Serial Lymphocyte Counts Research Articles

Severe Treatment-Related Lymphopenia in Patients with Newly Diagnosed Rectal Cancer

Background: Although treatment-related lymphopenia (TRL) is common in many cancers no data exists in rectal cancer. Methods: Serial lymphocyte counts were analyzed retrospectively in patients with newly diagnosed rectal cancer, serial blood counts, and complete records at Johns Hopkins Hospital. Results: Fifty-seven patients with normal pretreatment lymphocyte counts were studied. Two months after beginning chemoradiation, 35% of these patients developed grade III-IV lymphopenia [median lymphocyte counts fell from 1590 to 490 cell/mm3 (p < 0.001)] which persisted throughout one year of observation. Conclusion: Severe and prolonged TRL is common in rectal cancer. Further studies are required to determine TRL’s relationship to survival.

The Immune Phenotype of Patients with CHARGE Syndrome

Recurrent sinopulmonary infections are common in children with CHARGE (Coloboma, Heart disease, choanal Atresia, growth/mental Retardation, Genitourinary malformations, Ear abnormalities) syndrome, but no prospective studies on immune function have been conducted. This study aims to examine and compare the immune phenotype of patients with CHARGE syndrome to those with 22q11.2 deletion and healthy controls. A total of 21 patients attended a multidisciplinary CHARGE clinic. All patients had CHD7 mutational analysis performed. Patients with CHARGE syndrome had lymphocyte subsets, immunoglobulins (IgG, A, M), functional protein, and polysaccharide vaccine responses measured at initial evaluation. A total of 55 healthy controls were prospectively recruited, whereas 40 patients with 22q11.2 deletion were retrospectively identified through medical records. A separate analysis compared serial lymphocyte counts and ionized calcium levels between patients with CHARGE syndrome and those with 22q11.2 deletion in the first 72 months of life. Despite recurrent childhood ear and chest infections, only 2 children with CHARGE syndrome had an identifiable immune defect (reduced serum IgA). In contrast, T-cell lymphopenia, low immunoglobulin levels, and specific antibody deficiency were noted in patients with 22q11.2 deletion. A greater proportion of patients with 22q11.2 deletion had persistent lymphopenia (57% vs 30%) and hypocalcemia (60% vs 37.5%) compared with patients with CHARGE syndrome in the first 72 months of life. Although phenotypic overlap exists between CHARGE and 22q11.2 deletion syndromes, no significant immune defects were detected in this cohort of patients with CHARGE syndrome at the time of testing. Lymphopenia and hypocalcemia occur in both conditions early in life, but is more pronounced in patients with 22q11.2 deletion.

Survival in Patients With Severe Lymphopenia Following Treatment With Radiation and Chemotherapy for Newly Diagnosed Solid Tumors.

The immune system plays an important role in cancer surveillance and therapy. Chemoradiation can cause severe treatment-related lymphopenia (TRL) (<500 cells/mm3) that is associated with reduced survival. Data from 4 independent solid tumor studies on serial lymphocyte counts, prognostic factors, treatment, and survival were collected and analyzed. The data set included 297 patients with newly diagnosed malignant glioma (N=96), resected pancreatic cancer (N=53), unresectable pancreatic cancer (N=101), and non-small cell lung cancer (N=47). Pretreatment lymphocyte counts were normal in 83% of the patient population, and no patient had severe baseline lymphopenia. Two months after initiating chemoradiation, 43% developed severe and persistent lymphopenia (P=.001). An increased risk for death was attributable to TRL in each cancer cohort (gliomas: hazard rate [HR], 1.8; 95% CI, 1.13-2.87; resected pancreas: HR, 2.2; 95% CI, 1.17-4.12; unresected pancreas: HR, 2.9; 95% CI, 1.53-5.42; and lung: HR, 1.7; 95% CI, 0.8-3.61) and in the entire study population regardless of pathologic findings (HR, 2.1; 95% CI, 1.54-2.78; P<.0001). Severe TRL was observed in more than 40% of patients 2 months after initiating chemoradiation, regardless of histology or chemotherapy regimen, and was independently associated with shorter survival from tumor progression. Increased attention and research should be focused on the cause, prevention, and reversal of this unintended consequence of cancer treatment that seems to be related to survival in patients with solid tumors.

