BCR/ABL1–like acute lymphoblastic leukemia (ALL) accounts for 15% to 30% of B‐lineage ALL, with a peak of incidence occurring in adolescence. This subgroup of patients is characterized by a peculiar ...transcriptional profile that resembles that of true BCR/ABL1–positive cases, and have a heterogeneous genetic background and a poor outcome. Next‐generation sequencing studies have demonstrated that the majority of patients carry rearrangements of tyrosine kinases or cytokine receptors and mutations of janus kinase (JAK)/signal transducer and activator of transcription (STAT), thus opening the way to the possible use of targeted therapeutic approaches. However, several issues remain unresolved at both the diagnostic and therapeutic level, such as the definition of a standardized method to identify BCR/ABL1–like ALL and the design of ad hoc clinical trials examining tyrosine kinase inhibitors or other tailored treatments. These aspects are discussed in this review.
Patients with BCR/ABL1–like acute lymphoblastic leukemia are a poor‐prognosis subgroup who require identification of disease at the time of diagnosis to improve risk stratification, therapeutic decisions, and ultimately patient outcome. Several issues remain unsolved, including the lack of a standardized diagnostic assay with which to recognize patients with BCR/ABL1–like acute lymphoblastic leukemia at the time of diagnosis, the impact of the BCR/ABL1–like profile on minimal residual disease–guided clinical trials, and the best therapeutic approach for these patients.
Diffuse large B-cell lymphoma (DLBCL) is the most common form of human lymphoma. Although a number of structural alterations have been associated with the pathogenesis of this malignancy, the full ...spectrum of genetic lesions that are present in the DLBCL genome, and therefore the identity of dysregulated cellular pathways, remains unknown. By combining next-generation sequencing and copy number analysis, we show that the DLBCL coding genome contains, on average, more than 30 clonally represented gene alterations per case. This analysis also revealed mutations in genes not previously implicated in DLBCL pathogenesis, including those regulating chromatin methylation (MLL2; 24% of samples) and immune recognition by T cells. These results provide initial data on the complexity of the DLBCL coding genome and identify novel dysregulated pathways underlying its pathogenesis.
Follicular lymphoma (FL) is an indolent disease, but 30%–40% of cases undergo histologic transformation to an aggressive malignancy, typically represented by diffuse large B cell lymphoma (DLBCL). ...The pathogenesis of this process remains largely unknown. Using whole-exome sequencing and copy-number analysis, we show here that the dominant clone of FL and transformed FL (tFL) arise by divergent evolution from a common mutated precursor through the acquisition of distinct genetic events. Mutations in epigenetic modifiers and antiapoptotic genes are introduced early in the common precursor, whereas tFL is specifically associated with alterations deregulating cell-cycle progression and DNA damage responses (CDKN2A/B, MYC, and TP53) as well as aberrant somatic hypermutation. The genomic profile of tFL shares similarities with that of germinal center B cell-type de novo DLBCL but also displays unique combinations of altered genes with diagnostic and therapeutic implications.
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•FL and tFL arise from a common mutated precursor clone by divergent evolution•Epigenetic modifiers and antiapoptotic genes are mutated in the common precursor•Biallelic disruption of CDKN2A/B and deregulation of MYC are specific to tFL•tFL displays a unique genomic profile with only partial similarity to DLBCL
Follicular lymphoma (FL) is an indolent disease but can undergo transformation to a fatal malignancy, typically diffuse large B cell lymphoma (DLBCL). Pasqualucci, Dalla-Favera, and colleagues now find that the dominant clone of FL and transformed FL (tFL) arise by divergent evolution from a common mutated precursor through distinct genetic events, including CDKN2A/B loss, MYC deregulation, and aberrant somatic hypermutation being specifically acquired at transformation. The genomic profile of tFL shares similarities with that of germinal center B cell-type de novo DLBCL but also displays unique combinations of altered genes with diagnostic and therapeutic implications.
Quit Connect (QC), our specialty clinic smoking cessation intervention, supports clinic staff to check, advise, and connect willing patients to a state quit line or class. QC improved tobacco ...screening and quit line referrals 26-fold in a predominantly White academic health care system population. Implementing QC includes education, electronic health record (EHR) reminders, and periodic audit feedback. This study tested QC's feasibility and impact in a safety-net rheumatology clinic with a predominantly Black population.
