Presenting Features and Outcome of Elderly Chronic Lymphocytic Leukemia Patients Diagnosed at the Age of 80 Years or Above. An ICLLSG Study.

Abstract Abstract 4620 Chronic lymphocytic leukemia (CLL) is the most common leukemia of the elderly people in the western world. Its age-adjusted incidence rate is about 4.1 per 100,000 men and women per year. CLL increases exponentially with age and for patients above the age of 80 the CLL incidence rate increases to >20 per 100,000 per year. The clinical characteristics and outcome of CLL patients diagnosed at age 80 or above are unknown. The Israel Chronic Lymphocytic Leukemia Study Group reviewed retrospectively the records of 214 such patients diagnosed between the years 1979–2009 in 7 medical centers (118 males, 96 females; mean age: 84 years, range; 80–94). 153 (71%) were Ashkenazi Jews, 43 (20%) were Sephardic Jews, and 3 (1.4%) were Arabs. 104 (48%) were referred due to routine blood analysis and 80 (37%) due to disease manifestations. At diagnosis 120 (56%) had Rai stage 0, 67(31%) Rai stages I and II, and 27(13%) Rai stages III and IV. The mean hemoglobin level was 12.2g/dL (range 5.8–17.3), mean WBC 33,241/μ L (range 6,100-400,000) and mean platelets of 194,622/μ L (range 56,000-617,000). Lymphadenopathy was noted in 33% and splenomegaly in 22%. LDH at diagnosis was elevated in 26% of the patients. 161 patients (75%) were on follow-up only without any treatment. Fifty three patients received treatment for the CLL (25%). Treatment consisted of chlorambucil and or prednisone in 36 patients, COP (cyclophosphamide, vincristine and prednisone) in 6 patients, CHOP (cyclophosphamide, adriamycine, vincristine and prednisone) in 5 patients, FC (fludarabine and cyclophosphamide) in 3 patients and RCOP (rituximab and COP) in 2 patients, 1 patient received irradiation. By June 2010,155 patients (72%) have died with a mean overall survival of 68±5 months, median 56±5.4 months and 5 years survival of 47.2%±3.6. In univariate analysis a better survival was associated with younger age (the mean survival of patient age 80–84 years at diagnosis was 76±6.3 months, median 71±5.8 months compared to mean survival of 48.8±4.8 months and median 43±9.3 months for patients ≥85 years old at diagnosis, p=0.002), Rai stage (the mean survival of patients diagnosed at Rai stage 0 was79.5±8.5 months, median 62±6.5 months compared to mean of 55.7±6.2 months, median 47±7.6 months for patients diagnosed at Rai stages I and II, p=0.023), WBC count at diagnosis (the mean survival of patient with WBC count at diagnosis ≤30,000/μ L was 77±7.6 months, median 62±6.1 months compared to mean survival of 51.8±6.7 months, median 32±8 months in patients diagnosed with a WBC >30,000/μ L, p=0.015), β2 microglobulin levels (the mean survival of the 39 patients with β2 microglobulin level at diagnosis < 3mg/L was 103±19.6 months, median 70±13 months compared to mean of 50.2±7.6 months, median 39±8 months in the 28 patients with β2 microglobulin levels ≥ 3 mg/L, p=0.006), reason for diagnosis (the mean survival of patients diagnosed due to routine blood counts was 88.4±11.2 months, median 72±4.8 months, compared to 43.2±4.6 and 27±6.8 in patients diagnosed due to disease manifestations, p< 0.001), and CD38 level (the mean survival of 87 patients with CD38 levels ≤30% was 81.1±7.9 months, median 72±4.6 months compared to 52±8.9 32±6.9 months respectively in the 24 patients with CD 38 levels >30 %, p=0.036). No correlation was found between overall survival and patients’ gender, receiving or not chemotherapy, year of diagnosis before or after 2000, or ethnicity (Ashkenazi Jews vs. Sephardic Jews). Multivariate analysis using Cox regression analysis found younger age, low WBC count, and routine blood test as the reason for diagnosis as 3 independent good prognostic factors (HR 1.8, 1.6, 1.9 respectively). CLL patients diagnosed at the age of 80 or more can still expect to live long life. Disclosures: No relevant conflicts of interest to declare.

