Rai Stage Research Articles

First line therapy of CLL

AbstractChronic lymphocytic leukemia (CLL) is one of the most frequent types of leukemia. It typically occurs in elderly patients and has a highly variable clinical course. Only patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. When treatment is indicated, several therapeutic options exist today and need to be selected. A combination of the BCL2 inhibitor venetoclax with obinutuzumab, monotherapy with inhibitors of Bruton tyrosine kinase (BTK) such as ibrutinib, acalabrutinib or zanubrutinib, while chemoimmunotherapy (CIT) is disappearing as a therapeutic option.

Real-world outcomes by race in patients (pts) with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): Final analysis results from the informCLL registry.

7536 Background: informCLL is a large, US-based, prospective, observational registry of pts with CLL/SLL initiating treatment (tx) in the era after approval of ibrutinib (Ibr). Here, we report real-world tx patterns and outcomes by race and line of therapy (LOT) from the final analysis of informCLL. Methods: Pts with CLL/SLL who initiated FDA-approved tx were enrolled between 10/2015 and 6/2019. Baseline characteristics, tx patterns, time to next tx (TTNT), OS, and safety are summarized by race (focus on Black and White pts) and LOT (first-line [1L] or relapsed/refractory [R/R], with focus on 1L). Results: Of 1459 eligible pts enrolled, 105 were Black (1L, n=58; R/R, n=47), 1323 were White (1L, n=779; R/R, n=544), and 31 were of other races (Asian [n=6], Native American [n=4], other/not reported [n=21]). Relative to White pts, 1L-treated Black pts were younger (median age 65 vs 70 y) and had worse performance status (ECOG status ≥1: 59% vs 50%), more advanced disease (Rai stage III-IV: 55% vs 46%), shorter time from diagnosis to 1L tx (median 7 vs 19 mo), and lower rates of del(17p) among tested pts (6% vs 13%). Across race, Ibr was the most common 1L tx (Black, n=29 [50%]; White, n=346 [44%]) followed by CIT (Black, n=25 [43%]; White, n=331 [42%]). With median follow-up of approximately 32 mo in 1L-treated pts, the estimated rate of freedom from next-line therapy at 36 mo was similar between Black and White pts across all-treated pts and among Ibr-treated subgroups (Table). Estimated 36-mo OS rates in all-treated pts were also similar by race, with a high OS rate observed among Ibr-treated Black pts (97% at 36 mo). In multivariate analyses (MVA) in 1L-treated pts, male gender, poorer ECOG status, and increased comorbidity burden were independent predictors of decreased OS while race was not associated with OS. In 1L Ibr-treated pts, the only factor associated with decreased OS in MVA was longer time from diagnosis to 1L tx. Rates of serious AEs and AEs leading to tx discontinuation appeared similar across race (Table). Conclusions: Although historical retrospective studies from the pre-novel agent era have shown poorer clinical outcomes among Black pts with CLL relative to non-Black pts, results from informCLL show similar or potentially improved outcomes, including OS, among 1L Ibr-treated Black pts relative to White pts. These results suggest that access to novel agents such as Ibr may in part overcome historical disparities in clinical outcomes by race in pts with CLL. Clinical trial information: NCT02582879 . [Table: see text]

Relative Expression of BATF and CD112 in PBMC of Patients with Chronic Lymphocytic Leukemia.

BATF, as a transcription factor, and CD112, as a receptor for TIGIT, are involved in T-cell exhaustion. We investigated BATF and CD112 gene expression in the peripheral blood mononuclear cells from CLL patients and healthy subjects. In a case-control study, 33 patients with CLL and 20 sex- and age-matched healthy individual were enrolled. Diagnosis and classification of patients was done according to immunophenotyping via flow cytometry and RAI staging system, respectively. Relative mRNA expression of BATF and CD112 was measured using qRT-PCR. Our results showed that the expression of BATF and CD112 in CLL samples were significantly decreased in comparison those of the healthy controls (P = 0.0236 and P = 0.0002, respectively). These findings suggest the role of BATF and CD112 not only as a role in T cell exhaustion, but in effector differentiation program in CLL, which warrants further studies in future.

