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Impaired Humoral Immunity to SARS-CoV-2 Vaccination in Non-Hodgkin Lymphoma and CLL Patients

Diefenbach, Catherine; Caro, Jessica; Koide, Akiko; Grossbard, Michael; Goldberg, Judith D; Raphael, Bruce; Hymes, Kenneth; Moskovits, Tibor; Kreditor, Maxim; Kaminetzky, David; Fleur-Lominy, Shella Saint; Choi, Jun; Thannickal, Sara A; Stapleford, Kenneth A; Koide, Shohei
Patients with hematologic malignancies are a high priority for SARS-CoV-2 vaccination, yet the benefit they will derive is uncertain. We investigated the humoral response to vaccination in 53 non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), or CLL patients. Peripheral blood was obtained 2 weeks after first vaccination and 6 weeks after second vaccination for antibody profiling using the multiplex bead-binding assay. Serum IgG, IgA, and IgM antibody levels to the spike specific receptor binding domain (RBD) were evaluated as a measure of response. Subsequently, antibody-positive serum were assayed for neutralization capacity against authentic SARS-CoV-2. Histology was 68% lymphoma and 32% CLL; groups were: patients receiving anti-CD20-based therapy (45%), monitored with disease (28%), receiving BTK inhibitors (19%), or chemotherapy (all HL) (8%). SARS-CoV-2 specific RBD IgG antibody response was decreased across all NHL and CLL groups: 25%, 73%, and 40%, respectively. Antibody IgG titers were significantly reduced (p < 0.001) for CD20 treated and targeted therapy patients, and (p = 0.003) for monitored patients. In 94% of patients evaluated after first and second vaccination, antibody titers did not significantly boost after second vaccination. Only 13% of CD20 treated and 13% of monitored patients generated neutralizing antibodies to SARS-CoV-2 with ICD50s 135 to 1767, and 445 and > 10240. This data has profound implications given the current guidance relaxing masking restrictions and for timing of vaccinations. Unless immunity is confirmed with laboratory testing, these patients should continue to mask, socially distance, and to avoid close contact with non-vaccinated individuals.
PMID: 34100025
ISSN: n/a
CID: 4899722

Evolution of the epigenetic landscape in childhood B acute lymphoblastic leukemia and its role in drug resistance

Saint Fleur-Lominy, Shella; Evensen, Nikki A; Bhatla, Teena; Sethia, Gunjan; Narang, Sonali; Choi, Jun H; Ma, Xiaotu; Yang, Jun J; Kelly, Stephen; Raetz, Elizabeth; Harvey, Richard C; Willman, Cheryl; Loh, Mignon L; Hunger, Stephen P; Brown, Patrick A; Getz, Kylie M; Meydan, Cem; Mason, Christopher E; Tsirigos, Aristotelis; Carroll, William L
Although B cell acute lymphoblastic leukemia (ALL) is the most common malignancy in children and while highly curable, it remains a leading cause of cancer-related mortality. The outgrowth of tumor subclones carrying mutations in genes responsible for resistance to therapy has led to a Darwinian model of clonal selection. Previous work has indicated that alterations in the epigenome might contribute to clonal selection yet the extent to which the chromatin state is altered under the selective pressures of therapy is unknown. To address this, we performed chromatin immunoprecipitation, gene expression analysis, and enhanced reduced representation bisulfite sequencing on a cohort of paired diagnosis and relapse samples from individual patients who all but one relapsed within 36 months of initial diagnosis. The chromatin state at diagnosis varied widely among patients: while the majority of peaks remained stable between diagnosis and relapse, yet a significant fraction were either lost or newly gained with some patients showing few differences and others showing massive changes of the epigenetic state. Evolution of the epigenome was associated with pathways previously linked to therapy resistance as well as novel candidate pathways through alterations in pyrimidine biosynthesis and downregulation of polycomb repressive complex 2 targets. Three novel, relapse-specific super-enhancers were shared by a majority of patients including one associated with S100A8, the top upregulated gene seen at relapse in childhood B-ALL. Overall, our results support a role of the epigenome in clonal evolution and uncover new candidate pathways associated with relapse.
PMID: 33067268
ISSN: 1538-7445
CID: 4641772

Targeting Apoptosis in Acute Myeloid Leukemia: Current Status and Future Directions of BCL-2 Inhibition with Venetoclax and Beyond

Choi, Jun H; Bogenberger, James M; Tibes, Raoul
Acute myeloid leukemia (AML) is a disease of the hematopoietic system that remains a therapeutic challenge despite advances in our understanding of the underlying cancer biology over the past decade. Recent developments in molecular targeting have shown promising results in treating leukemia, paving the way for novel treatment strategies. The discovery of drugs that promote apoptosis in leukemic cells has translated to encouraging activity in clinical trials. B-cell lymphoma (BCL)-2 inhibition has been at the center of drug development efforts to target apoptosis in AML. Remarkable clinical success with venetoclax has revolutionized the ways we treat hematological malignancies. Several landmark trials have demonstrated the potent antitumor activity of venetoclax, and it is now frequently combined with traditional cytotoxic agents to treat AML. However, resistance to BCL-2 inhibition is emerging, and alternative strategies to address resistance mechanisms have become an important focus of research. A number of clinical trials are now underway to investigate a plurality of novel agents that were shown to overcome resistance to BCL-2 inhibition in preclinical models. Some of the most promising data come from studies on drugs that downregulate myeloid cell leukemia (MCL)-1, such as cyclin-dependent kinases (CDK) inhibitors. Furthermore, innovative approaches to target apoptosis via extrinsic pathways and p53 regulation have added new cytotoxic agents to the arsenal, including drugs that inhibit inhibitor of apoptosis protein (IAP) family proteins and murine double minute 2 (MDM2). This review provides a perspective on past and current treatment strategies harnessing various mechanisms of apoptosis to target AML and highlights some important promising treatment combinations in development.
PMID: 32319019
ISSN: 1776-260x
CID: 4397122

