Trisomy 12, the third most frequent chromosomal aberration in chronic lymphocytic leukemia (CLL), confers an intermediate prognosis. In our cohort of 104 untreated patients carrying +12, NOTCH1 ...mutations occurred in 24% of cases and were associated to unmutated IGHV genes (P=0.003) and +12 as a sole cytogenetic abnormality (P=0.008). NOTCH1 mutations in +12 CLL associated with an approximately 2.4 fold increase in the risk of death, a significant shortening of survival (P<0.01) and proved to be an independent predictor of survival in multivariate analysis. Analogous to +12 CLL with TP53 disruption or del(11q), NOTCH1 mutations in +12 CLL conferred a significantly worse survival compared to that of +12 CLL with del(13q) or +12 only. The overrepresentation of cell cycle/proliferation related genes of +12 CLL with NOTCH1 mutations suggests the biological contribution of NOTCH1 mutations to determine a poor outcome. NOTCH1 mutations refine the intermediate prognosis of +12 CLL.
In this study, we aimed to investigate the pathways of recognition of acute lymphoblastic leukemia blasts by natural killer cells and to verify whether differences in natural killer cell activating ...receptor ligand expression among groups defined by age of patients, or presence of cytogenetic/molecular aberrations correlate with the susceptibility to recognition and killing. We analyzed 103 newly diagnosed acute lymphoblastic leukemia patients: 46 adults and 57 children. Pediatric blasts showed a significantly higher expression of Nec-2 (P=0.03), ULBP-1 (P=0.01) and ULBP-3 (P=0.04) compared to adult cells. The differential expression of these ligands between adults and children was confined to B-lineage acute lymphoblastic leukemia with no known molecular alterations. Within molecularly defined subgroups of patients, a high surface expression of NKG2D and DNAM1 ligands was found on BCR-ABL(+) blasts, regardless of patient age. Accordingly, BCR-ABL(+) blasts proved to be significantly more susceptible to natural killer-dependent lysis than B-lineage blasts without molecular aberrations (P=0.03). Cytotoxic tests performed in the presence of neutralizing antibodies indicated a pathway of acute lymphoblastic leukemia cell recognition in the setting of the Nec-2/DNAM-1 interaction. These data provide a biological explanation of the different roles played by alloreactive natural killer cells in pediatric versus adult acute lymphoblastic leukemia and suggest that new natural killer-based strategies targeting specific subgroups of patients, particularly those BCR-ABL(+), are worth pursuing further.
In patients with Philadelphia-positive acute lymphoblastic leukemia, resistance to treatment with tyrosine kinase inhibitors is frequent and most often associated with the development of point ...mutations in the BCR-ABL kinase domain. We aimed to assess: (i) in how many patients BCR-ABL kinase domain mutations are already detectable at relatively low levels at the time of diagnosis, and (ii) whether mutation detection correlates with subsequent response to therapy.
We retrospectively analyzed samples collected at diagnosis from 15 patients with Philadelphia-positive acute lymphoblastic leukemia who subsequently received tyrosine kinase inhibitor therapy (dasatinib) by cloning the BCR-ABL kinase domain in a bacterial vector and sequencing 200 independent clones per sample.
Mutations at relatively low levels (2-4 clones out of 200) could be detected in all patients--eight who relapsed and seven who achieved persistent remission. Each patient had evidence of two to eight different mutations, the majority of which have never been reported in association with resistance to tyrosine kinase inhibitors. In two patients out of six who relapsed because of a mutation, the mutation (a T315I) was already detectable in a few clones at the time of diagnosis. On the other hand, a patient who was found to harbor an F317L mutation is in persistent remission on dasatinib.
Our results suggest that the BCR-ABL kinase domain is prone to randomly accumulate point mutations in Philadelphia-positive acute lymphoblastic leukemia, although the presence of these mutations in a relatively small leukemic subclone does not always preclude a primary response to tyrosine kinase inhibitors.
Management of CLL in the elderly Cuneo, A.; Foà, R.
Annals of oncology,
February 2017, 2017-02-01, 2017-02-00, 20170201, Letnik:
28, Številka:
2
Journal Article
Ocrelizumab is a humanized anti-CD20 antibody with increased antibody-dependent cellular cytotoxicity compared with rituximab. This phase I/II study evaluated its safety and efficacy in patients with ...relapsed/refractory follicular lymphoma (FL) after prior rituximab therapy.
Forty-seven patients were treated in three dose cohorts and received eight infusions every 3 weeks: cohort A, 200 mg/m2 (n = 15); cohort B, 375 mg/m2 (n = 16); cohort C, first dose 375 mg/m2, seven subsequent doses of 750 mg/m2 (n = 16). Patients were assessed for safety, efficacy, pharmacodynamics and pharmacokinetics.
The median patient age was 58 years, the majority had Ann Arbor stage III/IV disease and had received a median of 2 (range 1–6) prior regimens. Ocrelizumab was well tolerated with grade 3/4 toxicity occurring in 9% of patients. The most common toxicity was infusion-related reactions (74% patients), all grade 1/2 except one grade 3 event. The objective response rate was 38% and was similar in patients with low-affinity and high-affinity variants of the Fcγ receptor IIIa (FcγRIIIa). With follow-up of ∼28 months, the median progression-free survival was 11.4 months.
Ocrelizumab demonstrated activity in patients with relapsed/refractory FL following prior rituximab treatment, with safety similar to rituximab although adverse events appeared milder.
In order to evaluate the predictive value of positron emission tomography-computed tomography (PET/CT) in discriminating the presence of a Richter's syndrome (RS) or a second malignancy (SM), as well ...as to evaluate its prognostic value in patients with chronic lymphocytic leukemia (CLL), we retrospectively analyzed the data of 90 patients who, in the suspicion of a RS or a SM, underwent PET/CT followed by the biopsy of the involved tissue. The median maximum Standardized Uptake Value (SUV max) in the presence of a CLL/small lymphocytic lymphoma, a diffuse large B-cell lymphoma (DLBCL), a Hodgkin lymphoma (HL), a SM were 3.5, 14.6, 7.0 and 6.3, respectively (P ⩽ 0.0001). A SUV max cutoff value ⩾ 5 showed a sensitivity, specificity, positive and negative predictive values of 88.2, 71.2, 51.3 and 94%, respectively, for the presence of a more aggressive disease (DLBCL, HL and SM). A SUV max ⩾ 5 identified also a subset of treatment naive patients with an inferior progression-free survival (P = 0.011) and overall survival (P = 0.067). These findings suggest that PET/CT may helpfully integrate the biologically-based prognostic stratification of CLL. Prospective clinical trials including larger cohorts of patients are needed to conclusively define the role and prognostic impact of PET/CT in the routine management of CLL patients.
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