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Transplant Eligible and Ineligible Elderly Patients with AML-A Genomic Approach and Next Generation Questions

Sackstein, Paul; Williams, Alexis; Zemel, Rachel; Marks, Jennifer A; Renteria, Anne S; Rivero, Gustavo
The management of elderly patients diagnosed with acute myelogenous leukemia (AML) is complicated by high relapse risk and comorbidities that often preclude access to allogeneic hematopoietic cellular transplantation (allo-HCT). In recent years, fast-paced FDA drug approval has reshaped the therapeutic landscape, with modest, albeit promising improvement in survival. Still, AML outcomes in elderly patients remain unacceptably unfavorable highlighting the need for better understanding of disease biology and tailored strategies. In this review, we discuss recent modifications suggested by European Leukemia Network 2022 (ELN-2022) risk stratification and review recent aging cell biology advances with the discussion of four AML cases. While an older age, >60 years, does not constitute an absolute contraindication for allo-HCT, the careful patient selection based on a detailed and multidisciplinary risk stratification cannot be overemphasized.
PMCID:11117792
PMID: 38790937
ISSN: 2227-9059
CID: 5761352

Primary Extranodal NK/T-Cell Lymphoma Presenting as Neurolymphomatosis Involving Multiple Cranial Nerves: A Case Report [Case Report]

Ghosh, Sharmila; Azzi, Jacques; Chan, Amy M; Nael, Kambiz; Renteria, Anne S; Steinberg, Amir; Petersen, Bruce E
Neurolymphomatosis (NL) is a rare condition caused by the lymphomatous or leukemic infiltration of nerves and manifests as neuropathy. Most often, NL is associated with B-lineage non-Hodgkin lymphoma (NHL) and only infrequently occurs in conjunction with T- or NK-lineage NHL. Extranodal NK/T-cell lymphoma (ENKTL)-associated NL is exceedingly unusual, with only 9 cases described in the English language literature, in addition to our case. Diagnosis of NL is challenging, as the entity can mimic neuropathies of more common etiologies, and an adequate biopsy may be difficult to obtain. Timely diagnosis demands a high index of suspicion, especially for patients without a history of hematologic malignancy. We expand upon a unique case of NL exclusively involving cranial nerves and cauda equina nerve roots, as the initial manifestation of ENKTL, and contextualize our findings within the framework of previously reported NK/T-lineage NL cases.
PMID: 34569490
ISSN: 1421-9662
CID: 5761342

AML with BCR-ABL1 Fusion treated with Imatinib, a Hypomethylating Agent and Venetoclax [Case Report]

Low, Soon Khai; Nanua, Suparna; Patel, Mehul; Renteria, Anne S
A patient with history of myelodysplastic syndrome (MDS) presented with multifocal pneumonia and was found to have Philadelphia chromosomepositive (Ph+) acute myeloid leukemia (AML). A tyrosine kinase inhibitor (TKI) was added to decitabine and venetoclax combination, providing a molecular and cytogenetic complete response despite additional cytogenetic and molecular abnormalities. She remains in remission after eleven cycles of treatment. Our report describes the tolerability and success of a triplet regimen that incorporates a TKI to a backbone of decitabine and venetoclax in a patient with high-risk disease and with significant comorbidities.
PMCID:9240361
PMID: 35782581
ISSN: 2213-0489
CID: 5761592

A phase 2a randomized clinical trial of intravenous vedolizumab for the treatment of steroid-refractory intestinal acute graft-versus-host disease