Pegasperagase Toxicity in Adult Patients with Acute Lymphoblastic Leukemia: A Single Center Experience Comparing Patients Older and Younger Than 35 Years of Age [Meeting Abstract]

Choi, J H; Azzi, J; Hochman, T; Nierodzik, M L R; Saint, Fleur-Lominy S; Abdul, Hay M
Background: The treatment paradigm of adult patients with acute lymphoblastic leukemia (ALL) is primarily derived from successful pediatric chemotherapy regimens. Pegasparagase (PEG) is a key component of pediatric therapy and is the backbone of cytotoxic ALL regimens. However, among the adult population the use of PEG has been limited by the difficulty in tolerating prolonged asparagine depletion. Hepatotoxicity is among the most common adverse events reported with the use of PEG, with grade 3/4 hepatotoxicity seen in 20% of young adults compared to 40-60% of older adults. Incorporating PEG into the treatment of ALL patients under 40 remains an accepted practice despite some studies that report up to 75% of patients have grade 3/4 adverse events as a result of asparagine depletion. In a study of 85 patients with ALL, 3-year overall survival (OS) was significantly different between patients older and younger than 35 (52% vs 83% p = 0.003). Whether this difference is due to PEG toxicity or to other factors remains to be determined. At NYU hospitals, PEG-containing protocols are frequently deployed to treat adult ALL. In our study, we sought to look at the difference in PEG toxicity and response rate (RR) in patients older and younger than 35 and whether these toxicities contributed to a delay in subsequent treatments and to a worse outcome. XXMethod(s): We conducted a retrospective chart review of patients older than 18 diagnosed with ALL or lymphoblastic lymphoma, who received at least 1 dose of PEG at our institution between 2014 and 2018. All patients received PEG as part of their first line treatment protocol. Our main objective was to compare the tolerability and toxicity profile of intravenous PEG in patients >=35 years old versus <35. Our secondary objective was to investigate its effects on chemotherapy delay, RR, and relapse rate. XX= 35 (46%). Mean age was 34.4 (Range: 18.9-63.1). The 2 groups shared similar distributions in gender, race, and Philadelphia chromosome (Ph) subtypes (Table 1). The older group received significantly less PEG, 5114.8 vs. 25353.7 units (p=0.0007) and 1.65 vs. 3.59 doses (p<0.0001) compared to the younger group. Grade 1-4 toxicity profiles were similar as both groups had high hepatotoxicity rates: transaminitis 100% vs. 89% (p=0.079) and hyperbilirubinemia 78% vs. 78% (p=0.104) in the older vs younger group, respectively. Grade 3-4 hepatotoxicity was significantly more pronounced in patients >=35 years old (transaminitis 65% vs. 33% [p=0.0245], hyperbilirubinemia 48 vs. 15% [p=0.0111]). Coagulopathy rates evaluated with hypofibrinogenemia and thrombosis were similar between the older and the younger groups at 52% vs. 44% [p=0.104] and 17% vs. 7%, [p=0.855], respectively, and the frequency of pancreatitis and anaphylaxis were 4% vs. 18.5% (p=0.422) and 0% vs. 14.8% (p=0.115), respectively. In the older group, only 13% completed the planned PEG dosages compared to 59% in the younger group (p=0.0008), and delay in other chemotherapy by more than 30 days due to PEG hepatotoxicity occurred in 55% of older patients compared to 22% of younger patients (p=0.02). MRD negativity rate after induction was similar in the older and younger group (50% vs. 60% [p=0.491], respectively), but the 12-month relapse free survival was significantly lower in the older group (41%, [95% CI: 55.7%-89%] vs. 77%, [95% CI: 21%-61%], p=0.022) (Figure 1). XXConclusion(s): Patients aged >= 35 received significantly less PEG during their treatments but were more likely to develop severe grade 3-4 hepatotoxicity compared to their younger counterparts. The response rates were similar with comparable MRD negativity rates after induction regardless of total amount of PEG administered. However, relapse occurred more frequently in the older group, possibly resulting from more frequent delays in administering other chemotherapy agents due to PEG toxicity. Incorporation of PEG is important in the treatment of ALL but should be used with caution in patients >=35 years old, and will likely require dose and schedule modifications. A larger prospective trial investigating adequate dosing and scheduling of PEG in this age group is warranted, specifically comparing delays in chemotherapy, relapse, and survival rates in regimens with and without PEG. [Formula presented] Disclosures: No relevant conflicts of interest to declare.XXCopyright
ISSN: 0006-4971
CID: 4927832