We review the preclinical and clinical experience with first and subsequent generation Bruton's tyrosine kinase inhibitors in B-cell lymphoproliferative diseases, highlighting the rationale for their ...clinical use in primary central nervous system diffuse large B-cell lymphoma (PCNSL).
Growing knowledge on the molecular and genetic profile of PCNSL has provided the basis for new drug development targeting aberrantly activated oncogenic signal transduction pathways. PCNSL exhibits frequent genetic alterations of components of the B-cell and Toll-like receptor signalling pathways. On the basis of these discoveries and the limited efficacy obtained with chemotherapy in refractory and relapsed PCNSL, activity of new targeted agents, such as Bruton's tyrosine kinase inhibitors, has been explored with promising results.
Innovative therapeutic strategies, applied in first line, have contributed to improved outcomes in patients with PCNSL, making this disease potentially curable in young and fit patients. However, response to induction therapies remains suboptimal and the best consolidative therapy has yet to be defined. In this regard, given the activity of Bruton's tyrosine kinase inhibitors in the refractory and relapsed PCNSL setting, these agents are currently being explored as part of combination regimens for induction therapy of newly diagnosed PCNSL.
Introduction
Chronic myeloid leukemia (CML) is a malignant clonal disorder of hematopoietic stem cells characterized by a translocation of genetic material between chromosomes 9 and 22 resulting in ...the BCR-ABL fusion oncogene expression. Nilotinib is a potent second-generation tyrosine kinase inhibitor available as first line treatment. Among side effects QTc interval prolongation, pancreatitis, metabolic disorders and skin reactions are the most commonly seen.
Case Report
Here we describe a rare case of lichen planopilaris eruption that developed during therapy with nilotinib.
Management & Outcome
Nilotinib dosage was reduced together with introduction of hydroxychloroquine with progressive improvement of alopecia.
Discussion
Collaboration with dermatologist and nilotinib dose reduction allowed to continue the drug maintaining major molecular response and patient's quality of life.
Consolidation therapy has improved the outcome of newly diagnosed PCNSL patients. Whole-brain radiotherapy (WBRT) was the first consolidation strategy used and represented the gold standard for many ...years, but at the expense of a high risk of neurotoxicity. Thus, alternative strategies are being investigated in order to improve disease outcomes and to spare the neurocognitive side effects due to WBRT.
We reviewed published studies on PCNSL patients treated with HDC/ASCT, focusing on the efficacy and safety of the conditioning regimens. Prospective and retrospective studies, published in the English language from 1992 to 2022, in high-quality international journals were identified in PubMed.
Consolidation with HDC containing highly CNS-penetrating agents (thiotepa, busulfan or BCNU) followed by ASCT provided long-term disease control and survival in PCNSL patients. Two prospective randomized studies, comparing HDC/ASCT versus WBRT, reported similar progression-free survival (PFS) and similar results on the decline in neurocognitive functions in a substantial proportion of patients after WBRT but not after HDC-ASCT. A recent randomized study comparing HDC/ASCT versus non-myeloablative consolidation reported a longer PFS in transplanted patients.
ASCT conditioned with regimens, including highly CNS-penetrating agents, represents, to date, the best choice among the available consolidation strategies for fit newly diagnosed PCNSL patients.
Purpose
Primary central nervous system lymphoma (PCNSL) is a rare, aggressive form of extranodal non-Hodgkin lymphoma. To predict the overall survival (OS) in advance is of utmost importance as it ...has the potential to aid clinical decision-making. Though radiomics-based machine learning (ML) has demonstrated the promising performance in PCNSL, it demands large amounts of manual feature extraction efforts from magnetic resonance images beforehand. deep learning (DL) overcomes this limitation.
Methods
In this paper, we tailored the 3D ResNet to predict the OS of patients with PCNSL. To overcome the limitation of data sparsity, we introduced data augmentation and transfer learning, and we evaluated the results using
r
stratified
k
-fold cross-validation. To explain the results of our model, gradient-weighted class activation mapping was applied.
Results
We obtained the best performance (the standard error) on post-contrast T1-weighted (T1Gd)—area under curve
=
0.81
(
0.03
)
, accuracy
=
0.87
(
0.07
)
, precision
=
0.88
(
0.07
)
, recall
=
0.88
(
0.07
)
and
F
1-score
=
0.87
(
0.07
)
, while compared with ML-based models on clinical data and radiomics data, respectively, further confirming the stability of our model. Also, we observed that PCNSL is a whole-brain disease and in the cases where the OS is less than 1 year, it is more difficult to distinguish the tumor boundary from the normal part of the brain, which is consistent with the clinical outcome.