Efficacy of immune checkpoint inhibitors for the treatment of advanced melanoma (AM) in patients with concomitant chronic lymphocytic leukemia (CLL).

e19511 Background: CLL is the most prevalent adult leukemia and is associated with an increased risk of melanoma. CLL alters systemic immunity and can induce T-cell exhaustion, which may limit the efficacy of ICI in patients with CLL. Immune checkpoint inhibitors (ICI) have revolutionized management of AM, but data on ICI effectiveness have largely been restricted to clinical trials, thereby excluding patients with co-existing malignancies. We, therefore, sought to examine the efficacy of ICI for melanoma in patients with concomitant CLL and AM. Methods: In this international and multicentre retrospective study, review of clinical databases identified patients with concomitant CLL and AM treated with ICI from two US tertiary cancer centers (n = 39) and an Australian multi-institutional experience (AUS, n = 19). Objective response rates (ORR), defined as complete or partial response by RECIST v1.1, and survival outcomes (overall survival, OS, and progression-free survival, PFS) among patients with CLL and AM were assessed. Clinical factors associated with improved ORR and survival were explored. Results: Between 1997 and 2020, 58 patients with CLL were treated with ICI for concomitant AM. Among all patients with CLL and AM, ORR to ICI was 41% and median duration of response was 18 months. A majority were untreated for CLL (64%) at the time of ICI. Patients with prior history of treatment for CLL had significantly reduced ORRs (21% vs 51%, p = 0.04), PFS (3.6 vs. 14.6 months, p = 0.005), and OS (7.4 vs. 52.2 months, p = 0.002), compared to patients on observation for their CLL. Prior treatment with T-lymphocyte depleting chemoimmunotherapy (fludarabine, bendamustine, and alemtuzumab) was particularly associated with poor outcomes (median OS of 7.0 months, median PFS of 3.4 months). On univariate analysis, prior treatment for CLL, high risk CLL 17p deletion, and higher CLL Rai stage were associated with shorter PFS from ICI, though CLL treatment was the only factor independently associated with shorter PFS in the multivariate model (HR 6.5, [CI 2.1-20.3], p = 0.001]. Overall, 3 patients developed CLL progression while on ICI, though in two of these patients, the AM had an objective, durable clinical response to ICI. Overall, immune-related adverse events (irAE) occurred following 38% of ICI and rates of irAE were similar by CLL treatment status. Conclusions: Our case series of patients with concomitant CLL and melanoma demonstrate frequent, durable clinical responses to ICI However, those with prior chemoimmunotherapy treatment for CLL had significantly worse outcomes. We found that CLL disease course is largely unchanged by treatment with ICI.

Elevated expression of interleukin 16 in chronic lymphocytic leukemia is associated with disease burden and abnormal immune microenvironment

Interleukin-16 (IL-16) is a novel biomarker that has been implicated in many cancers as well as inflammatory diseases. In this study, we examined plasma levels of 30 cytokines and chemokines in chronic lymphocytic leukemia (CLL) and monoclonal B cell lymphocytosis (MBL) patients, and examined their association with disease stage, CLL biomarkers and T cell subsets. Interleukin 16 (IL-16) was identified as a relatively uncharacterized cytokine significantly elevated in CLL patients compared to healthy controls and MBL patients. Plasma levels of IL-16 were significantly elevated by Rai stage 0, increased by Rai stage 3–4, correlated strongly with lymphocyte count and were decreased after Ibrutinib treatment. CLL cells expressed IL-16 mRNA and spontaneously secreted IL-16 in vitro. CLL cells express IL-16 mRNA at significantly higher levels in lymphoid tissues than blood, and we observed that IL-16 release was increased in co-cultures of CLL and autologous CD4 + T cells. Elevated plasma IL-16 levels were associated with abnormalities in the immune microenvironment including multiple inflammatory cytokines and chemokines and expansion of type 1 follicular helper T cells. Taken together, our results identify IL-16 as a novel biomarker in CLL with potential functional roles in cellular interactions between CLL cells and T cells.

Empirical Study on Exploring the Role of CD180 and MD-1 Prognostic Indicators for the Chronic Lymphocytic Leukaemia (CLL) Disease.

<b>Background and Objective:</b> Chronic Lymphocytic Leukaemia (CLL) is a frequent type of leukaemia disease. This study was focused on investigating the role of prognostic indicators, such as CD180 and MD-1 for Chronic Lymphocytic Leukaemia (CLL) pathogenesis because they involve cell signalling and proliferation. <b>Materials and Methods:</b> A total of 12 normal controls and 52 patients were taken to determine the expressions of CD180 and MD-1 with different variations in comparison with the IgVH (Immunoglobulin Heavy Chain variable region gene) mutational status, FISH (fluorescence <i>in situ</i> hybridization) and Rai staging. <b>Results:</b> The quantitative data findings were evident that CD180 and MD-1 expressions showed insignificant differences among CLL patients at the protein level based on SPSS results. On the contrary, they resulted in significant differences for subgroups of established biomarkers like Rai staging (stages 0, I, II and III), FISH (13q and non-13q deletions) and IgVH (mutated and unmutated). <b>Conclusion:</b> The CD180 and MD-1 have been used as prognostic indicators to evaluate the outcomes relevant to the cell cycle and survival rate of CLL cells.

