Change In Absolute Lymphocyte Count Research Articles

Decreased Absolute Lymphocyte Count and Increased Neutrophil/Lymphocyte Ratio With Immune Checkpoint Inhibitor-Associated Myocarditis.

BackgroundMyocarditis attributable to immune checkpoint inhibitor (ICI) therapy is a potentially fatal immune‐related adverse event. Limited data have suggested an association between baseline and on‐treatment absolute lymphocyte count (ALC) and neutrophil/lymphocyte ratio (NLR) and the development of other immune‐related adverse events; there are no data characterizing the role of ALC and NLR in ICI‐associated myocarditis.Methods and ResultsThis was a case control study of 55 patients with ICI myocarditis and 55 controls without any post‐ICI immune‐related adverse events. We leveraged clinical testing, where patients underwent routine serial blood counts before and with each ICI cycle to compare the baseline and change in ALC and NLR between cases and controls. The association between the change in these parameters with clinical variables and major adverse cardiac events was also tested. In cases, there was a statistically significant decrease in ALC with myocarditis from baseline (1.6 thousands per cubic milliliter (K/μL); interquartile range, 1.1–1.9 K/μL) to admission (1.1 K/μL; interquartile range, 0.7–1.3 K/μL; P<0.001). Similarly, there was an increase in NLR from baseline (3.5; interquartile range, 2.3–5.4) to admission (6.6; interquartile range, 4.5–14.1; P<0.001). There was no statistically significant change in controls. In follow‐up, there were 20 events; larger decreases in ALC (44.6% versus 18.2%; P<0.001) or increases in NLR (156.5% versus 65.1%; P=0.019) were associated with major adverse cardiac events.ConclusionsA reduction in ALC and an increase in NLR was seen with ICI myocarditis. A greater decrease in ALC or increase in NLR was associated with subsequent major adverse cardiac events.

Prognostic Value of Delta Lymphocyte Index (DLIx) in Patients with Large B-Cell Lymphoma (LBCL) Treated with Chimeric Antigen Receptor (CAR) T-Cell Therapy

Prognostic Value of Delta Lymphocyte Index (DLIx) in Patients with Large B-Cell Lymphoma (LBCL) Treated with Chimeric Antigen Receptor (CAR) T-Cell Therapy

CLL-229: Efficacy of Immune Checkpoint Inhibitors in Metastatic Melanoma (MM) Patients with Concurrent Chronic Lymphocytic Leukemia (CLL)

Context CLL patients have a high incidence of melanoma, and checkpoint inhibitors (CPI) are approved for treatment of patients with metastatic disease. However, patients with CLL are known to have a profoundly impaired immune system with various types of T-cell abnormalities, and the impact of these defects on response to (CPI) is not known. We sought to evaluate the response to treatment with CPI in patients with concomitant MM and CLL. Objective Primary objective included objective response rate (ORR) by RECIST1.1 criteria. Secondary outcomes included progression-free survival (PFS), overall survival (OS), and duration of response (DOR). Setting Retrospective study of patients with concurrent CLL and MM treated with CPI therapies at MD Anderson Cancer Center between 1997 and 2020. Patients Twenty-four patients were included, with a median age of 64 years. Seventy-one percent were male, 67% had early-stage CLL, and 71% were untreated. Thirty-three percent had prior melanoma treatment; 83% of patients had stage IV, and 17% had stage III melanoma. Interventions Thirty-eight CPI therapies were administered to 24 patients: single-agent PD-1 inhibitors pembrolizumab or nivolumab (53%), CTLA-4 inhibitor ipilimumab (29%), and combination therapies (18%). Results The ORR was 25% after first-line CPI and 21% for subsequent treatments, with a DOR of 50 and 16 months, respectively. After a median follow-up of 37 months, 12 patients died, 9 due to melanoma progression. The OS and PFS were 26 and 6 months, respectively. Increased LDH was associated with lower OS, and high LDH, and intermediate/high-risk CLL with a lower PFS. There were no significant changes in absolute lymphocyte counts during CPI. 2 patients received CPI while on ibrutinib or ibrutinib+venetoclax therapy with ongoing CLL responses. Conclusions CPIs are an effective treatment option for patients with MM and concurrent CLL, with a portion of patients able to achieve durable responses. A lower ORR was observed after first-line CPI; however, the number of patients in this group is small, and 33% of them had received prior treatments. Further studies are needed to determine if concurrent treatment for CLL could improve the efficacy of treatment with CPIs by reducing some of the disease-related immunodysfunction.

Patient-Specific Lymphocyte Loss Kinetics as Biomarker of Spleen Dose in Patients Undergoing Radiation Therapy for Upper Abdominal Malignancies

