Median Absolute Neutrophil Count Research Articles

Machine Learning Prediction for Complete Response to Hypomethylating Agents with or without Additional Agents in Patients with Newly Diagnosed Myelodysplastic Syndrome

Machine Learning Prediction for Complete Response to Hypomethylating Agents with or without Additional Agents in Patients with Newly Diagnosed Myelodysplastic Syndrome

Incidence and Time Course of Neutropenia in Patients Treated with Rituximab-Based Therapy for Non-Malignant Immune-Mediated Hematologic Diseases

Background : Rituximab (RTX) is approved for various malignant hematologic and rheumatologic disorders. A noteworthy side effect, late-onset neutropenia, has been reported in patients (pts) treated for hematologic malignancies, often in combination therapies of RTX and chemotherapy with an incidence of 3% to 27%. Conversely, the lack of prospective data and the off-label use of RTX in non-malignant immune-mediated hematologic diseases (NMIHD) limits the availability of evidence on the rate, severity and time course of neutropenia on this patient population, particularly in RTX monotherapy. The present study was performed to determine the frequency, severity, and time course of development and resolution of neutropenia in NMIHD pts treated with RTX, with the goal of providing evidence for clinicians on the safety and potential implications of RTX use in this patient population. Methods : We retrospectively analyzed patients diagnosed with autoimmune hemolytic anemia (AIHA), acquired coagulation factor deficiency (ACFD), thrombotic thrombocytopenic purpura (TTP), immune thrombocytopenic purpura (ITP), and antiphospholipid syndrome (APS) between January 2013 and October 2017. Patients with a minimum of 1 laboratory visit every 8 weeks with 1-year of follow-up were included. Date of initial and last RTX infusion, RTX dosing and number of doses, and pre-treatment absolute neutrophil count (ANC) were obtained. ANCs were reviewed from first RTX infusion to at least 12 months from last infusion. For those pts who developed neutropenia, ANC nadir and date when ANC was 1 to 1.5 (mild), 0.5 to <1 (moderate), and <0.5 ˣ 103 cells/µL (severe neutropenia) was recorded. The time to recovery from neutropenia was determined from the time of first neutropenia occurrence to an ANC>1.5. Episodes of febrile neutropenia (FN), hospitalization, infection, and use of granulocyte-colony stimulating factor (GCSF) were also obtained. Kaplan-Meier estimators, and Log-rank Tests were applied to compare between groups. Results : 197 patients (ITP=94, TTP=34, AIHA=34, ACFD=22, APS=13) treated with RTX monotherapy (73%), or in combination with other immunosuppressant were included. Clinical features, treatment characteristics and outcomes are summarized in the table. The median age at diagnosis was 51 years (58% female) with a median ANC prior to RTX initiation of 5.6 ˣ 103 cells/µL. Most pts received RTX at 375 mg/m2 in 4 doses (83%). The 1-year estimated probability of developing neutropenia (ANC<1.5) was 18% (Figure 1). Of those who developed neutropenia, the median ANC nadir and time to neutropenia from initial RTX infusion was 1.2 ˣ 103 cells/µL and 4.4 months, respectively. Development of neutropenia was not statistically different by gender, age, hematologic disease type, or RTX dosing. However, RTX given for ≥ 4 doses (p=0.04), or in combination with other immunosuppressant different than steroids (p<0.01) were significantly associated. Severe neutropenia was frequent in pts receiving RTX in combination with other immunosuppressant (36% versus 2%) with longer time to recovery from first neutropenia occurrence to an ANC>1.5 (2.5 versus 1.1 months) (Figure 2) compared to pts receiving RTX alone or with steroids. No episodes of FN were reported, 3 pts were hospitalized for neutropenia workup, and 2 pts had documented infections (pneumonia and cellulitis) with uncomplicated clinical course. One pt, treated with 6-mercaptopurine, received GCSF. Conclusions : To the best of our knowledge, this is the first study reporting on the incidence, degree and time-course of development of neutropenia in patients treated with RTX for different NMIHD. Our analysis demonstrates an 18% rate of neutropenia at 1 year, mostly mild neutropenia. Conversely, RTX in combination with other immunosuppressant, as opposed to RTX alone or with steroids, represented a significant risk factor for the development of neutropenia, especially severe neutropenia with longer time to ANC recovery. The rate of hospitalizations, infections and the use of GCSF was low, even in severe neutropenia cases. In conclusion, development of neutropenia in pts treated with RTX for NMIHD is an expected but relatively benign side effect. Neutropenia is more frequent if RTX is given with other immunosuppressant other than steroids, and when the number of doses of RTX given are higher. Disclosures No relevant conflicts of interest to declare.

Severe Cytokine Release Syndrome Is Associated with Impaired Hematopoietic Recovery after CD19-Targeted CAR-T Cell Therapy