Invasion of chronic lymphocytic leukemia (cll/sll) bloodstream tumor cells by borrelia spirochetes

A sixty-six-year-old woman with a strong family history of breast cancer noted gradual onset of axillary lymph node enlargement in 2019. Axillary lymph node biopsies disclosed Lymph node involvement by Chronic Lymphocytic Leukemia (CLL/SLL). Immunophenotype analysis of nodal tissue and of bloodstream leukemic cells in immunohistochemistry and flow cytometry and next generation molecular diagnostics confirmed CLL/SLL. Replicate absolute peripheral blood lymphocyte counts in excess of 5.0x10e3/microliter confirmed the numerical threshold for diagnosis of Chronic Lymphocytic Leukemia in the bloodstream. FISH studies disclosed an immunoglobulin “mutation negative” CLL/SLL genotype without a light chain restriction pattern. No translocations or germline mutations were present. Borrelia spirochetes in the bloodstream were detected with simultaneous high spirochetemia of both borrelia miyamotoi and borrelia burgdorferi. FISH hybridization of leukemic lymphocytes disclosed extensive borrelia invasion of the cytoplasm and of the nucleus compartments of CLL/SLL tumor cells. Retrospective studies of the patient’s archival stored blood smears obtained three years prior in 2016 at age 63 disclosed no evidence of CLL/SLL but confirmed asymptomatic bloodstream borrelia miyamotoi and borrelia burgdorferi borrelia infection. Lyme serology had been reported as negative in 2016. Additionally, retrospective FISH DNA hybridizations focused on preleukemic bloodstream Lymphocytes disclosed rare borrelia spirochetal adherence to benign blood lymphocytes in the year 2016 in the preleukemic blood smears. This case report is the very first to describe precursor chronic asymptomatic Lyme borreliosis and Miyamotoi borrelia bloodstream infections three years prior to the diagnosis of Rai Stage 1 Chronic Lymphocytic leukemia.

First dose infusion reaction during anti-CD20 monoclonal antibody therapy in chronic lymphocytic leukemia associates with high IP-10 levels amid cytokine release syndrome

Abstract Intravenous (IV) anti-CD20 monoclonal antibody (mAb) therapy for chronic lymphocytic leukemia (CLL) patients often produces a first dose infusion reaction (FDIR) within the first 2 h that requires careful monitoring to avoid serious complications and fatalities. To better understand FDIR, we studied blood samples collected from 37 treatment-naïve CLL patients in our clinical trial NCT03788291 undergoing IV treatment with 50 mg of anti-CD20 mAb (rituximab). We analyzed four time points: baseline (prior to infusion), 1 h later (during infusion), at the end of infusion (~2.5 h) and at 48 h. Infusion reactions (CTCAE (v5) grade ≥2 events) were managed by interrupting the infusion and with symptomatic treatment. 24 (65%) patients had a FDIR and all patients completed the infusion. Patient and CLL characteristics including measures of disease severity (Rai stage, IGHV mutation status, cytogenetic defects) did not correlate with FDIR. High levels of CLL cells and/or CD20 and their subsequent depletion resulting in decreased serum mAb and/or complement are thought to be risks for FDIR. However, measurements of these parameters did not correlate. Induction of cytokine release syndrome (CRS) may correlate with FDIR. However, CRS was observed in all samples after mAb infusion. The only significant associations with FDIR were higher levels of IP-10, IL-6, and IL-8, with IP-10 most significant. Anti-CD20 mAb activated cytotoxic effector cells, such as tissue-resident macrophages that ingest CLL cells via antibody-dependent cellular phagocytosis (ADCP), may be responsible for these events leading to FDIR. A mouse model of anti-CD20 mAb FDIR and in vitro ADCP cell systems will be useful to further understand the biology of FDIR. Supported by funding from Acerta/AstraZeneca, the Cadregari Foundation, a generous donation by Elizabeth Aaron, and the NIH NCI grant number R21CA267040.