PurposeRadiation therapy (RT)–induced lymphopenia (RIL) is linked with inferior survival in esophageal and pancreatic cancers. Previous work has demonstrated a correlation between spleen dose and RIL risk. The present study correlates spleen dose-volume parameters with fractional lymphocyte loss rate (FLL) and total percent change in absolute lymphocyte count (%ΔALC) and suggests spleen dose constraints to reduce RIL risk. Methods and MaterialsThis registry-based study included 140 patients who underwent RT for pancreatic (n = 67), gastroesophageal (n = 61), or biliary tract (n = 12) adenocarcinoma. Patient-specific parameters of lymphocyte loss kinetics, including FLL and %ΔALC, were calculated based on serial ALCs obtained during RT. Spearman’s rho was used to correlate spleen dose-volume parameters with %ΔALC, end-treatment ALC, and FLL. Multivariable logistic regression was used to identify predictors of ≥grade 3 and grade 4 RIL. ResultsSpleen dose-volume parameters, including mean spleen dose (MSD), all correlated with %ΔALC, end-treatment ALC, and FLL. Controlling for baseline ALC and planning target volume (PTV), an increase in any spleen dose-volume parameter increased the odds of developing ≥grade 3 lymphopenia. Each 1-Gy increase in MSD increased the odds of ≥grade 3 RIL by 18.6%, and each 100-cm3 increase in PTV increased the odds of ≥grade 3 lymphopenia by 20%. Patients with baseline ALC < 1500 cells/μL had a high risk of ≥grade 3 RIL regardless of MSD or PTV. FLL was an equally good predictor of ≥grade 3 lymphopenia as any spleen dose-volume parameter. ConclusionsIn patients undergoing RT for upper abdominal malignancies, higher spleen dose is associated with higher per-fraction lymphocyte loss rates, higher total %ΔALC, and increased odds of severe lymphopenia. Spleen dose constraints should be individualized based on baseline ALC and PTV size to minimize RIL risk, although our findings require validation in larger, ideally prospective data sets.

Efficacy of immune checkpoint inhibitors for the treatment of metastatic melanoma (MM) in patients with concurrent chronic lymphocytic leukemia (CLL).

e22044 Background: Patients with CLL have immune impairment with abnormalities in T-cell subset composition and immune synapse formation. The impact of these defects on response to immune checkpoint inhibitors (CPI) is not known. Given the high incidence of melanoma in patients with CLL we sought to evaluate the response to CPI in patients with concomitant MM and CLL. Methods: Retrospective analysis of 24 patients (pts) with concurrent CLL and MM who received a total of 38 CPI therapies between July 1997 and July 2019. Primary objective was to determine objective response rate (ORR), defined as complete response (CR) or partial response (PR) by RECIST1.1. Secondary outcomes included event-free survival; overall survival (OS), and duration of response (DOR). Results: The median age at CLL and melanoma diagnosis was 62 and 63 years, respectively. 71% of patients were male. Most presented with early stage CLL at diagnosis (67%), 60% had mutated IGVH, and 47% had deletion of 13q by FISH. 71% remained on observation for their CLL. Median time from melanoma diagnosis to CPI initiation was 13.5 months. 83% had stage IV MM and 17% stage III MM at the time of therapy. 17% had increased LDH. The most common melanoma mutations were BRAF(35%), BRAFV600 (26%), TP53 (30%) and NRAS (26%). Median follow up was 37 months and the ORR was 24% (Table). Median DOR was 41 months and median OS is 26.4 months. Immune-mediated adverse events occurred in 42%, including 13% fever, 11% thrombotic events, 8% endocrine dysfunction. 13 pts are alive and 11 pts died (8 pts due to MM progression). There were no significant changes in absolute lymphocyte counts during CPI therapy. 2 pts received CPI while on ibrutinib or ibrutinib+venetoclax therapy with ongoing CLL responses. Conclusions: Our experience indicates that CPIs can be effective for the treatment of MM in patients with concurrent CLL, achieving durable responses. Immuno-mediated toxicities were frequently observed. A lower ORR was observed in first-line CPI in MM, however the numbers of pts are small. Further studies are needed to determine if initial or concurrent treatment for CLL could improve CPI outcomes and survival. Additional studies evaluating T cells function and tissue infiltration in these patients are ongoing. [Table: see text]

Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of Intravenous Siponimod: A Randomized, Open-label Study in Healthy Subjects

PurposeThe goal of this study was to assess the safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of intravenous (IV) siponimod in healthy subjects. MethodsThis randomized, open-label study was conducted in 2 parts. In Part 1, a total of 16 eligible subjects received either a single oral dose of siponimod (0.25 mg) followed by a single IV infusion (0.25 mg/3 h) in Sequence 1, or vice versa in Sequence 2. In Part 2, a total of 17 eligible subjects received single IV infusions of siponimod (1 mg/24 h). FindingsNo clinically relevant effect on mean 5-minute or hourly average heart rate was observed following the siponimod IV dosing regimens and both remained above 50 beats/min. Observed atrioventricular blocks and sinus pauses were asymptomatic. The mean change in absolute lymphocyte count from baseline was comparable for the siponimod 0.25 mg oral regimen and the two IV siponimod regimens. Oral siponimod displayed a good absolute bioavailability of 84%. The mean peak exposure of oral siponimod was approximately 48% lower than that of IV siponimod. The M17 metabolite was found to be the most prominent systemic metabolite of siponimod in humans. ImplicationsSiponimod IV infusions were well tolerated, with safety and PD (absolute lymphocyte count) profiles similar to those of oral siponimod. The PD/PK findings supported the development of an innovative rapid IV titration regimen for patients with intracerebral hemorrhage.

