Impact of immunotherapy on survival differences in patients with melanoma and chronic lymphocytic leukemia.

e21550 Background: Chronic lymphocytic leukemia (CLL) is well known to be associated with secondary malignancies like melanoma. Patients with melanoma and CLL are known to have poorer prognosis compared to patients without CLL. Checkpoint inhibitors (CPI) started gaining traction in 2011 after ipilimumab approval and are widely used in treatment of advanced melanoma. The objective of this study is to determine the survival of patients with melanoma and CLL in the era of CPI (2011 onwards) compared to previous years. Methods: We identified patients with melanoma and CLL reported to the Surveillance, Epidemiology, and End Results (SEER-18) program. We created cohorts of patients with melanoma and CLL vs. melanoma without CLL and split the cohorts into patients diagnosed from 2000-2010 and 2011-2017 to evaluate the impact of immunotherapy on overall all-cause survival. Kaplain-Meier survival curves were created for each of the four cohorts using the Ederer/direct-adjusted survival method. Standard Cox regression models adjusted for age and sex used to compare survival between subgroups. Two-sided p-values < 0.05 were considered significant. Results: From 2000-2017, 536,264 patients with melanoma were included in this study. 2,945 [0.55%] patients had coexisting CLL. Most patients were male (303,477 [56.6%]), age 60-79 (235,833 [44.0%]), non-Hispanic white (499,151 [93.08%]), and diagnosed from 2000-2010 (285,292 [53.2%]) with melanoma of the trunk (156,722 [29.2%]). From 2000-2010, patients with melanoma had an average survival of 91.4 months (95% CI 88.7-94.1) and those with coexisting CLL had an average survival of 59.3 months (95% CI 58.1-60.6). From 2011-2017, patients with melanoma had an average survival of 129.1 months (95% CI 127.7-130.5) and those with coexisting CLL had an average survival of 116.0 months (95% CI 113.5-118.5). The difference in survival in patients with melanoma vs. melanoma and CLL in 2000-2010 (32.1 months) is significantly greater than that of patients from 2011-2017 (13.1 months, p < 0.05). Conclusions: Although CLL continues to confer a survival disadvantage in patients with melanoma, the survival of patients with CLL and melanoma is better in the CPI-era. We also demonstrate that in the CPI era the gap between the survival of patients with melanoma and CLL and melanoma alone is also reducing significantly.

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The impact of immune checkpoint inhibitors in patients with chronic lymphocytic leukemia (CLL)

Medicine ◽

10.1097/md.0000000000021167 ◽

2020 ◽

Vol 99 (28) ◽

pp. e21167

Author(s):

Aviwe Ntsethe ◽

Phiwayinkosi Vusi Dludla ◽

Tawanda Maurice Nyambuya ◽

Siphamandla Raphael Ngcobo ◽

Bongani Brian Nkambule

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Lymphocytic Leukemia ◽

The Impact

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Clinical considerations about the coexistence of melanoma and chronic lymphocytic leukemia in the era of targeted therapies, triggered by rare clinical scenarios. A case series and review of the literature

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835920962369 ◽

2020 ◽

Vol 12 ◽

pp. 175883592096236

Author(s):

Panagiotis T. Diamantopoulos ◽

Dimitrios Ziogas ◽

Nora-Athina Viniou ◽

Amalia Anastasopoulou ◽

Georgios Kyriakakis ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Present Article ◽

Targeted Therapies ◽

Checkpoint Inhibitors ◽

Case Series ◽

Lymphocytic Leukemia ◽

Skin Cancer Screening ◽

Clinical Scenarios ◽

Anti Cd20 ◽

The Impact

The epidemiologic correlation of melanoma and chronic lymphocytic leukemia (CLL) has been the subject of several population studies. In the present article, through the presentation of five illustrative cases of patients with melanoma and CLL, several aspects of this complex relationship are highlighted, with a focus on the increased incidence of melanoma in patients with CLL, its speculated etiology, and the impact of CLL stage and disease duration on the incidence and prognosis of melanoma. Furthermore, the rare entity of the synchronous diagnosis of melanoma and CLL in biopsied lymph nodes is discussed, along with its implications on the diagnostic and therapeutic procedures. In addition, the available data on the treatment choices in patients with melanoma and CLL are presented and the efficacy and safety of fludarabine, anti-CD20 monoclonal antibodies, new targeted therapies for CLL, and checkpoint inhibitors are further discussed. Finally, since no formal guidelines are available for the management of this group of patients, guidelines are proposed for skin-cancer screening in patients with CLL, for the correct interpretation of BRAF mutation analysis in lymph-node specimens with ‘collision of tumors,’ and for the optimal use of imaging studies in the diagnosis of metastatic disease in patients with CLL and melanoma, while a treatment approach for such patients is also suggested. The information and proposed guidelines provided in the present article comprise a useful guide for physicians managing such patients, focusing on diagnostic challenges and therapeutic dilemmas posed by the coexistence of the two disease entities.

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The Predictive Value of MAP2K1/2 Mutations on Efficiency of Immunotherapy in Melanoma

Frontiers in Immunology ◽

10.3389/fimmu.2021.785526 ◽

2022 ◽

Vol 12 ◽

Author(s):

Ting Ye ◽

Jie-Ying Zhang ◽

Xin-Yi Liu ◽

Yu-Han Zhou ◽

Si-Yue Yuan ◽

...

Keyword(s):

Cox Regression ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Progression Free Survival ◽

The Cancer Genome Atlas ◽

Independent Predictive Factor ◽

Cox Regression Analysis ◽

Melanoma Patients ◽

The Impact

BackgroundMAP2K1/2 genes are mutated in approximately 8% of melanoma patients; however, the impact of MAP2K1/2 gene alterations on the efficiency of immunotherapy has not been clarified. This study focused on the correlation between MAP2K1/2 gene mutations and the treatment response.MethodsSix metastatic melanoma clinical cohorts treated with immune checkpoint inhibitors [anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) or anti-programmed cell death-1 (PD-1)] were recruited in this study. RNA expression profiling results from each of these six cohorts and the Cancer Genome Atlas (TCGA) melanoma cohort were analysed to explore the mechanism related to immune activation.ResultsCompared to patients with wild-type MAP2K1/2, those with MAP2K1/2 mutations in an independent anti-CTLA-4-treated cohort had higher objective response rates, longer progression-free survival, and longer overall survival (OS). These findings were further validated in a pooled anti-CTLA-4-treated cohort in terms of the OS. However, there was no correlation between MAP2K1/2 mutations and OS in the anti-PD-1-treated cohort. Subgroup Cox regression analysis suggested that patients with MAP2K1/2 mutations received fewer benefits from anti-PD-1 monotherapy than from anti-CTLA-4 treatment. Furthermore, transcriptome profiling analysis revealed that melanoma tumours with MAP2K mutation was enriched in CD8+ T cells, B cells, and neutrophil cells, also expressed high levels of CD33 and IL10, implying a potential mechanism underlying the benefit of melanoma patients with MAP2K1/2 mutations from anti-CTLA-4 treatment.ConclusionsMAP2K1/2 mutations were identified as an independent predictive factor for anti-CTLA-4 therapy in melanoma patients. Anti-CTLA-4 treatment might be more effective than anti-PD-1 therapy for patients with MAP2K1/2-mutated melanoma.

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The Impact of Chlorambucil and Valproic Acid on Cell Viability, Apoptosis and Expression of p21, HDM2, BCL2 and MCL1 Genes in Chronic Lymphocytic Leukemia

Cells ◽

10.3390/cells10051088 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1088

Author(s):

Katarzyna Lipska ◽

Agata Filip ◽

Anna Gumieniczek

Keyword(s):

Valproic Acid ◽

Chronic Lymphocytic Leukemia ◽

Cell Viability ◽

Antiepileptic Drug ◽

Drug Combination ◽

Target Genes ◽

Histone Deacetylation ◽

Lymphocytic Leukemia ◽

Malignant Cells ◽

The Impact

Malignant cells in chronic lymphocytic leukemia (CLL) show resistance to apoptosis, as well as to chemotherapy, which are related to deletions or mutations of TP53, high expression of MCL1 and BCL2 genes and other abnormalities. Thus, the main goal of the present study was to assess the impact of chlorambucil (CLB) combined with valproic acid (VPA), a known antiepileptic drug and histone deacetylation inhibitor, on apoptosis of the cells isolated from 17 patients with CLL. After incubation with CLB (17.5 µM) and VPA (0.5 mM), percentage of apoptosis, as well as expression of two TP53 target genes (p21 and HDM2) and two genes from Bcl-2 family (BCL2 and MCL1), were tested. As a result, an increased percentage of apoptosis was observed for CLL cells treated with CLB and VPA, and with CLB alone. Under the treatment with the drug combination, the expression of p21 gene was visibly higher than under the treatment with CLB alone. At the same time, the cultures under CLB treatment showed visibly higher expression of BCL2 than the cultures with VPA alone. Thus, the present study strongly suggests further investigations on the CLB and VPA combination in CLL treatment.

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The Impact of Atrial Fibrillation on hospitalization Outcomes for Patients With Chronic Lymphocytic Leukemia Using the National Inpatient Sample Database

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2021.08.006 ◽

2021 ◽

Author(s):

Mohammad Ammad Ud Din ◽

Samarthkumar Thakkar ◽

Harsh Patel ◽

Hassan Saeed ◽

Syed Ather Hussain ◽

...

Keyword(s):

Atrial Fibrillation ◽

Chronic Lymphocytic Leukemia ◽

Lymphocytic Leukemia ◽

National Inpatient Sample ◽

The Impact

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Association of a novel regulatory polymorphism (−938C>A) in the BCL2 gene promoter with disease progression and survival in chronic lymphocytic leukemia

Blood ◽

10.1182/blood-2006-03-007567 ◽

2006 ◽

Vol 109 (1) ◽

pp. 290-297 ◽

Cited By ~ 76

Author(s):

Holger Nückel ◽

Ulrich H. Frey ◽

Maja Bau ◽

Ludger Sellmann ◽

Jens Stanelle ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Cox Regression ◽

Gene Promoter ◽

Lymphocytic Leukemia ◽

Disease Stage ◽

Genotype Distribution ◽

Single Nucleotide ◽

Regulatory Polymorphism ◽

Time To First Treatment

Abstract Bcl-2 plays a key role in the regulation of apoptosis. We investigated the role of a novel regulatory single-nucleotide polymorphism (−938C>A) in the inhibitory P2 BCL2 promoter in B-cell chronic lymphocytic leukemia (B-CLL). The −938C allele displayed significantly increased BCL2 promoter activity and binding of nuclear proteins compared with the A allele. Concomitantly, Bcl-2 protein expression in B cells from CLL patients carrying the −938 AA genotype was significantly increased compared with CC genotypes. Genotype distribution between 123 CLL patients (42 AA, 55 AC, 26 CC) and 120 genotyped healthy controls (36 AA, 63 AC, 21 CC) was not significantly different, suggesting that genotypes of this polymorphism do not increase the susceptibility for B-CLL. However, median time from first diagnosis to initiation of chemotherapy and median overall survival were significantly shorter in patients with −938AA genotype (38 and 199 months, respectively) compared with AC/CC genotypes (120 and 321 months, respectively; P = .008 and P = .003, respectively). Multivariable Cox regression identified the BCL2−938AA genotype as an independent prognostic factor for the time to first treatment (hazard ratio [HR] 1.9; P = .034) together with disease stage at diagnosis (HR 2.5; P = .004) and ZAP-70 status (HR 3.0; P = .001). The BCL2−938AA genotype is associated with increased Bcl-2 expression and a novel unfavorable genetic marker in patients with B-CLL.

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The predictive value of MAP2K1/2 mutations for efficiency of immunotherapy in melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21587 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21587-e21587

Author(s):

Ting Ye ◽

Jieying Zhang ◽

Xinyi Liu ◽

Mengmei Yang ◽

Yuhan Zhou ◽

...

Keyword(s):

Overall Survival ◽

Predictive Value ◽

Cox Regression ◽

Treatment Options ◽

Objective Response ◽

Progression Free Survival ◽

Driver Mutations ◽

Cox Regression Analysis ◽

Melanoma Patients ◽

The Impact

e21587 Background: Immunotherapies targeting immune checkpoint receptors have become the cornerstone of systemic treatment options for malignant melanoma. The response to these immunotherapies may correlate with driver mutations. MAP2K1/2 genes are mutated in approximately 10% of melanomas, however, the impact of MAP2K1/2 gene alterations on the efficiency of immunotherapy has not been clarified. Methods: Six metastatic melanoma clinical cohorts treated with ICIs were included to investigate the association between clinical efficacy of immunotherapy and MAP2K1/2 mutations. Survival analyses were conducted in cohorts receiving two kinds of ICB agents, namely anti-CTLA-4 or anti-PD-1. RNA expression profiling from these cohorts and from the TCGA melanoma cohort were used to explore the potential mechanism related to immune activation. Results: In an independent anti-CTLA-4-treated cohort (n = 110), we found that MAP2K1/2 mutations are predictive of high objective response rate (17.6% vs 1.3%, p = 0.0185) and long progression-free survival [median OS, 49.2 months vs 8.3 months; hazard ratio (HR) = 0.37; 95% CI, 0.15–0.91; p = 0.0307] and overall survival (median PFS, 19.4 months vs 2.8 months; HR = 0.2; 95% CI, 0.05–0.83; p = 0.0262). This predictive value was further validated in a pooled anti-CTLA-4-treated cohort (n = 235) in terms of overall survival (median OS, 49.3 months vs 22.0 months; HR = 0.44; 95% CI, 0.22–0.91; p = 0.0255). However, no correlation between MAP2K1/2 mutations and overall survival was observed in the anti-PD-1-treated cohort (n = 285). Subgroup Cox regression analysis indicated that MAP2K-mutated patients receive less benefit from the anti-PD-1 monotherapy than from the anti-CTLA-4 treatment (median OS, 27.0 months vs 49.3 months; HR = 3.26; 95% CI, 1.18–9.02; p = 0.0225), which was contrary to the result obtained for the total population. Furthermore, transcriptome profiling analysis revealed that MAP2K-mutated tumors are enriched in CD8+ T cells, B cells, and neutrophil cells and also express high levels of CD33 and IL10, which might be the underlying mechanism for melanoma patients with MAP2K1/2-mutated benefit more from anti-CTLA-4 treatment. Conclusions: We identified mutations in MAP2K1/2 genes as the independent predictive factors for anti-CTLA-4 therapy in melanoma patients and found that anti-CTLA-4 treatment in patient harbouring MAP2K1/2 mutations might be more effective than the anti-PD-1 therapy.

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