In recent years, the outcome of mantle cell lymphoma (MCL) has improved, especially in younger patients, receiving cytarabine-containing chemoimmunotherapy and autologous stem cell transplantation. ...Nevertheless, a proportion of MCL patients still experience early failure. To identify biomarkers anticipating failure of intensive chemotherapy in MCL, we performed target resequencing and DNA profiling of purified tumor samples collected from patients enrolled in the prospective
(high-dose chemoimmunotherapy followed by autologous transplantation and randomized lenalidomide maintenance). Mutations of
and disruption of
by deletion or mutation associated with an increased risk of progression and death, both in univariate and multivariate analysis. By adding
mutations and
disruption to the MIPI-c backbone, we derived a new prognostic index, the "MIPI-genetic" ("MIPI- g"). The "MIPI-g" improved the model discrimination ability compared to the MIPI-c alone, defining three risk groups: i) low-risk patients (4-year progression free survival and overall survival of 72.0% and 94.5%); ii) inter-mediate-risk patients (4-year progression free survival and overall survival of 42.2% and 65.8%) and iii) high-risk patients (4-year progression free survival and overall survival of 11.5% and 44.9%). Our results: i) confirm that
disruption identifies a high-risk population characterized by poor sensitivity to conventional or intensified chemotherapy; ii) provide the pivotal evidence that patients harboring
mutations share the same poor outcome as patients harboring
disruption; and iii) allow to develop a tool for the identification of high-risk MCL patients for whom novel therapeutic strategies need to be investigated. (
).
Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in western countries, with an incidence of approximately 5.1/100,000 new cases per year. Some patients may never require ...treatment, whereas others relapse early after front line therapeutic approaches. Recent whole genome and whole exome sequencing studies have allowed a better understanding of CLL pathogenesis and the identification of genetic lesions with potential clinical relevance. Consistently, precision medicine plays a pivotal role in the treatment algorithm of CLL, since the integration of molecular biomarkers with the clinical features of the disease may guide treatment choices. Most CLL patients present at the time of diagnosis with an early stage disease and are managed with a watch and wait strategy. For CLL patients requiring therapy, the CLL treatment armamentarium includes both chemoimmunotherapy strategies and biological drugs. The efficacy of these treatment strategies relies upon specific molecular features of the disease.
disruption (including both
mutation and 17p deletion) is the strongest predictor of chemo-refractoriness, and the assessment of
status is the first and most important decisional node in the first line treatment algorithm. The presence of
disruption mandates treatment with biological drugs that inhibit the B cell receptor or, alternatively, the B-cell lymphoma 2 (BCL2) pathway and can, at least in part, circumvent the chemorefractoriness of
-disrupted patients. Beside
disruption, the mutational status of immunoglobulin heavy variable (IGHV) genes also helps clinicians to improve treatment tailoring. In fact, patients carrying mutated IGHV genes in the absence of
disruption experience a long-lasting and durable response to chemoimmunotherapy after fludarabine, cyclophosphamide, and rituximab (FCR) treatment with a survival superimposable to that of a matched general population. In contrast, patients with unmutated IGHV genes respond poorly to chemoimmunotherapy and deserve treatment with B cell receptor inhibitors. Minimal residual disease is also emerging as a relevant biomarker with potential clinical implications. Overall, precision medicine is now a mainstay in the management and treatment stratification of CLL. The identification of novel predictive biomarkers will allow further improvements in the treatment tailoring of this leukemia.
Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma. Approximately 60% of patients are cured with R-CHOP as a frontline treatment, while the remaining patients experience ...primary refractory or relapsed disease (R/R). The prognosis for R/R DLBCL patients who are neither eligible for autologous stem-cell transplantations nor CAR-T-cell treatment is poor, representing an important unmet need. Monoclonal antibodies (mAbs) have dramatically improved therapeutic options in anti-cancer strategies, offering new opportunities to overcome chemo-refractoriness in this challenging disease, even in cases of primary non-responder DLBCL. Several novel mAbs, characterized by different mechanisms of action and targets, are now available for R/R DLBCL. Unbound mAbs induce an immune response against cancer cells, triggering different mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), activation of antibody-dependent cell-mediated phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC). Antibody-drug conjugates (ADCs) and radioimmunotherapy (RIT), respectively, deliver a cytotoxic payload or a beta-emitter radionuclide to the targeted cells and nearby bystanders. Bispecific T-cell engagers (BiTes) and immune checkpoint inhibitors (ICIs) redirect and enhance the immune response against tumor cells. Here, we review therapeutic strategies based on monoclonal antibodies for R/R DLBCL.
