scholarly journals Efficacy of Front-Line Ibrutinib and Rituximab Combination and the Impact of Treatment Discontinuation in Unfit Patients with Chronic Lymphocytic Leukemia: Results of the Gimema LLC1114 Study

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 207
Author(s):  
Francesca Romana Mauro ◽  
Francesca Paoloni ◽  
Stefano Molica ◽  
Gianluigi Reda ◽  
Livio Trentin ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Treatment Discontinuation ◽  
Lymphocytic Leukemia ◽  
Front Line ◽  
Free Survival ◽  
Skin Cancers ◽  
Unfit Patients ◽  
Male Patients ◽  
The Impact

The GIMEMA group investigated the efficacy, safety, and rates of discontinuations of the ibrutinib and rituximab regimen in previously untreated and unfit patients with chronic lymphocytic leukemia (CLL). Treatment consisted of ibrutinib, 420 mg daily, and until disease progression, and rituximab (375 mg/sqm, given weekly on week 1–4 of month 1 and day 1 of months 2–6). This study included 146 patients with a median age of 73 years, with IGHV unmutated in 56.9% and TP53 disrupted in 22.2%. The OR, CR, and 48-month PFS rates were 87%, 22.6%, and 77%, respectively. Responses with undetectable MRD were observed in 6.2% of all patients and 27% of CR patients. TP53 disruption (HR 2.47; p = 0.03) and B-symptoms (HR 2.91; p = 0.02) showed a significant and independent impact on PFS. The 48-month cumulative rates of treatment discontinuations due to disease progression (DP) or adverse events (AEs) were 5.6% and 29.1%, respectively. AEs leading more frequently to treatment discontinuation were atrial fibrillation in 8% of patients, infections in 8%, and non-skin cancers in 6%. Discontinuation rates due to AEs were higher in male patients (HR: 0.46; p = 0.05), patients aged ≥70 years (HR 5.43, p = 0.0017), and were managed at centers that enrolled <5 patients (HR 5.1, p = 0.04). Patients who discontinued ibrutinib due to an AE showed a 24-month next treatment-free survival rate of 63%. In conclusion, ibrutinib and rituximab combination was an effective front-line treatment with sustained disease control in more than half of unfit patients with CLL. Careful monitoring is recommended to prevent and manage AEs in this patient population.

Notch Signaling Promotes Disease Initiation and Progression in Murine Chronic Lymphocytic Leukemia

Blood ◽  
2020 ◽  
Author(s):  
Delphine Tardivon ◽  
Mateusz Antoszewski ◽  
Nadine Zangger ◽  
Marianne Nkosi ◽  
Jessica Sordet-Dessimoz ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Notch Signaling ◽  
Disease Progression ◽  
Lymphocytic Leukemia ◽  
Gain Of Function ◽  
Human Pathology ◽  
Disease Initiation ◽  
The Impact

NOTCH1 gain-of-function mutations are recurrent in B cell chronic lymphocytic leukemia (B-CLL), where they are associated with accelerated disease progression and refractoriness to chemotherapy. The specific role of NOTCH1 in the development and progression of this malignancy is unclear. Herein we assess the impact of loss of Notch signaling and pathway hyperactivation in an in vivo mouse model of CLL (IgH.TEm) that faithfully recapitulates many features of the human pathology. Ablation of canonical Notch signaling using conditional gene inactivation of RBP-J in immature hematopoietic or B cell progenitors delayed CLL induction and reduced incidence of mice developing disease. In contrast, forced expression of a dominant active form of Notch resulted in more animals developing CLL with early disease onset. Comparative analysis of gene expression and epigenetic features of Notch gain-of-function and control CLL cells revealed direct and indirect regulation of cell cycle-associated genes, which led to increased proliferation of Notch gain-of-function CLL cells in vivo. These results demonstrate that Notch signaling facilitates disease initiation and promotes CLL cell proliferation and disease progression.