Kinetics of CLL cells in tissues and blood during therapy with the BTK inhibitor ibrutinib

AbstractThe Bruton tyrosine kinase (BTK) inhibitor ibrutinib has excellent clinical activity in patients with chronic lymphocytic leukemia (CLL). Characteristically, ibrutinib causes CLL cell redistribution from tissue sites into the peripheral blood during the initial weeks of therapy. To better characterize the dynamics of this redistribution phenomenon, we correlated serial lymphocyte counts with volumetric changes in lymph node and spleen sizes during ibrutinib therapy. Kinetic parameters were estimated by applying a mathematical model to the data. We found that during ibrutinib therapy, 1.7% ± 1.1% of blood CLL cells and 2.7% ± 0.99% of tissue CLL cells die per day. The fraction of the tissue CLL cells that was redistributed into the blood during therapy was estimated to be 23.3% ± 17% of the total tissue disease burden. These data indicate that the reduction of tissue disease burden by ibrutinib is due more to CLL cell death and less to egress from nodal compartments.

Abstract 1242: The association between treatment-related lymphopenia and survival in patients with solid tumors.

Abstract Background: This retrospective review was conducted to determine: 1) the frequency and severity of treatment related lymphopenia (TRL) in solid tumors, 2) its association with survival accounting for prognostic variables, and 3) its relationship to radiation or chemotherapy. Methods: Serial lymphocyte counts (pre-treatment and monthly for one year), prognostic factors, treatment details, and survival were retrospectively reviewed in 338 newly diagnosed patients with 1) high grade glioma, 2) resected pancreatic cancer, 3) unresectable pancreatic cancer, 4) stage III lung cancer, and 5) HPV- head and neck cancer in this IRB approved study. Severe TRL was defined as grade III-IV lymphopenia (&amp;lt;500 cells/mm3). Results: The findings in each patient cohort are similar: 1) About 40% of patients develop severe TRL two months after initiating radiation and this persists for many months, 2) There is an association between TRL at two months and shorter survival from tumor progression, and 3) The hazard ratio for reduced survival is high after adjusting for known prognostic factors. Lung cancer patients treated with neoadjuvant chemotherapy did not experience TRL until after radiation was initiated. Conclusions: Severe TRL is common, severe, long-lasting and associated with earlier death from tumor progression in patients with solid tumors receiving radiation and chemotherapy. These studies suggest that radiation likely plays a major role in the development of TRL and that novel approaches to protect and/or restore immunologic function in patients with solid tumors are critical. NeoplasmTotal number patientsPatients developing grade III-IV TRLMedian Survival &amp;lt;500 vs &amp;gt;500 lymphocytes (months)Multivariate association with reduced survival:HR, (CI), pvalueHigh grade glioma9640%13 vs 19.7 (p = 0.002)OS: 1.66, (1.05–2.64), 0.03Pancreatic resected5345%14 vs 20 (p = 0.048)OS: 2.2, (1.17–4.12), 0.01Pancreatic unresectable12074%9.2 vs 14.6 (p = 0.013)OS: 1.34, (0.09–2.0), 0.15NSCLC Stage III4750%21.8 vs 28.3 (p = 0.38)OS: 1.7, (0.8–3.6), 0.17HEENT (HPV)2236%PFS onlyPFS: 6.2, (1.1–35.2), 0.04 Citation Format: Stuart A. Grossman, Susannah Yovino, Jian Campian, Aaron Wild, Joseph Herman, Daniel Laheru, Malcolm Brock, Shanthi Marur, Ani Balmanoukian, Xiaobu Ye. The association between treatment-related lymphopenia and survival in patients with solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1242. doi:10.1158/1538-7445.AM2013-1242

Treatment-related Lymphopenia in Patients With Stage III Non-Small-Cell Lung Cancer

Background: This study sought to estimate the severity, etiology, and clinical importance of treatment-related lymphopenia in patients with stage III non-small-cell lung cancer. Methods: Serial lymphocyte counts and survival were analyzed retrospectively in 47 patients accounting for known prognostic factors. Results: Total lymphocyte counts (TLCs) were normal before therapy and did not change following neoadjuvant chemotherapy. Following radiation, TLC fell by 67% (median 500 cells/mm3, p <.00001). Multivariate analysis revealed an association between severe TLC and survival (HR 1.70, 95% CI: 0.8–3.6). Conclusions: Rapid and severe lymphopenia occurred in 50% of patients following radiation which was associated with reduced survival.