Fløisand, Yngvar; Schroeder, Mark A; Chevallier, Patrice; Selleslag, Dominik; Devine, Steven; Renteria, Anne S; Mohty, Mohamad; Yakoub-Agha, Ibrahim; Chen, Chunlin; Parfionovas, Andrejus; Quadri, Syed; Jansson, Johan; Akbari, Mona; Chen, Yi-Bin
Steroid-refractory (SR) acute graft-versus-host disease (aGvHD) remains a significant complication after allogeneic hematopoietic cell transplantation. Systemic corticosteroids are first-line therapy for aGvHD, but apart from ruxolitinib, there are no approved treatments for SR aGvHD. Vedolizumab is approved for treatment of ulcerative colitis and Crohn's disease, and may be effective for treatment of SR intestinal aGvHD. We conducted a phase 2a trial (NCT02993783) to evaluate the clinical efficacy, tolerability, and safety of vedolizumab 300 and 600 mg for SR intestinal aGvHD. This study was terminated before full enrollment was completed because early results failed to demonstrate positive proof-of-concept in efficacy. Before termination, 17 participants had enrolled and an early response in intestinal aGvHD was observed in 11 and eight participants at days 15 and 28, respectively. All adverse events observed were consistent with those expected in a population with SR intestinal aGvHD. Overall, vedolizumab did not meet the primary efficacy endpoint (overall response at day 28), likely owing to premature study drug discontinuation, lack of efficacy, and the competing risks inherent with a population with advanced SR intestinal aGvHD. Nevertheless, this study provides valuable insights into the considerations needed when conducting studies in patients with SR intestinal aGvHD.
PMCID:8486663
PMID: 34108672
ISSN: 1476-5365
CID: 5761762

Multiple myeloma, race, insurance and treatment

Joshi, Himanshu; Lin, Sylvia; Fei, Kezhen; Renteria, Anne S; Jacobs, Hannah; Mazumdar, Madhu; Jagannath, Sundar; Bickell, Nina A
PURPOSE/OBJECTIVE:Multiple Myeloma (MM), the second leading blood malignancy, has complex and costly disease management. We studied patterns of treatment disparities and unplanned interruptions among the MM patients after the Affordable Care Act to assess their prevalence and effect on survival. MATERIALS AND METHODS/METHODS:This retrospective study of 1002 MM patients at a tertiary referral center used standard guidelines as a reference to identify underuse of effective treatments. We used multivariate logistic regression and Cox proportionate hazard to study the prognostic effect on survival. RESULTS:Median age in the cohort was 63.0 [IQR: 14] years. Non-Hispanic White (NHW) patients were older (p = 0.007) and more likely to present with stage I disease (p = 0.02). Underuse of maintenance therapy (aOR = 1.98; 95 % CI 1.12-3.48) and interruptions in treatment were associated with race/ethnicity and insurance (aOR = 4.14; 95 % CI: 1.78-9.74). Only underuse of induction therapy was associated with overall patient survival. CONCLUSION/CONCLUSIONS:Age, race, ethnicity and primary insurance contribute to the underuse of treatment and in unplanned interruptions in MM treatment. Addressing underuse causes in such patients is warranted.
PMID: 34243048
ISSN: 1877-783x
CID: 4933702

Where you live can impact your cancer risk: a look at multiple myeloma in New York City

Kamath, Geetanjali R; Renteria, Anne S; Jagannath, Sundar; Gallagher, Emily Jane; Parekh, Samir; Bickell, Nina A
PURPOSE/OBJECTIVE:To visualize variation in multiple myeloma (MM) incidence and mortality rates by race-ethnicity and geographic location and evaluate their correlation with neighborhood-level population covariates within New York City (NYC). METHODS:Trends and racial differences in MM incidence and mortality for the United States [Surveillance, Epidemiology, and End Results Cancer Registry (SEER), National Center for Health Statistics], and NYC [New York State Cancer Registry] were compared using Joinpoint regression. Pearson's correlation coefficients measured neighborhood-level MM-covariate relationships (n = 34). RESULTS:MM incidence rates are double in African-Americans compared with Whites, in SEER-13 areas (rate ratio (RR) = 2.27; 95% confidence interval [CI] = 2.22-2.32) and NYC (RR = 2.11; 95% CI = 2.03-2.20). Incidence rates increased faster in NYC (average annual percentage change difference, -1.1; 95% CI, -2.3 to -0.1). NYC African-American men experienced the steepest increase in mortality rates after 2001. In NYC, strong neighborhood-level correlations exist between incidence and mortality rates and high prevalence of residents of African ancestry, Latin American birth, daily sugary beverage and low fruit and vegetable consumption, and neighborhood walkability. Higher MM mortality also correlates with Hispanic ethnicity, obesity, diabetes, poverty, HIV/AIDS, air benzene concentration, and indoor pesticide use. CONCLUSIONS:NYC neighborhoods with large minority populations have higher prevalence of poverty-related factors associated with MM incidence and mortality, warranting public health policies to address exposures and access to care.
PMID: 32620423
ISSN: 1873-2585
CID: 4517222