Deletion Size Influences Clinical Outcome In Patients with Chronic Lymphocytic Leukemia; 13q Deletion Anatomy, Cooperating Lesions and Cancer Pathogenesis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 757-757 ◽  
Author(s):  
Helen Parker ◽  
Matthew JJ Rose-Zerilli ◽  
Anton Parker ◽  
Tracy Chaplin ◽  
Anne Catherine Gardiner ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Clinical Outcome ◽  
Disease Progression ◽  
Gene Cluster ◽  
Class Ii ◽  
Lymphocytic Leukemia ◽  
Dna Repeats ◽  
Deletion Size ◽  
The Impact ◽  
13Q Deletion

Abstract Abstract 757 Chromosomal deletions involving 13q14 are the commonest genetic abnormality in chronic lymphocytic leukemia, occurring in ~60% of cases and are associated with a favourable clinical outcome when identified as a sole abnormality. A minimally deleted region (MDR), found in most cases, encompasses DLEU2, DLEU1, and miR15a/16-1. However, deletions this small do not occur in all patients and are a simplification of the impact larger heterogeneous deletions have during carcinogenesis. We have previously shown that large 13q14 deletions are associated with disease progression (Strefford et al, ASH 2009, 114(22), 671). To further characterize this abnormality and identify putative cancer genes, we report an updated analysis of our Affymetrix SNP 6.0 genomic profiling study of 224 patients. These patients were subdivided into three cohorts: Cohort I samples were taken at disease presentation, from patients with either stable disease for >5 years (n=38) or progressive disease within 3 years (n=25). Cohort II comprised 64 unselected patient samples taken at disease progression. Cohort III consisted of samples taken at enrollment to the UK CLL4 treatment trial from patients treated with fludarabine and cyclophosphamide, sub-divided based on complete (n=49), partial (n=40) or no response (n=8) to treatment. In total 205 copy number alterations targeted 13q14 in 132 cases, facilitating the identification of a MDR encompassing DLEU2 and the miR15a/16-1 cluster in 119 cases. The remaining cases had partial loss of the MDR, including (n=11) or excluding (n=2) miR15a/16-1. Although deletion size and location was heterogeneous (0.13-96.2Mb), a 210kb proximal breakpoint cluster region (p-BCR) was identified, targeting TRIM13, KCNRG and exons 7–11 of the DLEU2 gene (n=31), whilst a 210kb distal BCR (d-BCR) targeted RNASEH2B and GUCY1B2 (n=46). Breakpoints in these regions frequently targeted DNA repeats, specifically short (SINE) and long interspersed nuclear elements (LINE) in the p- and d-BCR, respectively. Based on size and location, we defined two deletion classes; both encompassed the MDR, whilst class I deletions were <2Mb in size, were often defined by the two BCRs identified and included FAM10A4, BCMS and DLEU7; class II deletions extended beyond this region in either a centromeric and/or telomeric direction, encompassing a large number of additional genes. Rather than being the result of consistent BCRs, class II deletions displayed highly heterogeneous breakpoints suggesting that these classes of deletion may be mechanistically dissimilar. Using these definitions we show that a) at diagnosis, larger deletions (class II) were associated with a significantly increased risk of disease progression (OR=12.3; P=0.005), implicating genes positioned centromeric to the MDR in the poor prognosis observed in these patients b) in progressive patients, class II deletions were enriched (p=0.02), and c) this association was independent of IgVH mutational status, ZAP70 expression and ATM/TP53 deletion. Deletion of a 1Mb gene cluster (48.2-49.2Mb), including SETDB2, PHF11 and RCBTB1, was significantly associated (P<0.01) with disease progression. In conclusion we confirm the association between 13q deletion size and disease progression, and propose a novel gene cluster centromeric to the 13q MDR that may contribute to clinical outcome. 13q deletion size represents a new biomarker for predicting outcome of CLL, whose target gene(s) could provide new therapeutic strategies. The expansion of this approach into other tumour types, will facilitate the identification of a large number of novel genes, expanding our understanding of carcinogenesis and ultimately leading to improved management of cancer patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Genomic mutation profile in progressive chronic lymphocytic leukemia patients prior to first-line chemoimmunotherapy with FCR and rituximab maintenance (REM)

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257353
Author(s):  
Julia González-Rincón ◽  
José A. Garcia-Vela ◽  
Sagrario Gómez ◽  
Belén Fernández-Cuevas ◽  
Sara Nova-Gurumeta ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Somatic Mutations ◽  
Lymphocytic Leukemia ◽  
Front Line ◽  
First Line ◽  
Mutational Status ◽  
Mutation Profile ◽  
Massive Sequencing ◽  
The Impact ◽  
Generation Sequencing