Association of pre-surgery to pre-radiotherapy lymphocyte counts ratio with disease-free survival in rectal cancer patients receiving neoadjuvant concurrent chemoradiotherapy

BackgroundColorectal cancer is the fourth most common cancer globally and neoadjuvant concurrent chemoradiotherapy (nCRT) and surgery are the standard treatments for locally advanced colorectal carcinoma. This study investigated the association between dynamic changes in absolute lymphocyte counts (ALCs) and disease-free survival (DFS) in rectal cancer patients receiving nCRT and identified factors associated with these changes.MethodsWe retrospectively examined 34 patients with locally advanced rectal cancer who received nCRT followed by surgery and adjuvant chemotherapy. The association between ALCs and DFS and that between ALCs and downstaging were analyzed and potential clinical- and treatment-related factors related to dynamic changes in ALCs were subsequently evaluated. The patient eligibility criteria were as follows: pathologically confirmed rectal adenocarcinoma, clinical stages II–III, ≥ 18 years of age, and so on. Pre-RTL was defined as ALCs obtained before the initiation of nCRT and pre-SL was defined as ALCs obtained before surgery. We measured pre-SL to pre-RTL ratio (pre-SLR), DFS, and ALCs.ResultsThe median ALC declined significantly during nCRT. A lower pre-SLR was associated with poorer DFS with statistical significance in Kaplan–Meier (p = 0.007), univariate regression (hazard ratio [HR] = 6.287, 95% confidence interval [CI] 1.374–28.781, p = 0.018), and multivariable regression (HR = 7.347, 95% CI 1.595–33.850, p = 0.011) analyses. Neither patient characteristics nor treatment-related factors were related to downstaging. The pelvic bone marrow (PBM) volume receiving at least 30 Gy (V30) was significantly associated with pre-SLR in the univariate (HR = 5.760, 95% CI 1.317–25.187, p = 0.020) and multivariable (HR = 5.760, 95% CI 1.317–25.187, p = 0.020) regression analyses.LimitationsOur study had several limitations. The sample size was small and the study was performed in a selected population, which may limit the generalization of the findings.ConclusionsRadiotherapy had a profound impact on the change in ALCs. A lower pre-SLR was significantly associated with poorer DFS in rectal cancer patients receiving nCRT. The V30 of PBM was a predictor of pre-SLR.

Impact of Palliative Radiation on Lymphocyte Count and Neutrophil-to-Lymphocyte Ratio in Patients Receiving PD-1 Inhibitors

Immune checkpoint inhibitors (ICI) are increasingly used in patients receiving palliative radiation (RT). However, studies suggest that RT, and particularly protracted RT courses, may decrease circulating lymphocytes, which could adversely impact ICI efficacy. We therefore evaluated circulating lymphocytes in a contemporary cohort of melanoma, non-small cell lung cancer and renal cell carcinoma patients treated with ICI and radiation. We reviewed consecutive patients treated with palliative RT and ICI. We recorded absolute lymphocyte count (ALC), neutrophil count, and neutrophil to lymphocyte ratio (NTL) before and after palliative RT, and start of ICI. Patients who received other intervening systemic therapy were excluded. Survival was analyzed using the Kaplan-Meier method and log-rank tests. Chi-squared and non-parametric tests evaluated differences between groups. We identified 110 patients treated with PD-1 inhibitors; 38 also received CTLA-4 inhibitors (23 sequentially, 15 concurrently). The most common site irradiated was the brain (71 patients, 120 courses, 40% SRS). Among all patients, median change in ALC (dALC) and NTL (dNTL) after RT was -161 and 0.8, respectively. Changes were more pronounced after extracranial RT (dALC -384 vs. -48 for brain-directed RT p=0.01, dNTL 0.2 vs. 2.5, p=0.001), RT to the spine, lung, or chest wall vs. brain, extremity, or abdomen/pelvis (dALC -438, -384 or -470 vs. 252, 204, or -7, p=0.002, dNTL 11.6, 15.8 or 10.8 vs. 0.2, 1.2, or 3.4, p=0.05) or RT courses >5 fractions (dALC -328 vs. -11 p=0.003, dNTL 1.6 vs. 0.05, p=0.02). The association of dALC with >5 fractions RT remained significant after excluding brain-directed RT (dALC -443 vs. -26, p=0.01, dNTL 2.7 vs. 0.03, p=0.09), but not in brain-directed RT patients (dALC -128 vs 11, p=0.5, dNTL 0.5 vs 0.1, p=0.97). There was no association between timing of RT in relation to ICI on dALC and dNTL. Median survival (MS) was 319 days from PD-1 therapy onset. ALC<500 and NTL>4 at PD-1 therapy onset was associated with decreased MS (359 vs. 100 days, p<.0001, and 472 vs 250 days, p=0.01, respectively). In a MVA correcting for performance status and serum albumin, this association of ALC with survival persisted (HR 2.3, p=0.01). RT before PD-1 therapy onset was associated with ALC<500 or NTL>4 at onset when RT was extracranial (OR 3.9, p=0.0008 and 2.4, p=0.02) or >5 fractions (OR 2.9, p=0.01 and 2.3, p=0.03). There was no such association with RT performed after initiation of PD-1 therapy. Among RT patients treated <30d prior to PD-1 therapy, dALC after RT was associated with decreased MS (p=0.009). In a contemporary cohort of patients treated with palliative RT and PD-1 inhibitors, we confirm that RT can decrease ALC and increase NTL, particularly extracranial RT and more protracted regimens. These parameters are associated with worse outcomes following treatment with ICI, suggesting the need for further optimization of combined RT/ICI regimens.