Background Chimeric antigen receptor therapy (CAR-T) directed against CD19 has demonstrated efficacy in patients with relapsed/refractory (R/R) B-cell malignancies. Delayed hematopoietic recovery with grade 3/4 neutropenia and thrombocytopenia, requiring extended growth factor administration or transfusions, has been observed in patients undergoing CAR-T cell therapy, although the factors influencing recovery are poorly understood. In this study, we performed multivariable analyses to identify factors associated with hematopoietic recovery in patients undergoing CD19 CAR-T cell therapy. Methods We retrospectively analyzed 125 patients with R/R acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), and chronic lymphocytic leukemia (CLL), treated with CD19-targeted CAR-T cells on a phase 1/2 clinical trial in our institution (NCT01865617). Patients receiving more than one CAR-T infusion were excluded. Criteria for neutropenia, thrombocytopenia, and recovery were defined as per the Center for International Blood and Marrow Transplant Research (CIBMTR) reporting guidelines: neutropenia, absolute neutrophil count (ANC) ≤ 500/mm3; thrombocytopenia, platelet (Plt) count ≤ 20 x 109/L; neutrophil recovery, ANC > 0.5 x 109/L for three consecutive laboratory values obtained on different days irrespective of growth factor administration; platelet recovery, Plt > 20 x 109/L for three consecutive values obtained on different days in the absence of platelet transfusion for seven days. For competing risk analysis, an event was defined as having achieved ANC or Plt recovery, with the following considered as competing events: death, new cytotoxic therapy, relapse with marrow involvement in the absence of ANC or platelet recovery. Patients who never met the CIBMTR criteria for neutropenia of thrombocytopenia were considered as having recovered at time = 0. To identify factors associated with impaired hematopoietic recovery after CD19 CAR-T cell therapy, patient-, disease- and CAR-T cell therapy-related variables were included in a multivariable Fine and Gray model prior to variable selection using LASSO penalization (Table 2 footnote). Results We included 125 patients (ALL, n=44; CLL, n=37; NHL, n=44) with a median age of 55 (range, 20-76). Patients were heavily pre-treated with a median of 4 prior therapies (range, 1-10); 31% had undergone prior autologous or allogeneic hematopoietic cell transplantation (HCT). Median ANC and Plt prior to lymphodepletion were 2 x 109/L (range 0-23) and 112 x 109/L, range 3-425), respectively. Patient and treatment characteristics are summarized in Table 1. ANC and Plt recovery after CD19 CAR-T cell therapy were observed in 91% (ALL, 86%; CLL, 92%; NHL, 95%) and 86% (ALL, 86%; CLL, 86%; NHL, 84%) of patients, respectively. Median time to ANC recovery was 9 days and the probability of ANC recovery at day 28, 60, and 90 was 80% (95%CI, 73-87), 86% (95%CI, 80-92) and 89% (95%CI, 83-94), respectively. The probability of platelet recovery on the day of CAR-T cell infusion was 55% (95%CI, 46-64); rising to 74% (95%CI, 67-82), 83% (95%CI, 76-90), and 84% (95%CI, 77-90) at day 28, 60, and 90, respectively. A competing event was always observed in patients without ANC or Plt recovery. In multivariable analysis, higher pre-lymphodepletion Plt count (HR=1.08 per 25 x 109/L increase, p=0.006) and higher peak CD8+ CAR-T cells in blood (HR=1.47 per log10 cells/µL increase, p<0.001) were associated with faster ANC recovery. ALL diagnosis and higher cytokine release syndrome (CRS) grade were associated with slower ANC recovery (CLL vs ALL, HR=1.60, p=0.02; NHL vs ALL, HR=2.07, p=0.007). Higher CRS grade was also associated with slower Plt recovery (HR=0.67 per grade increase, p<0.001). Higher pre-lymphodepletion platelet count and higher peak CD8+ CAR-T cell in blood were associated with faster platelet recovery (HR=1.08 per 25 x 109/L increase, p=0.001; HR=1.41 per log10 cells/µL increase, p<0.001). Of note, lymphodepletion intensity did not seem to affect hematopoietic recovery. Table 2 summarizes the results of the multivariable analysis. Figure 1 shows ANC and Plt recovery by CRS grade. Conclusion We identified CRS grade as independently associated with impaired hematopoietic recovery after CD19 CAR-T cell therapy. Our findings suggest that the prevention of CRS may improve hematopoietic recovery after CD19 CAR-T cell therapy. Figure Disclosures Hirayama: DAVA Oncology: Honoraria. Maloney:Celgene,Kite Pharma: Honoraria, Research Funding; BioLine RX, Gilead,Genentech,Novartis: Honoraria; Juno Therapeutics: Honoraria, Patents & Royalties: patients pending , Research Funding; A2 Biotherapeutics: Honoraria, Other: Stock options . Turtle:Caribou Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Other: Ad hoc advisory board member, Research Funding; Allogene: Other: Ad hoc advisory board member; Novartis: Other: Ad hoc advisory board member; Juno Therapeutics: Patents & Royalties: Co-inventor with staff from Juno Therapeutics; pending, Research Funding; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; T-CURX: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Other: Ad hoc advisory board member; Humanigen: Other: Ad hoc advisory board member.

Serum Electrolyte Dynamics in Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation

Despite advent of a rich anti-myeloma armamentarium, autologous hematopoietic cell transplant (HCT) has been increasingly utilized to achieve prolonged survival for patients (pts) with multiple myeloma (MM). Short-term metabolic abnormalities have been associated with this treatment modality. Electrolyte abnormalities may lead to increased patient morbidity by prolonging hospital stay as well as central line use. The incidence, temporal course, severity, and impact of metabolic derangement during the peri-engraftment period on clinical outcomes have not thoroughly been studied in MM pts. Here, we sought to investigate the dynamics of electrolyte changes throughout the course of transplant and assess its association with decline and rise in peripheral blood cell count. Methods: All consecutive MM pts that underwent inpatient autologous SCT from January 2012 through July 2016 in our institutions were included. Engraftment Speed (ES) was calculated as the period between the first rise in the absolute neutrophil count (ANC) to engraftment (fist of 3 consecutive days in which ANC>500 mm3). Time to "no need for electrolyte replacement" was calculated from the day of stem cell infusion to the last day of replacement. Survival distribution was estimated using Kaplan-Meier methods. The effect of electrolyte abnormalities on OS and PFS was estimated using a Cox model after controlling for the effects of age, gender, number of prior therapies, and time from diagnosis to transplant. Results: Patient characteristics are listed in Table 1. Pre- and post-SCT nadir values, total amount of replaced electrolyte and replacement frequency are listed in Table 2. The most frequently replaced electrolyte was K followed by Mg, Ca, and P. As expected, there was a direct correlation between magnitude of drop in K, Ca, and Mg and total amount of replacement (Pearson coefficient: 0.673, p = 0.001). Pts dropped a median of 17 ml/min in GFR throughout the transplant process and the nadir occurred on median of transplant day 6. Median ANC nadir occurred on day 6 (range: 2-8) while ANC<500/ml was recorded on median day 5. One hundred and six pts (90%) had all-grade diarrhea while 37 pts (31%) had grade II or higher. Grade II and higher diarrhea was associated with significant drop in K but not with drop in P, Ca or Mg. (Figs. 1, 2). All-grade nausea occurred among 113 pts (95%), while grade II and higher nausea complicated the transplant course in 42 pts (35%). All-grade oral mucositis happened in 68 pts (57%), while 27 pts (23%) suffered from grade II and higher. There was no statistically significant difference between the drop in P, Ca, Mg or K based on severity of nausea or oral mucositis. A multivariate model to assess the impact of potential risk factors on electrolyte abnormalities, included age, gender, CD34+ cell dose, pre-HCT performance status and presence of severe GI toxicity (Table 3). Median ES was 3 days (range: 0-5) and 40 pts (36%) had ES ≤ 2 days. Engraftment occurred at a median of 11 days (standard deviation (SD): 1.50 days, after HCT). The median time-to-nadir for both P and K was 10 days (SD: 3.10 days and 4.28 days for P and K, respectively). The drop in P was statistically higher in the group with ES ≤ 2 days in comparison to the group with ES > 2 days (Median: 1.4 vs. 0.9 mg/dL, p-value: 0.000) as well as the drop in K (median: 1.1 vs. 0.7 mmol/L, p=0.039). There was no difference in the Ca or Mg drop between the two ES groups. (Fig. 1). There was also no statistical significance in frequency of post-engraftment Hb<7.5 gr/dL between two cohorts, whereas more pts in the cohort with ES>2 had post-engraftment Plt<10 x 106/L than pts with ES ≤ 2 (45% vs 15%, p=0.001) suggesting a more robust graft in the latter group. There was no significant difference in post-transplant PFS or OS between the two ES patient cohorts. Conclusions: Our results indicate that there is a significant correlation between the magnitude of drop in potassium and phosphorous following stem cell transplant and a steep rise in neutrophil counts around engraftment period. These events are consistent with a "genesis syndrome" which is characterized by a rapid, massive transfer of electrolytes into proliferating cells as has been previously described in certain high-grade lymphomas and leukemias. Disclosures Malek: Celgene: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Medpacto: Research Funding; Janssen: Speakers Bureau; Amgen: Speakers Bureau; Adaptive: Consultancy.

1740. Title: Outcomes of a Clinical Algorithm for the Early Diagnosis and Treatment of Invasive Fungal Sinusitis among Children with Hematologic Malignancy or Prior Hematopoietic Stem Cell Transplantation

BackgroundInvasive fungal sinusitis (IFS) is a cause of significant morbidity and mortality among children with hematologic malignancy and hematopoietic stem cell transplant (HSCT) recipients, with an estimated mortality of 18–80%. Since 2007, our center has employed a clinical algorithm for the early detection and treatment of IFS among children with prolonged febrile neutropenia.MethodsWe reviewed all EORTC defined cases of proven IFS among children with underlying hematologic malignancy or prior HSCT admitted to our institution between July 1, 2004 and December 31, 2018, and compared clinical characteristics and outcomes (including underlying malignancy, chemotherapy regimen at the time of viremia, absolute neutrophil count, absolute lymphocyte count, treatment regimens, and 6 month mortality) between the pre (July 1, 2004–December 31, 2006) and post-protocol (January 1, /2007–December 31, 2018) periods.ResultsWe identified 33 cases of proven IFS during the study period, with 6 in the pre-protocol and 27 in the post-protocol period. The most common underlying primary diagnosis was acute lymphoblastic leukemia (ALL) at > 50% with 8% of individuals with prior HSCT. Twenty-five cases (92%) during the protocol period were diagnosed via nasal endoscopy per protocol, with 17 (63%) reporting no clinical complaints of sinusitis. Median absolute neutrophil count (ANC) at the time of IFS diagnosis was 155/mm3 (IQR 0 – 375/ mm3; n = 12) with median duration of neutropenia 16.5 days (IQR 10.5–18.25, n = 12) at the time of diagnosis. Most individuals required one definitive debridement. Isolated fungal specimens included Bipolaris spp. (24%), Aspergillus spp. (20%), Curvularia spp. (20%), with Fusarium and Exserohilum spp. each at 12%, and Rhizopus spp. At least one patient had a co-infection with more than one fungal species. Pre-protocol cause-specific mortality at 6 months was 33.3% compared with 14.8% (P = 0.29) in the post- protocol period.ConclusionIFS is a cause of significant morbidity and mortality among children with hematologic malignancy or prior HSCT. An aggressive protocol with early nasal endoscopy and targeted debridement may help decrease morbidity and mortality associated with this entity. Additional well-designed studies are needed to assess the potential benefits of this approach in the diagnosis and management of IFS among high-risk children. Disclosures All authors: No reported disclosures.

1760. Outcomes of Acyclovir-Resistant Herpes Simplex Virus Infections in Hematologic Malignancies and Hematopoietic Cell Transplant