Incidence, severity, and etiology of treatment-related lymphopenia in patients with stage III non-small cell lung cancer (NSCLC).

e17552 Background: Severe treatment-related lymphopenia (TRL) is associated with shorter survival in patients with glioblastoma and pancreatic cancer treated with concurrent chemotherapy and radiation (chemo/RT). This retrospective study sought to determine if patients with stage III NSCLC develop TRL and if this results from chemotherapy or radiation. Methods: Patients selected for this retrospective analysis had newly diagnosed stage III NSCLC, Karnofsky performance status &gt;60, and chemo/RT and follow-up blood counts at Johns Hopkins Hospital. Patients were divided into those who received neoadjuvant chemotherapy followed by chemo/RT and those who received only chemo/RT. Serial lymphocyte counts were analyzed. Results: Forty-six adults met the above eligibility criteria. Their median age was 62 years (range 43-79), 65% were female, 74% were stage IIIA and 26% were IIIB, 72% had adenocarcinoma, and 68% were poorly differentiated. Surgery included pneumonectomy (7%), lobectomy (43%), wedge resection (7%), or biopsy (43%). Twenty patients received neoadjuvant chemotherapy consisting of 2 cycles of taxol/carboplatin (85%) or gemcitabine/carboplatin (15%). Their mean total lymphocyte count (TLC) prior to chemotherapy was 1416 cells/mm3 (SD 899). TLC remained unchanged after the neoadjuvant chemotherapy (mean 1519, SD 553). These patients then received concurrent chemo/RT (mean dose 58.4 Gy). TLC fell 68% at two months from a mean of 1519 (SD 553) to 490 (SD 305) (p&lt;0.00001) with 55% having TLC ≤500 cells/mm3. The remaining 26 patients received only concurrent chemo/RT. Their initial TLCs were normal (mean 1807, SD 644) but two months later had fallen by 70% (mean 545, SD 397) (p&lt;0.00001) with 54% having TLC ≤500 cells/mm3. Reductions in TLCs occurred irrespective of the chemotherapy administered with RT. Conclusions: TLCs are normal in patients with newly diagnosed stage III NSCLC and are unaffected by 2 cycles of neoadjuvant chemotherapy. However, with the addition of radiation TLCs drop in ~50% of patients to levels associated with severe immunosuppression. Further studies are needed to determine if this is associated with reduced survival as reported in other malignancies.

Effect of treatment-related lymphopenia on survival in newly diagnosed patients with resected adenocarcinoma of the pancreas.

270 Background: Severe treatment-related lymphopenia is associated with shorter survival in patients with high grade gliomas. This study was performed to determine if patients with resected pancreatic adenocarcinoma treated with post-operative radiation and chemotherapy develop significant lymphopenia and if this affects overall survival. Methods: Patients selected for this retrospective analysis underwent pancreatic cancer resection between 1997 and 2008, and received post-operative radiation with gemcitabine or 5-FU based chemotherapy at Johns Hopkins Hospital. Serial lymphocyte counts were recorded and survival was analyzed as a function of lymphopenia and known prognostic factors. Results: Fifty-three adults met the eligibility criteria. Their median age was 64, median tumor size was 3 centimeters, 83% underwent a pancreaticoduodenectomy, 47% had positive margins, and 92% had positive nodes. Total lymphocyte counts were normal in 91% of patients prior to receiving radiation and concomitant chemotherapy with 5FU(59%) or gemcitabine (41%). Total lymphocyte counts fell to &lt;500 cells/mm3 in 45% of patients two months after initiating therapy with a median reduction of 63% from the baseline (p&lt;0.0001). The median survival of patients with lymphocyte counts &lt;500 cells/mm3 at 2 months was 14 months versus 20 months in patients with more lymphocytes (p=0.0485). Univariate analysis revealed no significant association between pre-treatment patient characteristics and survival. Multivariate analysis revealed a significant association between survival and lymphocyte count (&lt;500 vs ≥ 500 cells/mm3) at 2 months (HR 2.2, p = 0.014). Conclusions: Adjuvant radiation and chemotherapy induced lymphopenia is frequent, severe, and an independent predictor for survival in patients with resected pancreatic adenocarcinoma.

Effect of chemoradiation-related lymphopenia on survival in patients with unresectable, locally advanced pancreatic adenocarcinoma.