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Revelance of Gammaglobulin Levels at Diagnosis and during Disease Course in Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v128.22.5561.5561 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5561-5561

Author(s):

Erin Streu ◽

Jayce Bi ◽

Mandy DeSousa ◽

Versha Banerji ◽

Dhali H.S. Dhaliwal ◽

...

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Replacement Therapy ◽

Lymphocytic Leukemia ◽

Age At Diagnosis ◽

Disease Course ◽

Β2 Microglobulin ◽

Igg Replacement Therapy ◽

Over Time

Abstract Introduction: Hypogammaglobulinemia is commonly observed in chronic lymphocytic leukemia (CLL), likely worsens over time and with chemoimmunotherapy, and eventually leads to infections which are a major cause of death in this disease. Unfortunately, newer therapies, such as ibrutinib, may not prevent the ongoing immunosuppression in CLL as a major cause of discontinuing this drug is increased infections. Nowadays, most patients present with early stage CLL, with an increasing number having monoclonal B cell lymphocytosis (MBL) and being followed for many years. CLL treatment is typically intensive, using chemoimmunotherapy with the therapeutic goal being to minimize tumor load. For these reasons, a reassessment of Ig levels in a CLL Clinic at diagnosis and during disease course in the 'real-life' setting has been carried out, along with an assessment of the need for Ig replacement. Methods: All CLL/SLL/MBL cases referred to the CLL clinic at CancerCare Manitoba, Winnipeg, Canada from 2007 to 2011 were included in this study. Immunoglobulin (Ig) levels (G, A, and M) were measured at the time of referral/diagnosis (baseline) and annually thereafter. Ig levels were correlated with patient characteristics (age at diagnosis, gender, comorbidities), CLL prognostic indicators (Rai stage, lymphocyte doubling time, creatinine, LDH, β2- microglobulin, IGHV mutational status, ZAP-70, CD38) and time to first treatment (TTFT). A subset analysis of patients treated with replacement gammaglobulin was also conducted. Results: There were 293 patents in this cohort with median age at diagnosis of 68 years. Of these, 62.5% were male, 38% had received treatment, and 24% died during the follow up time (median follow up of 71 months). Seventy percent of patients had CLL (of those 85% were diagnosed with Rai 0/I), 15% MBL and 15% SLL. At baseline, 41% had normal Ig levels while 59% had a reduced level of one or more Ig (32% had reduced levels of one Ig type, 18% two, and 9% all three). Overall, 53% of patients had low IgM, 24% low IgG and 17% low IgA. However, no consistent correlation was found between the Ig levels at diagnosis and any of the prognostic markers outlined above. Hypogammaglobulinemia (at least two consecutive values < normal) was associated with need for CLL treatment (HR 3.45, 95% CI 1.63-7.30, p=0.0012), while hypogammaglobinemia at diagnosis predicted a shorter TTFT (p=0.0008). Baseline IgA was also predictive of TTFT as well as overall survival, with patients with normal IgA having a longer TTFT, patients with high/low IgA a shorter TTFT (p=0.0012) and those with high IgA a shorter overall survival (p=0.0032). Furthermore, there was a positive correlation between baseline IgG and number of comorbidities (r=0.17, p = 0.0057) as measured by the Cumulative Index Rating Scale (CIRS) and β2-microglobulin levels. Eighteen patients (6.14%) required Ig replacement therapy, of those 13 (72%) were male and 13 (72%) had received chemotherapy. These patents also had a shorter overall survival than those not requiring IgG replacement therapy (p=0.0006). CLL cases with high baseline IgG are seven times more likely to require IgG replacement therapy (HR 6.92, 95% CI 1.78 - 29.91, p=0.0052) while cases with low baseline IgG are 5 times more likely (HR 4.99, 95% CI 1.59 - 9.43, p=0.0254) as compared to those with normal baseline IgG. Baseline IgA and IgM were not predictive of need for IgG replacement therapy. Interestingly, over a median follow-up of 4 years, one-third of patients with normal baseline IgG developed a low IgG and this was unrelated to receiving chemotherapy (Figure 1). Summary This study demonstrates that baseline Ig levels in CLL are informative of the underlying biology of this disease, and could provide valuable information regarding disease progression, survival and need for subsequent IgG replacement therapy or CLL treatment. Importantly, Ig levels may be elevated in CLL and this is associated with increased CIRS and a high β2-microglobulin level, suggesting that the increase is related to underlying comorbidities. Further studies are required to examine the cause for the progressive decline in Ig levels over time, despite an otherwise stable disease, and to determine whether this decline can be eliminated by earlier treatment with novel new therapies. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Clinical characteristics of chronic lymphocytic leukemia in young versus old age patients in Kurdistan region- Iraq

