Decrease In White Blood Cell Count Research Articles

The efficacy and safety of dalpiciclib, a cyclin-dependent kinase 4/6 inhibitor, in patients with advanced head and neck mucosal melanoma harboring CDK4 amplification

BackgroundMucosal melanoma (MM) is a rare but devastating subtype of melanoma. Our previous studies have demonstrated robust anti-tumor effects of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors in head and neck MM (HNMM) patient-derived xenograft models with CDK4 amplification. Herein, we aimed to investigate the efficacy and safety of dalpiciclib (SHR6390), a CDK4/6 inhibitor, in HNMM patients harboring CDK4 amplification.MethodsThe anti-tumor efficacy of dalpiciclib was assessed by HNMM patient-derived xenograft (PDX) models and patient-derived tumor cells (PDC) in vivo and in vitro. Immunohistochemical analyses and western blot were then performed to assess the markers of cell proliferation and CDK4/6 signaling pathway. For the clinical trial, advanced recurrent and/or metastatic HNMM patients with CDK4 amplification were treated with dalpiciclib 125 mg once daily for 21 consecutive days in 28-day cycles. The primary endpoint was disease control rate (DCR). Secondary endpoints included safety, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).ResultsDalpiciclib profoundly suppressed growth of HNMM-PDX and PDC with CDK4 amplification, whereas it showed relatively weak suppression in those with CDK4 wild type compared with vehicle. And dalpiciclib resulted in a remarkable reduction in the expression levels of Ki-67 and phosphorylated Rb compared with control group. In the clinical trial, a total of 17 patients were enrolled, and 16 patients were evaluable. The ORR was 6.3%, and the DCR was 81.3%. The estimated median PFS was 9.9 months (95% CI, 4.8-NA), and the median OS was not reached. The rate of OS at 12 months and 24 months was 68.8% (95% CI, 0.494–0.957) and 51.6% (95% CI, 0.307–0.866), respectively. The most frequent adverse events were neutrophil count decrease, white blood cell count decrease, and fatigue.ConclusionsDalpiciclib was well-tolerated and displayed a durable benefit for HNMM patients with CDK4 amplification in this study. Further studies on CDK4 inhibitors and its combination strategy for MM are worth further exploration.Trial registrationChiCTR2000031608.

Abstract PO2-04-13: TWT-203: PHASE 1b/2 STUDY OF CFI-402257 AS MONOTHERAPY IN ADVANCED SOLID TUMORS AND IN COMBINATION WITH FULVESTRANT IN PATIENTS WITH ER+/HER2- ADVANCED BREAST CANCER AFTER PROGRESSION ON PRIOR CDK4/6 INHIBITORS AND ENDOCRINE THERAPY