BackgroundAcyclovir-resistant (ACVr) herpes simplex virus (HSV) infection management is a challenge in patients with hematologic malignancies (HM) and hematopoietic cell transplant (HCT) recipients.MethodsRetrospective review of patients aged ≥ 18 years with underlying HM and/or HCT and culture-positive ACVr HSV between 1/1/2009 and December 1/2017 at a tertiary cancer center. Clinical, laboratory, microbiological, and treatment data collected.Results33 patients identified; 25 (76%) acute leukemias, 3 (9%) chronic myeloid leukemia/chronic lymphocytic leukemia (CML/CLL), 3 (9%) lymphoma, 2 (6%) other HM, and 32 (97%) had HCT. Median age of patients was 59 years (25–73) and 64% of them are females. HCT type: 22 (67%) matched unrelated donor, 3 (9%) cord blood, and 7 (21%) matched related donor. All patients were on acyclovir prophylaxis prior to diagnosis. The median time to onset of ACVr HSV infection was 147 days after transplant. Infection site: 16 (49%) oral, 10 (30%), ano-genital, 5 (15%) oral and esophagus/lung, 2 (6%) esophagus/lung. Pertinent laboratory data on day of viral culture (median/range): white blood cell (WBC) 4.6 cells/µL (0.1–85.9), absolute neutrophil count (ANC) 2,316 cells/µL (0–17,000), absolute lymphocyte count (ALC) 574.5 cells/µL (0–84,182). Serum creatinine at start and end of treatment are 0.8 mg/dL (0.32–1.98) and 0.92 mg/dL (0.36–2.7), respectively. The median duration of treatment was 30 days (4–116). Treatment: 20 (61%) foscarnet, 2 (6%) cidofovir, 4 (12%) foscarnet and cidofovir, 1 (3%) valacyclovir, 5 (15%) high-dose acyclovir, 1 (3%) unknown. 8 (24%) received adjunctive topical therapy: 5 imiquimod, 3 cidofovir. 31 included in outcome analysis (data missing in 2). Infection resolved in 15/31 (48%) while 5/31 (16%) had persistent infection. Median ANC and ALC in those with resolved vs. persistent infection (respectively): 3,082 cells/µL and 642 cells/µL vs. 1,895 cells/µL and 380 cells/µL with a trend toward lower ANC and ALC in patients with persistent infection. Overall mortality was 35% (9/31) while ACVr HSV attributable mortality was 6.4% (2/31).ConclusionACVr HSV is predominantly encountered in allogeneic HCT, particularly the unrelated donor recipients, and lower ANC/ALC may predispose to persistent infection. Disclosures All authors: No reported disclosures.

Post-Treatment ANC is Predictive of Poorer Overall Survival and Disease-Free Survival in Esophageal Cancer Patients after Tri-Modality Therapy

Although neutrophils serve important roles in inflammation and host defense, increasing evidence points towards their involvement in tumorigenesis and progression. Recent studies show that increased pre-treatment neutrophils associate with disease recurrence and survival rates in esophageal cancer. Here, we evaluate the association of post-treatment absolute neutrophil count (ANC) with survival outcomes in primary non-metastatic esophageal cancer patients who have received tri-modality therapy. We reviewed 219 consecutive patients with stage I-III esophageal cancer who completed tri-modality therapy at our center between 1/2007 and 12/2015. Of the 219 patients, 123 completed all treatments within 5 months of starting radiation and had available ANC at 6 months after start of radiation (range: +/- 1 month). 70 (57%) were > 60 years old, and 110 (89%) were male. 116 (94%) tumors were adenocarcinoma, 89 (72%) were stage III, and 120 (98%) were located distally. 120 (98%) received induction chemotherapy of which 77 (64%) received platinum-taxane (PT). All received concurrent chemotherapy of which 69 (56%) received PT. 90 (73%) had the same induction and concurrent agents. 118 (96%) received intensity modulated radiation therapy, with median dose of radiation being 5040cGy in 28 fractions (range: 4320-5600cGy). Kaplan-Meier survival, log-rank tests, and multivariate Cox regression were used to analyze the association of ANC with survival outcomes. The median follow up was 31 months (range: 5.7-119.9 months). Multivariate Cox regression using age, gender, KPS, stage, histology, tumor location, time to surgery, induction PT, concurrent PT, lung V20, mean heart dose, PTV size, and pre- and post-treatment ANC showed that increased 6-month ANC was predictive of worse overall survival/OS (p=0.0001, HR 1.3). The median ANC was 3.9 K/microliter (range: 0.9-30.4). When stratified by median ANC, patients with ANC > 3.9 had significantly worse OS compared to those with ANC ≤ 3.9 (5-year OS=35% vs 57%, p=0.049), and the disease-free survival (DFS) was also worse although this was not significant (5-year DFS=11% vs 24%, p=0.09). Subgroup analysis showed that the predictive value of ANC is influenced by choice of concurrent chemotherapy agent. In patients receiving concurrent non-PT, ANC > 3.9 predicted for worse 5-year OS (25% vs 57%, p=0.024) and 5-year DFS (4% vs 30%, p=0.022). This relationship was not seen for concurrent PT. Higher post-treatment ANC is predictive of poorer survival in primary non-metastatic esophageal cancer patients who have received tri-modality therapy, and this effect is influenced by choice of concurrent chemotherapy agent. Further investigation could consider individual neutrophil subpopulations, how they are affected by different treatment regimens, and their roles in cancer progression.

Prognostic Significance of Hematological Indices in Malignant Melanoma Treated With Immune Checkpoint Inhibitors.

Local and systemic inflammation significantly effects tumor progression and its response to therapy. We aim to evaluate the prognostic significance of inflammatory cells, their ratios, and a change in these indices while patients are receiving immune checkpoint inhibitors (ICIs). We retrospectively reviewed 120 malignant melanoma patients who had received any ICIs from 2011 until December 2017 and evaluated the effect of hematological indices on survival and radiographic responses. We followed the trends of these indices at 0, 6, and 12 weeks while on ICIs. Univariate and multivariate survival analyses were performed. The Student t tests and logistic regression were performed as well. Patients with neutrophil to lymphocyte ratio (NLR) <5 and derived neutrophil to lymphocyte ratio (dNLR) <3 had better overall survival and progression-free survival. The objective response rate was significantly higher in patients with absolute neutrophil count (ANC) <5 and dNLR<3 at baseline. Responder to ICIs had downtrending median ANC, NLR, dNLR, and an uptrending median lymphocyte to monocyte ratio compared with those of nonresponders. Moreover, in responders, the decrease in mean ANC, NLR, and dNLR were statistically significant compared with that of nonresponders at 6 and 12 weeks while on ICIs. Hematological indices can predict the response to ICIs and prognosis in malignant melanoma. Besides, the changes in these indices from their baseline values could be monitored in real-time to predict an earlier response even before a radiographic evaluation. However, the prospective and validation studies are needed before these models can be used in routine clinical practices.

