This article highlights the importance of monitoring for immune-mediated adverse events (IMAEs) in patients with Hodgkin lymphoma (HL) who receive anti-programmed death-1 (anti-PD-1) therapy, with particular attention given to the recognition and management of such events. The risk of individual IMAEs differs between patients with HL and those with solid tumors, as prior treatments may predispose certain organ systems to specific IMAEs. Accurate and prompt diagnosis of IMAEs is essential for optimal management, allowing PD-1 inhibitor therapy to be restarted in order to maintain disease control. Potential difficulties, such as distinguishing disease progression from pneumonitis, or colitis from diarrhea, are highlighted to raise clinical awareness.
Background: Both multiple myeloma and its precursor, monoclonal gammopathy of undetermined significance (MGUS), occur twice as often within Black compared to White populations, suggesting that racial disparities lie within the development of MGUS. Nonetheless, MGUS has been studied mainly in White cohorts; the study that first described the natural history of MGUS was conducted in 97.3% White Olmsted County, Minnesota. Methods: We determined the prevalence of MGUS among 386 Black South African (SA) men >30 years at Chris Hani Baragwanath Hospital in Johannesburg. We conducted serum protein electrophoresis and free light chain quantification to define MGUS by the same criteria as the Olmsted County studies. We also investigated the association between MGUS and various clinical factors, including HIV infection and smoking. Results: We found the prevalence of MGUS to be 8.03% (95%CI 5.32-10.74), nearly 1.6-fold higher than in the White Olmsted County male population. In a univariable logistic regression model, MGUS was associated with HIV status (Odds Ratio, OR 2.39, 95%CI 0.95-5.49), but in an adjusted model that included body mass index and cigarette use, the association was not statistically significant. Those who were current (vs. never) cigarette smokers were more likely to have MGUS in both univariable (OR 5.60, 95%CI 2.16-17.42) and multivariable models (OR 4.49, 95%CI 1.63-14.56). Conclusions: The prevalence of MGUS in Black SA men is substantially higher than in White populations and may be associated with HIV status and cigarette use. Impact: Racial disparities in MGUS exist and may be associated with potentially modifiable risk factors.
BACKGROUND: Despite recent advances, outcomes remain poor in secondary and relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We previously demonstrated that combination thioguanine (6TG) and decitabine restores therapeutic efficacy in vitro in R/R AML (O'Dwyer K et al. Blood 2010;114:2657). Based on these data, we completed a Phase I dose-escalation study of 6TG with decitabine in advanced myeloid malignancies with an overall response rate (ORR) of 67% and median progression-free survival (PFS) of 42 weeks in responding patients (Lee DJ, et al. Blood 2016;128:2816). Moreover, 5 of the 6 study participants who had previously received a hypomethylating agent (HMA) responded, suggesting that 6TG in combination with decitabine can overcome HMA resistance. Because of these results, a cohort of patients with high-risk and R/R AML and MDS were treated with combination 6TG and decitabine at Columbia University Irving Medical Center, and we now report our clinical experience with this regimen. METHODS: A retrospective chart review was performed of all adult patients at our institution with advanced myeloid malignancies who had received at least one cycle of 6TG and decitabine between 2013-2017. The treatment regimen utilized the maximum tolerated dose of 6TG identified in the phase I trial. Up to 2 cycles of induction with 6TG 80 mg/m2/day PO in 2 divided doses was given on Days 1-12. Decitabine 20 mg/m2 IV was given on Days 3-12. Following this, maintenance cycles consisted of 6TG on Days 1-7 and decitabine on Days 3-7 at the same doses. Treatment was continued until the time of hematopoietic stem cell transplant (HSCT), disease progression, or toxicity. The primary objective of this retrospective analysis was to determine the ORR. Secondary objectives were to evaluate PFS and overall survival (OS) in this population. RESULTS: Forty-two patients were identified, 55% of whom were female, with a median age of 68 years (range, 23-83 years). Thirty-three percent of the patients had secondary AML; 62% had R/R AML; 2% had R/R MDS; and 2% had chronic myelomonocytic leukemia. By ELN genetic risk stratification, 38% were adverse-risk, 43% were intermediate, and 17% were favorable, while 2% were unknown. However, 36 (86%) patients failed prior therapy, suggesting that nearly all of the treated patients were poor-risk. Nineteen (45%) patients had received prior HMA therapy, and 6 (14%) had undergone previous HSCT. Patients received a median of 2 cycles of therapy (range, 1-10). Five (12%) patients achieved complete remission (CR), 7 (16%) obtained a CR with incomplete count recovery (CRi/p), and 2 (5%) had morphologic leukemia-free state (MLFS), for an ORR of 33% (CR+CRi/p+MLFS). One notable patient who achieved CR was a 73-year-old with secondary AML, complex cytogenetics, and a TP53 mutation who subsequently went on to HSCT. Another 5 (36%) responders had complex karyotypes or poor-risk genetics. Ten of the 14 responders (71%) failed prior therapy. Of the 19 who had received prior HMA therapy, 6 (32%) responded. Six of 14 (43%) responders proceeded to HSCT. Two additional patients had significant blast reduction and underwent HSCT. Responses and maximum blast reduction were obtained after two cycles of therapy. For the responders, the median PFS was 38 weeks (range, 11-not reached), while the median OS was 43 weeks (range, 11-not reached). CONCLUSIONS: Combined 6TG and decitabine is a highly active regimen in advanced myeloid malignancies, with an ORR of 33% in this cohort, and median PFS and OS of 38 and 43 weeks, respectively, in responding patients. This compares favorably to the expected response rate of 10-20% with decitabine monotherapy in this poor-risk population consisting of mostly secondary and R/R AML. These data also confirm our prior phase I study findings that the addition of 6TG to decitabine can overcome prior HMA resistance, with 32% of those who had previously failed HMA therapy responding. This combination remains a viable therapeutic option for elderly and unfit patients with high-risk and R/R AML who cannot tolerate intensive chemotherapy. Disclosures Heaney: BMS: Research Funding; Partner Therapeutics: Consultancy; Roche: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; AbbVie: Consultancy; Deciphera: Research Funding; Constellation: Research Funding; Blueprint: Research Funding; CTI: Research Funding. Lamanna:Ming: Research Funding; Celgene: Consultancy; Oncternal: Research Funding; TG Therapeutics: Research Funding; Infinity/ Verastem: Research Funding. Jurcic:Syros Pharmaceuticals: Research Funding; Astellas: Research Funding; AbbVie Inc: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Incyte: Consultancy; Kura Oncology: Research Funding; Forma Therapeutics: Research Funding; Genentech: Research Funding; Novartis: Consultancy; Actinium Pharmaceuticals: Research Funding. Frattini:Celgene: Employment, Equity Ownership; Lin Bioscience: Consultancy. Lee:Abbvie: Research Funding; Roche: Research Funding; Tolero: Research Funding; Forty Seven, Inc.: Research Funding; Bayer: Research Funding.
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