The Impact of Radiation Therapy on Lymphocyte Count and Survival in Metastatic Cancer Patients Receiving PD-1 Immune Checkpoint Inhibitors

Therapeutic radiation has conflicting immune effects: radiation therapy (RT)-induced immunogenic cell death can contribute to immune response, but lymphocytes are also sensitive to RT. It is unknown whether palliative RT leads to lymphopenia in patients treated with immune checkpoint inhibitors (ICIs) and whether this affects outcomes. As such, we sought to assess the impact of palliative RT on circulating lymphocyte count and neutrophil-to-lymphocyte ratio in patients being treated with PD-1-directed ICI and associations with survival. We identified patients from 5 radiation oncology centers, treated with palliative RT and either pembrolizumab or nivolumab with non-small cell lung cancer, metastatic melanoma, and renal cell carcinoma. Patients who received intervening cytotoxic chemotherapy were excluded. We recorded absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratio before and after palliative RT and at the start of ICI. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazard models. One hundred ten patients received 225 courses of palliative RT. Median change in ALC after RT was -161cells/mL. Decreases in ALC were greater with RT to the spine, lung/mediastinum, and chest wall compared with the brain, extremity, or abdomen/pelvis (P=.002) and after courses >5 fractions (P=.003). Extracranial and >5-fraction RT was associated with increased odds of severe lymphopenia (ALC <500) at the end of RT (odds ratio [OR], 3.7; P=.001; and OR, 3.9; P=.001, respectively). Patients who developed RT-induced severe lymphopenia were more likely to have severe lymphopenia when ICI was initiated (OR, 6.4; P=.0001), particularly when RT was administered in the previous 3months (OR, 189; P<.0001). Severe lymphopenia at onset of ICI therapy was associated with increased mortality on multivariable analysis (hazard ratio, 2.1; P=.03). Extracranial or prolonged courses of RT increase the risk of severe lymphopenia, which is associated with poorer survival in patients treated with ICI.

Absolute Lymphocyte Count in Preoperative Chemoradiotherapy for Rectal Cancer: Changes Over Time and Prognostic Significance.

We analyzed the changes in absolute lymphocyte count and its changes over time in 139 patients treated with preoperative chemoradiotherapy for locally advanced rectal cancer. The baseline absolute lymphocyte count was defined as the median of absolute lymphocyte count levels measured during 30 days before preoperative chemoradiotherapy. Absolute lymphocyte count at 1 month, 0.5 to 1 year, 1 to 2 years, and 2 to 3 years were determined by the median values of the absolute lymphocyte counts during the respective periods. Absolute lymphocyte count decreased after delivering preoperative chemoradiotherapy, reached minimum level at 1 month, and then gradually increased after the completion of chemoradiotherapy. Baseline absolute lymphocyte count had significant correlations with the absolute lymphocyte count of every period (range of coefficient, 0.41-0.64, P < .001). The overall survival of the group with high baseline absolute lymphocyte count was significantly higher than that of the group with low baseline absolute lymphocyte count (5-year overall survival: 82.4% vs 62.9%, P = .012). In multivariable analyses, the baseline absolute lymphocyte count remained as a significant prognostic factor for overall survival, favoring the group with a high baseline absolute lymphocyte count (hazard ratio = 0.405, P = .017). This study showed that the level of baseline absolute lymphocyte count was an independent prognostic factor, and it correlated with the absolute lymphocyte counts across varying periods of treatments and follow-up in patients treated with preoperative chemoradiotherapy for rectal adenocarcinoma.

Absolute lymphocyte and neutrophil counts in neonatal ischemic brain injury.

Objectives:This study aimed to identify differences in absolute neutrophils, lymphocytes, and neutrophil-to-lymphocyte ratio between neonates with two forms of ischemic brain injury, hypoxic-ischemic encephalopathy, and acute ischemic stroke, compared to controls. We also aimed to determine whether this neutrophil/lymphocyte response pattern is associated with disease severity or is a consequence of the effects of total-body cooling, an approved treatment for moderate-to-severe hypoxic-ischemic encephalopathy.Methods:A retrospective chart review of 101 neonates with hypoxic-ischemic encephalopathy + total-body cooling (n = 26), hypoxic-ischemic encephalopathy (n = 12), acute ischemic stroke (n = 15), and transient tachypnea of the newborn (n = 48) was conducted; transient tachypnea of the newborn neonates were used as the control group. Absolute neutrophil count and absolute lymphocyte count at three time-intervals (0–12, 12–36, and 36–60 h after birth) were collected, and neutrophil-to-lymphocyte ratio was calculated.Results:Hypoxic-ischemic encephalopathy + total-body cooling neonates demonstrated significant time-interval-dependent changes in absolute lymphocyte count and neutrophil-to-lymphocyte ratio levels compared to transient tachypnea of the newborn and acute ischemic stroke patients. Pooled analysis of absolute lymphocyte count for neonates with acute ischemic stroke and hypoxic-ischemic encephalopathy (not hypoxic-ischemic encephalopathy + total-body cooling) revealed that absolute lymphocyte count changes occurring at 0–12 h are likely due to disease progression, rather than total-body cooling treatment.Conclusion:These data suggest that the neutrophil/lymphocyte response is modulated following neonatal ischemic brain injury, representing a possible target for therapeutic intervention. However, initial severity of hypoxic-ischemic encephalopathy among these patients could also account for the observed changes in the immune response to injury. Thus, additional work to clarify the contributions of cooling therapy and disease severity to neutrophil/lymphocyte response following hypoxic-ischemic encephalopathy in neonates is warranted.

Changes in uninvolved immunoglobulins during induction therapy for newly diagnosed multiple myeloma

Little is known about the impact of multiple myeloma (MM) treatment on uninvolved immunoglobulins (Ig). We identified 448 patients who received high-dose dexamethasone (HD-DEX), lenalidomide and dexamethasone (RD), bortezomib and dexamethasone (VD), bortezomib, cyclophosphamide and dexamethasone (VCD) or bortezomib, lenalidomide and dexamethasone (VRD) for newly diagnosed MM at our institution between 2000 and 2013, and who had available data on absolute lymphocyte count (ALC) and quantitative uninvolved Ig at baseline and at the end of four cycles of therapy. Changes in ALC and uninvolved Ig were significantly different across treatments, with VCD and HD-DEX producing reductions in uninvolved Ig, and RD, VD and VRD leading to increases in uninvolved Ig. In addition, treatment with RD, VD and VRD was independently associated with higher odds of achieving a ⩾25% increase in or normalization of the primary uninvolved Ig on multivariate analysis. Although achievement of a humoral response in the primary uninvolved Ig was associated with a higher odds of achieving VGPR or better after four cycles of therapy, it was not associated with improved overall survival. These data highlight the different mechanisms of action of MM drugs and point toward a possible role for the use of VCD in treating antibody-mediated autoimmune disease.