Chronic Lymphocytic Leukemia (CLL) is the most prevalent leukemia in Western countries and is notable for its variable clinical course. This variability is partly reflected by the mutational status of IGHV genes. Many CLL samples have been studied in recent years by next-generation sequencing. These studies have identified recurrent somatic mutations in NOTCH1, SF3B1, ATM, TP53, BIRC3 and others genes that play roles in cell cycle, DNA repair, RNA metabolism and splicing. In this study, we have taken a deep-targeted massive sequencing approach to analyze the impact of mutations in the most frequently mutated genes in patients with CLL enrolled in the REM (rituximab en mantenimiento) clinical trial. The mutational status of our patients with CLL, except for the TP53 gene, does not seem to affect the good results obtained with maintenance therapy with rituximab after front-line FCR treatment.

Beta-2 Microglobulin Is a Strong Prognostic Marker in Patients with Chronic Lymphocytic Leukemia Submitted to Allogeneic Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1244-1244
Author(s):  
Carol Moreno ◽  
Kate E Hodgson ◽  
Montserrat Rovira ◽  
Jordi Esteve ◽  
Carmen Martinez ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Lymphocytic Leukemia ◽  
Free Survival ◽  
Beta 2 ◽  
Beta 2 Microglobulin ◽  
The Impact

Abstract Abstract 1244 Poster Board I-266 Allogeneic stem cell transplantation (SCT) is the only curative treatment for chronic lymphocytic leukemia (CLL). Advanced age, extensive prior therapy, lack of response to treatment, and T-cell depletion of the graft are poor prognostic factors which have been identified in many studies. Beta-2 microglobulin (B2M) has important prognostic value in patients treated with chemotherapy or chemoimmunotherapy, but has been scarcely investigated in the context of allogeneic SCT. In two studies (Khouri et al. Cytotherapy 2002; Sorror et al. J Clin Oncol 2008) no correlation was found between B2M and transplant outcome. Against this background, we analyzed the influence of B2M and other prognostic parameters in 32 patients (median age 50 yrs [range, 29-63], 20 males) who received an allogeneic SCT in our institution between 1991 and 2006. Interval between diagnosis and transplantation was 44 months (range, 6-116). Median number of prior therapies was 2 (range, 1-6). Six patients had previously received an autologous SCT. Most patients had adverse biologic features (high ZAP-70 expression, unmutated IGHV, poor cytogenetics). Serum B2M was increased (≥2.5 mg/L) in 13 out of 29 patients prior to transplant. Creatinine levels and glomerular filtration rate were normal. Median follow-up after transplantation was 7 years (range, 1.8- 16.9). The relapse risk (RR) at 5 and 10 years was 5 % (95% CI, 0-14%) and 23% (95% CI, 2-44), respectively. At one and 10 years the cumulative non-relapse mortality (NRM) was 34% (95% CI, 17-51) and 38% (95% CI, 20-55), respectively. Five and 10-year progression free survival (PFS), event free survival (EFS) and overall survival (OS) were 85% (CI, 66-100) and 65% (CI, 35-94), 58% (CI, 40-76) and 40% (CI, 19-62), and 62% (CI, 45-79) and 57% (CI, 38-75). In the univariate analysis, factors associated with a higher NRM were prior autologous SCT (p=0.006), chemorefractory disease (p=0.04), and high serum B2M levels at the time of SCT (p=0.03). Parameters associated with EFS and OS were high B2M levels (p=0.001 and p=0.002), prior autologous SCT (p<0.001 and p=0.001), and number of prior lines of chemotherapy (≤ 1 vs. ≥ 2) (p=0.018 and p=0.042). In the multivariate analysis, prior autologous SCT (RR=4.4, CI: 1.2-16.3; p=0.02) and chemorefractory disease (RR=3.82, CI: 1.06-13.7; p=0.04) were associated with a higher NRM whereas B2M at the time of SCT was a strong independent factor associated with EFS (RR=5.34, CI: 1.7-16.6; p=0.004) and OS (RR=6.20, CI: 1.6-23; p=0.006). The figure shows the impact of B2M on survival after allogeneic SCT. In contrast, IGHV mutational status, high ZAP-70 expression, > 30% bone marrow infiltration, and disease status (CR vs. no CR) at the time of SCT were not associated with outcome. In summary, this study indicates that, as in patients treated with chemo or chemoimmunotherapy, B2M is a strong predictor of clinical outcome in patients with CLL submitted to allogeneic SCT. Disclosures No relevant conflicts of interest to declare.