In this pre-post study, adult rheumatology visits were analyzed 12 months before through 18 months after QC intervention (November 2019 through November 2021, omitting COVID-19 peak April through November 2020). EHR data compared process and clinical outcomes, including offers, referrals to resources, completed referrals, and documented cessation. Clinic staff engaged in pre-post focus groups and questionnaires regarding intervention feasibility and acceptability. Cost-effectiveness was also assessed.
Visit-level patients who smoked were 89.8% Black and 69.5% women (n = 550). Before intervention, clinic staff rarely asked patients about readiness to cut back smoking (<10% assessment). After QC intervention, staff assessed quit readiness in 31.8% of visits with patients who smoked (vs 8.1% before); 58.9% of these patients endorsed readiness to cut back or quit. Of 102 accepting cessation services, 37% (n = 17) of those reached set a quit date. Staff found the intervention feasible and acceptable. Each quit attempt cost approximately $4 to $10.
In a safety-net rheumatology clinic with a predominantly Black population, QC improved tobacco screening, readiness-to-quit assessment, and referrals and was also feasible and cost-effective.
Acute lymphoblastic leukemia (ALL) is the first neoplasm where the assessment of early response to therapy by minimal residual disease (MRD) monitoring has proven to be a fundamental tool to guide ...therapeutic choices. The most standardized methods to study MRD in ALL are multi-parametric flow cytometry (MFC) and polymerase chain reaction (PCR) amplification-based methods. Emerging technologies hold the promise to improve MRD detection in ALL patients. Moreover, novel therapies, such as monoclonal antibodies, bispecific T-cell engagers, and chimeric antigen receptor T cells (CART) represent exciting advancements in the management of B-cell precursor (BCP)-ALL.
Through a review of the literature and
data, we analyze the current status of MRD assessment in ALL to better understand how some of its limitations could be overcome by emerging molecular technologies. Furthermore, we highlight the future role of MRD monitoring in the context of personalized protocols, taking into account the genetic complexity in ALL.
Molecular rearrangements (gene fusions and immunoglobulin and T-cell receptor-IG/TR gene rearrangements) are widely used as targets to detect residual leukemic cells in ALL patients. The advent of novel techniques, namely next generation flow cytometry (NGF), digital-droplet-PCR (ddPCR), and next generation sequencing (NGS) appear important tools to evaluate MRD in ALL, since they have the potential to overcome the limitations of standard approaches. It is likely that in the forthcoming future these techniques will be incorporated in clinical trials, at least at decisional time points. Finally, the advent of new powerful compounds is further increasing MRD negativity rates, with benefits in long-term survival and a potential reduction of therapy-related toxicities. However, the prognostic relevance in the setting of novel immunotherapies still needs to be evaluated.
Nodal marginal zone lymphoma (NMZL) is a rare, indolent B-cell tumor that is distinguished from splenic marginal zone lymphoma (SMZL) by the different pattern of dissemination. NMZL still lacks ...distinct markers and remains orphan of specific cancer gene lesions. By combining whole-exome sequencing, targeted sequencing of tumor-related genes, whole-transcriptome sequencing, and high-resolution single nucleotide polymorphism array analysis, we aimed at disclosing the pathways that are molecularly deregulated in NMZL and we compare the molecular profile of NMZL with that of SMZL. These analyses identified a distinctive pattern of nonsilent somatic lesions in NMZL. In 35 NMZL patients, 41 genes were found recurrently affected in ≥3 (9%) cases, including highly prevalent molecular lesions of MLL2 (also known as KMT2D; 34%), PTPRD (20%), NOTCH2 (20%), and KLF2 (17%). Mutations of PTPRD, a receptor-type protein tyrosine phosphatase regulating cell growth, were enriched in NMZL across mature B-cell tumors, functionally caused the loss of the phosphatase activity of PTPRD, and were associated with cell-cycle transcriptional program deregulation and increased proliferation index in NMZL. Although NMZL shared with SMZL a common mutation profile, NMZL harbored PTPRD lesions that were otherwise absent in SMZL. Collectively, these findings provide new insights into the genetics of NMZL, identify PTPRD lesions as a novel marker for this lymphoma across mature B-cell tumors, and support the distinction of NMZL as an independent clinicopathologic entity within the current lymphoma classification.
•PTPRD lesions are among the most recurrent alterations in NMZL and appear to be enriched in this lymphoma type across mature B-cell tumors.•NMZL and SMZL genetics overlap with the exceptions of PTPRD lesions, supporting their distinction as independent entities.
