Early recognition of Ph-like acute lymphoblastic leukemia cases could impact on the management and outcome of this subset of B-lineage ALL. To assess the prognostic value of the Ph-like status in a ...pediatric-inspired, minimal residual disease (MRD)-driven trial, we screened 88 B-lineage ALL cases negative for the major fusion genes (BCR-ABL1, ETV6-RUNX1, TCF3-PBX1 and KTM2Ar) enrolled in the GIMEMA LAL1913 front-line protocol for adult BCR/ABL1-negative ALL. The screening - performed using the BCR/ABL1-like predictor - identified 28 Ph-like cases (31.8%), characterized by CRLF2 overexpression (35.7%), JAK/STAT pathway mutations (33.3%), IKZF1 (63.6%), BTG1 (50%) and EBF1 (27.3%) deletions, and rearrangements targeting tyrosine kinases or CRLF2 (40%). The correlation with outcome highlighted that: i) the complete remission (CR) rate was significantly lower in Ph-like compared to non-Ph-like cases (74.1% vs 91.5%, p=0.044); ii) at time point 2 (TP2), decisional for transplant allocation, 52.9% of Ph-like cases vs 20% of non-Ph-like were MRD-positive (p=0.025); iii) the Ph-like profile was the only parameter associated with a higher risk of being MRD-positive at TP2 (p=0.014); iv) at 24 months, Ph-like patients had a significantly inferior event-free and disease-free survival compared to non-Ph-like patients (33.5% vs 66.2%, p=0.005 and 45.5% vs 72.3%, p=0.062, respectively). This study documents that Ph-like patients have a lower CR rate, EFS and DFS, as well as a greater MRD persistence also in a pediatric-oriented and MRD-driven adult ALL protocol, thus reinforcing that the early recognition of Ph-like ALL patients at diagnosis is crucial to refine risk-stratification and to optimize therapeutic strategies.
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.
Among indolent non-Hodgkin lymphomas (iNHLs), the analysis of measurable/minimal residual disease (MRD) has been extensively applied to follicular lymphoma (FL). Treatment combinations have deeply ...changed over the years, as well as the techniques to measure MRD, which is currently evaluated only in the setting of clinical trials. Here, we discuss the evidence on the role of molecular monitoring in the management of FL. Mature data support the quantification of molecular tumor burden at diagnosis as a tool to stratify patients in risk categories and of MRD evaluation at the end of treatment to predict progression-free survival and overall survival. Moreover, MRD deserves further studies as a tool to refine the clinical/metabolic response and to modulate treatment intensity/duration. Patients with a higher relapse probability can be identified, but the relevance of continuous molecular follow-up should be clarified by kinetic models of MRD analysis. Being the BCL2/heavy chain immunoglobulin gene hybrid rearrangement detectable in about 50% to 60% of advanced FL and in 30% of positron emission tomography/computed tomography-staged localized FL, technical advancements such as next-generation sequencing/target locus amplification may allow broadening the FL population carrying a molecular marker. Droplet digital polymerase chain reaction can better quantify MRD at low levels, and novel sources of DNA, such as cell-free DNA, may represent a noninvasive tool to monitor MRD. Finally, MRD in other iNHLs, such as lymphoplasmacytic lymphoma/Waldenström macroglobulinemia and marginal zone lymphoma, is beginning to be explored.
In acute lymphoblastic leukemia, flow cytometry detects more accurately leukemic cells in patients' cerebrospinal fluid compared to conventional cytology. However, the clinical significance of flow ...cytometry positivity with a negative cytology - occult central nervous system disease - is not clear. In the framework of the national Campus ALL program, we retrospectively evaluated the incidence of occult central nervous system disease and its impact on outcome in 240 adult patients with newly diagnosed acute lymphoblastic leukemia. All cerebrospinal fluid samples were investigated by conventional cytology and flow cytometry. The presence of ≥10 phenotypically abnormal events, forming a cluster, was considered as flow cytometry positivity. No central nervous system involvement was documented in 179 patients, while 18 were positive by conventional morphology and 43 were occult central nervous system disease positive. The relapse rate was significantly lower in central nervous system disease negative patients and the disease-free and overall survival were significantly longer in central nervous system disease negative patients than in those with manifest or occult central nervous system disease positive. In multivariate analysis, the status of manifest and occult central nervous system disease positivity was independently associated with a worse overall survival. In conclusion, we demonstrate that in adult acute lymphoblastic leukemia patients at diagnosis flow cytometry can detect occult central nervous system disease at high sensitivity and that the status of occult central nervous system disease positivity is associated with an adverse outcome. (Clinicaltrials.gov NCT03803670).