Abstract Background: TTK (Threonine Tyrosine Kinase also known as Monopolar spindle 1), is a dual-specificity serine-threonine kinase critical for anaphase promoting complex inhibition at the spindle assembly checkpoint and is required for chromosome alignment and error correction. TTK inhibition results in premature mitosis exiting with unattached chromosomes potentially leading to aneuploidy and cell death. High TTK tumor levels correlate with worse prognosis and contribute to the survival and proliferation of aneuploid cells. CFI-402257, a potent and selective inhibitor of TTK, inhibits the growth of a variety of human cancer-derived cell lines. A first-in-human phase 1 study of CFI-402257 (NCT02792465) demonstrated a tolerable safety profile when enrolled as a monotherapy in solid tumors, and in combination with fulvestrant in hormone receptor positive, HER2 negative (HR+/HER2-) breast cancer1. The dose for expansion was 168 mg, dose limiting toxicity was dose-dependent neutropenia which was manageable and reversible. Investigator-confirmed partial responses (cPR) were observed in 5 pts (8%) with 32 (50.8%) exhibiting disease control. In the HR+/HER2- breast cancer population previously treated with cyclin dependent kinase 4/6 inhibitors (CDK4/6i) and aromatase inhibitors (N=25), there were 4 cPR’s with a median duration of response of 223 days, with responses emerging after 2 cycles of therapy. Responses were observed with CFI-402257 as a single agent and in combination with fulvestrant. Based on these data, study TWT-203 will focus on advanced solid tumors for dose confirmation then focus on advanced HR+/HER2- breast cancers in combination with an approved endocrine therapy. Methods: In TWT-203 study, safety and clinical activity of CFI-402257 monotherapy will be evaluated in patients (pts) with advanced solid tumors (Part A) or in combination with fulvestrant in pts with HR+/HER2- advanced breast cancer (Part B). Part A will confirm the RP2D using a 3+3 design with a starting dose of 126 mg daily. Part B evaluates CFI-402257 in combination with fulvestrant in pts with HR+/HER2- advanced breast cancer following progression on prior CDK4/6i and endocrine therapy. Efficacy endpoints include overall response rate and disease control rate. Safety endpoints include incidence of treatment emergent adverse events. Exploratory objectives include characterization of protein and molecular alterations relevant to the cell cycle and CFI-402257 response. Results: At data cutoff of 11 May 2023, 14 pts were enrolled. All received monotherapy treatment. Median treatment duration was 2.1 months (range, 0.2-7.3+). Median age was 67 years (57-76). Median number of prior regimens was 3.5 (2-12). Tumor types enrolled were colorectal (n=6, 43%), breast (3, 21%), and endometrial, hepatocellular, leiomyosarcoma, pancreatic, and sarcoma (1 each, 7%). 4 dose levels, from 126 to 252 mg, were studied. Most pts (12, 86%) experienced ≥1 treatment emergent adverse event (TEAE). More than half of pts (8, 57%) experienced ≥1 treatment related TEAE. Most common TEAEs were fatigue (5, 36%) and nausea (4, 29%). 5 pts (36%) experienced TEAEs grade ≥3, most common were fatigue, neutrophil count decrease, white blood cell count decrease (2 pts each, 14.3%). 1 pt (7%) experienced a serious adverse event (hematuria), not related to study therapy. No patients discontinued treatment due to TEAE. All pts who ended treatment were due to disease progression (8, 57%). No grade 5 TEAEs occurred. No dose limiting toxicities were reported. Disease control rate (CR, PR, or SD ≥ 6 weeks from baseline) was 54.5% (6 pts/11): all achieved SD. 3 of the 6 pts remain on study. Conclusion: CFI-402257 is a potent inhibitor of TTK. It is well tolerated with manageable TEAEs, no dose limiting or treatment limiting toxicities, and no treatment related deaths. Dose expansion in the patient population of interest will commence. 1. John Hilton et al. Cancer Res 2023;83(5 Suppl): P6-10-13. Citation Format: Justin Call, Muralidhar Beeram, Alexander I. Spira, Mark Bray, Dih-Yih Chen, Long Kwei, Emily Roberts-Thomson, Trisha Denny, Roger Sidhu, Robert Wesolowski. TWT-203: PHASE 1b/2 STUDY OF CFI-402257 AS MONOTHERAPY IN ADVANCED SOLID TUMORS AND IN COMBINATION WITH FULVESTRANT IN PATIENTS WITH ER+/HER2- ADVANCED BREAST CANCER AFTER PROGRESSION ON PRIOR CDK4/6 INHIBITORS AND ENDOCRINE THERAPY [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-13.

Camrelizumab, chemotherapy and apatinib in the neoadjuvant treatment of resectable oesophageal squamous cell carcinoma: a single-arm phase 2 trial

In resectable oesophageal squamous cell carcinoma (ESCC), the efficacy of camrelizumab combined with chemotherapy and apatinib followed by minimally invasive oesophagectomy is not clear. We aimed to fill this knowledge gap. This investigator-initiated, single-arm, prospective, phase 2 trial was performed at the Second Affiliated Hospital of Zhejiang University, China. Patients (aged 18-75 years) who were histologically or cytologically diagnosed with ESCC were deemed suitable to participate in this trial. Patients received 2-3 cycles of neoadjuvant therapy with camrelizumab, nedaplatin, albumin paclitaxel, and apatinib; each cycle was repeated every 14 days. Surgery occurred 4-6 weeks after the last neoadjuvant treatment cycle. The primary outcome was the pathological complete response (PCR) rate of the tumour and lymph nodes. The changes in the peripheral blood immunoprofile among patients without PCR (ie, non-PCR [NPCR]) and with PCR were assessed by mass cytometry. This study was registered with ClinicalTrials.gov, NCT04666090. 42 patients were enrolled between November 23, 2020 and December 31, 2022. The disease control rate was 100.0% (95% CI, 91.6-100%), and the objective response rate was 83.3% (95% CI, 68.6-93.0%). Six (14.3%) patients experienced grade 3 adverse events. The most common were white blood cell count decrease (31.0%), alopecia (81.0%), asthenia (38.1%), and reactive cutaneous capillary endothelial proliferation (35.7%). 41 patients received minimally invasive oesophagectomy; all 41patients achieved R0 resection, and 18 (43.9%, 95% CI, 28.5-60.3%) patients achieved PCR. The median follow-up was 23 months and the 2-year survival rate was 85.9%. T-cell subsets in both the PCR and NPCR groups exhibited consistency in response to neoadjuvant therapy. In contrast, some of natural killer (NK) cells (NK-C03, NK-C11), B cells (B-C06) and monocytes (M-C05), exhibited significant differences between the PCR and NPCR groups before neoadjuvant therapy. M-C06 had a significant difference in the PCR group and NPCR group after neoadjuvant therapy. NK-C12 and B-C15 showed significant differences both before and after neoadjuvant therapy. The application of camrelizumab, chemotherapy and apatinib in the neoadjuvant setting for locally advanced ESCC has shown promising antitumour activity and an acceptable safety profile in this single-arm study. In the neoadjuvant setting, NK cell, B cell, and monocyte subsets exhibited greater predictive power for immunotherapy responsiveness than T-cell subsets. Longer follow-up to assess survival outcomes and a phase 3 randomised trial are needed to further evaluate the proposed treatment. The China Anti-Cancer Association and the "Leading Goose" Research and Development Project of Zhejiang Province.