Abstract 6523: A case of stage I HPV-mediated oropharyngeal squamous cell carcinoma (SCC) diagnosed using a multi-cancer early detection (MCED) test

Abstract There are no routine screening tests for head and neck (H&N) cancers, which account for approximately 4% of all cancers in the US. Risk factors for oropharyngeal cancer include smoking and human papillomavirus (HPV) infection. An MCED test that uses a cell-free DNA-based targeted methylation assay and machine learning classifiers to detect a shared cancer signal and predict the cancer signal origin (CSO) is available as a complement to existing single-cancer screening tests. If a cancer signal is detected, the positive result is reported with 1 or 2 CSO prediction(s). We report here a tonsil cancer case detected using an MCED test and review the CSO-guided diagnostic journey. An asymptomatic 74-year-old White male (BMI: 29.9 kg/m2) with history of chronic lymphocytic leukemia (CLL; Rai stage 0; 13q, CD38, and ZAP-70 negative; no treatment was needed) 17 years prior and papillary thyroid cancer (stage IVa; pT3N1bM0; thyroidectomy and radiation therapy; no recurrence) 8 years prior was screened using the MCED test. Patient had an elevated PSA level (9-10 ng/mL) and was a nonsmoker. Fifteen days after a blood sample was collected for analysis, a positive test result (CSO prediction=H&N) was communicated to the patient (Day 1). PET showed abnormal uptake in the right tonsil (Day 28). The patient was referred for an ENT consult and underwent a right lymph node biopsy (Day 54). The biopsy showed invasive moderately differentiated SCC, non-keratinizing, forming a 3 × 2.1 × 1.2 cm mass (Day 57). Patient underwent right tonsillectomy (the surgical margins were negative for invasive or in situ carcinoma) and lymph node dissection (Day 57). The cancer was diagnosed as HPV-mediated p16+, pT2, pN1, cM0 (stage I) SCC of the oropharynx (Day 57). No chemotherapy or radiation was required due to the early stage of detection. The patient will follow-up with ENT and radiation oncology. The MCED test detected a cancer signal and predicted an accurate CSO for an asymptomatic individual with stage I HPV-mediated oropharyngeal SCC. Notably, despite a history of CLL and an elevated PSA level, the test accurately predicted CSO leading to a directed workup diagnosing asymptomatic cancer in less than 2 months, while the cancer was still at stage I. In the case-control Circulating Cell-free Genome Atlas study, the MCED test sensitivity to detect a cancer signal was 63% in stage I H&N cancer. The use of this MCED test led to detection of cancer in a patient with CLL history and treatment (surgery without complications and without chemotherapy or radiation) with curative intent. Citation Format: Janet Vittone, Julia Feygin, Jason Carey. A case of stage I HPV-mediated oropharyngeal squamous cell carcinoma (SCC) diagnosed using a multi-cancer early detection (MCED) test [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6523.

CCL3 as Possible Negative Prognostic Factor in Chronic Lymphocytic Leukemia

Introduction: Both microenvironmental signals from surrounding cells and changes in the genome of leukemic cells play essential role in the development of chronic lymphocytic leukemia. Nurse-like cells (NLCs) are one of the important elements of the microenvironment of CLL cells. The key role in the interactions of leukemic cells with NLCs is played by chemokines, which may interfere with the programmed cell death process in the leukemic lymphocytes. The aim of our study was analysis of selected microenvironmental factors having a potential impact on the leukemic cells survival, as well as their association with clinical, cytogenetic, and molecular parameters. For this study, we selected three types of molecules which can modulate microenvironment: chemokines IL-8 and CCL3 (which are classically secreted to extracellular matrix), soluble forms of adhesion molecules JAG1 and CD163, and secreted form of endogenous protein BIRC5. We assessed their expression in the serum of CLL patients as well as in medium of long-term NLCs cultures. Methods: Long-term cell culture was prepared from mononuclear cells derived from the blood of 34 patients with CLL. Number of NLCs cells was evaluated, under a light inverted microscope. The concentration of IL-8, CCL3, sBIRC5, sCD163, and sJAG1 in culture medium and serum was assessed by enzyme-linked immunosorbent assays. Results: There were significant differences in the concentration of IL-8, sBIRC5, CCL3, sCD163, and sJAG1 between the patient’s blood serum and the culture medium. The concentrations of IL-8, CCL3, and JAG1 were higher in the culture medium, which confirmed the role of the microenvironment in the production of these proteins. In addition, the concentration of CCL3 chemokine in both patient’s blood serum and in the culture medium correlated with the number of NLCs and with known prognostic factors in the course of CLL, e.g., Rai stage, WBC, expression of ZAP-70, CD38, and CD5/19. Conclusion: The microenvironment of CLL cells, which includes NLCs, plays an important role in the pathogenesis of CLL. The CCL3 chemokine seems to be a good factor representing microenvironment of CLL cells. Chronic lymphocytic leukemia is a complex and very heterogeneous disease; therefore, its progress should be considered both in the context of genetic changes and the interaction with microenvironmental cells.