10.53350/pjmhs211571930 ◽

2021 ◽

Vol 15 (7) ◽

pp. 1930-1935

Author(s):

Lara Lateef Abdulrahman ◽

Ranan Kardagh Polus ◽

Ghanim Salim Numan

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Old Age ◽

International Workshop ◽

Lymphocytic Leukemia ◽

Older Age ◽

Survival Duration ◽

Age Group ◽

Kurdistan Region ◽

Younger Age ◽

The Mean

Background: Chronic lymphocytic leukemia is the common adulthood leukemic type, although the incidence rate in the Kurdistan region is low. It is well known that chronic lymphocytic leukemia is prevalent among the elderly age group, however frequent cases of chronic lymphocytic leukemia are newly diagnosed at a younger age. Aim of the study: To analyze the difference in disease presentation, progression, and outcome between young and old age group patients with chronic lymphocytic leukemia in the Kurdistan region/Iraq. Patients & Methods: A retrospective cross-sectional review study carried out in three oncology centers in the Kurdistan region (Nanakaly Hospital in Erbil city, Hiwa center in Sulaimani city, and Azadi center in Duhok city) for ten years through the period from 1st of January, 2010 to 31st of December, 2019 on a convenient sample of 152 patients with chronic lymphocytic leukemia. Diagnosis of chronic lymphocytic leukemia was done by the Oncologists in Kurdistan tumor centers according to the International Workshop on Chronic Lymphocytic Leukemia. The age of patients at diagnosis was categorized into two groups and ranged from 25 years to 94 years. The age cutoff value in the current study was (55 years) depending on previous kinds of literature. Results: The mean age at diagnosis of patients was (63 years); 28% of them were diagnosed at age of ≤50 years and 72% of them were diagnosed at age of more than 55 years. Older age patients were significantly presented with weight loss, while younger age patients were significantly presented with neck lumps. There was a highly significant association between the advanced ECOG performance scale and older age patients at diagnosis. A significant association was observed between the death outcome of chronic lymphocytic leukemia and older age patients at diagnosis. The mean survival duration of younger age patients at diagnosis was significantly longer than the mean survival duration of older age patients at diagnosis. Conclusions: clinical presentation, physical status, death rates, and survival of patients with chronic lymphocytic leukemia in Kurdistan region-Iraq are different between young and older age patients. Keywords: Chronic Lymphocytic Leukemia, age, death, Survival.

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The VH3-21 Gene Status Correlates with Elevated β2-Microglobulin Serum Levels and Shorter Overall Survival of Patients with Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v106.11.4988.4988 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4988-4988

Author(s):

Ewa Lech-Maranda ◽

Tadeusz Robak ◽

Anna Szmigielska-Kaplon ◽

Hanna Makuch-Lasica ◽

Iwona Solarska ◽

...