A phase 3b study of venetoclax and azacitidine or decitabine in an outpatient setting in patients with acute myeloid leukemia.

Venetoclax, a highly selective BCL-2 inhibitor, combined with hypomethylating agents (HMAs) azacitidine or decitabine, is approved for the treatment of newly diagnosed acute myeloid leukemia (ND AML) in patients who are ineligible to receive intensive chemotherapy. Previous clinical studies initiated venetoclax plus HMA in an inpatient setting owing to concerns of tumor lysis syndrome (TLS). This study (NCT03941964) evaluated the efficacy and safety of venetoclax plus HMA in a United States community-based outpatient setting in patients with ND AML (N=60) who were treatment naïve for AML, ineligible to receive intensive chemotherapy, had no evidence of spontaneous TLS at screening, and were deemed as appropriate candidates for outpatient initiation of venetoclax plus HMA by the investigator. Patients received venetoclax in combination with azacitidine (75mg/m2) or decitabine (20mg/m2) for up to 6 cycles during the study. With a median time on study of 18.3weeks, the best response rate of composite complete remission was 66.7%, and the overall post-baseline red blood cell (RBC) and platelet transfusion independence rate was 55.0%, consistent with results of studies in which treatment was initiated in an inpatient setting. Key adverse events included nausea, anemia, thrombocytopenia, neutropenia, and white blood cell count decrease of any grade (≥50% of patients). The observed safety profile was generally consistent with that of venetoclax plus HMA observed in inpatient AML studies. With close monitoring, 2 cases of TLS were identified, appropriately managed, and the patients were able to continue study treatment. CLINICAL TRIALS REGISTRATION: This study is registered at ClinicalTrials.gov. The registration identification number is NCT03941964.

Abstract CT116: Preclinical antitumor activity and first-in-human phase I study of NB004/GDC-0570, a novel pan-PIM kinase inhibitor, in patients with advanced solid tumors

Abstract PIM proto-oncogenes encode a family of three serine/threonine kinases (PIM1, PIM2, PIM3), which are frequently overexpressed in human hematological malignancies and solid cancers. PIM kinases are promising cancer therapeutic targets for pharmacological inhibition. NB004 (aka GDC-0570) is a novel, potent, selective, orally available small molecule pan-PIM inhibitor, which exhibits antiproliferative activity as a single agent in a variety of preclinical models and can augment the activity of standard of care or targeted therapies, both in vitro and in vivo. In multiple patient-derived xenograft (PDX) models of human solid tumors, NB004 demonstrates both single agent and combination activity with agents targeting the RTK/RAS/MAPK pathways, including synergistic effects with KRAS inhibitors (KRASis). Remarkably, in NSCLC PDX models with acquired resistance to KRASis, strong combination efficacy was observed between NB004 and sotorasib, resulting in complete tumor regression. Based on the promising preclinical data, NB004 is currently being assessed in an open-label, first-in-human phase I clinical trial as monotherapy or combination therapy in patients with advanced solid tumors. The primary objective is to characterize the safety and tolerability and to recommend the phase 2 dose (RP2D). Secondary objectives include PK characterization and preliminary antitumor activity evaluation. In the phase I monotherapy dose escalation part, NB004 was administered daily in 5 dose levels, ranging from 75mg to 600mg, following a standard 3+3 design. As of December 22, 2023, a total of 18 patients were treated. Of the 13 patients (72.2%) who reported any treatment-related adverse events (TRAEs), 12 (66.7%) had Grade 1 or 2 TRAEs, 1 patient (5.6%) experienced Grade 3 neutrophil count decrease and white blood cell count decrease. No dose-limiting toxicity (DLT) or treatment-related serious adverse event (SAE) was reported, and PK exposure is in general dose proportional. These results warrant further evaluation of this drug in combination with other therapeutic agents. The combination part of the trial is currently open for enrollment (NCT05036291). Citation Format: Siqing Fu, Rachel E. Sanborn, Minxia Cai, Lijia Zhang, Yanhua Xu, Kui Lin. Preclinical antitumor activity and first-in-human phase I study of NB004/GDC-0570, a novel pan-PIM kinase inhibitor, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT116.