Conclusions
All these findings indicate that T1Gd can improve prognosis predictions of patients with PCNSL. To the best of our knowledge, this is the first time to use DL to explain model patterns in OS classification of patients with PCNSL. Future work would involve collecting more data of patients with PCNSL, or additional retrospective studies on different patient populations with rare diseases, to further promote the clinical role of our model.
Primary Central Nervous System Lymphoma (PCNSL) is an aggressive neoplasm with a poor prognosis. Although therapeutic progresses have significantly improved Overall Survival (OS), a number of ...patients do not respond to HD-MTX-based chemotherapy (15-25%) or experience relapse (25-50%) after an initial response. The reasons underlying this poor response to therapy are unknown. Thus, there is an urgent need to develop improved predictive models for PCNSL. In this study, we investigated whether radiomics features can improve outcome prediction in patients with PCNSL. A total of 80 patients diagnosed with PCNSL were enrolled. A patient sub-group, with complete Magnetic Resonance Imaging (MRI) series, were selected for the stratification analysis. Following radiomics feature extraction and selection, different Machine Learning (ML) models were tested for OS and Progression-free Survival (PFS) prediction. To assess the stability of the selected features, images from 23 patients scanned at three different time points were used to compute the Interclass Correlation Coefficient (ICC) and to evaluate the reproducibility of each feature for both original and normalized images. Features extracted from Z-score normalized images were significantly more stable than those extracted from non-normalized images with an improvement of about 38% on average (
-value < 10-12). The area under the ROC curve (AUC) showed that radiomics-based prediction overcame prediction based on current clinical prognostic factors with an improvement of 23% for OS and 50% for PFS, respectively. These results indicate that radiomics features extracted from normalized MR images can improve prognosis stratification of PCNSL patients and pave the way for further study on its potential role to drive treatment choice.
The natural history of follicular lymphoma is usually characterized by an indolent course with a high response rate to the first line therapy followed by recurrent relapses, with a time to next ...treatment becoming shorter after each subsequent treatment line. More than 80% of patients have advanced stage disease at diagnosis. The time of initiation and the nature of the treatment is mainly conditioned by symptoms, tumor burden, lymphoma grading, co-morbidities and patients preference. A number of clinical and biological factors have been determined to be prognostic in this disease, but the majority of them could not show to be predictive of response to treatment, and therefore can't be used to guide the treatment choice. CD20 expression is the only predictive factor recognized in the treatment of FL and justifies the use of "naked" or "conjugated" anti-CD20 monoclonal antibodies as a single agent or in combination with chemo- or targeted therapy. Nevertheless, as this marker is almost universally found in FL, it has little role in the choice of treatment. The outcome of patients with FL improved significantly in the last years, mainly due to the widespread use of rituximab, autologous and allogeneic transplantation in young and fit relapsed patients, the introduction of new drugs and the improvement in diagnostic accuracy and management of side effects. Agents as new monoclonal antibodies, immuno-modulating drugs, and target therapy have recently been developed and approved for the relapsed setting, while studies to evaluate their role in first line treatment are still ongoing. Here we report our considerations on first line treatment approach and on the potential factors which could help in the choice of therapy.
Abstract Pegfilgrastim has equivalent efficacy to daily G-CSF in enhancing neutrophil recovery after chemotherapy, but conclusive data concerning its use for peripheral blood stem cell (PBSC) ...mobilization are lacking. From 2003 to 2008 we used high-dose chemotherapy in 64 lymphoma patients. At mobilization chemotherapy (ESHAP) the first 26 patients used unconjugated G-CSF, while the remaining 38 patients received Pegfilgrastim. At the time of harvest 25 patients collected stem cells after the use of G-CSF and 36 in the Peg group. No statistical by significant differences were observed in median peripheral CD34+ cells mobilized (77 μL versus 71 μL) and in collected PBSC (12.3 × 106 /kg versus 9.4 × 106 /kg p = 0.76). In the PEG group all patients collected the target PBSC with a single apheresis with a greater proportion of “optimal” mobilizers (83% versus 64%; p = 0.05). In conclusion a single dose of Pegfilgrastim could be a valid alternative to unconjugated G-CSF to mobilize PBSC in lymphoma patients.
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