Relationships between T-lymphocytes and physical function in adults with chronic lymphocytic leukemia: Results from the HEALTH4CLL pilot study.

Examine physical function and T-cell phenotype in patients with chronic lymphocytic leukemia (CLL) before and after a physical activity (PA) intervention. Physical function measures and blood samples were collected from CLL patients (Rai stage 0-4, 50% receiving targeted therapy, N = 24) enrolled in a 16-week intervention of at-home aerobic and/or resistance exercise. Flow cytometry characterized T-cells in cryopreserved peripheral blood cells. Wilcoxon signed-rank test compared physical function and T-cell phenotype at baseline and 16-weeks; Kendall's Tau assessed associations between variables. Godin leisure-time PA score increased from baseline to 16-weeks (mean difference: 14.61, p < .01) and fatigue decreased (mean difference: 6.71, p < .001). At baseline, lower fatigue correlated with a lower proportion of CD8+ T-cells (τ = 0.32, p = .03) and cardiorespiratory fitness (CRF) inversely correlated with the percentage of PD-1+CD8+ T-cells (τ -0.31, p = .03). At 16-weeks, CRF inversely correlated with the proportion of PD-1+CD4+ T-cells (τ -0.34, p = .02). Reduced fatigue at 16-weeks correlated with an increased CD4:CD8 ratio (τ = 0.36, p = .02) and lower percentage of HLA-DR+PD-1+CD4+ T-cells (τ = -0.37, p = .01). This intervention increased leisure-time PA and decreased fatigue in CLL patients. These changes correlated with an increased CD4:CD8 T-cell ratio and reduced proportion of T-cells subsets previously associated with poor outcomes in CLL patients. ClinicalTrials.gov Identifier: NCT02194387.

The Clinical and Prognostic Significance of Ribonucleotide Reductase Subunits RRM1 and RRM2 mRNA Levels in Patients with Chronic Lymphocytic Leukemia

Ribonucleotide Reductase (RNR) converts ribonucleotides to deoxyribonucleotides required for DNA replication and repair. RNR consists of subunits M1 and M2. It has been studied as a prognostic factor in several solid tumors and in chronic hematological malignancies, but not in chronic lymphocytic leukemia (CLL). Peripheral blood samples were collected from 135 CLL patients. M1/M2 gene mRNA levels were measured and expressed as a RRM1-2/GAPDH ratio. M1 gene promoter methylation was studied in a patients’ subgroup. M1 mRNA expression was higher in patients without anemia (p = 0.026), without lymphadenopathy (p = 0.005) and 17p gene deletion (p = 0.031). Abnormal LDH (p = 0.022) and higher Rai stage (p = 0.019) were associated with lower M1 mRNA levels. Higher M2 mRNA levels were found in patients without lymphadenopathy (p = .048), Rai stage 0 (p = 0.025) and Trisomy 12 (p = 0.025). The correlation between RNR subunits and clinic-biological characteristics in CLL patients demonstrate RNR’s potential role as a prognostic factor.

Vitamin D Level in Patients with Chronic Lymphocytic Leukemia and Relationship Between Rai Stage

Vitamin D Level in Patients with Chronic Lymphocytic Leukemia and Relationship Between Rai Stage

Additional malignancies shorten overall survival in chronic lymphocytic leukemia irrespective of chromosomal aberrations: A retrospective cohort study.

The aim of this study was to determine the incidence of other malignancies (OMs) in patients with chronic lymphocytic leukemia (CLL) and to identify parameters associated with the occurrence of OMs in addition to CLL. This retrospective cohort study was conducted by examining the records of CLL patients who applied to a tertiary hospital between January 2013 and December 2021. The cases were divided into 2 groups, CLL (n = 107) and CLL + OM (n = 25), according to the presence of additional malignancy. Lymphocyte count (P = .014), white blood cell count (P = .006), and hemoglobin (P = .034) were significantly higher in the CLL group. Rai stage IV percentage (P = .015), Binet stage B percentage (P = .043), progression, and sepsis percentages (P = .008) were significantly higher in the CLL + OM group. Overall survival time was significantly lower in the CLL + OM group (P = .032). Most OMs had been diagnosed before CLL (63.64%) in the no-treatment group, while the majority of OMs were diagnosed after CLL (78.57%) in the treatment group (P = .032). CLL patients with OM had a more advanced CLL stage, and survival was significantly shorter in these patients. In addition, CLL-associated OM appears to occur more frequently in the post-treatment period.