Pooled analysis of pralatrexate single-agent studies in patients with relapsed/refractory peripheral T-cell lymphoma

AbstractPatients with relapsed or refractory (R/R) mature natural killer cell and T-cell lymphoma have limited treatment options. To evaluate pralatrexate’s performance and factors influencing its safety and efficacy in R/R peripheral T-cell lymphoma (PTCL), we performed a pooled analysis of data from 4 similarly designed, regulatory-mandated prospective clinical trials. Of 221 patients (median age, 59 years; 67.0% male) in the study population, 48.9% had PTCL not otherwise specified (PTCL-NOS), 21.3% angioimmunoblastic T-cell lymphoma, and 11.8% ALK-negative anaplastic large cell lymphoma (ALCL). Patients received pralatrexate for a median of 2.56 months (range, 0.03-24.18) and had a 40.7% objective response rate with a median duration of response of 9.1 months, progression-free survival 4.6 months, and overall survival 16.3 months. The most common treatment-related all-grade adverse events were stomatitis, thrombocytopenia, white blood cell count decrease, pyrexia, and vomiting. Subgroup exploratory analyses suggest improved efficacy with 1 prior line of chemotherapy vs 2 or ≥4 prior lines; PTCL-NOS or ALCL vs transformed mycosis fungoides; chemotherapy and transplant before pralatrexate vs chemotherapy alone or chemotherapy with other nontransplant treatments. In conclusion, these pooled analysis results further support using pralatrexate in patients with R/R PTCL. Prospective studies are needed to confirm the findings of subgroups analyses.

The efficacy and safety of tinengotinib in patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC).

133 Background: Tinengotinib is a spectrum-selective multi-kinase inhibitor that targets cell proliferation, angiogenesis, and immune-oncology pathways by inhibiting Aurora kinases A/B, Janus kinases (JAK), and receptor tyrosine kinases (FGFRs, VEGFRs). It has been reported that the activation of JAK/STAT and fibroblast growth factor receptor (FGFR) signaling drives prostate tumor plasticity. Here we present the preliminary safety and efficacy data of tinengotinib in patients with mCRPC from three early phase clinical trials conducted in the US and China. Methods: Eligible mCRPC patients who have no available standard therapeutic treatment options were enrolled to the three studies. Tinengotinib was given as monotherapy at 8 mg QD, 10 mg QD and 12 mg QD. Efficacy tumor assessments were based on RECIST v1.1 for measurable disease and Prostate Cancer Working Group 3 criteria for non-measurable (bone) disease. PSA50 response was also evaluated. CTCAE v5.0 was used for safety assessments. Results: As of 28AUG2023, 30 patients with mCRPC were treated at dose levels of 8 mg QD (n=1), 10 mg QD (n=19) and 12 mg QD (n=10). Median age was 67 years (range 52-82) with ECOG performance status of 1 in 93% of patients. All patients had at least 2 prior therapies including 77% prior docetaxel, 87% prior abiraterone, and 30% prior enzalutamide. The median follow-up time is 5.4 months. Twenty-two (22) patients were efficacy evaluable, of which 13 were evaluable per RECIST v1.1. Fourteen (14) patients were PSA evaluable. The median radiographic progression-free survival (rPFS) was 5.6 months (95% CI, 3.3-7.3). Overall response rate (ORR) was 46% (6/13) and the disease control rate (DCR) was 85% (11/13). Median duration of response (DoR) was 3.0 months. The PSA50 response rate was 50% (7/14). Treatment-related adverse events (TRAEs) occurred in 28 patients (93%). The most common TRAEs (≥20%) included blood thyroid stimulating hormone increase (43%), anemia (37%), hypertension (27%), aspartate aminotransferase increase (23%), electrocardiogram QT prolongation (20%) and white blood cell count decrease (20%). Conclusions: Tinengotinib safety profile was tolerable and manageable. The preliminary efficacy data showed promising clinical benefit of tinengotinib monotherapy in patients with heavily pretreated mCRPC. Further study of tinengotinib in this disease is warranted. Clinical trial information: NCT03654547 , NCT04742959 , NCT05253053 .

QL1604 plus paclitaxel-cisplatin/carboplatin in patients with recurrent or metastatic cervical cancer: an open-label, single-arm, phase II trial.

QL1604 is a highly selective, humanized monoclonal antibody against programmed death protein 1. We assessed the efficacy and safety of QL1604 plus chemotherapy as first-line treatment in patients with advanced cervical cancer. This was a multicenter, open-label, single-arm, phase II study. Patients with advanced cervical cancer and not previously treated with systemic chemotherapy were enrolled to receive QL1604 plus paclitaxel and cisplatin/carboplatin on day 1 of each 21-day cycle for up to 6 cycles, followed by QL1604 maintenance treatment. Forty-six patients were enrolled and the median follow-up duration was 16.5 months. An 84.8% of patients had recurrent disease and 13.0% had stage IVB disease. The objective response rate (ORR) per Response Evaluation Criteria in Advanced Solid Tumors (RECIST) v1.1 was 58.7% (27/46). The immune ORR per immune RECIST was 60.9% (28/46). The median duration of response was 9.6 months (95% confidence interval [CI]=5.5-not estimable). The median progression-free survival was 8.1 months (95% CI=5.7-14.0). Forty-five (97.8%) patients experienced treatment-related adverse events (TRAEs). The most common grade≥3 TRAEs (>30%) were neutrophil count decrease (50.0%), anemia (32.6%), and white blood cell count decrease (30.4%). QL1604 plus paclitaxel-cisplatin/carboplatin showed promising antitumor activity and manageable safety profile as first-line treatment in patients with advanced cervical cancer. Programmed cell death protein 1 inhibitor plus chemotherapy may be a potential treatment option for the patient population who have contraindications or can't tolerate bevacizumab, which needs to be further verified in phase III confirmatory study. Trial RegistrationClinicalTrials.gov Identifier: NCT04864782.

