutic agents have proven to be efficacious in relapsed or refractory disease and are now being investigated in frontline treatment regimens. Blinatumomab (a bispecific T-cell engager that targets cluster of differentiation [CD]-19) and inotuzumab ozogamicin (a humanized antibody-drug conjugate to CD22) have shown the most promise. Chimeric antigen receptor T (CAR-T) cells, a form of adoptive immunotherapy, rely on the transfer of genetically modified effector T cells that have the potential to persist in vivo for years, providing ongoing long-term disease control. In this article, we discuss the clinical biology and treatment of B-ALL with an emphasis on the role of immunotherapy in overcoming the challenges of conventional cytotoxic therapy. As immunotherapy continues to move into the frontline of pediatric B-ALL therapy, we also discuss strategies to address unique side effects associated with these agents and efforts to overcome mechanisms of resistance to immunotherapy.
PMID: 32860590
ISSN: 1179-2019
CID: 4587042