Vedolizumab for prevention of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Chen, Yi-Bin; Shah, Nirav N; Renteria, Anne S; Cutler, Corey; Jansson, Johan; Akbari, Mona; Chen, Chunlin; Quadri, Syed; Parfionovas, Andrejus; Devine, Steven M
Acute graft-versus-host disease (aGVHD) remains a significant complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Vedolizumab could help prevent aGVHD by inhibiting the migration of both naive and activated lymphocytes into gut-associated lymphoid tissues and the lamina propria. We carried out a phase 1b, open-label, dose-finding study in adults undergoing allo-HSCT to evaluate the tolerability, safety, and pharmacokinetics of vedolizumab, and its effectiveness in reducing aGVHD. IV vedolizumab was administered on day -1, +13, and +42 with respect to allo-HSCT, starting at 75 mg and with dose escalation guided by tolerability and pharmacokinetics. A total of 24 participants was enrolled, and no dose-limiting toxicities were observed in either the 75-mg cohort (n = 3) or the dose-escalated 300-mg cohort (n = 21). Treatment-emergent adverse events related to vedolizumab occurred in 8 participants. Overall, 4 deaths occurred during the 12 months following allo-HSCT. No participants in the 75-mg cohort developed modified Glucksberg grade II to IV aGVHD by 100 days after allo-HSCT. Four participants (19.0%) in the 300-mg cohort developed grade II to IV aGVHD by 100 days after allo-HSCT, including 3 participants who developed stage 1 aGVHD of the lower-intestinal tract. Vedolizumab IV 300 mg was well tolerated as aGVHD prevention, and the incidence of overall and lower-intestinal aGVHD was low. These findings support further evaluation of vedolizumab in this patient population. This trial was registered at www.clinicaltrials.gov as #NCT02728895.
PMCID:6963235
PMID: 31821456
ISSN: 2473-9537
CID: 5761752

Acquired amegakaryocytic thrombocytopenia as a rare cause of thrombocytopenia during pregnancy [Case Report]

Zimmerman, Brittney S; Marcellino, Bridget; El Jamal, Siraj M; Renteria, Anne S
A rare case of acquired amegakaryocytic thrombocytopenia (AATP) in a 35-year-old woman who presented with anaemia and thrombocytopenia at 22 weeks gestation. The first diagnostic impression was of an evolving aplastic anaemia; however, the patient was simultaneously diagnosed with severe vitamin B12 deficiency in the setting of vegetarianism. Once the cyanocobalamin deficiency was corrected, a repeat bone marrow biopsy revealed an isolated depletion of megakaryocytes, which suggested the diagnosis of AATP. Supportive care was provided for her anaemia and thrombocytopenia and she delivered a healthy baby girl with a normal platelet count. The patient was subsequently started on romiplostim with steady improvement in her platelet counts. This rare AATP case presentation highlights the importance of a well-structured diagnostic approach to thrombocytopenia during pregnancy and supports the successful use of thrombopoietin agonists for the management of AATP.
PMCID:6606057
PMID: 31229978
ISSN: 1757-790x
CID: 5761742

Amphiregulin modifies the Minnesota Acute Graft-versus-Host Disease Risk Score: results from BMT CTN 0302/0802