Orelabrutinib for the treatment of relapsed or refractory marginal zone lymphoma: A phase 2, multicenter, open-label study.

Marginal zone lymphoma (MZL) is an indolent type of non-Hodgkin lymphoma that develops through pathological B cell receptor signaling. Orelabrutinib, a new-generation oral small molecule Bruton's tyrosine kinase inhibitor, was evaluated in relapsed/refractory (r/r) MZL patients. Previously treated r/r MZL patients received orelabrutinib 150 mg once daily in a phase 2, multicenter, single-arm study conducted in China. The primary endpoint was overall response rate (ORR) assessed by an Independent Review Committee (IRC) based on the Lugano 2014 classification. Other efficacy, safety, and pharmacokinetic profiles were evaluated as secondary outcome measures. A total of 111 patients were enrolled, of which 90 patients had MZL confirmed by central pathology review, who were mainly with extra-nodal MZL of mucosa-associated lymphoid tissue (MALT, 46.7%) and nodal MZL (35.6%). The majority had late-stage disease, with stage IV accounting for 75.6%. After a median follow-up duration of 24.3 months, the IRC-assessed ORR was 58.9% (95% confidence interval [CI], 48.0-69.2), with rates of complete response and partial response being 11.1% and 47.8%, respectively. The IRC-assessed median duration of response was 34.3 months, and the IRC-assessed median progression-free survival (PFS) was not reached with a 12-month PFS rate of 82.8% (95% CI, 72.6-89.5). The rate of overall survival at 12 months was 91.0% (95% CI, 82.8-95.4). Common all-grade treatment-related adverse events (TRAEs) included anemia (27.9%), neutrophil count decrease (23.4%), white blood cell count decrease (18.0%), platelet count decrease (17.1%), blood present in urine (16.2%), rash (14.4%), and upper respiratory tract infection (10.8%). Thirty-four patients (30.6%) experienced grade 3 or higher TRAEs. Serious TRAEs occurred in 18 patients (16.2%), of which pneumonia (5.4%) was the most common. Seven patients (6.3%) discontinued orelabrutinib due to TRAEs. Orelabrutinib demonstrated high response rates with durable disease remission and was well tolerated in Chinese patients with r/r MZL.

Orelabrutinib, a new‐generation bruton tyrosine kinase inhibitor, demonstrates safety and efficacy in relapsed/refractory marginal zone lymphoma

Introduction: Marginal zone lymphoma (MZL) is an indolent type of non-Hodgkin lymphoma that develops through pathological B cell receptor signaling. Orelabrutinib, a new-generation oral small molecule Bruton’s tyrosine kinase (BTK) inhibitor, was evaluated in relapsed/refractory (r/r) MZL patients. Methods: Previously treated r/r MZL patients received orelabrutinib 150 mg once daily in a phase 2, multicenter, single-arm study conducted in China. The primary endpoint was overall response rate (ORR) assessed by an Independent Review Committee (IRC) based on the Lugano 2014 classification. Other efficacy, safety, and pharmacokinetic parameters were evaluated as secondary outcome measures. Results: Between April 2019 and November 2021, 111 Chinese patients with a median age of 60 y/o (range 23–77) were enrolled. Among those, 83 patients who received at least 1 prior therapy with an anti-CD20 antibody-containing regimen were confirmed with MZL by the central pathological review, who were mainly with extranodal MZL of mucosa-associated lymphoid tissue (MALT, 45.8%) and nodal MZL (36.1%). The majority had late-stage diseases, the stage IV accounting for 75.9%. After a median follow-up of 22.3 months, the IRC-assessed ORR was 57.8% (95% CI, 46.5% to 68.6%). Ten patients achieved a complete response (CR, 12%), and 38 achieved a partial response (PR, 45.8%). The IRC-assessed median duration of response (DoR) and median progression-free survival (PFS) was 34.3 months and 36.0 months, respectively, with a 12-month PFS rate of 84.3% (95% CI, 73.9% to 90.8%). The rate of overall survival (OS) was 91.5% (95% CI, 82.9% to 95.8%) at 12 months. Treatment was well tolerated with most treatment-related adverse events (TRAE) being grade 1 or 2. In all the 111 patients, common all-grade TRAEs included anemia (27.9%), neutrophil count decrease (23.4%), white blood cell count decrease (18.0%), platelet count decrease (17.1%), rash (14.4%), and upper respiratory tract infection (10.8%). Thirty-four patients (30.6%) experienced grade 3 or higher TRAEs. Serious TRAEs occurred in 18 patients (16.2%), of which pneumonia (5.4%) was the most common. Seven patients (6.3%) discontinued orelabrutinib due to TRAEs. Conclusions: Orelabrutinib demonstrated high response rates with durable disease remission and was well tolerated in Chinese patients with r/r MZL. This trial is registered at ClinicalTrials.gov as NCT03797456. Keyword: Indolent non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

Safety and performance of the Spectra Optia apheresis system for white blood cell depletion in patients with elevated white blood cell counts.