Modulation of peripheral blood immune cells by early use of steroids and its association with clinical outcomes in patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors

BackgroundSteroids are frequently used in patients with metastatic non-small cell lung cancer (mNSCLC), but they could be detrimental for patients treated with immune checkpoint inhibitors (ICIs). Here, we assessed the association between early use of steroids, clinical outcomes and peripheral immune blood cells modulation in patients with mNSCLC treated with ICIs.MethodsWe reviewed patients with mNSCLC treated at our institution between April 2013 and December 2017. Early use of steroids was defined as the use of a daily prednisone-equivalent dose ≥10 mg for at least 1 day within 28 days after ICI initiation. Peripheral immune blood cell counts were retrieved at baseline and at 4 and 6 weeks after ICI initiation.ResultsOut of 151 patients included, 35 (23%) made early use of steroids that was associated with poor disease control (OR 0.32, p=0.006), progression-free survival (HR 1.80, p=0.003) and overall survival (HR 2.60, p<0.001). Early use of steroids significantly correlated with higher median absolute neutrophil count, neutrophil to lymphocyte ratio (NLR) and derived NLR, and lower median absolute and relative eosinophil count, both at 4 and 6 weeks after ICI initiation.ConclusionsIn patients with mNSCLC treated with ICIs, early use of steroids was associated with worse clinical outcomes and remarkable modulation of peripheral blood immune cells, which could contribute to restraining the activation of antitumour immunity. If confirmed in prospective studies, these findings would highlight the importance of carefully evaluating and, whenever possible, avoiding steroids during early phases of ICI treatment.

Ethnic Differences in Hematologic Toxicity from Imatinib in Patients with Gastrointestinal Stromal Cell Tumor (GIST): Coincidence or a Real Phenomenon.

Objectives:There is a wide variability in the pharmacokinetics, pharmacodynamics and tolerance of anticancer drugs based on ethnicity. GIST is a rare cancer, (~1% of GI cancers). Imatinib is used in the neo-adjuvant, adjuvant and metastatic setting. The purpose of this study was to report the difference in hematologic toxicities to imatinib among different ethnicities when treated for GIST either in the adjuvant or metastatic setting.Methods:We performed a retrospective study to collect data on patients with GIST (in any stage), who were on imatinib and presenting with grade 2 or more anemia, neutropenia and/or thrombocytopenia from July 1, 2005 to January 31, 2018. The degree of cytopenia was graded as per National Cancer Institute Common Toxicity criteria; version 4.0. We collected included age, gender, ethnicity, pathology, adverse effects-hematologic and non-hematologic, management of toxicities including dose modifications and administration of pegfilgrastim.Results:Among 57 patients (median age 61 years, M: F=41:16 (F); ethnicities: White 65%, African-American (AA 19%, Asian 12% and Hispanic 4%), neutropenia (Grade 3 & 4) was seen in 6 patients (10%): 5 AA and 1 Asian. 45% of all AA patients developed neutropenia. Median absolute neutrophil count (ANC) nadir was 700/μL, median duration on drug prior to onset of neutropenia was 4.5 weeks and median duration of neutropenia was 4 weeks. One patient developed febrile neutropenia. Dose interruptions were needed in 3, dose-reductions in all patients, and 3 patients required pegfilgrastim. One patient had to discontinue imatinib, while one patient was escalated back to 400mg daily dose.Conclusion:This is the first study to examine ethnic variations in myelosuppression following imatinib in patients with GIST.

Blood neutrophil counts in HIV-infected patients with cryptococcal meningitis: Association with mortality.

BackgroundThe mortality from cryptococcal meningitis remains high, despite the availability of antiretroviral therapy (ART) and amphotericin-based fungal regimens. The role of neutrophils in cryptococcosis is controversial. Our objective was to examine the association between blood neutrophil counts and outcomes in terms of mortality, the incidence of bacterial infections (including Mycobacterium tuberculosis) and hospitalization among HIV-infected patients presenting with cryptococcal meningitis.MethodsWe used data from participants from the Cryptococcal Optimal ART Timing (COAT) trial (2010–2012; Uganda and South Africa) and the Adjunctive Sertraline for Treatment of Cryptococcal Meningitis (ASTRO-CM) trial (2013–2017; Uganda). We estimated 30-day mortality risk with Cox proportional hazards models by baseline neutrophil counts (a) on a continuous scale and (b) with indicators for both relatively high (> 3,500 cells/mm3) and low (≤ 1,000 cells/mm3) counts. Follow-up neutrophil counts from the COAT trial were used to examine the time-dependent association of neutrophil counts with 12-month mortality and rehospitalization.Results801 participants had an absolute neutrophil value at meningitis diagnosis. The median baseline absolute neutrophil count was 2100 cells/mm3 (IQR, 1400 to 3300 cells/mm3). Baseline neutrophil count was positively associated with 30-day mortality (adjusted hazard ratio = 1.09, 95%CI, 1.04–1.13, per 1000 cells/mm3 increase; p<0.001). Baseline absolute neutrophil counts ≤ 1000 cells/mm3 did not have increased risk of 30-day mortality compared to those with baseline neutrophils of 1001–3500 cells/mm3; however, baseline >3500 cells/mm3 had significantly increased risk, with an adjusted hazard ratio of 1.85(95%CI, 1.40–2.44; p<0.001). Among the COAT participants with follow-up neutrophil data, there was a strong association between time-updated neutrophil count and 12-month mortality (adjusted hazard ratio = 1.16, 95% CI 1.09–1.24; p<0.001.ConclusionHigher blood neutrophil counts in HIV-infected patients with cryptococcal meningitis were associated with mortality. Neutrophils role requires further investigation as to whether this may be a mediator directly contributing to mortality or merely a marker of underlying pathologies that increase mortality risk.

Infections in patients with aplastic Anemia in Chiang Mai University

BackgroundInfection is a major complication in aplastic anemia (AA) patients. Primary objectives of this study were to determine the prevalence of infections and to determine types of pathogens associated with infections in patients with AA. Secondary objectives were to evaluate overall survival after infections as well as risk factors of infections in patients with AA.MethodsThe authors retrospectively evaluated the infectious episodes (IEs), type of infections, associated pathogens, and outcomes of infections in patients with AA who were diagnosed and treated at Chiang Mai University between January 2010 and December 2015.ResultsSixty-seven patients with a median age of 51 years (range, 15–87 years) were enrolled. Forty two patients (62.6%) were severe AA. Median absolute neutrophil count (ANC) was 984 /mm3 (range, 120–5500/mm3). Twenty five patients (37.3%) received antithymocyte globulin plus cyclosporine A, 41 patients (61.1%) received anabolic hormone, and 2 patients (2.9%) underwent allogeneic hematopoietic stem cell transplantation. Overall, 31 IEs were documented in 22 patients (32.8%). The most common microbiologically documented site of infection was bloodstream infection (23.4%) followed by pulmonary infection (14.9%). Culture-negative febrile neutropenia occurred in 12.7%. Common pathogens identified were bacteria (73.9%), mainly gram-negative (52.9%) including Acinetobacter baumannii (23.5%) and Pseudomonas aeruginosa (17.6%). Fungal infections were diagnosed in 21.7% and all were Aspergillus spp. Six patients (9%) died during the study period. All of them died from infection which gram-negative bacteria were most common pathogens (66.7%). Patients with infections had 5-year overall survival of 72% that is significantly less than patients without infection (100%) (p = 0.0002). Only risk factor that correlates with high probability of infection was ANC < 500/mm3. (HR 2.29, 95%CI 1.03–7.72, p = 0.043).ConclusionsPrevalence of infections in AA patients in Chiang Mai University was 32.8% Bacterial infections especially gram-negative bacteria were the major pathogens. Patients with ANC < 500/mm3 had higher risk of infections. Infection was the most important cause of death in AA.

Impact of a Standardized Hydroxyurea Dose Regimen for Extreme Thrombocytosis in Children after Pancreatectomy with Islet Autotransplantation

Total pancreatectomy with islet autotransplantation (TPIAT) is a therapeutic option for debilitating acute recurrent or chronic pancreatitis. While postoperative diabetes and pain outcomes are well-described in these patients, the hematologic outcomes have not been thoroughly examined. Specifically, the natural history and optimal management of the nearly universal post-IAT extreme thrombocytosis (platelets >1000 K/μL) beginning within days of surgery and often lasting for months remains enigmatic. Concern for thrombosis risk from the extreme thrombocytosis has prompted empiric, widely-employed pharmacologic alteration of platelet count (hydroxyurea) and function (aspirin, ASA); however, the optimal dosing strategy and efficacy of these therapies after IAT are poorly characterized.Patients who underwent TPIAT (n=28) or subtotal pancreatectomy with islet autotransplantation (n=2), all with splenectomy, at Cincinnati Children's Hospital Medical Center between January 1, 2015 and April 30, 2018 were retrospectively reviewed. Hydroxyurea management strategies, hematologic trends, and hydroxyurea side effects were evaluated.The mean age of the patients was 12.3 years (range 3-19 years). All started ASA on post-operative day (POD) 2-3 at a median daily dose of 2 mg/kg [Interquartile Range (IQR) 1.7-2.13). This was continued until hydroxyurea was discontinued and platelet count remained normal for 4 weeks. All received prophylactic heparin and later enoxaparin post-operatively per protocol until discharge. VerifyNow® ASA testing was performed after aspirin initiation, with dose increases as necessary to reach therapeutic result. Among the 30 patients evaluated, 26 developed extreme thrombocytosis (median maximum platelet count 1298 K/μL, IQR 1046-1563), peaking at a median of 16 days (IQR 14-20). Two patients developed portal vein thromboses (POD 4 in a 13 year old with platelets 321 K/μL at diagnosis, and POD 11 in a 15 year old with platelets 1458 K/μL at diagnosis, respectively). Both patients had clot resolution while on therapeutic enoxaparin for 3 months.On July 1, 2016, a more standardized regimen for aspirin and hydroxyurea initiation, dose modification and weaning was implemented. These changes resulted in earlier hydroxyurea initiation [median 7 (IQR 6-8) versus 9 (IQR 8-10) days postoperatively, p=0.03] at lower platelet counts [median 529 (IQR 501-600) versus 938 (IQR 776-1085) K/μL, p<0.001] and potentially lower initial doses [15 (14-16) versus 20 (15-21) mg/kg/day, p=0.09]. Nine patients required hydroxyurea to be restarted after an initial wean (33% before protocol standardization, 29% afterwards). Four patients after protocol standardization never reached a platelet count >1000 K/μL, while all patients before standardization had extreme thrombocytosis. VerifyNow® ASA testing was performed earlier after standardization (POD 6 versus 7, p=0.01) with similar percentages of non-therapeutic ASA measurements in each group (22 versus 19%). The MCV rose a median 13 fL (IQR 8.75-20) while on hydroxyurea. With the current sample size, no statistically significant differences were detected between the two groups for maximum hydroxyurea dose, treatment duration, maximal platelet count, the number of patients with multiple episodes of extreme thrombocytosis, or number of days with extreme thrombocytosis. Of the 25 patients who were fully weaned off hydroxyurea as of July 31, 2018, the therapeutic course was a median 175 days (IQR 90-259). Median absolute neutrophil count (ANC) was 4140 K/μL (IQR 2700-7080). Neutropenia (ANC <1500 K/μL) was rare (24/678 measurements, 3.5%) over 5498 hydroxyurea treatment days, only necessitating hydroxyurea cessation on 4 occasions. Three patients had mild alopecia. No bleeding or gastritis occurred to necessitate ASA cessation, even while on prophylactic or therapeutic anticoagulation.Hydroxyurea and ASA are well-tolerated and appear to favorably modulate post-IAT thrombocytosis and mitigate post-surgical thrombotic risks. Earlier hydroxyurea initiation with a standardized protocol may provide more predictable platelet count responses including decreasing the risk of extreme thrombocytosis. Future studies are needed to optimize hydroxyurea treatment in this setting. DisclosuresPalumbo:Ionis Pharmaceuticals: Research Funding.

Granulocyte Transfusions for Neutropenic Patients with Perirectal and Perineal Infections

Granulocyte Transfusions for Neutropenic Patients with Perirectal and Perineal Infections

Safety and Efficacy of Non-Irradiated Granulocyte Transfusions (GTX) in Neutropenic Patients with Severe or Refractory Abdominal Infections: A Single Center Retrospective Analysis of 119 Transfusions in 22 Patients

Safety and Efficacy of Non-Irradiated Granulocyte Transfusions (GTX) in Neutropenic Patients with Severe or Refractory Abdominal Infections: A Single Center Retrospective Analysis of 119 Transfusions in 22 Patients

1786. Safety, Efficacy, and Clinical Impact of Penicillin Allergy Skin Testing in Immunocompromised Cancer Patients at a Comprehensive Cancer Center

BackgroundPatients reporting penicillin (PCN) allergies often receive alternative antibiotic therapy associated with significant health and economic disadvantages. The use of penicillin allergy skin testing (PST) to rule out PCN allergies is safe and effective in immunocompetent patients, yet data in immunocompromised patients are limited.MethodsA quality improvement process using PST to clarify PCN allergies and guide antibiotic therapy was implemented at MD Anderson Cancer Center (April–October 2017). Patients admitted to Leukemia and Genitourinary Medical Oncology (GUMO) services with a history of Type 1 reactions to PCN were eligible.ResultsA total of 218 consecutive patients with reported PCN allergies were screened; 100 met inclusion criteria, were consented, and underwent PST (67 Leukemia, 33 GUMO). Sixty-one percent of tested patients reported cutaneous reactions, and 79% reported reactions >20 years ago. The most common reported allergy was to penicillin V/G (64%). Forty-eight percent were on steroids and 49% were on immunosuppresive therapy at the time of PST. For leukemia patients the median absolute neutrophil count was 0.78 (0–64.88 K/μL) and absolute lymphocyte count was 0.81 (0–116.71 K/μL). Ninety-five percent patients tested negative for PCN allergy and 4% were positive (three Leukemia, one GUMO). One test was indeterminate (negative histamine control). After PST, 25 of 67 (37%) patients receiving antibiotic therapy were changed to PCN-based antibiotics (PBA) (Figure 1). During the follow-up period (median: 177; range: 3–316 days), 65 patients who tested negative were readmitted (total 185 readmissions) and PBAs were prescribed in 58 of those readmissions (Figure 2). The most common indications for PBAs included neutropenic fever, pneumonia, and bacteremia. No patients given PBAs after negative PST experienced allergic reactions.ConclusionPST is safe and effective to rule out PCN allergies in immunocompromised patients, with 95% of patients testing negative for PCN allergy, suggesting that patient-reported allergy is unreliable. The rate of negative tests is comparable to data in immunocompetent patients. The use of PST in cancer patients allows for optimization of antimicrobial therapy and stewardship, which is vital in this patient population at increased risk for infections and infectious complications. Disclosures M. Taremi, ALK-Abello: Educational grant recipient, Educational grant.

Clinical, Laboratory, and Molecular Characteristics and Remission Status in Children With Severe Congenital and Non-congenital Neutropenia.

Objectives: Severe congenital neutropenia (SCN) is a primary immunodeficiency disease characterized by the early onset of recurrent infections and persistent severe neutropenia, with or without genetic defect. We aimed to study the different clinical features and hematological and bone marrow characteristics of patients with SCN and the non-congenital form of severe neutropenia (SN) with unknown etiology.Methods: Thirty-nine Chinese children with severe neutropenia for longer than 6 months unrelated to virus infection or autoimmune diseases were enrolled in the study to analyse the clinical, laboratory, and molecular characteristics. They were followed clinically to observe their remission status.Results: Seven patients were found to have SCN mutations, including ELANE and G6PC3. Among 26 patients with close follow-up, one died for an unknown reason, and 10 resolved spontaneously with a median neutropenia duration of 14.5 months; these patients were designated as having recovered SN. The demographic characteristics of both groups were similar, with a median infection rate of 5 times/year. SCN patients had more frequent infection than recovered SN patients (4 times/year, P = 0.039). The median absolute neutrophil count (ANC) was 0.40 × 109/L in SCN patients, which was significantly higher than 0.2 × 109/L in SN with unknown etiology and 0.21 × 109/L in recovered SN patients (P = 0.021, P = 0.017). The median monocyte count was 1.60 × 109/L in SCN patients, which was also significantly higher than 0.57 × 109/L in SN of unknown etiology and 0.55 × 109/L in recovered SN patients (P = 0.018, P = 0.001). Bone marrow examinations demonstrated myeloid maturation arrest at the myelocyte-metamyelocyte stage in SCN patients and normal findings in SN with unknown etiology and recovered SN patients.Conclusions: Patients with severe neutropenia due to gene mutations demonstrate more serious symptoms than patients with unknown etiology. Patients with relatively higher ANC and monocyte counts are more likely to have known gene mutations. Future studies should focus on more detailed laboratory investigation, prolonged follow-up and advanced molecular biology tools to facilitate accurate diagnosis and effective treatment.

Cost-effectiveness and Improved Parent and Provider Satisfaction With Outpatient Management of Pediatric Oncology Patients, With Low-risk Fever and Neutropenia

On the basis of significant evidence for safety, the international pediatric fever and neutropenia committee recommends the identification and management of patients with "low-risk fever and neutropenia" (LRFN), outpatient with oral antibiotics, instead of traditional inpatient management. The aim of our study was to compare the cost-per-patient with these 2 strategies, and to evaluate parent and provider satisfaction with the outpatient management of LRFN. Between March 2016 and February 2017, 17 LRFN patients (median absolute neutrophil count, 90/μL) were managed at a single institution, per new guidelines. Fifteen patients were discharged on presentation or at 24 to 48 hours postadmission on oral levofloxacin, and 2 were inadvertently admitted off protocol. The mean cost of management for the postimplementation cohort was compared with a historic preimplementation control group. Satisfaction surveys were completed by parents and health care providers of LRFN patients. The mean total cost of an LRFN episode was $12,500 per patient preimplementation and $6168 postimplementation, a decrease of $6332 (51%) per patient. All parents surveyed found outpatient follow-up easy; most (12/14) parents and all (16/16) providers preferred outpatient management. Outpatient management of LRFN patients was less costly, and was preferred by a majority of parents and all health care providers, compared with traditional inpatient management.

(P37) Radiation-Induced Immunosuppression in Locally Advanced Non-Small Cell Lung Cancer: Another Cardiac Toxicity?

Recent reports have associated increased radiation therapy (RT) dose to the heart with higher rates of cardiac toxicity. Other reports have correlated RT-related immunosuppression with worsened survival in patients with solid malignancies. Given the large vascularized volumes exposed to RT during locally advanced non-small cell lung cancer (LA-NSCLC) treatment, we hypothesized that there is an association between increased heart dose and immunosuppression. A total of 400 LA-NSCLC patients with follow up laboratory values treated at a single institution with definitive intent RT +/- chemotherapy between 2001-2016 were identified. Organs at risk were reviewed and re-contoured according to the RTOG 0617 cardiac secondary analysis atlas. Absolute lymphocyte counts (ALC), absolute neutrophil counts (ANC), and neutrophil to lymphocyte ratio (NLR = ANC/ALC) were analyzed pre-RT, during RT, and at 2 and 4 months post-RT start. Patient, tumor, treatment, and dosimetric factors were correlated with hematologic toxicity and treatment outcomes. An upper tertile threshold to increase specificity of NLR was chosen to dichotomize continuous hematologic variables and identify cutpoints for hematologic values as a predictor of mortality. The median follow up was 17 (range 0.2-174) months in all patients and 46 (range 0.2-161) months in survivors. Patients received a median dose of 66 Gy (range 50-75.25 Gy) in median 2 Gy (range 1.8-2.5 Gy) fractions delivered with IMRT in 41% of patients. The estimated median overall survival (OS) was 17.9 months and progression free survival (PFS) 12.8 months. The estimated 5 year freedom from local recurrence (FFLR) and freedom from distant metastasis (FFDM) were 49% and 34%, respectively. There were 331/363 (91%) cases of ≥ grade 3 lymphopenia and 129/362 (36%) ≥ grade 4 lymphopenia at the nadir. At 4 months after RT start (290 patients), the median ALC, ANC, and NLR were 600 cells/mm3 (range: 100-4600), 4700 cells/mm3 (range: 300-113,600), and 7.2 (range: 0.60-259), respectively. On multivariable analysis, male gender (Hazard Ration [HR] 1.66; 95% CI 1.20-2.29; p=0.02), RT alone (HR 2.08; 95% CI 1.9-3.96; p=0.026), heart V50 (HR 1.02; 95% CI 1.01-1.03; p<0.001), and higher NLR at 4 months (HR 1.015, 95% CI 1.005-1.025; p=0.002) were significantly associated with worse OS. An upper tertile cutpoint of NLR > 10.5 at 4 months post RT, was associated with decreased OS (p<0.001) and decreased FFDM (p=0.04). The median OS stratified by NLR > 10.5 and NLR ≤ 10.5 was 11 months and 24 months, respectively (p < 0.001). NLR > 10.5 was associated with worse FFDM (p=0.04) and was borderline for PFS (p=0.08). On multivariable analysis, CRT with adjuvant chemotherapy (HR 2.55; 95% CI 1.30-4.98; p=0.006), RT alone (HR 3.56; 95% CI 1.07-11.88; P=0.039), and heart V50 > 25% (HR 1.98; 95% CI 1.11-3.54; p=0.021) were associated with an NLR>10.5 at 4 months post-RT. Higher RT dose to the heart is associated with increased immunosuppression and worse tumor control, and may represent an additional actionable cause of increased mortality beyond cardiac toxicity alone.

The clinical utility of fluorodeoxyglucose-positron emission tomography for investigation of fever in immunocompromised children.

Fever in immunocompromised children presents significant challenges. We aimed to determine the clinical impact of fluorodeoxyglucose-positron emission tomography (FDG-PET) in combination with computed tomography (CT) in children with malignancy or following haematopoietic stem cell transplantation with prolonged or recurrent fever. Immunocompromised children who underwent FDG-PET/CT for investigation of prolonged or recurrent fever were identified from hospital databases. The clinical impact of the FDG-PET/CT was considered 'high' if it contributed to any of the following: diagnosis of a new site infection/inflammation, change to antimicrobials or chemotherapy, or additional investigations or specialist consult contributing to final diagnosis. Fourteen patients underwent an FDG-PET/CT for prolonged or recurrent fever. Median age was 11 years and 46% had diagnosis of acute lymphoblastic leukaemia. The median absolute neutrophil count on the day of FDG-PET/CT was 0.47 cells/μL. The clinical impact of FDG-PET/CT was 'high' in 11 (79%) patients, contributing to rationalisation of antimicrobials in three, and cessation of antimicrobials in five. Compared to conventional imaging, FDG PET/CT identified seven additional sites of clinically significant infection/inflammation in seven patients. Of the 10 patients who had a cause of fever identified, FDG-PET/CT contributed to the final diagnosis in six (60%). This study has identified potential utility for FDG-PET/CT in immunocompromised children with prolonged or recurrent fever. Further prospective studies are needed to compare FDG-PET/CT versus conventional imaging, to identify the optimal timing of FDG-PET/CT and to study the role of subsequent scans to monitor response to therapy.