Changes in Uninvolved Immunoglobulins during Multiple Myeloma Therapy

▪BackgroundSuppression of uninvolved immunoglobulins is a common finding in multiple myeloma and the preservation of uninvolved immunoglobulins at diagnosis is associated with improved progression-free and overall survival. However, little is known about the impact of myeloma treatment on levels of uninvolved immunoglobulins, and the link between changes in uninvolved immunoglobulins during therapy and treatment response, disease progression and survival.MethodsWe identified patients who received therapy for newly diagnosed multiple myeloma at our institution between 2001 and 2014, and who had data available on absolute lymphocyte count (ALC) and quantitative uninvolved immunoglobulins (Ig) before commencing treatment. The ALC and levels of uninvolved Ig after 4 cycles of therapy were abstracted from the electronic medical record; patients who switched or stopped treatment, or died, before this time point were excluded. To assess change in ALC, the percentage difference in ALC between baseline and 4 cycles was calculated; for uninvolved Ig, the average of the percentage difference between baseline and 4 cycles for each uninvolved Ig (IgA and IgM for IgG myeloma, IgG and IgM for IgA myeloma, IgG and IgA for IgM and IgD myeloma, and IgG, IgM and IgA for light-chain only myeloma) was calculated. Treatment response at 4 cycles was retrospectively assigned according to International Myeloma Working Group criteria. Time to treatment failure (TTF) was defined as time from start of initial therapy to start of next line of therapy or death (if no additional treatment was received). A landmark analysis was used to calculate overall survival (OS) from the date of follow-up after 4 cycles of therapy. The Kruskal-Wallis, Chi-Square, and log rank tests were used to detect differences in medians, proportions, and survival times respectively.ResultsA total of 421 patients were included in this analysis. The median age was 63 years (range 33-91), 254 patients (60.3%) were male and median follow-up was 6.5 years (95% CI 5.6-7.3); the vast majority of patients had IgG (n=247 [58.7%]), IgA (n=98 [23.3%]) or light-chain only myeloma (n=68 [16.2%]). First line therapy comprised of pulse-dose dexamethasone (DEX, n=92 [21.9%]), lenalidomide-dexamethasone (RD, n=176 [41.8%]), bortezomib-dexamethasone (VD, n=22 [5.2%]), bortezomib-cyclophosphamide-dexamethasone (VCD, n=84 [20.0%]), and bortezomib-lenalidomide-dexamethasone (VRD, n=47 [11.2%]).Across the entire cohort, the median change in ALC and uninvolved Ig after 4 cycles of treatment was -11.0% (range: -92.7 to +718.8) and +9.0% (-77.7 to +1094.4) respectively; treatment with VCD was associated with the greatest median declines in ALC (DEX: -0.1%; RD: -9.9%; VD: -20.8%; VCD: -40.9%; VRD: -15.3%) and uninvolved Ig (DEX: -0.5%; RD: +15.5%; VD: +44.0%; VCD: -14.0%; VRD: +76.0%, both p<0.001). Conversion from suppression to normalization of the primary uninvolved Ig (IgA in IgG myeloma, and IgG in all other myeloma types) after 4 cycles was seen more frequently with the use of RD (13.1%) and VRD (12.8%) compared to DEX (4.7%), VCD (1.3%), or VD (4.8%), χ2=21.8, p=0.040. When considering only patients in whom the primary uninvolved Ig remained suppressed between baseline and 4 cycles, a ≥25% reduction in the primary uninvolved Ig occurred more frequently with the use of DEX (51.5%) and VCD (34.5%) compared to RD (24.8%), VD (23.5%) or VRD (25.7%), χ2=15.1, p=0.005 (Table 1).Although an average reduction in uninvolved Ig between baseline and 4 cycles (ΔIg<0) was independently associated with a lower likelihood of achieving very good partial response (VGPR) of better on multivariate analysis adjusting for age, sex and treatment regimen (OR=0.40 [0.24-0.63], p<0.001), there were no differences in TTF (2.0yrs vs. 2.0yrs, p=0.783) or OS (8.0yrs vs. 8.0yrs, p=0.721) between patients with ΔIg<0 (n=169) and those with ΔIg≥0 (n=222).ConclusionsMyeloma treatments produce differential impacts on immune parameters, with VCD causing the greatest reduction in lymphocytes and uninvolved Ig, implying general targeting of plasma cells, in comparison to lenalidomide, which appeared to be more tumor-specific with relative sparing of lymphocytes and uninvolved Ig. While an average decrease in uninvolved Ig was an independent predictor of a lower likelihood of achieving VGPR or better after 4 cycles of therapy, it was not associated with a shorter TTF or poorer OS. [Display omitted] DisclosuresKumar:BMS: Consultancy; Glycomimetics: Consultancy; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Kesios: Consultancy; Millennium: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Research Funding. Dispenzieri:GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding; Jannsen: Research Funding; Alnylam: Research Funding; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:Amgen: Research Funding; Celgene: Research Funding; Takeda: Research Funding. Bergsagel:Amgen, BMS, Novartis, Incyte: Consultancy; Novartis: Research Funding.

Highlights of This Issue

Martens and colleagues describe changes in circulating immune cells in metastatic melanoma patients treated with ipilimumab, a CTLA-4 inhibitor, and the impact on clinical outcome. Routine blood counts of T cells, Tregs, and MDSCs were performed in an international cohort of 82 melanoma patients. Changes in absolute lymphocyte counts, CD4+ T cells, and CD8+ T cells were associated with overall survival and clinical response. Increases in all three cell populations identified patients with excellent outcome. These changes reflect the positive mode of action of ipilimumab, underline the importance of the specific T cell response for immunologic tumor control, and represent surrogate marker candidates for outcome.Somatic mutations in the tyrosine kinase domain of HER2 may be an alternative mechanism to HER2 activation and affect breast cancer sensitivity toward HER2-targeted therapies. In this study by Zuo and colleagues, 1,248 primary tumors and 18 paired metastatic samples were sequenced for HER2 mutations. Functional analysis found that HER2 negative breast cancer with novel activating mutations may benefit from HER2-targeted therapies, while HER2-positive tumors harboring novel resistance mutations did not. These findings will help illustrate the potential clinical implications of HER2 somatic mutations and assist in identifying patients who would benefit from HER2-targeted therapies in choosing the most beneficial treatment.Lenalidomide, thalidomide and pomalidomide (LTP) are immunomodulatory agents for the treatment of multiple myeloma; however, they may increase the incidence of secondary primary malignancies, particularly with lenalidomide use in the maintenance setting. Jones and colleagues show that LTP are able to stimulate the Epstein-Barr virus (EBV) lytic cycle, both in vitro and in vivo, primarily by activating phosphoinositide 3-kinase signaling. This provides a potential mechanism through which use of LTP in immunocompromised patients could promote the development of EBV-associated malignancies, such as Hodgkin disease, through immune suppression, and could also provide a new approach for EBV-related cancers in combination with ganciclovir.Lumican is an extracellular matrix protein whose presence with primary pancreatic ductal adenocarcinoma (PDAC) tumors is associated with improved patient outcome. Kang and colleagues find that activated pancreatic stellate cells isolated from primary PDAC tumors secrete large amounts of lumican that augment adhesion and migration of activated pancreatic stellate cells in a collagen-rich environment. TGF-β inhibits lumican transcription and secretion in activated stellate cells through its canonical signaling pathway and binding of SMAD4 to novel SMAD-binding elements. These findings underscore the influential role of lumican within the stroma of localized PDAC and its impact on tumor biology and patient outcome.

Abstract 5261: Prognosis of baseline absolute lymphocyte count (ALC) and neutrophil to lymphocyte ratio (NLR) in patients with pancreatic adenocarcinoma

Abstract Introduction There are no established prognostic biomarkers in pancreatic adenocarcinoma (PDAC). ALC and NLR have recently been of considerable interest in a variety of cancers including pancreatic cancer as a potential prognostic biomarker. In this single institution, retrospective study, we evaluated ALC and NLR as prognostic indicators for pancreatic cancer. Methods: We performed a retrospective chart review of patients diagnosed at LSU Health Shreveport with PDAC from Jan 1, 2000 to December 31, 2010. Various clinical, laboratory, imaging and treatment data were recorded. NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. Results A total of 152 patients had analyzable data. Median overall survival across all patients examined was 5.34 months. Univariate COX analysis showed hazard ratio favorable for patients with early stage pancreatic cancer, better performance status, those who received chemo-radiation and surgery, ALC ≥ 1000 and NLR &amp;lt; 10 (table 1). Hazard ratio for NLR ≥10 vs &amp;lt;10 was 2.575 (CI 1.50-4.39) on multivariate analysis (table 1). Median Overall Survival (OS) for subjects with NLR ≤10 = 5.65 months in comparison to 1.68 months for those with NLR over &amp;gt;10 (P = 0.001). Median OS for subjects with ALC ≤999 = 2.47 months compared to those with ALC &amp;gt;1000 = 6.02 months (P &amp;lt; 0.001). Table 1.Univariate &amp; multivariate analysis of hazard ratios of survival with respect to various clinical characteristics in patients with pancreatic adenocarcinoma.Univariate analysisRisk factorsHRP valueStage 1 or 2 vs Stage 3 or 40.520.0035African American vs caucacian0.8660.4051Insurance vs No Insurance1.3750.1544Female vs Male1.1660.3834Bilirubin Elevated No vs Yes1.2840.1871Chemo Radiation No vs Yes2.2280.0055Surgery No vs Yes1.7770.0078Tobacco No vs Yes1.1160.6096Performance Status ≤2 vs &amp;gt; 20.4130.0012agex ≤ 60 vs &amp;gt;600.980.9063Absolute Lymphocyte count ≤ 999 vs &amp;gt;9992.2240.001NlLR ≥ 10 vs &amp;lt;102.2540.0015Multivariate analysisHRConfidence IntervalPerformance Status ≤2 vs &amp;gt; 20.3080.173 - 0.548Stage 1 or 2 vs Stage 3 or 40.4910.272 - 0.884NlLR ≥ 10 vs &amp;lt;102.5751.508 - 4.398CA199 ≤200 vs &amp;gt; 2000.9880.632 - 1.544 Conclusion: ALC and NLR are routinely performed laboratory tests which are inexpensive and have prognostic value in pancreatic cancers. The biological mechanisms underlying changes in ALC and NLR needs further exploration and could be a potential area for translational research. Citation Format: Kartik Anand, Erkut Borazanci, Sachin Pai, Runhua Shi, Syed H. Jafri, Glenn Mills. Prognosis of baseline absolute lymphocyte count (ALC) and neutrophil to lymphocyte ratio (NLR) in patients with pancreatic adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5261. doi:10.1158/1538-7445.AM2015-5261