For the past 30 years, white blood cell depletion (WBCD) or leukocytapheresis has been conducted to rapidly reduce excessive circulating white blood cell (WBC) concentrations in patients at risk for or with symptoms of leukostasis due to hyperleukocytosis. The goal of leukocytapheresis is to prevent or treat acute complications from leukostasis, thereby enabling patients to receive potentially curative chemotherapy. This report details the results from a retrospective and a prospective clinical study conducted in the European Union and the People's Republic of China, which assessed the use of the Spectra Optia Apheresis System for leukocytapheresis in patients with hyperleukocytosis. The primary objective of both studies was to the assess the safety and performance of the WBCD procedure in patients with elevated WBC counts. Data were collected from 72 participants completing 87 WBCD procedures. The mean percent change in participant WBC counts post-procedure was 50.3 ± 21.2% and the collection efficiency (CE1) of the WBCD procedures was 53.7 ± 19.8%. Sixty-one participants (95.3%) experienced a total of 279 adverse events (AEs) with the majority of the AEs related to post-procedure changes in laboratory values, which is an anticipated AE in this patient population. The data collected within these studies indicate that the WBCD procedure is safe and well tolerated in patients with hyperleukocytosis as evaluated by percent decrease in WBC count, CE1, and AE incidence.

Real-World Experience of Ropeginterferon in Myeloproliferative Neoplasm Patients

INTRODUCTION: Ropeginterferon alfa-2b njft (Ropeg) is a novel mono-pegylated alfa interferon that was recently approved for the first-line treatment of polycythemia vera (PV). In the phase 3 PROUD-PV/CONTINUATION studies ropeg was efficacious and safe. However, little is known about this agent in real-world practice. We present our experience with myeloproliferative neoplasm (MPN) patients treated with ropeg at our institution. METHODS: We identified patients who had received prior authorization for ropeg in the Massachusetts General Brigham (MGB) specialty pharmacy. We then collected clinical data and assessed the safety and preliminary efficacy of ropeg in 12 MPN patients treated across the MGB institute. RESULTS: A total of 12 MPN patients were included in this series, including 11 PV patients and 1 essential thrombocythemia (ET) patient. Median age at ropeg initiation was 53 years (range 31-69), and 67% of patients were male. Of the 11 PV patients, 8 were considered high-risk for PV by National Comprehensive Cancer Network (NCCN) Guidelines, and 3 were considered low-risk. The one ET patient was a low-risk patient by Revised International Prognostic Score of Thrombosis (R-IPSET). Indications for starting therapy included need for cytoreduction due to high-risk status (N=8, including 4 patients who had prior thrombosis); extreme thrombocytosis or worsening platelets and white blood cell (WBC) counts with phlebotomy (N=2), symptoms (N=2), and patient desire to prevent disease progression (N=1). Five patients required phlebotomy within 1 month of starting ropeg. Five patients were transitioned from a prior therapy, including 3 patients from hydroxyurea, 1 from peginterferon alfa-2a, and 1 from ruxolitinib. In 2 patients transitioning from hydroxyurea, ropeg was started at 50 mcg and the hydroxyurea was tapered off after 11 and 26 days (data not available for the third patient). In the 1 patient transitioning from peginterferon alfa-2a 180 mcg, peginterferon alfa-2a was stopped and ropeg was started at 300 mcg, and then increased by 100 mcg every 2 weeks to a maximum dose of 500 mcg. In the 1 patient transitioning from ruxolitinib, ropeg was started at 100 mcg and ruxolitinib was tapered off after 50 days. All patients tolerated the transition well without any significant cytopenias or need to hold the ropeg. Patients who were not on prior therapy were started on a dose of 100 mcg. All patients except for the patient previously on peginterferon alfa-2a were instructed to increase their dose by 50 mcg every 2 weeks to a maximum dose of 500 mcg per the Food and Drug Administration (FDA) label. Ropeg was overall well-tolerated in all patients. Two patients had grade 1 increases in liver function tests (LFTs), 1 patient had minor injection site reactions, and 2 patients had malaise which was mild in severity. LFTs resolved after alcohocl cessation in 1 patient, and after dose reduction of ropeg in another; no other dose reductions of ropeg occurred. At time of analysis, the median time on ropeg was 99 days, and the median dose was 350 mcg. Four patients have reached the maximum dose of ropeg at 500 mcg. Four patients required an additional phlebotomy session after starting ropeg. Follow-up complete blood cell counts (CBC) were obtained at a median of 62 days after ropeg initiation. We found significant decreases in WBC counts compared to baseline (p<0.01), but no significant decreases in hematocrit or platelet counts. At a median follow-up time of 99 days, no patient has yet obtained a complete hematologic response. CONCLUSIONS: Overall, we found that ropeg is remarkably well-tolerated with improvements seen in hematologic parameters. However, responses are slow, especially with the need for gradual dose up titration, which is consistent with published data. More mature data will be presented at the time of the meeting. Our experience is informative as real-world practices with ropeg can differ significantly from that seen in clinical trials.