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Clinical Characteristics ◽

Gene Segment ◽

Serum Levels ◽

Lymphocytic Leukemia ◽

Polish Population ◽

Β2 Microglobulin ◽

Gene Status

Abstract Introduction: The prognostic role of immunoglobulin variable heavy chain (IgVH) region somatic hypermutation status in B-cell chronic lymphocytic leukemia (B-CLL) is now well established. However, an overrepresentation of the VH3-21 gene segment has been recently reported to influence clinical course of B-CLL regardless of the IgVH mutational status in different geographic populations. It might suggest the role of a common antigen epitope in the pathogenesis of some B-CLL cases. Aims: We therefore investigated the frequency of the VH3-21 gene usage in IgVH rearrangements in Polish population of B-CLL patients, and assessed whether it might influence B-CLL clinical characteristics and prognosis. Patients and Methods: The study comprised of 97 B-CLL patients treated at the Department of Hematology, Medical University of Lodz in Poland. Peripheral blood mononuclear cells were separated on Ficoll and DNA was isolated using column method. The monoclonal population of lymphocytes with VH3-21-JH rearrangement was tested using framework 3 region primer and consensus JH primer described by Davies et al. (Leukemia 2004, 18: 872). The PCR reactions were followed with heteroduplex analysis of PCR products and separation in polyacrylamide gel. The positive VH3-21-JH samples were also confirmed by sequencing. Results: The frequency of the VH3-21 gene segment in VH-JH rearangements in B-CLL patients reached 9% in Polish population. Beyond an elevated β2-microglobulin serum levels (p=0.03, Mann-Whitney test), no association were found between the VH3-21 gene status and clinical characteristics including CD38 expression at diagnosis The mortality rate was significantly higher in patients carrying VH3-21 (p=0.03, χ2 test), and majority of deaths were related to CLL. With a median follow-up of the surviving patients of 55,5 months (range 2–209 months), the subgroup of patients with the VH3-21 had significantly shorter overall survival (p=0.025, log-rank test). However, this genetic marker was not associated with freedom from progression survival. Conclusions: We conclude that the frequency of the VH3-21 gene segment in VH-JH rearrangements in Polish population is similar to those previously published for British and Belgian populations and seems to be lower than in Mediterranean area populations (Blood2005, 15: 1678). The presence of VH3-21 gene segment correlates with increased β2-microglobulin levels at presentation and predicts shorter overall survival of B-CLL patients.

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The Impact of Agent Orange Exposure On Presentation and Prognosis of Patients with Chronic Lymphocytic Leukemia (CLL): An Exploratory Analysis

Blood ◽

10.1182/blood.v120.21.4575.4575 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4575-4575

Author(s):

Lisa M Baumann Kreuziger ◽

Vicki A. Morrison

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Doubling Time ◽

Hazard Ratio ◽

Lymphocytic Leukemia ◽

Agent Orange ◽

Disease Stage ◽

Younger Age ◽

Significant Difference ◽

The Impact

Abstract Abstract 4575 Background: From 1962–1971, 19 million gallons of Agent Orange (AO) and other herbicides were sprayed in South Vietnam and Cambodia to destroy dense jungle and crops used to conceal and feed enemy troops. In 2004, the Department of Veterans Affairs added chronic lymphocytic leukemia (CLL) to the list of Veterans Diseases Associated with Agent Orange, based upon data from agricultural exposure suggesting a causative association. In our retrospective cohort study, we evaluated if Agent Orange exposure was associated with an altered prognosis, time to treatment, or overall survival in veterans with newly diagnosed CLL. Methods: Clinical data was reviewed from 205 patients (pts) with CLL diagnosed from 2000–2010, identified through the Minneapolis MN VA Tumor Registry. Demographic information and laboratory parameters at diagnosis were collected, and Rai disease stage, marrow cytogenetics and lymphocyte doubling time were determined. Baseline labs, lymphocyte doubling time and time to initial CLL treatment were compared between exposed and unexposed pts using Student's t-test. Kaplan Meier analysis compared overall survival between Agent Orange-exposed and unexposed pts. Results: Of the 199 (97%) pts confirmed to have CLL, 33 pts (16.6%) had Agent Orange exposure. Median follow-up time was 40.7 months (0.1–123 months). Pts with Agent Orange exposure were younger at diagnosis (61 vs. 72 years, p=0.001). WBC, hemoglobin, platelet count, Rai stage, and LDH at diagnosis were similar between the groups. Mean lymphocyte doubling time was comparable in exposed and unexposed pts (27 vs. 23 months (mos), respectively p=0.6). Cytogenetic analysis was limited as 24% of pts underwent a bone marrow biopsy. Poor risk cytogenetics (17p-, 11q-) were found in 1 of 10 (10%) pts with Agent Orange exposure and 3 of 37 (8%) unexposed pts. Time to first CLL treatment was significantly shorter in pts with Agent Orange exposure [9.6 (range 0.1–23.7) vs. 30.2 mos (range 0.1–163.3), respectively; p=0.02]. No significant difference in reason for treatment initiation was found between the groups. First line fludarabine therapy was used more often in exposed than unexposed pts, which may have been due to their younger age at diagnosis (100% AO exposed vs 36% AO unexposed, Fisher's Exact p=0.01). No difference in overall survival was found between exposed and unexposed pts (Wilcoxon p=0.28). In a multivariable Cox regression model adjusted for age, Agent Orange exposure had a hazard ratio of death of 1.8 compared to non-exposure (95% CI: 0.7– 4.5, p = 0.24). Conclusions: CLL pts with Agent Orange exposure were diagnosed at a younger age and had a shorter time to first treatment, as compared to unexposed pts. Agent Orange exposure was not associated with a difference in prognosis in these patients. Although our hazard ratio result was not statistically significant, the high estimate of the mortality hazard combined with the relatively low numbers in the exposure group suggest that further examination of this issue in a larger patient population is warranted. Disclosures: No relevant conflicts of interest to declare.

