Faculty Bibliography

BACKGROUND: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 in the past decade. It is also an affliction of the elderly that predominantly affects patients above 60 years of age. Standard therapy involves intensive chemotherapy that is often difficult to tolerate in older populations. Fortunately, recent developments in molecular targeting have shown promising results in treating leukemia, paving the way for novel treatment strategies that are easier to tolerate. SUMMARY/CONCLUSIONS:Venetoclax, a BCL-2 inhibitor, when combined with a hypomethylating agent, has proven to be a highly effective and well-tolerated drug, and established itself as a new standard for treating AML in patients who are unfit for standard intensive therapy. Other targeted therapies include clinically proven and FDA approved agents, such as IDH1/2 inhibitors, FLT3 inhibitors, and Gemtuzumab, as well as newer and more experimental drugs such as magrolimab, PI-kinase inhibitors, and T-cell engaging therapy. Some of the novel agents such as magrolimab and menin inhibitors are particularly promising, providing therapeutic options to a wider population of patients than ever before. Determining who will benefit from intense or novel low intense therapy remains a challenge and it requires careful assessment of individual patient's fitness and disease characteristics. KEY MESSAGES/CONCLUSIONS:This article reviews past and current treatment strategies that harness various mechanisms of leukemia-targeting agents and introduces novel therapies on the horizon aimed at exploring therapeutic options for elderly and unfit patient population. It also provides a strategy to select the best available therapy for elderly patients with both newly diagnosed and relapsed/refractory AML.

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.

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.

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.

Graft-versus-host disease (GvHD) in its acute and chronic forms continues to represent a significant barrier to the success and wide-applicability of blood and marrow transplantation as a potentially curative treatment modality for a number of benign and malignant blood conditions. Presently, calcineurin inhibitor (CNI)-based regimens remain the most commonly used prevention strategy, although post-transplant cyclophosphamide is emerging as an alternative approach, and is providing a backbone for innovative CNI-free combinations. In this paper, we review the current strategies used for the prevention of GvHD, and highlight some of the developing and promising combinations.

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

BACKGROUND:Activated vitamin D analog, paricalcitol, has been shown to attenuate the development of cardiac hypertrophy in Dahl salt sensitive (DSS) rats. To determine whether an antihypertrophic effect is class specific, we tested if doxercalciferol (a pro-hormone vitamin D2 analog) could also attenuate the development of cardiac hypertrophy in DSS rats. METHODS AND RESULTS/RESULTS:Male DSS rats were fed a high salt (HS) diet for 6 weeks beginning at 6 weeks of age. Doxercalciferol was administered intraperitoneally at 150 ng, 3 times per week (Monday, Wednesday, Friday) for 6 weeks. Pathological and echocardiographic findings demonstrated that rats on HS diet with doxercalciferol administration had significant decrease in cardiac hypertrophy and improved cardiac function compared to the HS + vehicle. In addition, there was a significant decrease in plasma brain natriuretic peptide (BNP) level and tissue atrial natriuretic factor (ANF) mRNA level with doxercalciferol treatment. Doxercalciferol also significantly reduced the level of protein kinase C-α (PKCα) suggesting that PKC-mediated cardiac hypertrophy may be associated with vitamin D deficiency. CONCLUSIONS:Administration of doxercalciferol attenuated the development of HS diet induced cardiac hypertrophy and cardiac dysfunction in DSS rats.

Exposure to tobacco smoke is known to have deleterious cardiovascular effects. In this study, we tested whether exposure to tobacco smoke exacerbates the severity of viral myocarditis in mice. Viral myocarditis was generated in 4-week-old male BALB/c mice by injection of Encephalomyocarditis virus (EMCV). Four groups were studied: (1) control (C, no smoke and no virus); (2) smoke only (S, exposure to cigarette smoke for 90 min/day for 15 days); (3) virus only (V); and (4) exposure to smoke for 5 days before plus 10 days following virus injection (S+V). We found that viral inoculation preceded by smoke exposure increased mortality more than twofold compared with virus inoculation alone. In addition, the mRNA level of atrial natriuretic factor was significantly higher in S+V than among any of the other 3 groups. Virus injection significantly decreased cardiac function compared with controls, with further deterioration observed in the S+V group. We also observed a significantly increased rate of apoptosis, with an increased activation of apoptosis-inducing factor in hearts exposed to S+V compared with those exposed to V alone. Our results suggest that preexposure to smoke significantly exacerbates the severity of viral myocarditis, likely through increased viral load and increased cardiomyocyte cell death.

AIMS/OBJECTIVE:The caspases are thought to be central mediators of the apoptotic program, but recent data indicate that apoptosis may also be mediated by caspase-independent mechanisms such as apoptosis-inducing factor (AIF). The role of AIF-induced apoptosis in heart, however, is currently not well understood. The aim of this study was to investigate the presence of and conditions for AIF-induced cardiac apoptosis in vitro. METHODS AND RESULTS/RESULTS:Hypertrophic cardiomyocyte (H-CM) cultures were prepared from the hearts of Dahl salt-sensitive rats fed a high salt diet. Apoptotic stimulation induced by hypoxia/reoxygenation or staurosporine (1 microM) enhanced AIF release in H-CMs compared with non-hypertrophic cardiomyocytes (N-CMs). Caspase inhibition using zVAD.fmk (25 microM) or overexpression of CrmA using recombinant adenovirus only partially protected N-CMs from apoptosis (63 +/- 0.93%) and provided no significant protection against apoptosis in hypertrophic cells (23 +/- 1.03%). On the other hand, poly-ADP-ribose polymerase inhibition using 4-AN (20 microM) during apoptotic stimulation blocked the release of AIF from mitochondria and significantly improved cell viability in hypertrophied cardiomyocytes (74 +/- 1.18%). CONCLUSION/CONCLUSIONS:A caspase-dependent, apoptotic pathway is important for N-CM death, whereas a caspase-independent, AIF-mediated pathway plays a critical role in H-CMs.