Zeta-associated protein 70 expression in chronic lymphocytic leukemia: Relevance in Indian context.

Chronic lymphocytic leukemia (CLL) is prognosticated using the Rai and the Binet's staging. In the past few years, new parameters have been considered for prognostication. One such marker that has been a subject of speculation and found useful by some western studies is zeta-associated protein 70 (ZAP-70). To investigate the prevalence of ZAP-70 and find out its association with other prognostic markers like Rai and Binet's stage and CD38 in Indian CLL patients. Twenty-nine newly diagnosed cases of CLL were selected over 1 year. Immunophenotyping was done and expression of CD38 and ZAP-70 was evaluated on gated CLL cells. Qualitative data were expressed as frequency and percentage. Differences between groups were evaluated using Student's t-test for quantitative data and Chi-square test/Fisher's exact t-test for qualitative variables. A P value less than 0.05 was considered significant. We found a lower prevalence rate of ZAP-70 (2/29, 6.89%) with no association with any of the conventional poor prognostic factors. A large number of our CLL patients fall into the good prognostic group (22/29, ZAP 70-/CD38-) with a least number in the poor prognostic group (2/29, ZAP-70 + CD38+). Also, no association was found between ZAP-70 and CD38. The findings of the present study suggest that the majority of CLL patients in India have a good prognosis, may not require treatment, and have good overall survival. Geographical variations, genetic makeup, and natural history of the CLL could be the cause of such differences from western literature.

Clinical Characteristics and Long-Term Survival of Patients with Chronic Lymphocytic Leukemia

To analyze the factors affecting the long-term survival of patients with chronic lymphocytic leukemia (CLL). The clinical data of 101 newly diagnosed CLL patients from January 2010 to January 2021 were retrospectively analyzed. Rai and Binet staging systems were used for clinical staging, and CLL-IPI was used for risk stratification of the patients. There were 61 males and 40 females, the median age at diagnosis was 64 (28-84) years, the median PFS (progression-free survival) was 77（66-88） months, the 2-year and 5-year PFS rates were 85% and 64% respectively. The median OS (overall survival) was 108（103-112） months, the 5-year and 9-year OS rates were 74% and 46% respectively. Univariate analysis showed that high or very high risk of CLL-IPI, TP53 aberrations, del(17p), need for treatment and different treatment methods were the factors affecting OS (P<0.05); high or very high risk of CLL-IPI, TP53 aberrations, del(17p) and complex karyotype were associated with PFS (P<0.05). By X-tile analysis, it was found that the white blood cell count, the absolute neutrophil count, the hemoglobin level, and β2-microglobulin level were associated with OS (P<0.05); the white blood cell count, the absolute lymphocytes count, the hemoglobin level, the platelet count, and the lactate dehydrogenase level were associated with PFS（P＜0.05）. The high or very high risk of CLL-IPI, TP53 aberrations, del(17p), need for treatment and different treatment methods are the factors affecting the OS of CLL patients, and high or very high risk of CLL-IPI, TP53 aberrations, del(17p) and complex karyotype are the factors affecting the PFS of CLL patients.

Time to second treatment can be used to predict overall survival in chronic lymphocytic leukemia: identifying risk factors to help guide treatment selection

Targeted therapies have largely replaced chemoimmunotherapy (CIT) in first-line treatment of chronic lymphocytic leukemia (CLL). We aimed to develop a prognostic model to determine who would benefit from first-line CIT vs target therapy. In follicular lymphoma, time from diagnosis to second treatment (TT2T) correlates better with overall survival (OS) than time from diagnosis to first treatment (TT1T). We hypothesized that TT2T is a potential surrogate for OS in CLL. In a model-building cohort (n = 298), we evaluated potential predictors for TT2T and derived a risk score, which we validated in an external cohort (n = 1141). Our data demonstrated that TT2T and OS were more strongly correlated than TT1T and OS. Our risk score model consisted of three predictors (unmutated IGHV, β2-microglobulin >297 nmol/L, and Rai stage I–IV), and was prognostic for TT2T and OS. TT2T is a promising surrogate for OS in CLL, but further validation is needed to establish this association.

Low plateletcrit is associated with reduced progression: Free and overall survival in chronic lymphocytic leukemia.