A Phase II Trial of Ofatumumab for Older Patients and Patients Who Refuse Fludarabine-Based Regimens with Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3912-3912
Author(s):  
Ian W. Flinn ◽  
William N. Harwin ◽  
Inés M. Macias-Pérez ◽  
Patrick S. Tucker ◽  
David M. Waterhouse ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Maintenance Therapy ◽  
Older Patients ◽  
Research Funding ◽  
Single Agent ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Front Line ◽  
Small Lymphocytic Lymphoma ◽  
Free Survival

Abstract Abstract 3912 Background: Fludarabine (FLU), cyclophosphamide and rituximab (FCR) or other FLU-based regimens have shown improvement in response rates, progression-free survival, and in some studies overall survival in patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). However, a randomized trial of older patients demonstrated no improvement in progression-free and overall survival with FLU-based therapy (Eichhorst BF, et al: Blood 114; 3382, 2009). A recent retrospective analysis of serial CALGB trials (Woyach J, et al: ASH 2011) confirmed the lack of PFS and OS advantage of fludarabine in elderly patients but did find benefit of the anti-CD20 antibody rituximab across all age groups. Ofatumumab (OFA) is a fully human immunoglobulin G1 kappa, monoclonal antibody that targets a unique epitope on the CD20 molecule. Pre-clinical data indicate that OFA has greater NK cell and monocyte-mediated killing, complement-dependent cytotoxicity and direct killing against CLL cells. Based on pre-clinical and clinical studies indicating possible increased efficacy of OFA in patients with CLL, our aim was to develop an antibody-only regimen for older patients and patients who refuse FLU-based regimens. Methods: Eligible patients had previously untreated, symptomatic CD20+ B-cell chronic lymphocytic leukemia (B-CLL) or small lymphocytic lymphoma (SLL), ECOG PS of ≤ 2, and were either ≥ 65 years of age, or patients 18–64 years of age who had declined FLU-based regimens. All patients in this study received OFA as an IV infusion once weekly for a total of 8 weeks. To reduce the possibility of infusion reactions, the first dose of OFA was administered at a dose of 300 mg. If the initial 300-mg dose of OFA was well tolerated, without occurrence of any infusion associated AEs of ≥ grade 3, subsequent doses of OFA (i.e., Week 2 through Week 8) were given at a dose of 2000 mg. Eight weeks after the 8-week study treatment period ended, patients were assessed for response to the treatment. Patients who progressed received no further treatment. Patients who responded to the treatment or who did not have disease progression received maintenance therapy consisting of OFA at a dose of 2000 mg IV every 2 months for 2 years (for a total of 12 doses, in the absence of PD or intolerable toxicity) beginning 3 months after the last dose of OFA. Results: Between 8/2010 and 4/2011, 42 patients were enrolled and are included in this analysis. Patients were 57% male with median age 69 yrs (range: 47–88 yrs). Fourteen patients (33%) were < age 65. All but 1 patient had CLL; 1 patient had SLL. The median WBC at study entry was 41.1 (range 1.7–236.5). Rai stage at entry to study was Stage 0 = 8, Stage I = 8, Stage II – 4, Stage III – 10, Stage IV – 11. Interphase cytogenetics demonstrated 2/42 (5%) 17p-, 4/42 (10%) 11q-, 11/42 (26%) trisomy 12, 9/42 (21%) normal, 14/42 (33%) 13q-, and 2 (5%) unknown. To-date, 41 (98%) patients remain on study and 35 have completed 8 weeks of initial therapy with 24 (57%) having already begun maintenance therapy. Lymphocyte count normalized in 85% of patients at the end of the initial 8 weeks of therapy. Thirty patients have been evaluated for response according to IWCLL criteria (Hallek 2008): 13 patients (44%) achieved an objective response (CR, 0; PR, 13); 16 (53%) patients had SD; 1 patient (3%) had PD. SAEs were infrequent with 2 patients hospitalized for unrelated events: g2 fracture, g3 chest pain, g3 hematoma and g4 pulmonary emboli; 2 patients hospitalized for events possibly OFA-related had g2 fever, g3 anemia and g3 pneumonia. Only 1 patient experienced significant infusion-related toxicity that required repeat administration of the initial 300-mg dose instead of dose escalation at dose 2. Baseline FcγR polymorphisms for patients enrolled are currently being analyzed and will be presented. Conclusion: Single-agent OFA is a highly active and well tolerated front-line therapy for older patients with CLL or patients refusing FLU as evidenced by both early response and also ability of virtually all patients to proceed to maintenance therapy. A low incidence of serious infusion toxicity, infectious morbidity and other heme / non-heme toxicities was observed. Continued long-term assessment will further characterize the toxicity and efficacy of this single-agent OFA regimen in patients with CLL, as well as overall and progression-free survival rates. Disclosures: Flinn: GSK: Research Funding. Off Label Use: Ofatumumab in front-line CLL. Jones:Abbott Labs: Research Funding; GSK: Consultancy.