Addition of Rituximab Abrogates Ibrutinib-Induced Lymphocytosis and Promotes More Rapid Decrease in Absolute Lymphocyte Counts in Patients with Relapsed Chronic Lymphocytic Leukemia

Introduction: The Bruton tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) has proved to be an effective targeted therapy in patients with chronic lymphocytic leukemia (CLL). A multicenter phase Ib/II study of ibrutinib in 85 patients with relapsed CLL or small lymphocytic lymphoma (SLL) showed the overall response rate of 71% with an additional 15 to 20% of patients having a partial response with lymphocytosis. A phase II trial of ibrutinib in combination with rituximab in 40 high-risk CLL patients conducted at MD Anderson Cancer Center demonstrated an overall response rate of 95%. However efficacy of ibrutinib in combination with rituximab vs. ibrutinib alone has not been directly compared. A randomized study of ibrutinib vs. ibrutinib+rituximab in patients with relapsed CLL was designed to compare long-term progression free survival rate in two groups (NCT02007044). Here we test a hypothesis that addition of rituximab may abrogate ibrutinib-induced lymphocytosis and accelerate response of other biomarkers, including plasma levels of chemokines CCL3 (MIP-1a) and CCL4 (MIP-1b), which are known to reflect the activation status of CLL cells.Methods: Patients were randomized to ibrutinib alone (arm A) or ibrutinib plus rituximab arm (arm B). Patients on arm A were treated with ibrutinib 420 mg orally once daily continuously throughout the study. Patients randomized to arm B received ibrutinib starting at day 1 or day 2. Rituximab (375 mg/m2) was administered intravenously on days 1, 8, 15, and 22 (cycle 1), then monthly during cycles 2-6. Study inclusion required previously treated CLL/SLL or treated or untreated high-risk disease (del17p or TP53 mutation). Serial blood samples were drawn at pre-treatment, then weekly during the first month, and monthly until 5/6 months. Plasma levels of CCL3 and CCL4 were measured at pre-treatment, 1 week, 1 month, 3 months and 5 months of follow-up by ELISA. A linear mixed effects model with randomly varying intercepts and slopes was constructed for each absolute lymphocyte count (ALC) measured repeatedly over time using SAS PROC MIXED. Models included an unstructured covariance and the Kenward-Rogers degrees of freedom adjustment to take into account unequally spaced unbalanced data. Models over at least 4 months of measurements included both linear and quadratic components.Results: Accrual began in December 2013; currently 93 of 208 patients are enrolled. 45 patients (48%) were randomized to arm A and 48 (52%) to arm B.Median ALC at pre-treatment was similar on both arms (26.28 and 25.14 K/µl). A mixed model with quadratic trend was used to assess the dynamic changes in ALC during the first month of treatment. The model confirmed a curvature pattern for arm A, consistent with lymphocytosis: ALC rose immediately after initiation of treatment and then began to stabilize. In arm B, however, no statistically significant changes in ALC were observed during this initial period.To appreciate the difference between two treatment arms over a longer time period, changes in ALC were analyzed in the 52 patients who had 4 or more months of follow-up. A mixed model with a quadratic trend demonstrated ALC downward trend for both arms, with a more rapid decrease in arm B (p=0.03 for the linear component; p=0.004 for the quadratic). The curvature in ALC reflecting initial lymphocytosis was clear in arm A, but not arm B. Descriptive analysis suggested that arm B had higher percentage of patients with normal (<5 K/µl) or normalizing (<10 K/µl) ALC following 4 and 5 months of treatment.Concentration of CCL3 and CCL4 was significantly reduced after one week of treatment on both arms and remained low (Figure 1). Formal statistical comparison of CCL3 and CCL4 patterns is in process.Conclusion: In this randomized evaluation of ibrutinib vs. ibrutinib+rituximab an initial analysis suggests that addition of rituximab to ibrutinib abrogates the transient lymphocytosis and is associated with faster clearing of the bloodstream of leukemia cells in patients with relapsed CLL. Significant reduction of CCL3 and CCL4 levels was observed on both treatment arms. [Display omitted] DisclosuresKipps:Pharmacyclics: Research Funding. O’Brien:Pharmacyclics, Inc.: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Burger:Pharmacyclics: Consultancy, Honoraria, Research Funding.

Abstract 2546: Analysis of immune cell subsets in a multidrug therapeutic regimen for patients with metastatic castration-resistant prostate cancer