Liquid biopsy consists in a simple blood sampling that allows to analyze cell free DNA (cfDNA), containing specific genomic clues released by the tumor into the bloodstream. In this review, we shall ...focus on the analysis of cfDNA in lymphoma and, in particular, on its application in the genotyping and monitoring of two common types of B-cell lymphoma, i.e., diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL). From a diagnostic standpoint and based upon the current international guidelines, lymphoma diagnosis has so far relied on the analysis of the tissue biopsy. From a molecular viewpoint, though, the tissue biopsy does not reflect the entire molecular heterogeneity of lymphomas. In fact, in an individual patient, lymph nodes at different anatomical sites, as well as different areas of the same lymph node, may show different genetic profiles. Consequently, molecular analysis of genomic DNA extracted from a single lymph node biopsy may not recapitulate the whole mutational landscape of the disease. Liquid biopsy may overcome this hurdle, since cfDNA is released by all tumoral cells and can reveal the entire molecular complexity of lymphomas. From a translational perspective, liquid biopsy may also be used to evaluate clonal evolution, response to therapy and minimal residual disease. Consistently, in DLBCL as well in cHL, the drop of the mutational burden during the treatment course provides complementary information to conventional imaging techniques. The integration of liquid biopsy with imaging techniques may prove useful for a better prediction of patients' outcome and for a better treatment tailoring.
Summary
Richter syndrome (RS) is mostly due to the direct transformation of the chronic lymphocytic leukaemia (CLL) clone, as documented by the same immunoglobulin heavy‐chain variable region (IGHV) ...rearrangement in both CLL and RS cells. In rare cases characterized by a better outcome, the RS clone harbours a different IGHV rearrangement compared to the CLL phase. We investigated the CLL phase of clonally unrelated RS to test whether the RS clone was already identifiable prior to clinicopathologic transformation, albeit undetectable by conventional approaches. CLL cells of eight patients with unrelated RS were subjected to an ultra‐deep next‐generation sequencing (NGS) approach with a sensitivity of 10−6. In 7/8 cases, the RS rearrangement was not identified in the CLL phase. In one case, the RS clone was identified at a very low frequency in the CLL phase, conceivably due to the concomitance of CLL sampling and RS diagnosis. Targeted resequencing revealed that clonally unrelated RS carries genetic lesions primarily affecting the TP53, MYC, ATM and NOTCH1 genes. Conversely, mutations frequently involved in de novo diffuse large B‐cell lymphoma (DLBCL) without a history of CLL were absent. These results suggest that clonally unrelated RS is a truly de novo lymphoma with a mutational profile reminiscent, at least in part, of clonally related RS.
Background. Chronic lymphocytic leukemia (CLL) is the most common leukemia of adults in western countries. CLL is a highly heterogeneous disease; some patients may never require treatment, whereas ...other relapse early after frontline therapy. In approximately 70% of newly diagnosed cases, CLL presents at an early clinical stage and is managed with a watch & wait strategy. Until now, few clinical and molecular predictors inform on the risk of treatment requirement and the impact of CLL gene mutations is not completely understood.
Purpose. We aimed at identifying new molecular markers that may predict early treatment requirement and may help clinicians to better plan the watch & wait strategy in asymptomatic early stage CLL patients.
Methods. This study includes 295 Binet A CLL patients referring at our institution who did not require treatment for at least 3 months after diagnosis. Tumor genomic DNA (gDNA) was isolated from peripheral blood mononuclear cells at the time of diagnosis. gDNA was analyzed in the coding exons plus splice sites of the most frequently mutated genes in CLL with a next-generation-sequencing (NGS) approach. NGS analysis was performed on the Illumina MiSeq instrument (coverage >2000x in >80% of the target region). The somatic function of VarScan2 was used for variant calling and a stringent bioinformatic pipeline was developed to protect against the false call of polymorphisms and sequencing errors. A threshold of 5% of variant allele frequency was set for variant calling. The primary endpoint was time to first treatment (TTFT) defined as the timeinterval between the date of CLL diagnosis and the date of first CLL treatment. Statistical analysis was performed using SPSS version 24.0.
Results. The median age of the study cohort was 70.8 years old, 136 (46.1%) patients were female, 71 (24.1%) harbored unmutated IGHV genes, 44 (14.9%) had trisomy 12, 12 (4.1%) had 17p deletion, 15 (5.1%) had 11q deletion and 150 (50.8%) had 13q deletion. NGS mutational analysis showed that NOTCH1 was the most frequently mutated gene occurring in 25 (8.5%) patients, followed by ATM in 18 (6.1%), TP53 in 17 (5.8%), MYD88 in 12 (4.1%), SF3B1 in 10 (3.4%), XPO1 in 7 (2.4%), EGR2 in 6 (2.0%), NFKBIE in 4 (1.4%), POT1 in 2 (0.7%), and BIRC3 in 1 (0.3%) patients. After a median follow-up of 9.5 years, 80 (27.1%) patients required treatment. In univariate analysis, molecular characteristics associated with a shorter TTFT were trisomy 12 (HR: 2.42; 95% CI 1.43-4.15; p=0.001), unmutated IGHV genes (HR: 4.51; 95% CI 2.83-7.05; p<0.0001) and mutations of XPO1 (HR: 8.88; 95% CI 3.77-20.95; p<0.0001), NOTCH1 (HR: 3.02; 95% CI 1.66-5.51; p<0.001) and SF3B1 (HR: 2.65; 95% CI 1.15-6.10; p=0.022). Interestingly, neither 17p deletion nor TP53 mutations associated with a shorter TTFT, in line with the notion that TP53 disruption interacts with treatment but not with a watch & wait strategy. By multivariate analysis, XPO1 mutations (HR: 4.24; 95% CI 1.72-10.44; p=0.002) maintained an independent association with a shorter TTFT (Table 1). At 10 years, XPO1 mutated patients had a probability of remaining free from treatment of 0% compared to 69.3% for wild type cases (p<0.0001) (Figure 1).
Conclusions. Mutations of the XPO1 gene, encoding for exportin 1 which mediates the nuclear export of proteins and RNA, are an independent predictor of shorter TTFT and, if validated, might help clinicians in a better management of the watch & wait strategy for Binet A CLL patients. Moreover, since most of mutations, approximately 90%, affect the glutamic acid in position 571, polymerase chain reaction based methods may be used to identify XPO1 mutations in a simple and time effective manner.
Display omitted
Rossi:Abbvie: Honoraria, Other: Scientific advisory board; Janseen: Honoraria, Other: Scientific advisory board; Roche: Honoraria, Other: Scientific advisory board; Astra Zeneca: Honoraria, Other: Scientific advisory board; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gaidano:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra-Zeneca: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesys: Consultancy, Honoraria.
Summary
We aimed at molecularly dissecting the anatomical heterogeneity of small lymphocytic lymphoma (SLL), by analysing a cohort of 12 patients for whom paired DNA from a lymph node biopsy and ...circulating cells, as well as plasma‐circulating tumour DNA (ctDNA) was available. Notably, the analyses of the lymph node biopsy and of circulating cells complement each other since a fraction of mutations (20·4% and 36·4%, respectively) are unique to each compartment. Plasma ctDNA identified two additional unique mutations. Consistently, the different synchronous sources of tumour DNA complement each other in informing on driver gene mutations in SLL harbouring potential prognostic and/or predictive value.
Background: Patients with chronic lymphocytic leukemia (CLL) have a higher risk of developing other malignancies (OMs) compared to the general population. However, the impact of CLL-related risk ...factors and CLL-directed treatment is still unclear and represents the focus of this work. Methods: We conducted a retrospective international multicenter study to assess the incidence of OMs and detect potential risk factors in 19,705 patients with CLL, small lymphocytic lymphoma, or high-count CLL-like monoclonal B-cell lymphocytosis, diagnosed between 2000 and 2016. Data collection took place between October 2020 and March 2022. Findings: In 129,254 years of follow-up after CLL diagnosis, 3513 OMs were diagnosed (27.2 OMs/1000 person-years). The most common hematological OMs were Richter transformation, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Non-melanoma skin (NMSC) and prostate cancers were the most common solid tumors (STs).The only predictor for MDS and AML development was treatment with fludarabine and cyclophosphamide with/without rituximab (FC ± R) (OR = 3.7; 95% CI = 2.79–4.91; p < 0.001). STs were more frequent in males and patients with unmutated immunoglobulin heavy variable genes (OR = 1.77; 95% CI = 1.49–2.11; p < 0.001/OR = 1.89; 95% CI = 1.6–2.24; p < 0.001).CLL-directed treatment was associated with non-melanoma skin and prostate cancers (OR = 1.8; 95% CI = 1.36–2.41; p < 0.001/OR = 2.11; 95% CI = 1.12–3.97; p = 0.021). In contrast, breast cancers were more frequent in untreated patients (OR = 0.17; 95% CI = 0.08–0.33; p < 0.001).Patients with CLL and an OM had inferior overall survival (OS) than those without. AML and MDS conferred the worst OS (p < 0.001). Interpretation: OMs in CLL impact on OS. Treatment for CLL increased the risk for AML/MDS, prostate cancer, and NMSC. FCR was associated with increased risk for AML/MDS. Funding: AbbVie, and EU/EFPIA Innovative Medicines Initiative Joint Undertaking HARMONY grant n° 116026.
PDF