Alterations of plateletcrit and mean platelet volume (MPV) and pathogenesis of chronic lymphocytic leukaemia (CLL) have been linked to various inflammatory disorders. The prognostic impact of plateletcrit and MPV were evaluated. MPV and plateletcrit levels of both CLL and control group were compared and then in CLL patients, additional diseases, leukocyte count, platelet count, lactate dehydrogenase, Rai stage, progression-free and overall survival, mutations, if any, and chemotherapy, if any, were recorded. Then, the relationship between MPV and plateletcrit values and these parameters were evaluated in CLL patients. Platelet and plateletcrit values were found to be significantly lower in CLL patients than the control group (p<0.001) for both. Plateletcrit and MPV values of patients who did not receive chemotherapy were higher than those who received chemotherapy (p=0.03, p=0.02, respectively). Being over 75 years old, plateletcrit value less than 0.1565 %, platelet level below 175 x 109/L, and leukocyte count greater than 53.5 x 109/L was found to significantly reduce overall survival. Male gender, each stage increase, plateletcrit less than 0.1565 % and leukocyte count greater than 53.5 x 109/L was related to reduce treatment-free survival in CLL patients. Plateletcrit can be a viable prognostic marker for defining both treatment free and overall survival.

Early Treatment with Ofatumumab in Patients with High-Risk CLL

Introduction Early treatment initiation for patients with high-risk CLL has not been shown to be associated with clinical benefit in studies utilizing rituximab and rituximab in combination with alemtuzumab. Ofatumumab is a fully human monoclonal antibody targeting CD20. It is well-tolerated and has improved target binding and cytotoxicity compared to rituximab. We therefore sought to evaluate the efficacy of ofatumumab as early treatment in patients with high-risk CLL. Methods This was a single-arm, open label, phase II trial for treatment-naïve, watch-and-wait patients with high-risk for progression to need treatment. Based on currently available models, high-risk CLL was defined as presence of one or more of the following: Rai stage 2 disease or Rai stage 0-1 with disease related fatigue, β2M ≥ 3mg/L, ALC ≥ 25K/µL, unmutated IGHV, ZAP70-positive, CD38-positive, or FISH with del(11q) or del(17p). Patients who met 2008 iwCLL criteria for treatment were excluded. The primary objective was overall response rate (ORR) with secondary objectives of progression-free survival (PFS), time-to-next treatment (TTNT), and overall survival (OS). Treatment consisted of a total of 8 weekly doses of ofatumumab. The first weekly dose was 300mg to reduce infusion reactions, subsequently ofatumumab 1000mg was then administered weekly for 7 weeks. Results Between 04/2011 and 06/2015, 44 pts were enrolled in the study and initiated treatment. The median age at study entry was 60 years with a median time from diagnosis to study entry of 15.3 mo. The median ALC, HGB and PLT counts were 20.1K/µL, 14mg/dL, and 166K/µL, respectively. The median LDH was 481U/L (range 345 - 855). When characterized based on FISH alterations, 19(43%) pts had del(13q), 7(16%) pts had trisomy 12, 8(18%) pts had del(11q), 3(7%) pts had del(17p), and 7(16%) pts had no abnormalities. When characterized based on other high-risk features: 24(55%) pts had unmutated IGHV, 21(48%) pts were ZAP70(+), 15(34%) pts were CD38(+), 6(14%) had elevated β2M, and 21(48%) had an ALC over 25K/µL. The ORR to ofatumumab (complete + partial remission) was 63% with 3(7%) pts attaining undetectable MRD status at 10-4 sensitivity. At a median follow up of 8 years, the median PFS, TTNT, and overall survival (OS) were 16.3 mo, 42.8 mo, and not reached. Thirty (68%) pts went on to receive further treatment (19 pts on BTK based regimens, 2 pts received venetoclax monotherapy, 5 pts received combined venetoclax and ibrutinib, 3 pts received chemoimmunotherapy, and 1 pt received obinutuzumab monotherapy). This regimen of early treatment with ofatumumab was well tolerated. The most common adverse reaction was infusion reactions occurring in 16 pts (36%) with all reactions being amendable to antihistamine and/or steroid treatment. In all of these pts the infusion was restarted. One pt had to discontinue ofatumumab treatment after the second infusion due to autoimmune hepatitis. Conclusion In a population of patients with CLL at high-risk for proceeding to treatment, early treatment with ofatumumab resulted in a PFS and TTNT of 16.3 mo and 42.8 mo, respectively. The PFS was similar to that of similarly designed trials with rituximab monotherapy and rituximab in combination with alemtuzumab, respectively. Further internal matched analysis is being conducted to compare time to second treatment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Outcomes with First-Line Ibrutinib (Ibr) Versus Chemoimmunotherapy (CIT) in Patients with Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL): Final Analysis Results from the InformCLL Registry