Abstract Purpose: To investigate the effects of docetaxel-based combination therapy with bevacizumab and dexamethasone premedication on the immune response in patients with metastatic castration-resistant prostate cancer (mCRPC). Experimental Design: We studied immune responses in 13 patients enrolled in a phase II trial at the National Cancer Institute (NCI). The study was designed as a 13 patient expansion of a previously reported phase II study to evaluate the immunologic response after 2 cycles of treatment with a docetaxel-based chemotherapy regimen including docetaxel (75 mg/m2 every 3 weeks) and bevacizumab (15 mg/kg every 3 weeks). Dexamethasone pre-medication (4 mg) was given 12 h and 1 h prior to chemotherapy, and again after 12 h. Patients were evaluated before treatment and on day 40, 3 weeks after the second cycle. We compared PBMC and serum samples collected at baseline and after 40 days of treatment. We investigated CD4+ and CD8+ T-cells and regulatory T-cells (CD4+ CD25hi CD127- FoxP3+) by flow cytometry. T-cell proliferation, as well as NK-cell functional activity, was evaluated. Serum samples were analyzed for levels of cytokines, chemokines, sCD27, sCD40L and vascular endothelial growth factor (VEGF). Results: The baseline characteristics were: median age 64 years, Gleason score 9, PSA 100 ng/ml, and Halabi Predicted Survival 10.6 months. Patients had a median PSA decline of 66% after 2 cycles. The median TTP was 14.1 months, and OS 18.7 months. At 3 weeks after the second cycle we found no significant changes in absolute lymphocyte count, CD4+ and CD8+ T-cell proliferation and NK-cell function. The number of CD4+ T-cells decreased. CTLA4+ regulatory T-cells did not change. There was no change in the serum levels of IL-6, IL-8, IL-10 and TNFα. As expected, the serum levels of VEGF decreased substantially after therapy. The serum levels of sCD40L did not change after treatment. Interestingly, an increase in the serum level of sCD27 correlated with longer OS (P= 0.037, R= 0.58). Conclusions: Treatment of mCRPC patients with docetaxel-based combination therapy with bevacizumab and dexamethasone premedication for 40 days did not alter the immune response in a way that would decrease the likelihood of successful immunotherapy, either before or after this treatment. Citation Format: Caroline Jochems, Benjamin Boyerinas, Ravi A. Madan, Diane J. Poole, Yang-Min Ning, William D. Figg, David J. Liewehr, Seth M. Steinberg, James L. Gulley, Kwong-Yok Tsang, Jeffrey Schlom. Analysis of immune cell subsets in a multidrug therapeutic regimen for patients with metastatic castration-resistant prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2546. doi:10.1158/1538-7445.AM2014-2546

Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study

Ibrutinib and other targeted inhibitors of B-cell receptor signaling achieve impressive clinical results for patients with chronic lymphocytic leukemia (CLL). A treatment-induced rise in absolute lymphocyte count (ALC) has emerged as a class effect of kinase inhibitors in CLL and warrants further investigation. We here report correlative studies in 64 patients with CLL treated with ibrutinib. We quantified tumor burden in blood, lymph nodes, spleen, and bone marrow, assessed phenotypic changes of circulating cells, and measured whole blood viscosity. With just one dose of ibrutinib the average increase in ALC was 66%, and in over 40% of patients the ALC peaked within 24 hours of initiating treatment. Circulating CLL cells on day 2 showed increased Ki67 and CD38 expression, indicating an efflux of tumor cells from the tissue compartments into the blood. The kinetics and degree of the treatment-induced lymphocytosis was highly variable; interestingly in patients with a high baseline ALC the relative increase was mild and resolution rapid. After two cycles of treatment the disease burden in lymph node, bone marrow, and spleen decreased irrespective of the relative change in ALC. Whole blood viscosity was dependent on both ALC and hemoglobin. No adverse events were attributed to the lymphocytosis.

THU0252 Relationship between Lymphocyte Count and Risk of Infection in Rheumatoid Arthritis Patients Treated with Tofacitinib

BackgroundTofacitinib is a novel oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). Cytokines (e.g., interleukin (IL)-2, -4, -7, -15, -21) involved in lymphocyte development, function and...

Pharmacodynamic effect of ipilimumab on absolute lymphocyte count (ALC) and association with overall survival in patients with advanced melanoma.

9052 Background: Ipilimumab (Ipi) is a fully human monoclonal antibody that augments antitumor T-cell responses. Ipi has been shown to improve overall survival (OS) in 2 phase (ph) III trials of advanced melanoma, as monotherapy at 3 mg/kg in previously treated patients (pts) (MDX010-20) or at 10 mg/kg with dacarbazine in previously untreated pts (CA184-024). In preclinical and clinical studies, inhibition of CTLA-4 by Ipi resulted in increases in activation and proliferation of peripheral T cells and increases in ALC. Baseline ALC may be a prognostic biomarker in several cancer types. The current analyses aim to increase understanding of changes in ALC with Ipi treatment and association of these changes with OS. Methods: Data were from 6 studies of Ipi with chemotherapy (CT) (ph I 078; N=59) or without CT (ph III MDX010-20; ph II trials 004, 007, 008, and 022; N=1203), and Ipi monotherapy in an Expanded Access Program (N=117) or with commercially available Ipi (N=71) or BRAF inhibitors (N=39). ALC was measured at baseline, prior to each dose during induction (weeks 1, 4, 7, and 10) and at the end of induction (week 13). Cox proportional hazards models were used to estimate and test associations between ALC measures and OS. Results: In all studies, mean ALC increased significantly over time in pts who received Ipi, with or without CT (P&lt;.0001 to P=.03). There was no significant mean increase in ALC in pts who received gp100 or BRAF-inhibitor monotherapy. In study MDX010-20, pts with a greater rate of change in ALC from baseline to week 7 tended to have longer OS (P=.0003). A similar association was found between OS and ALC ≥1000/µL after 2 Ipi doses. However, pts in MDX010-20 had an OS benefit from Ipi relative to gp100, regardless of rate of change in ALC (P=.14). Conclusions: In these analyses, consistent with inhibition of CTLA-4, Ipi induced an increase in mean ALC, even with the addition of CT. A positive association between rate of ALC increase and OS was observed, but this was not specifically predictive of OS benefit from Ipi. Therefore, ALC cannot currently be used to guide clinical management with Ipi. However, further prospective investigation may be warranted.