Phase 1 dose escalation study of MH048, a novel and non-covalent BTK inhibitor in patients with relapsed or refractory B-cell malignancies.

7547 Background: Despite impressive clinical response of covalent Bruton’s tyrosine kinase (BTK) inhibitors in multiple B cell malignancies, treatment failure often occurs through drug resistance most commonly due to BTK cysteine-481 (C481) mutation or intolerance due to off-target toxicities. We evaluated the safety, pharmacokinetics (PK) and preliminary antitumor efficacy of MH048, an orally bioavailable, potent, and reversible inhibitor of both wild type and C481S-mutant BTK, in selected patients with relapsed or refractory (R/R) B-cell malignancies. Methods: Eligible patients with R/R B-cell malignancies were enrolled in a Phase 1, multicenter, open-label, dose escalation study. The primary objectives were to assess the safety and tolerability of MH048, and to determine the maximal tolerated dose (MTD) and the recommended dose for expansion. The secondary objectives were to assess the PK profile and preliminary evidence of anti-tumor activity. Results: Twelve patients were treated with MH048 across six dose levels (5 mg, 15 mg, 45 mg, 90 mg, 135 mg, 200 mg QD) in fast state. No dose-limiting toxicities were observed and the MTD was not reached. The most common drug-related TEAEs (Any grade) that occurred in &gt; 2 patients were platelet count decrease (n=5), anemia (n=4), neutrophil count decrease (n=4), lipase increase (n=3), and white blood cell count decrease (n=3). Drug-related grade 3 TEAEs included platelet count decrease, neutrophil count decrease, lipase increase, and hypertension (one patient for each). Plasma exposure of MH048 and its active metabolite (M3) increased in a dose-proportional manner from 5 to 200 mg dose levels. Sign of efficacy was observed starting from 15 mg. Among eleven efficacy-evaluable patients (one patient in 200 mg cohort is yet to be evaluated), one complete response (CR) and four partial responses (PRs) were achieved in ≥90 mg cohorts, including patients with MZL (n=1, CR), MCL (n=2), SLL (n=1) and DLBCL (n=1). Of the two MCL patients with PRs, one was heavily pretreated including ibrutinib prior to the enrollment. The recommended doses for expansion were selected as 135 and 200 mg. Conclusions: MH048 was well-tolerated and efficacy in heavily pre-treated patients with B-cell malignancies was observed. Pharmacokinetics studies suggest once-daily dosing. The dose expansion study is ongoing at 135 and 200 mg QD for CLL and MCL patients. Clinical trial information: NCT04689308.

Efficacy and safety of venetoclax in combination with azacitidine or decitabine in an outpatient setting in patients with untreated acute myeloid leukemia.

7044 Background: Venetoclax (Ven), a highly selective BCL-2 inhibitor, combined with hypomethylating agents (HMAs) azacitidine (Aza) or decitabine (Dec) is approved for the treatment of newly diagnosed acute myeloid leukemia (ND AML) in patients (pts) who are ineligible to receive intensive chemotherapy. Previous clinical studies initiated Ven + HMA in an inpatient setting due to concerns of tumor lysis syndrome (TLS). This Phase 3b, single-arm, multicenter, open-label study (NCT03941964) evaluated the efficacy and safety of Ven + HMA in a US community-based outpatient setting. Methods: Pts with ND AML who were ineligible to receive intensive chemotherapy, had no evidence of spontaneous TLS at screening, and were deemed an appropriate candidate for outpatient initiation of Ven + HMA by the investigator were eligible. Pts received Ven (400 mg) in combination with Aza (75 mg/m2) or Dec (20 mg/m2) for up to 6 cycles during the study period. Pts could continue receiving commercially acquired Ven after the study period. All pts received TLS prophylaxis. The primary endpoint was the composite complete remission (CR) rate (CR + CR with incomplete hematologic recovery [CRi]) per modified International Working Group criteria. Secondary endpoints included CR or CRi rates and transfusion independence (TI). TLS was assessed per Howard criteria (Howard. N Engl J Med. 2011;364:1844). Results: At the 19 Oct 2021 cutoff date, 60 pts were enrolled and treated (Ven + Aza, n=30; Ven + Dec, n=30). Efficacy outcomes are shown in the Table. The composite CR rate was 58%. CR and CRi rates were 13% and 45%, respectively. Most pts (&gt;50%) maintained TI, and 41% and 57% of pts dependent on red blood cells or platelets, respectively, converted to TI. Bone marrow blast clearance was achieved in 42 pts (70%) at a median 26 days after treatment initiation. The most common (≥50%) AEs were anemia (75%), neutrophil count decrease (55%), white blood cell count decrease (52%), and nausea (50%). Serious AEs occurred in 67% of pts, most commonly (≥15%) febrile neutropenia (28%) and sepsis (15%). Two pts (3%) had TLS; neither event led to treatment discontinuation. Of pts who achieved blast clearance, 12/42 (29%) had a new event of myelosuppression post-blast clearance and prior to the next cycle. Conclusions: The results of this US community-based study indicate that Ven + HMA is an effective treatment option for pts with ND AML and, with appropriate TLS prophylaxis and monitoring, can safely be initiated in an outpatient setting. Clinical trial information: NCT03941964. [Table: see text]