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Telomere length predicts progression and overall survival in chronic lymphocytic leukemia: data from the UK LRF CLL4 trial

Leukemia ◽

10.1038/leu.2015.217 ◽

2015 ◽

Vol 29 (12) ◽

pp. 2411-2414 ◽

Cited By ~ 28

Author(s):

J C Strefford ◽

L Kadalayil ◽

J Forster ◽

M J J Rose-Zerilli ◽

A Parker ◽

...

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Telomere Length ◽

Lymphocytic Leukemia ◽

The Uk ◽

Leukemia Data

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Reduced Intensity Conditioning Yields Superior Overall Survival Rates Compared to Myeloablative Regimens for Allogeneic HCT in Chronic Lymphocytic Leukemia: A Side-By-Side Systematic Review/Meta-Analysis

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2016.12.170 ◽

2017 ◽

Vol 23 (3) ◽

pp. S269 ◽

Cited By ~ 1

Author(s):

Jessica El-Asmar ◽

Tea Reljic ◽

Ambuj Kumar ◽

Mohamed A. Kharfan-Dabaja

Keyword(s):

Systematic Review ◽

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Meta Analysis ◽

Survival Rates ◽

Lymphocytic Leukemia ◽

Reduced Intensity Conditioning ◽

Allogeneic Hct ◽

Reduced Intensity ◽

Overall Survival Rates

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Impact of Idelalisib Treatment Interruption with or without Dose Reduction on Outcomes in Relapsed / Refractory Indolent Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2019-124541 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5468-5468

Author(s):

Shuo Ma ◽

Rebecca J Chan ◽

Lin Gu ◽

Guan Xing ◽

Nishan Rajakumaraswamy ◽

...

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Dose Reduction ◽

Clinical Outcomes ◽

Research Funding ◽

Treatment Interruption ◽

Lymphocytic Leukemia ◽

Hodgkin's Lymphoma ◽

Advisory Committees

Introduction: Idelalisib (IDELA) is the first-in-class PI3Kδ inhibitor and is approved as a monotherapy for relapsed or refractory (R/R) follicular lymphoma and in combination with rituximab for R/R chronic lymphocytic leukemia (CLL). We previously evaluated IDELA treatment interruption as a mechanism to mitigate treatment-emergent adverse events (TEAEs) and found that limited interruption with clinically appropriate re-challenging resulted in superior clinical outcomes. These findings did not comprehensively address the potential confound of interruptions inherently being associated with longer duration of therapy (DoT). Furthermore, the compound effect of IDELA dose reduction together with treatment interruption on IDELA efficacy was not assessed. Objectives: 1) To evaluate whether the benefit of IDELA interruption is retained in patients on therapy >180 days, a duration previously found to be associated with longer overall survival among patients who discontinued IDELA due to an AE; and 2) To compare clinical outcomes of patients who reduced IDELA dosing in addition to interrupting IDELA with those of patients who interrupted IDELA without additional dose reduction. Methods: Using data from Gilead-sponsored trials of patients with R/R indolent non-Hodgkin's lymphoma (iNHL) treated with IDELA monotherapy (N=125, Gopal et al., N. Engl. J. Med., 2014) or with R/R CLL treated with IDELA + anti-CD20 (N=110, Furman et al., N. Engl. J. Med., 2014; and N=173, Jones et al., Lancet Haematol., 2017), DoT, progression-free survival (PFS), and overall survival (OS) were compared between patients on IDELA therapy >180 days with vs. without interruption and between patients who experienced Interruption and Dose Reduction (IDR) vs. patients who experienced Interruption but NoDose Reduction (INoDR) at any point during IDELA treatment. Interruption was defined as missing at least one IDELA treatment day due to an AE and dose reduction could have occurred before or after the first interruption. PFS and OS were estimated using the Kaplan-Meier method and were compared using a log-rank test. Results: Sixty-nine of 125 patients with R/R iNHL (55.2%) and 222 of 283 patients with R/R CLL (78.4%) remained on IDELA therapy >180 days with 29 (42.0%) and 103 (46.4%) of them, respectively, experiencing interruption on or after day 180 (Table 1). The proportions of patients with interruption before day 180 were similar within each of these populations. Among patients on therapy >180 days, those with treatment interruption on or after 180 days had a longer median (m) DOT than patients without interruption (Table 1). Both PFS and OS were longer in CLL patients who interrupted compared to those who did not interrupt (mPFS=28.9 mos. vs. 17.3 mos. and mOS=not reached [NR] vs. 40.4 mos. for with interruption vs. without interruption, respectively, Table 1 and Figure 1). In patients with iNHL, no difference was observed in PFS or OS between patients who interrupted vs. those who did not (Table 1). Of patients who experienced at least one AE-induced interruption at any point during IDELA therapy (n=63 iNHL and n=157 CLL), 47 iNHL patients (74.6%) and 84 CLL patients (53.5%) also had dose reduction. Two iNHL patients (1.6%) and 5 CLL patients (1.8%) had IDELA dose reduction but no interruption. Both iNHL and CLL patients with IDR experienced a similar PFS compared to patients with INoDR (mPFS=16.5 mos. vs. 14.2 mos. for iNHL and 21.8 mos. vs. 22.1 mos. for CLL with IDR vs. INoDR, respectively, Table 2). However, OS was longer in both iNHL and CLL patients with IDR compared to INoDR (mOS=61.2 mos. vs. 35.3 mos. for iNHL and NR vs. 42.4 mos. for CLL, respectively, Table 2; CLL patients shown in Figure 2). Discussion: IDELA treatment interruption is not associated with rapid clinical deterioration, as observed with some B-cell receptor signaling pathway inhibitors. No clear relationship between IDELA DoT and frequency of interruption was observed. When normalized for DoT >180 days, IDELA treatment interruption retained its clinical benefit in the CLL population. When utilized together with IDELA interruption, dose reduction did not lead to inferior clinical outcomes but instead extended OS in both iNHL and CLL populations. Adherence to treatment interruption and dose reduction guidance as outlined in the IDELA USPI may optimize IDELA tolerability and efficacy for patients with iNHL and CLL. Disclosures Ma: Janssen: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Gilead: Research Funding; Abbvie: Research Funding; Juno: Research Funding; Incyte: Research Funding; Xeme: Research Funding; Beigene: Research Funding; Novartis: Research Funding; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy; Acerta: Research Funding; Bioverativ: Consultancy; Genentech: Consultancy. Chan:Gilead Sciences, Inc.: Employment, Equity Ownership. Gu:Gilead Sciences, Inc.: Employment. Xing:Gilead Sciences, Inc.: Employment. Rajakumaraswamy:Gilead Sciences, Inc.: Employment. Ruzicka:Gilead Sciences, Inc.: Employment. Wagner-Johnston:Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees.

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Prognostic Impact of NOTCH1 Hotspot Mutation in TP53-Mutated Patients with Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v124.21.3283.3283 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3283-3283

Author(s):

Barbara Kantorova ◽

Jitka Malcikova ◽

Veronika Navrkalova ◽

Jana Smardova ◽

Kamila Brazdilova ◽

...

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Tp53 Mutation ◽

Direct Sequencing ◽

Lymphocytic Leukemia ◽

The Other ◽

Wild Type ◽

Tp53 Mutations ◽

Time To First Treatment ◽

Hotspot Mutation

Abstract Introduction A presence of activating mutations in NOTCH1 gene has been recently associated with reduced survival and chemo-immunotherapy resistance in chronic lymphocytic leukemia (CLL). However, a prognostic significance of the NOTCH1 mutations with respect to TP53mutation status has not been fully explained yet. Methods An examined cohort included 409 patients with CLL enriched for high risk cases; in 121 patients consecutive samples were investigated. To determine the TP53 mutation status, a functional analysis of separated alleles in yeast (FASAY, exons 4-10) combined with direct sequencing was performed; the ambiguous cases were retested using an ultra-deep next generation sequencing (MiSeq platform; Illumina). The presence of NOTCH1 hotspot mutation (c.7544_7545delCT) was analyzed using direct sequencing complemented by allele-specific PCR in the selected samples. In several patients harboring concurrent NOTCH1 and TP53 mutations, single separated cancer cells were examined using multiplex PCR followed by direct sequencing. A correlation between mutation presence and patient overall survival, time to first treatment and other molecular and cytogenetic prognostic markers was assessed using Log-rank (Mantel-cox) test and Fisher's exact test, respectively. Results The NOTCH1 and TP53 mutations were detected in 16% (65/409) and 27% (110/409) of the examined patients, respectively; a coexistence of these mutations in the same blood samples was observed in 11% (19/175) of the mutated patients. The detected increased mutation frequency attributes to more unfavorable profile of the analyzed cohort; in the TP53-mutated patients missense substitutions predominated (75% of TP53 mutations). As expected, a significantly reduced overall survival in comparison to the wild-type cases (147 months) was observed in the NOTCH1-mutated (115 months; P = 0.0018), TP53-mutated (79 months; P < 0.0001) and NOTCH1-TP53-mutated patients (101 months; P = 0.0282). Since both NOTCH1 and TP53 mutations were strongly associated with an unmutated IGHV gene status (P < 0.0001 and P = 0.0007), we reanalyzed the IGHV-unmutated patients only and interestingly, the impact of simultaneous NOTCH1 and TP53 mutation presence on patient survival was missed in this case (P = 0.1478). On the other hand, in the NOTCH1 and/or TP53-mutated patients significantly reduced time to first treatment was identified as compared to the wild-type cases (41 months vs. 25 months in NOTCH1-mutated, P = 0.0075; 17 months in TP53-mutated, P < 0.0001; and 18 months in NOTCH1-TP53-mutated patients, P = 0.0003). The similar results were observed also in the subgroup of the IGHV-unmutated patients, with the exception of patients carrying sole NOTCH1 mutation (P = 0.2969). Moreover, in the NOTCH1-TP53-mutated patients an increased frequency of del(17p)(13.1) was found in comparison to the TP53-mutated patients only (72% vs. 56%); this cytogenetic defect was not detected in the patients with sole NOTCH1 mutation. Our results might indicate, that NOTCH1 mutation could preferentially co-selected with particular, less prognostic negative type of TP53 defects. Notably, in our cohort the NOTCH1 mutation predominated in the patients harboring truncating TP53 mutations localized in a C-terminal part of the TP53 gene behind the DNA-binding domain (P = 0.0128). Moreover, in one of the NOTCH1-TP53-mutated patients the analysis of separated cancer cells revealed a simultaneous presence of NOTCH1 mutation and TP53 in-frame deletion in the same CLL cell. In contrast, in the other examined NOTCH1-TP53-mutated patient the concurrent NOTCH1 mutation and TP53 missense substitution (with presumed negative impact on patient prognosis) were found in different CLL cells. Conclusions The parallel presence of NOTCH1 hotspot mutation might be detected in a significant proportion of TP53-mutated patients and it seems to be associated with less prognostic unfavorable TP53 mutations. Nevertheless, these preliminary data should be further confirmed in a large cohort of patients. This study was supported by projects VaVPI MSMT CR CZ.1.05/1.1.00/02.0068 of CEITEC, IGA MZ CR NT13493-4/2012, NT13519-4/2012 and CZ.1.07/2.3.00/30.0009. Disclosures Brychtova: Roche: Travel grants Other. Doubek:Roche: Travel grants Other.

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