307 Background: Pancreatic ductal adenocarcinoma (PDA) has been shown to elicit antitumor cell-mediated immune responses. In high grade gliomas, treatment-related lymphopenia has been associated with shorter survival. This study was performed to determine if patients with locally advanced PDA treated with definitive chemoradiation therapy (CRT) develop significant lymphopenia and if this affects overall survival (OS). Methods: A retrospective analysis of patients with locally advanced PDA treated at a single institution with CRT from 1997-2009 was performed. Serial lymphocyte counts were recorded and OS was analyzed as a function of lymphopenia and known prognostic factors. Results: 99 patients met eligibility criteria (≥18 years of age, ECOG performance status 0-2, and had baseline/follow-up lab values measured at our institution). Mean age was 61.6 years (SD, 11.6), 55% were male, mean tumor size 4.1 cm (SD, 1.6), and 97 had stage III disease. Median pre/post-CRT CA19-9 values were 241.5 and 105.2 U/mL, respectively. Total lymphocyte counts were normal in 87% of patients prior to RT. Mean RT dose was 47.3 Gy (SD, 8.2) and concurrent chemotherapy was 5-FU (67%), gemcitabine (20%), taxotere (7%), or none (6%). Chemotherapy dose reduction was necessary in 9%, and 39% required a RT break. Total lymphocyte counts fell to ≤500 cells/mm3 in 51% two months after initiating CRT with a median reduction of 66% from baseline (p&lt;0.0001). Median OS of patients with lymphocyte counts ≤500 cells/mm3 at 2 months was 7.7 months (95% CI, 6.8-8.7) versus 15.4 (95% CI, 11.9-19.0) for patients with &gt;500 cells/mm3 (p&lt;0.001). Univariate analysis additionally revealed that among pre-treatment patient characteristics, only age ≥65 was significantly associated with OS (8.8 vs. 11.4 months; p=0.043). Type of concurrent chemotherapy was not significantly associated with OS. Multivariate analysis revealed a significant association between survival and lymphocyte count (&lt;500 vs. ≥500 cells/mm3) at 2 months post-CRT (HR 3.8, p&lt;0.001). Conclusions: Definitive CRT induced lymphopenia is frequent, severe, and appears to be an independent predictor for OS in patients with locally advanced PDA.

Factors Influencing Varicella-Zoster Virus (VZV) Infection after Allogeneic Peripheral Blood Stem Cell Transplantation: Low-Dose Acyclovir Prophylaxis and Pre-Transplant Diagnosis of Lymphoproliferative Disorders.

Introduction: Varicella-zoster virus (VZV) is a frequent opportunistic infection among long-term survivors after allogeneic stem cell transplantation with relatively high incidence of around 30 to 50%. A recent study reported that the cumulative incidence of VZV infection at 5 year reaches up to 63% after allogeneic bone marrow transplantation (Koc, BBMT 2000). It has been suggested that peripheral blood stem cell transplantation (PBSCT) may facilitate immune reconstitution compared to BMT. However, no data has been reported on VZV infection after allogeneic PBSCT. The current study attempted 1) to estimate the incidence of VZV infection, 2) to identify the risk factor for VZV infection, and 3) to analyze the clinical relevance of lymphocyte recovery on VZV infection after allogeneic PBSCT.Patients and methods: We report a retrospective analysis of VZV infection in 192 recipients of allogeneic PBSCT at Princess Margaret Hospital, Toronto, Canada transplanted between June 2001 and December 2005. The median duration of follow up among survivors was 26 months (2 to 60 months). The pre-transplant diagnoses included AML (77, 40%), ALL (18, 9%), CLL (20, 10%), CML (23, 12%), HD (2, 1%), MDS (15, 8%), myelofibrosis (10, 5%), MM (3, 2%), NHL (22, 12%), and renal cell carcinoma (2, 1%). Twenty-seven patients (14%) received long-term courses of low dose acyclovir prophyaxis (200mg bid po for more than 3 months) for recurrent oral (n=21) or genital HSV infection (n=5) after PBSCT or previous history of recurrent VZV infection before PBSCT (n=1).Results: Of 192 recipients, 42 patients (22%) developed VZV infection including localized (n=37) and disseminated infections (n=5). The cumulative incidence of VZV infection at 1, 2 and 3 years was 19.3±3.3, 27.0±4.1 and 36.8±5.2%, respectively. Eighteen patients (43%) developed post-herpetic neuralgia for 2 months' duration (1–21 months). Other complications included secondary bacterial infections (n=3) and intracranial hemorrhage complicated with visceral VZV infection (n=1). One risk factor was identified: pre-translpant diagnosis of a lymphoproliferative disorder (LPD; CLL, HD or NHL) (p=0.021, 52.5±11.7% in LPD group vs 32.6±5.7% in non-LPD group). The use of low dose acyclovir prophylaxis (p=0.007, 0.0% in acyclovir group vs 41.6±6.0% in non-acyclovir group) was found to be protective. While no VZV infection episode were noted in the patients on long-term acyclovir prophyaxis, 3 episodes of VZV infection were noted after cessation of acyclovir. Time-dependent Cox regression analysis confirmed these 2 factors as independent risk factors: 1) diagnosis of LPD (p=0.039, HR 1.965, 95% C.I. 1.033–3.731) and 2) the use of low dose acyclovir prophylaxis (p=0.048, HR 0.305 95% C.I. 0.094–0.991). However, no difference was noted between the group with and without VZV infection in serial lymphocyte counts which has been done before and 3,6,9,and 12 months after transplantation.Conclusion: The incidence of VZV infection after allogeneic PBSCT still remained quite high on 36.8% at 3 years with patients transplanted for LPDs at higher risk. The use of low dose acyclovir (200mg bid po) seemed to be protective from VZV infection, even though it may not completely prevent late VZV infection. The quantitative serial measurement of lymphocyte count could not predict the risk of VZV infection after allogeneic PBSCT.