scholarly journals Dose Intensive Rituximab and High-Dose Methylprednisolone in Elderly or Unfit Patients with Relapsed Chronic Lymphocytic Leukemia

Medicina ◽  
2019 ◽  
Vol 55 (11) ◽  
pp. 719
Author(s):  
Pileckyte ◽  
Valceckiene ◽  
Stoskus ◽  
Matuzeviciene ◽  
Sejoniene ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
High Dose ◽  
Meaningful Improvement ◽  
Free Survival ◽  
High Dose Methylprednisolone ◽  
Unfit Patients

Background and Objectives: BTK and BCL2 inhibitors have changed the treatment paradigms of high-risk and elderly patients with chronic lymphocytic leukemia (CLL), but their long-term efficacy and toxicity are still unknown and the costs are considerable. Our previous data showed that Rituximab (Rtx) and high-dose methylprednisolone (HDMP) can be an effective and safe treatment option for relapsed high-risk CLL patients. Materials and Methods: We explored the efficacy and safety of a higher Rtx dose in combination with a shorter (3-day) schedule of HDMP in relapsed elderly or unfit CLL patients. Results: Twenty-five patients were included in the phase-two, single-arm trial. The median progression free survival (PFS) was 11 months (range 10–12). Median OS was 68 (range 47–89) months. Adverse events (AE) were mainly grade I–II° (77%) and no deaths occurred during the treatment period. Conclusions: 3-day HDMP and Rtx was associated with clinically meaningful improvement in most patients. The median PFS in 3-day and 5-day HDMP studies was similar and the toxicity of the 3-day HDMP schedule proved to be lower. The HDMP and Rtx combination can still be applied in some relapsed high-risk and elderly or unfit CLL patients if new targeted therapies are contraindicated or unavailable. (ClinicalTrials.gov identifier: NCT01576588).

Rituximab Added to Cyclophosphamide, Vincristine and Prednisolone in Heavily Pretreated Chronic Lymphocytic Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5023-5023
Author(s):  
Henrique Coelho ◽  
Cristina Gonçalves ◽  
Claudia Casais ◽  
Marisol Guerra ◽  
Alexandra Mota ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Front Line ◽  
Pulmonary Aspergillosis ◽  
Heavily Pretreated ◽  
Treatment Complication ◽  
Binet Stage

Abstract Purpose: Although patients with chronic lymphocytic leukemia (CLL) typically respond to available front-line chemotherapy, the response is often temporary, and patients frequently undergo relapse. The authors report the beneficial clinical activity and tolerability of an immunochemotherapeutic regimen consisting of rituximab added to cyclophosphamide, vincristine and prednisolone (R-CVP), in patients with heavily pretreated CLL. Methods: The therapeutic regimen consisted of: cyclophosphamide 750 mg/m2 iv on day one, vincristine 1.4 mg/m2 iv on day one and prednisolone 100 mg po for five consecutive days every 4 weeks, combined with rituximab at a dose of 375 mg/m2 on day 1 of each cycle. Patients were evaluated after three cycles, with responding patients receiving up to eight cycles. No infectious prophylaxis was administered. Results: Five patients have been treated with R-CVP: median age 65 years (range 52–68), advanced Binet stage (four stage C and one stage B) and heavily pretreated (range 1–3 prior therapies). All patients received at least three cycles of R-CVP. Clinical and hematological response was achieved in two patients. Three patients had stable disease. One patient was re-induced once after disease progression. Data from a median follow-up of 112 months (range 52–128 months) showed that three patients remained free of disease progression 8 months after the first cycle of R-CVP (range 2–14 months). The principle treatment complication was pulmonary aspergillosis. Conclusion: These promising results suggest salvage therapy with R-CVP is beneficial in patients with heavily pretreated CLL.

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