The role of the minimal residual disease (MRD) in follicular lymphoma is still debated. In this study, we assessed whether the BCL2/IGH rearrangement could have a prognostic role in patients ...receiving R-CHOP, R-FM, or R-CVP.
DNAs from 415 patients among the 504 cases enrolled in the FOLL05 trial (NCT00774826) were centralized and assessed for the BCL2/IGH at diagnosis, at the end of treatment, and after 12 and 24 months.
At diagnosis, the molecular marker was detected in 53% of cases. Patients without molecular marker or with a low molecular tumor burden (<1 × 10(-4) copies) showed higher complete remission (CR) rate and longer progression-free survival (PFS; 3-year PFS 80% vs. 59%; P = 0.015). PFS was significantly conditioned by the PCR status at 12 and 24 months, with 3-year PFS of 66% for MRD(-) cases versus 41% for those MRD(+) at 12 months (P = 0.015), and 84% versus 50% at 24 months (P = 0.014). The MRD negativity at 12 and 24 months resulted in an improved PFS both in CR and in partial remission (PR) patients (3-year PFS = 72% for cases CR/PCR(-) vs. 32% for those CR/PCR(+) vs. 62% for those PR/PCR(-) and 25% for patients in PR/PCR(+); P = 0.001). The prognostic value of MRD at 12 and 24 months of follow-up was confirmed also in multivariate analysis.
In this study, standardized molecular techniques have been adopted and applied on bone marrow samples from a large cohort. Data reported show that the MRD detection is a powerful independent predictor of PFS in patients with follicular lymphoma receiving conventional chemoimmunotherapy.
Heavy chain diseases are rare B-cell neoplasms consisting of the production of a monoclonal immunoglobulin composed of the only heavy chain without corresponding light chains. It is a rare adult ...disease that may involve several sites with a variable clinical course. It manifests itself on a large spectrum from indolent to rapidly progressive. We present a case of heavy chain disease and concomitant T- cell large granular lymphoproliferative disorder, an association described in only six cases before.
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Minimal residual disease (MRD) has been increasingly investigated in mantle cell lymphoma (MCL), including for individual therapeutic ...stratification and pre‐emptive treatment in clinical trials. Although patient/allele specific real‐time quantitative polymerase chain reaction (qPCR) of IGH or BCL1‐IGH clonal markers is the gold‐standard method, its reliance on a standard curve for relative quantification limits quantification of low‐level positivity within the 1E‐4 to 1E‐5 range; over half of positive MRD samples after treatment fall below the quantitative range (BQR) of the standard curve. Droplet digital PCR (ddPCR), in contrast, allows absolute quantification, including for samples with no baseline determination of tumor infiltration by multicolor flow cytometry (MFC), avoiding the need for a reference standard curve. Using updated, optimized, ddPCR criteria we compared it with qPCR in 416 MRD samples (and with MFC in 63), with over‐representation (61%) of BQR results by qPCR, from a total of 166 patients from four prospective MCL clinical trials. ddPCR, qPCR and MFC gave comparable results in MRD samples with at least 0.01% (1E‐4) positivity. ddPCR was preferable to qPCR since it provided more robust quantification at positivity between 1E‐4 and 1E‐5. Amongst 240 BQR samples with duplicate or triplicate analysis, 39% were positive by ddPCR, 49% negative and only 12% remained positive below quantifiable ddPCR limits. The prognostic relevance of ddPCR is currently under assessment in the context of prospective trials within the European MCL Network.
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