Background: The therapeutic landscape for CLL/SLL has rapidly evolved with the introduction of novel agents such as Ibr. The informCLL registry (PCYC-1134; NCT02582879) is the largest US-based prospective, observational registry of patients (pts) initiating FDA-approved treatment for CLL/SLL in the era after approval of Ibr. Here, we report real-world (RW) outcomes in pts with CLL/SLL receiving first-line (1L) therapy, including comparison of 1L Ibr versus CIT, from the final analysis of informCLL. Methods: Pts with CLL/SLL who initiated FDA-approved treatment (within ±45 days of enrollment) were enrolled between 10/2015 and 6/2019. Pts were primarily enrolled from community-based practices (comprising 93% of sites). Data were collected for baseline characteristics, treatment patterns, and safety. Time to next treatment (TTNT) was estimated by Kaplan-Meier method and for comparison of outcomes with 1L Ibr versus CIT, by Cox proportional hazards regression analysis in weighted cohorts. Inverse probability of treatment weighting (IPTW) was performed to balance the baseline characteristics between cohorts. Adverse events (AEs) were evaluated using overall incidence and exposure-adjusted incidence rates (EAIRs). Results: Of the 1459 eligible pts enrolled, 854 were treated in the 1L setting (59%). In the overall 1L cohort, median age was 70 years (≥75 years in 33%); 90% had ECOG performance status of 0 or 1; 47% had Rai stage III/IV (among n=547 with Rai staging); median Charlson Comorbidity Index (CCI) score was 1 (range 0-12) with CCI ≥3 in 16%; median time from initial diagnosis to 1L treatment was 19 mo. FISH testing data were available in 57% of pts in the 1L cohort; among these pts, 12% had del(17p). The most common 1L therapies were Ibr (45%; single-agent Ibr in 43% of all 1L therapies) and CIT (43%: most commonly BR, 24%); immunotherapy was given in 11% while chemotherapy (0.9%) and other novel agents (0.7%) were rare. With a median follow-up of 31.8 mo in the 1L cohort, median TTNT was not reached (NR); estimated proportions of pts without next-line therapy (NLT) were 79% at 24 mo, 71% at 36 mo, and 64% at 48 mo. The 1L cohort included 383 pts treated with Ibr and 363 pts treated with CIT; median follow-up was 31.4 mo for the Ibr cohort and 34.3 mo for CIT. Compared with the CIT cohort, pts in the Ibr cohort were older, had longer time from diagnosis to treatment, were more likely to have a history of other malignancy, and were more likely to have del(17p) or TP53 mutation (Table). Baseline characteristics in the weighted cohorts were balanced. In the IPTW-adjusted cohorts, median TTNT was NR for Ibr and 56.5 mo for CIT; TTNT was improved with Ibr relative to CIT (hazard ratio 0.744; 95% CI, 0.563-0.981) (Figure). Estimated proportions free of NLT in the weighted Ibr cohort were 75% at 36 mo and 69% at 48 mo; rates in the weighted CIT cohort were 66% and 57%, respectively. Median duration of index treatment was 24.0 mo for 1L Ibr and 4.7 mo for CIT. In the Ibr cohort (n=383), serious AEs occurred in 144 pts (38%), most commonly (≥3% of pts) pneumonia (n=23; 6%) and atrial fibrillation (Afib; n=21; 5%); AEs led to discontinuation of Ibr in 135 pts (35%), most commonly Afib (n=19; 5%) and fatigue (n=12; 3%). In the CIT cohort (n=363), serious AEs occurred in 85 pts (23%), most commonly febrile neutropenia (n=13; 4%) and pneumonia (n=11; 3%). AEs led to discontinuation of CIT in 61 pts (17%), and no single AE term led to discontinuation in ≥3% of pts (most common was anemia, 2%). EAIRs per 100 pt-mo for serious AEs were 1.93 with Ibr and 4.55 with CIT. EAIRs per 100 pt-mo for AEs leading to discontinuation were 1.53 with Ibr and 3.09 with CIT. Conclusion: In this large RW registry of pts with CLL/SLL, results from IPTW-adjusted analysis showed that 1L Ibr was associated with longer TTNT than CIT, with sustained benefit up to 4 years of follow-up. Pts receiving 1L Ibr therapy tended to be older, more often had a history of other malignancy, and more often had high-risk genomic features (del(17p) or TP53 mutation among those tested) than pts treated with CIT. The spectrum and frequency of AEs observed with these 1L regimens appear consistent with data from clinical studies and other RW studies. When adjusted for exposure, rates of AEs leading to discontinuation and serious AEs were lower with Ibr than CIT. Future analyses examining the impact of factors such as age/comorbidity and race are warranted to further our understanding of RW outcomes in pts with CLL/SLL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal