Disease overview
Acute myeloid leukemia (AML) is a frequently fatal bone marrow stem cell cancer characterized by unbridled proliferation of malignant marrow stem cells with associated infection, ...anemia, and bleeding. An improved understanding of pathophysiology, improvements in measurement technology and at least 10 recently approved therapies have led to revamping the diagnostic, prognostic, and therapeutic landscape of AML.
Diagnosis
One updated and one new classification system were published in 2022, both emphasizing the integration of molecular analysis into daily practice. Differences between the International Consensus Classification and major revisions from the previous 2016 WHO system provide both challenges and opportunities for care and clinical research.
Risk assessment and monitoring
The European Leukemia Net 2022 risk classification integrates knowledge from novel molecular findings and recent trial results, as well as emphasizing dynamic risk based on serial measurable residual disease assessment. However, how to leverage our burgeoning ability to measure a small number of potentially malignant myeloid cells into therapeutic decision making is controversial.
Risk adapted therapy
The diagnostic and therapeutic complexity plus the availability of newly approved agents requires a nuanced therapeutic algorithm which should integrate patient goals of care, comorbidities, and disease characteristics including the specific mutational profile of the patient's AML. The framework we suggest only represents the beginning of the discussion.
Mixed-phenotype acute leukemia (MPAL) encompasses a heterogeneous group of rare leukemias in which assigning a single lineage of origin is not possible. A variety of different terms and ...classification systems have been used historically to describe this entity. MPAL is currently defined by a limited set of lineage-specific markers proposed in the 2008 World Health Organization monograph on classification of tumors of hematopoietic and lymphoid tissues. In adult patients, MPAL is characterized by relative therapeutic resistance that may be attributed in part to the high proportion of patients with adverse cytogenetic abnormalities. No prospective, controlled trials exist to guide therapy. The limited available data suggest that an “acute lymphoblastic leukemia–like” regimen followed by allogeneic stem-cell transplant may be advisable; addition of a tyrosine kinase inhibitor in patients with t(9;22) translocation is recommended. The role of immunophenotypic and genetic markers in guiding chemotherapy choice and postremission strategy, as well as the utility of targeted therapies in non–Ph-positive MPALs is unknown.
Herein, we present the long-term follow-up of the randomized E1912 trial comparing the long-term efficacy of ibrutinib-rituximab (IR) therapy to fludarabine, cyclophosphamide, and rituximab (FCR) and ...describe the tolerability of continuous ibrutinib. The E1912 trial enrolled 529 treatment-naïve patients aged ≤70 years with chronic lymphocytic leukemia (CLL). Patients were randomly assigned (2:1 ratio) to receive IR or 6 cycles of FCR. With a median follow-up of 5.8 years, median progression-free survival (PFS) is superior for IR (hazard ratio HR, 0.37; P < .001). IR improved PFS relative to FCR in patients with both immunoglobulin heavy chain variable region (IGHV) gene mutated CLL (HR: 0.27; P < .001) and IGHV unmutated CLL (HR: 0.27; P < .001). Among the 354 patients randomized to IR, 214 (60.5%) currently remain on ibrutinib. Among the 138 IR-treated patients who discontinued treatment, 37 (10.5% of patients who started IR) discontinued therapy due to disease progression or death, 77 (21.9% of patients who started IR) discontinued therapy for adverse events (AEs)/complications, and 24 (6.8% of patients who started IR) withdrew for other reasons. Progression was uncommon among patients able to remain on ibrutinib. The median time from ibrutinib discontinuation to disease progression or death among those who discontinued treatment for a reason other than progression was 25 months. Sustained improvement in overall survival (OS) was observed for patients in the IR arm (HR, 0.47; P = .018). In conclusion, IR therapy offers superior PFS relative to FCR in patients with IGHV mutated or unmutated CLL, as well as superior OS. Continuous ibrutinib therapy is tolerated beyond 5 years in the majority of CLL patients. This trial was registered at www.clinicaltrials.gov as #NCT02048813.
Data regarding the efficacy of treatment with ibrutinib-rituximab, as compared with standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, in patients with previously ...untreated chronic lymphocytic leukemia (CLL) have been limited.
In a phase 3 trial, we randomly assigned (in a 2:1 ratio) patients 70 years of age or younger with previously untreated CLL to receive either ibrutinib and rituximab for six cycles (after a single cycle of ibrutinib alone), followed by ibrutinib until disease progression, or six cycles of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. The primary end point was progression-free survival, and overall survival was a secondary end point. We report the results of a planned interim analysis.
A total of 529 patients underwent randomization (354 patients to the ibrutinib-rituximab group, and 175 to the chemoimmunotherapy group). At a median follow-up of 33.6 months, the results of the analysis of progression-free survival favored ibrutinib-rituximab over chemoimmunotherapy (89.4% vs. 72.9% at 3 years; hazard ratio for progression or death, 0.35; 95% confidence interval CI, 0.22 to 0.56; P<0.001), and the results met the protocol-defined efficacy threshold for the interim analysis. The results of the analysis of overall survival also favored ibrutinib-rituximab over chemoimmunotherapy (98.8% vs. 91.5% at 3 years; hazard ratio for death, 0.17; 95% CI, 0.05 to 0.54; P<0.001). In a subgroup analysis involving patients without immunoglobulin heavy-chain variable region (
) mutation, ibrutinib-rituximab resulted in better progression-free survival than chemoimmunotherapy (90.7% vs. 62.5% at 3 years; hazard ratio for progression or death, 0.26; 95% CI, 0.14 to 0.50). The 3-year progression-free survival among patients with
mutation was 87.7% in the ibrutinib-rituximab group and 88.0% in the chemoimmunotherapy group (hazard ratio for progression or death, 0.44; 95% CI, 0.14 to 1.36). The incidence of adverse events of grade 3 or higher (regardless of attribution) was similar in the two groups (in 282 of 352 patients 80.1% who received ibrutinib-rituximab and in 126 of 158 79.7% who received chemoimmunotherapy), whereas infectious complications of grade 3 or higher were less common with ibrutinib-rituximab than with chemoimmunotherapy (in 37 patients 10.5% vs. 32 20.3%, P<0.001).
The ibrutinib-rituximab regimen resulted in progression-free survival and overall survival that were superior to those with a standard chemoimmunotherapy regimen among patients 70 years of age or younger with previously untreated CLL. (Funded by the National Cancer Institute and Pharmacyclics; E1912 ClinicalTrials.gov number, NCT02048813.).
Despite decades of successful use of cytotoxic chemotherapy in acute myelogenous leukemia (AML), the biological basis for its differential success among individuals and for the existence of a ...therapeutic index has remained obscure. Rather than taking a genetic approach favored by many, we took a functional approach to ask how differential mitochondrial readiness for apoptosis (“priming”) might explain individual variation in clinical behavior. We found that mitochondrial priming measured by BH3 profiling was a determinant of initial response to induction chemotherapy, relapse after remission, and requirement for allogeneic bone marrow transplantation. Differential priming between malignant myeloblasts and normal hematopoietic stem cells supports a mitochondrial basis to the therapeutic index for chemotherapy. BH3 profiling identified BCL-2 inhibition as a targeted strategy likely to have a useful therapeutic index. BH3 profiling refines predictive information provided by conventional biomarkers currently in use and thus may itself have utility as a clinical predictive biomarker.
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► Mitochondrial priming of AML versus HSCs determines the chemotherapeutic index ► Pretreatment BH3 profiling may have utility as a clinical decision-making tool ► Myeloblasts tend to be BCL-2 dependent, but human HSCs tend to be MCL-1 dependent ► Targeting BCL-2 is selectively toxic to even chemorefractory myeloblasts over HSCs
If the HSCs are more “primed” for apoptosis than the leukemia, then the patient will be severely affected by chemotherapy without curing the cancer, whereas in the opposite scenario, the leukemia is targeted effectively while the patient recovers well.
Purpose
While the use of transthoracic echocardiography (TTE) in the ICU is rapidly expanding, the contribution of TTE to altering patient outcomes among ICU patients with sepsis has not been ...examined. This study was designed to examine the association of TTE with 28-day mortality specifically in that population.
Methods and results
The MIMIC-III database was employed to identify patients with sepsis who had and had not received TTE. The statistical approaches utilized included multivariate regression, propensity score analysis, doubly robust estimation, the gradient boosted model, and an inverse probability-weighting model to ensure the robustness of our findings. Significant benefit in terms of 28-day mortality was observed among the TTE patients compared to the control (no TTE) group (odds ratio = 0.78, 95% CI 0.68–0.90,
p
< 0.001). The amount of fluid administered (2.5 vs. 2.1 L on day 1,
p
< 0.001), use of dobutamine (2% vs. 1%,
p
= 0.007), and the maximum dose of norepinephrine (1.4 vs. 1 mg/min,
p
= 0.001) were significantly higher for the TTE patients. Importantly, the TTE patients were weaned off vasopressors more quickly than those in the no TTE group (vasopressor-free days on day 28 of 21 vs. 19,
p
= 0.004).
Conclusion
In a general population of critically ill patients with sepsis, use of TTE is associated with an improvement in 28-day mortality.
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