Holtan, Shernan G; DeFor, Todd E; Panoskaltsis-Mortari, Angela; Khera, Nandita; Levine, John E; Flowers, Mary E D; Lee, Stephanie J; Inamoto, Yoshihiro; Chen, George L; Mayer, Sebastian; Arora, Mukta; Palmer, Jeanne; Cutler, Corey S; Arai, Sally; Lazaryan, Aleksandr; Newell, Laura F; Jagasia, Madan H; Pusic, Iskra; Wood, William A; Renteria, Anne S; Yanik, Gregory; Hogan, William J; Hexner, Elizabeth; Ayuk, Francis; Holler, Ernst; Bunworasate, Udomsak; Efebera, Yvonne A; Ferrara, James L M; Pidala, Joseph; Howard, Alan; Wu, Juan; Bolaños-Meade, Javier; Ho, Vincent; Alousi, Amin; Blazar, Bruce R; Weisdorf, Daniel J; MacMillan, Margaret L
Amphiregulin (AREG) is an epidermal growth factor receptor ligand that can restore integrity to damaged intestinal mucosa in murine models of acute graft-versus-host disease (aGVHD). We previously reported that circulating AREG is elevated in late-onset aGVHD (occurring after 100 days posttransplant), but its clinical relevance in the context of aGVHD risk is unknown. We measured AREG in 251 aGVHD onset blood samples from Blood and Marrow Clinical Trials Network (BMT CTN) primary treatment trials and determined their association with GVHD severity, day 28 complete or partial response (CR/PR) to first-line therapy, overall survival (OS), and nonrelapse mortality (NRM). Every doubling of plasma AREG was associated with a 33% decrease in the odds of day 28 CR/PR (odds ratio [OR], 0.67; P < .01). An AREG threshold of 33 pg/mL or greater divided patients with Minnesota standard-risk (SR) aGVHD into a distinct group with a significantly lower likelihood of: day 28 CR/PR (72% vs 85%; P = .02); greater 2-year NRM (42% vs 15%; P < .01); and inferior OS (40% vs 66%; P < .01). High AREG ≥ 33 pg/mL also stratified patients with Minnesota high-risk (HR) aGVHD: day 28 CR/PR (54% vs 83%; P = .03) and 2-year NRM (53% vs 11%; P < .01), with a trend toward inferior 2-year OS (37% vs 60%; P = .09). High-circulating AREG (≥33 pg/mL) reclassifies patients into HR subgroups and thereby further refines the Minnesota aGVHD clinical risk score.
PMCID:6093743
PMID: 30087106
ISSN: 2473-9537
CID: 5761732

Role of minimal residual disease in the management of acute myeloid leukemia-a case-based discussion [Case Report]

Coltoff, A; Houldsworth, J; Keyzner, A; Renteria, A S; Mascarenhas, John
AML is stratified into risk-categories based on cytogenetic and molecular features that prognosticate survival and facilitate treatment algorithms, though there is still significant heterogeneity within risk groupings with regard to risk of relapse and prognosis. The ambiguity regarding prognosis is due in large part to the relatively outdated criteria used to determine response to therapy. Whereas risk assessment has evolved to adopt cytogenetic and molecular profiling, response criteria are still largely determined by bone marrow morphologic assessment and peripheral cell count recovery. Minimal residual disease refers to the detection of a persistent population of leukemic cells below the threshold for morphologic CR determination. MRD assessment represents standard of care for ALL and PML, but concerns over prognostic capability and standardization have limited its use in AML. However, recent advancements in MRD assessment and research supporting the use of MRD assessment in AML require the reconsideration and review of this clinical tool in this disease entity. This review article will first compare and contrast the major modalities used to assess MRD in AML, such as RQ-PCR and flow cytometry, as well as touching upon newer technologies such as next-generation sequencing and digital droplet PCR. The majority of the article will discuss the evidence supporting the use of MRD assessment to prognosticate disease at various time points during treatment, and review the limited number of studies that have incorporated MRD assessment into novel treatment algorithms for AML. The article concludes by discussing the current major limitations to the implementation of MRD assessment in this disease. The manuscript is bookended by a clinical vignette that highlights the need for further research and refinement of this clinical tool.
PMID: 29704019
ISSN: 1432-0584
CID: 5761332