To shed light onto the molecular basis of Philadelphia chromosome-positive acute lymphoblastic leukemia and to investigate the prognostic role of additional genomic lesions, we analyzed copy number ...aberrations using the Cytoscan HD Array in 116 newly diagnosed adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia enrolled in four different GIMEMA protocols, all based on a chemotherapy-free induction strategy. This analysis showed that patients with Philadelphia chromosome-positive acute lymphoblastic leukemia carry an average of 7.8 lesions/case, with deletions outnumbering gains (88%
12%). The most common deletions were those targeting
,
and
, which were detected in 84%, 36% and 32% of cases, respectively. Patients carrying simultaneous deletions of
plus
and/or
had a significantly lower disease-free survival rate (24.9%
43.3%;
=0.026). The only
isoform affecting prognosis was the dominant negative one (
=0.003). Analysis of copy number aberrations showed that 18% of patients harbored
deletions, which were of two types, differing in size: the longer deletions were associated with the achievement of a complete molecular remission (
=0.05) and had a favorable impact on disease-free survival (64.3%
32.1% at 36 months;
=0.031). These findings retained statistical significance also in multivariate analysis (
=0.057).
deletions, detected in 6% of cases, were associated with the achievement of a complete molecular remission (
=0.009). These results indicate that in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia a detailed evaluation of additional deletions - including
,
,
,
and
- has prognostic implications and should be incorporated in the design of more personalized treatment strategies.
To address high blood pressure (BP) in rheumatology patients, we previously implemented BP Connect, a brief staff-driven protocol to address high BP. Although timely follow-up and hypertension rates ...improved for patients with in-system primary care (PC), many receive PC and rheumatology care in separate health systems. In this cohort study, we compared rates of timely PC follow-up for high BP across-system health maintenance organizations (HMOs) before and after BP Connect implementation.
All adult patients with high rheumatology clinic BP and PC in that HMO were eligible. BP Connect's protocol engaged the staff in remeasuring high BP (≥140/90 mm Hg), advising cardiovascular disease risk, and connecting timely PC follow-up, which for patients with PC across system includes written follow-up instructions. After an eligible rheumatology visit, the next HMO PC visit with BP was used to determine rates and odds of timely follow-up before and after using multivariable logistic regression.
Across 1327 rheumatology visits with high BP and across-system PC (2013-2019), 951 occurred after 2015 BP Connect implementation; 400 had confirmed high BP. Primary care follow-up rose from 20.5% to 23.5%. The odds of timely PC BP follow-up insignificantly changed (odds ratio, 1.19; confidence interval, 0.85-1.68). For visits with Black patients, the odds of timely follow-up did significantly increase (1.95; confidence interval, 1.02-3.79).
Timely follow-up for Black patients did improve, highlighting protocol interventions for more equitable health care. In contrast to our prior in-system study, BP Connect did not significantly improve follow-up with an across-system PC, indicating a need for direct scheduling. Future directions include piloting direct across-system scheduling.
Patients with rheumatologic conditions are at elevated risk of cardiovascular disease (CVD) due to inflammatory and traditional risk factors, such as high blood pressure (BP) and smoking. However, ...rheumatology clinics rarely address traditional risk factors, although they are routinely assessed and modifiable in primary care. The present study sought to (1) characterize rheumatology clinic staff's work process for addressing high BP and smoking and (2) identify barriers and strategies for effective management of these risk factors.
We conducted 7 focus groups with medical assistants, nurses, and scheduling staff from 4 adult rheumatology clinics across 2 health systems (BP focus groups, n = 23; smoking, n = 20). Transcripts were analyzed using thematic analysis to elucidate barriers and strategies.
We found 3 clinic work processes for the management of high BP and smoking risk: (1) risk identification, (2) follow-up within the clinic, and (3) follow-up with primary care and community resources. Within these processes, we identified barriers and strategies grouped into themes: (1) time, (2) clinic workflows, (3) technology and resources, (4) staff's attitudes and knowledge, and (5) staff's perceptions of patients. The most pervasive barriers were (1) no structured system for follow-up and (2) staff confidence and skill in initiating conversations about health-related behavior change.
Our study identified generalizable gaps in rheumatology staff's work processes and competencies for addressing high BP and smoking in patients. Future efforts to support staff needs should target (1) systems for follow-up within and outside the clinic and (2) conversation support tools.
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