Preclinical models have shown that blocking PD-1/PD-L1 pathways enhances antileukemic responses. Azacitidine upregulates PD-1 and IFNγ signaling. We therefore conducted this single-arm trial, in ...which patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) were treated with azacitidine 75 mg/m
days 1 to 7 intravenously or subcutaneously with nivolumab 3 mg/kg intravenously on days 1 and 14, every 4 to 6 weeks. For the seventy patients who were treated, the median age was 70 years (range, 22-90) and the median number of prior therapies received was 2 (range, 1-7). The overall response rate (ORR) was 33%, including 15 (22%) complete remission/complete remission with insufficient recovery of counts, 1 partial response, and 7 patients with hematologic improvement maintained >6 months. Six patients (9%) had stable disease >6 months. The ORR was 58% and 22%, in hypomethylating agent (HMA)-naïve (
= 25) and HMA-pretreated (
= 45) patients, respectively. Grade 3 to 4 immune-related adverse events occurred in 8 (11%) patients. Pretherapy bone marrow and peripheral blood CD3 and CD8 were significantly predictive for response on flow cytometry. CTLA4 was significantly upregulated on CD4
Teff in nonresponders after 2 and 4 doses of nivolumab. Azacitidine and nivolumab therapy produced an encouraging response rate and overall survival in patients with R/R AML, particularly in HMA-naïve and salvage 1 patients. Pretherapy bone marrow aspirate and peripheral blood CD3 percentage may be biomarkers for patient selection. SIGNIFICANCE: Azacitidine in combination with nivolumab appeared to be a safe and effective therapy in patients with AML who were salvage 1, prior hypomethylator-naïve, or had increased pretherapy CD3
bone marrow infiltrate by flow cytometry or IHC. Bone marrow CD3 and CD8 are relatively simple assays that should be incorporated to select patients in future trials.
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Castleman disease (CD) comprises 3 poorly understood lymphoproliferative variants sharing several common histopathological features. Unicentric CD (UCD) is localized to a single region of lymph ...nodes. Multicentric CD (MCD) manifests with systemic inflammatory symptoms and organ dysfunction due to cytokine dysregulation and involves multiple lymph node regions. Human herpesvirus 8 (HHV-8) causes MCD (HHV-8–associated MCD) in immunocompromised individuals, such as HIV-infected patients. However, >50% of MCD cases are HIV and HHV-8 negative (defined as idiopathic iMCD). The clinical and biological behavior of CD remains poorly elucidated. Here, we analyzed the clinicopathologic features of 74 patients (43 with UCD and 31 with iMCD) and therapeutic response of 96 patients (43 with UCD and 53 with iMCD) with HIV-/HHV-8–negative CD compared with 51 HIV-/HHV-8–positive patients. Systemic inflammatory symptoms and elevated inflammatory factors were more common in iMCD patients than UCD patients. Abnormal bone marrow features were more frequent in iMCD (77.0%) than UCD (45%); the most frequent was plasmacytosis, which was seen in 3% to 30.4% of marrow cells. In the lymph nodes, higher numbers of CD3+ lymphocytes (median, 58.88 ± 20.57) and lower frequency of CD19+/CD5+ (median, 5.88 ± 6.52) were observed in iMCD patients compared with UCD patients (median CD3+ cells, 43.19 ± 17.37; median CD19+/CD5+ cells, 17.37 ± 15.80). Complete surgical resection is a better option for patients with UCD. Siltuximab had a greater proportion of complete responses and longer progression-free survival (PFS) for iMCD than rituximab. Centricity, histopathological type, and anemia significantly impacted PFS. This study reveals that CD represents a heterogeneous group of diseases with differential immunophenotypic profiling and treatment response.
•HIV-negative UCD and iMCD are heterogeneous at the clinical, immunophenotypic, and pathologic levels.•Complete surgical resection is the primary option of treatment of UCD, while siltuximab is more effective for iMCD than rituximab.
Abstract
Background
The majority of studies that provide insights into the influence of the microbiome on the health of hematologic malignancy patients have concentrated on the transplant setting. ...Here, we sought to assess the predictive capacity of the gastrointestinal microbiome and its relationship to infectious outcomes in patients with acute myeloid leukemia (AML).
Methods
16s rRNA-based analysis was performed on oral swabs and stool samples obtained biweekly from baseline until neutrophil recovery following induction chemotherapy (IC) in 97 AML patients. Microbiome characteristics were correlated with clinical outcomes both during and after IC completion.
Results
At the start of IC, higher stool Shannon diversity (hazard ratio HR, 0.36; 95% confidence interval CI, .18–.74) and higher relative abundance of Porphyromonadaceae (HR, 0.36; 95% CI, .18–.73) were associated with increased probability of remaining infection-free during neutropenia. A baseline stool Shannon diversity cutoff of <2 had optimal operating characteristics for predicting infectious complications during neutropenia. Although 56 patients received therapy >72 hours with a carbapenem, none of the patients had an infection with an extended spectrum β-lactamase–producing organism. Patients who received carbapenems for >72 hours had significantly lower α-diversity at neutrophil recovery (P = .001) and were approximately 4 times more likely to have infection in the 90 days following neutrophil recovery (HR, 4.55; 95% CI, 1.73–11.93).
Conclusions
Our results suggest that gut microbiome evaluation could assist with infectious risk stratification and that improved targeting of antibiotic administration during IC could decrease subsequent infectious complications in AML patients.
Baseline microbiome diversity is a strong independent predictor of infection during acute myeloid leukemia induction chemotherapy (IC) among clinical and microbiome covariates. Higher baseline levels of Porphyromonadaceae appear protective against infection, while carbapenem use is associated with consequences to the microbiome and infection susceptibility post-IC.
Background
The revised 2017 European LeukemiaNet (ELN) classification (ELN‐2017) of acute myeloid leukemia (AML) divides patients into 3 prognostic risk categories, with additional factors such as ...the fms‐like tyrosine kinase 3 (FLT3)–internal tandem duplication (ITD) allele ratio (AR) considered for risk stratification. To the best of the authors' knowledge, the prognostic usefulness of ELN‐2017 in comparison with ELN‐2010 in younger patients with AML has not been validated to date.
Methods
The authors performed a retrospective study on patients aged <60 years who received idarubicin plus cytarabine (IA)–based induction chemotherapy for newly diagnosed AML.
Results
According to ELN‐2017 criteria, the number of patients in the favorable (Fav), intermediate (Int), and adverse (Adv) risk categories was 192 patients (27%), 331 patients (46%), and 192 patients (27%), respectively. Overall survival probabilities at 5 years in the Fav, Int, and Adv groups were 57%, 37%, and 18%, respectively. In comparison, the 5‐year overall survival probabilities in the Fav (169 patients), intermediate (IR)‐1 (80 patients), IR‐2 (306 patients), and Adv (160 patients) ELN‐2010 categories were 59%, 32%, 40%, and 14%, respectively. Although ELN‐2010 historically distinguishes prognosis into IR‐1 and IR‐2 categories in younger patients, this difference was nullified in the current study cohort. When comparing patients with a low FLT3‐ITD AR with those with a high FLT3‐ITD AR, no significant differences in survival were noted among patients with nucleophosmin 1 (NPM1)‐mutated AML (P = .28) or wild‐type NPM1 (P = .35), and in those treated with IA alone (P = .79) or those treated with IA and a FLT3 inhibitor (P = .10).
Conclusions
The ELN‐2017 more accurately distinguishes prognosis in patients with newly diagnosed AML. The lack of prognostic significance for the FLT3‐ITD AR needs further evaluation in different treatment settings.
The 2017 European LeukemiaNet (ELN‐2017) classification system more accurately distinguishes prognosis compared with the ELN‐2010 in patients with de novo acute myeloid leukemia. The prognostic significance of the fms‐like tyrosine kinase 3 (FLT3)–internal tandem duplication allele ratio is controversial and needs further evaluation in different treatment settings.
The application of next‐generation sequencing (NGS) has enhanced our understanding of the genetic landscape in acquired aplastic anemia (AA). Parallel progress has been in addressing aspects ...underlying immune dysregulation in disease pathogenesis. Novel insights into the molecular and biologic mechanisms have led to a shift in the paradigm of AA, from a solely autoimmune pathogenic concept toward its recognition as a multifaceted pathophysiology characterized by cytogenetic abnormalities, recurrent somatic mutations, telomere attrition, and immune dysregulation. The detection of recurrent driver mutations disrupting myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)‐associated genes has suggested a pathophysiologic link between clonal hematopoiesis in AA and the later development of these clonal disorders. Further, certain AA‐related somatic genetic alterations may have clinical implications on treatment response, disease progression, and survival following immunosuppressive therapy. Going forward, wider validation of these genetic abnormalities will allow for their incorporation into a more informative risk stratification system that does not rely solely on clinical factors.
Cardiovascular or arteriothrombotic adverse events (CV- or AT-AEs) are reported in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs). The incidence and ...characteristics across different TKI have not been systematically analyzed. We analyzed 531 patients treated with frontline TKIs in different prospective trials: imatinib 400 mg (n = 71) and 800 mg (n = 203), nilotinib (n = 108), dasatinib (n = 106), and ponatinib (n = 43). Characteristics and incidence of new-onset CV-AEs and AT-AEs were analyzed. Poisson regression models assessed factors associated with AE incidence. Median follow-up was 94 months (range, 2-195). Overall, 237 patients (45%) developed CV-AEs and 46 (9%) developed AT-AEs. Hypertension was the most common AE seen in 175 patients (33%; grade 3/4 in 17%). CV-AE and AT-AE incidence ratios (IRs) with 95% confidence intervals (CIs) were 8.6 (7.6-9.8) and 1.7 (1.2-2.2) per 100 person-years. Among the TKIs, ponatinib showed the highest IR (95% CI) for CV-AEs and AT-AEs at 40.7 (27.9-59.4) and 9.0 (4.1-20.1). In multivariate analysis, ponatinib therapy was associated with increased incidence rate ratio (IRR) for CV-AEs (4.62; 95% CI, 2.7-7.7; P < .0001) and AT-AEs (6.38; 95% CI, 1.8-21.8; P < .0001) compared with imatinib 400. In summary, there is an increased risk of CV-AEs (except hypertension) and AT-AEs in CML patients treated with newer TKIs, particularly with ponatinib. Patients on TKIs must be informed and closely monitored for vascular AEs. These studies were registered at www.clinicaltrials.gov as #NCT00048672, #NCT00038649, #NCT00050531, #NCT00254423, #NCT00129740, and #NCT01570868.
Jain et al take on a major issue in the era of tyrosine kinase inhibitor (TKI) therapy for patients with chronic myeloid leukemia (CML). While these patients now have many options for targeted therapy, many are expensive, and they prominently include cardiovascular and arteriothrombotic adverse events. The authors systematically analyzed 531 CML patients treated with multiple TKIs in different trials. These included imatinib, nilotinib, dasatinib, and ponatinib. The authors found an increased risk of hypertension with all TKIs. Furthermore, when compared to imatinib dosed at 400 mg, there was an increased risk of cardiovascular events in CML patients with preexisting cardiovascular risk factors, and importantly, in those treated with second and third generation TKIs, particularly ponatinib. This study underscores the importance of vigilant assessment and management of cardiovascular comorbidities in all CML patients treated with TKIs.
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Patients with acute myeloid leukemia (AML) who achieve morphologic remission in the bone marrow after initial treatment often continue to harbor residual leukemic cells that can give rise to disease ...relapse. Achievement of a deeper remission has been associated with a reduced risk of relapse and improved event-free and overall survival in several studies. However, standardization of diagnostic techniques, sample acquisition and test timing are needed before minimal, also known as measurable, residual disease (MRD) quantification can be used to guide treatment decision making. Furthermore, clinical trial evidence that preemptive intervention at MRD level can alter the natural history of AML is required. Herein, we outline the current landscape of MRD assessment in AML, summarize the available evidence and challenges, and highlight the potential for MRD status to serve as a surrogate endpoint for hard clinical outcomes and as an approvable endpoint in clinical trials for regulatory purposes.
Obesity poses an increased risk of developing metabolic syndrome and closely associated nonalcoholic fatty liver disease, including liver cancer. Satiety hormone leptin-deficient ( ob/ob ) mice, ...considered paradigmatic of nutritional obesity, develop hepatic steatosis but are less prone to developing liver tumors. Sustained activation of peroxisome proliferator–activated receptor α (PPARα) in ob/ob mouse liver increases fatty acid oxidation (FAO), which contributes to attenuation of obesity but enhances liver cancer risk. To further evaluate the role of PPARα-regulated hepatic FAO and energy burning in the progression of fatty liver disease, we generated PPARα-deficient ob/ob (PPARαΔ ob/ob ) mice. These mice become strikingly more obese compared to ob/ob littermates, with increased white and brown adipose tissue content and severe hepatic steatosis. Hepatic steatosis becomes more severe in fasted PPARαΔ ob/ob mice as they fail to up-regulate FAO systems. PPARαΔ ob/ob mice also do not respond to peroxisome proliferative and mitogenic effects of PPARα agonist Wy-14,643. Although PPARαΔ ob/ob mice are severely obese, there was no significant increase in liver tumor incidence, even when maintained on a diet containing Wy-14,643. We conclude that sustained PPARα activation–related increase in FAO in fatty livers of obese ob/ob mice increases liver cancer risk, whereas deletion of PPARα in ob/ob mice aggravates obesity and hepatic steatosis. However, it does not lead to liver tumor development because of reduction in FAO and energy burning.
Most acute myeloid leukemia (AML) patients will be aged more than 65 years. Chronological aging is accompanied by decreasing stem cell and solid organ reserve as well as an increased incidence of ...medical comorbidity. For the older patient with AML, these patient-specific factors are compounded by an association with complexity of disease biology, chemoresistance, poor tolerance and early mortality with intensive induction therapy. However, the investigation and availability of therapies targeted against various molecular drivers of leukemogenesis, leukemic stem cell persistence, and chemoresistance have provided more options for the patient ineligible for intensive or classical induction therapy, often guided by age >60-65 years by some treatment algorithms. Many providers remain appropriately optimistic that such therapies may overtake the longstanding recommendation for frontline intensive therapy in certain circumstances. Traditional algorithms dichotomizing the optimal treatment modality based on AML patient age are aging themselves and are very likely to soon be outdated.
•About 10–15% patients with BPDCN harbor 8q24/MYC rearrangement.•MYC often partners with a non-immunoglobulin gene in BPDCN.•MYC rearrangement does not convey a more aggressive clinical course in ...BPDCN.•BPDCN with MYC rearrangement often response well to ALL-based chemotherapy.
8q24/MYC rearrangements resulting in MYC overexpression occur most frequently in lymphoid neoplasms. MYC rearrangements rarely have been described in blastic plasmacytoid dendritic cell neoplasm (BPDCN). Over an 8-year period in our hospital, 5 of 41 (12%) patients with BPDCN were shown 8q24/MYC rearrangements, including 2 with t(6;8)(p21;q24), 1 with t(8;14)(q24;q32), 1 with t(X;8)(q24;q24), and 1 with t(3;8)(p25;q24). 8q24/MYC rearrangement was present in the stemline in 4 patients and in the sideline in one; the latter was a patient with primary myelofibrosis who then developed BPDCN. MYC overexpression by immunohistochemistry was variable, but largely correlated with the percentage of blasts. Four patients were treated with acute lymphoblastic leukemia-type chemotherapy regimens and 3 had a good response; 1 patient was treated with acute myeloid leukemia-type regimens and was refractory to therapy. By the end of the follow-up, 3 patients died and 2 were alive in complete remission. We conclude that 8q24/MYC rearrangements occur in 10–15% of BPDCN, often partnered with non-immunoglobulin chromosomal loci, and may play a role in BPDCN pathogenesis. In this small patient sample, patients with BPDCN and MYC rearrangement often responded to therapy with acute lymphoblastic leukemia-type chemotherapy regimens.
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