MEDICAL MANAGEMENT OF RADIOLOGICAL CASUALTIES

Victims of radiological terrorism events require prompt diagnosis and treatment of medical and surgical conditions as well as conditions related to radiation exposure. Hospital emergency personnel should triage victims using traditional medical and trauma criteria. Radiation dose can be estimated early post-event using rapid-sort, automated biodosimetry and clinical parameters such as the clinical history, the time to emesis (TE), and lymphocyte depletion kinetics. For TE < 2 h, the effective whole-body dose is at least 3 Gy. If TE < 1 h, the whole-body dose most probably exceeds 4 Gy. Lymphocyte depletion follows dose-dependent, first order kinetics after high-level gamma and criticality incidents. Patient radiation dose can be estimated very effectively from the medical history, serial lymphocyte counts, and TE, and subsequently confirmed with chromosome-aberration bioassay, the current gold standard. These data are effectively analyzed using the Armed Forces Radiobiology Research Institute Biodosimetry Assessment Tool. The medical management of patients with acute, moderate to severe radiation exposure (effective whole-body dose >3 Gy) should emphasize the rapid administration of colony stimulating factors. All of these compounds decrease the duration of radiation-induced neutropenia and stimulate neutrophil recovery, albeit with some variability, in patients who have received myelotoxic chemotherapy, and all have demonstrated benefit in irradiated animals. For those patients developing febrile radiation-induced neutropenia, adherence to the current Infectious Diseases Society of America guidelines for high-risk neutropenia is recommended.

Early dose assessment following severe radiation accidents.

Early treatment of victims of high level acute whole-body x-ray or gamma exposure has been shown to improve their likelihood of survival. However, in such cases, both the magnitude of the exposure and the dosimetry profile(s) of the victim(s) are often not known in detail for days to weeks. A simple dose-prediction algorithm based on lymphocyte kinetics as documented in prior radiation accidents is presented here. This algorithm provides an estimate of dose within the first 8 h following an acute whole-body exposure. Early lymphocyte depletion kinetics after a severe radiation accident follow a single exponential, L(t) = L(o)e(-k(D¿t), where k(D) is a rate constant, dependent primarily on the average dose, D. Within the first 8 h post-accident, K(D) may be calculated utilizing serial lymphocyte counts. Data from the REAC/TS Radiation Accident Registry were used to develop a dose-prediction algorithm from 43 gamma exposure cases where both lymphocyte kinetics and dose reconstruction were felt to be reasonably reliable. The inverse relationship D(K) may be modeled by a simple two parameter curve of the form D = a/(1 + b/K) in the range 0 < or = D < or = 15 Gy, with fitting parameters (mean +/- SD): a = 13.6 +/- 1.7 Gy, and b = 1.0 +/- 0.20 d(-1). Dose estimated in this manner is intended to serve only as a first approximation to guide initial medical management.

PRE-ECLAMPSIA—A STATE OF MOTHER-FETUS IMMUNE IMBALANCE

Serial lymphocyte counts and function tests were done during and after pre-eclamptic pregnancies, and in the offspring. Compared with normal pregnancies, pre-eclamptic pregnancies were associated with lower B-lymphocyte counts in the fathers; lower T-lymphocyte count, lower B-lymphocyte count, and impaired T-lymphocyte function in mothers; a low response in mixed lymphocyte culture (MLC) tests between the mother and father; and an increased B-cell count in the children. Follow-up of one pre-eclamptic woman throughout pregnancy showed important immune changes at the beginning of the second trimester. These findings suggest that pre-eclampsia is caused by a combination of maternal and paternal hyporesponsiveness together with fetal hyperresponsiveness.