Hematology and biochemical values in equines naturally infected with Theileria equi in Nigeria.

Equine piroplasmosis (EP) is a tick-borne disease of equines with resultant economic consequences. To date, little information is available regarding the effects of EP on the health of equids in Nigeria. Therefore, this study was carried out to ascertain the effects of natural sub-clinical infection with T. equi on the hematology and biochemical profiles of horses and donkeys. Blood and serum samples were subjected to hematology and serum biochemistry analyses, respectively. Data corresponding to PCR-positive (infected) and PCR-negative (uninfected) was computed to ascertain changes in any of the parameters. Hematological significant findings (P<0.001) in both horses and donkeys include decreased packed cell volume (PCV), red blood cell (RBC) count, hemoglobin (Hb) concentration, and white blood cell (WBC) counts in the infected group compared to the uninfected group. In horses, the PCV (%) and Hb (g/dL) values were 40.6±1.0 and 13.4±1.7 in the uninfected group compared with 30.8±0.6 and 10.1±0.3 in the infected group respectively and differs significantly (P<0.001). Similarly, in the donkeys, the PCV (%) and Hb (g/dL) values were 32.2 ± 0.5 and 10.5 ± 0.2 in the uninfected group compared with 28.5±0.7 and 9.5±0.2 in the infected group respectively with significant difference (P<0.001). Additionally, we observed a slight decrease in WBC counts (×103/μL) in the infected group in horses (9.9±0.4) and donkeys (10.2±4.3) compared with 10.5±2.0 and 13.0±0.8 from the uninfected respectively. Serum biochemical profiles revealed slight increase in the levels of total proteins principally the globulin fractions in the infected group in both equids. The findings from this study will be helpful in the diagnosis, prognosis, and treatment evaluation of equines in Nigeria.

Age-Associated Decline in Blood Parameters in Individuals with Sickle Cell Disease

IntroductionIndividuals with sickle cell disease (SCD) in resource-rich countries are now living longer due to the implementation of newborn screening, use of prophylactic penicillin, and introduction of hydroxyurea. The impact of SCD on the bone marrow and peripheral blood counts as individuals with SCD age is not well described in the hydroxyurea era. As a result of increased red blood cell (RBC) turnover due to hemolysis in SCD, potential ineffective erythropoiesis, and well-described systemic inflammatory processes, the increased stress in the bone marrow may manifest as decreased peripheral blood cell counts over time in a during an aging process unique to those with SCD.ObjectiveThe objective was to model routine clinical blood measurements (n=5,328) with a longitudinal cohort of 447 patients, resulting in models of circulating blood counts as a potential marker of bone marrow function across the lifespan in adults with SCD. Our working hypothesis was that increasing age would be associated with decreases in certain blood counts, with trends modified by SCD genotype severity.MethodsIn this large, single institution retrospective cohort study, we analyzed blood count measurements from adults with SCD. We used an accelerated longitudinal cohort design to examine changes in white blood cell count (WBC), hemoglobin (HGB), absolute reticulocyte count (ARC), and platelet count over time. Genotypes were grouped as severe (HbSS or HbSβ 0-thalassemia; n=301), non-severe (HbSC or HbSβ +-thalassemia; n=136), or other (n=10). For HGB and ARC, we adjusted for estimated glomerular filtration rate (eGFR) and serum creatinine.ResultsPatients ranged in age at enrollment from 18 to 84 (M = 31.9, SD=12.9), with median follow-up time of 3.6 years and a median of 6 measurements per patient. Overall, HGB and ARC decreased across the lifespan; however, trends were moderated by genotype. Compared to individuals with non-severe genotypes, those with the severe genotypes had consistently lower HGB levels that did not differ by age. For ARC, the severe genotypes had higher levels in young adulthood, which slowly decreased with age. WBC also decreased with age for this group. In contrast, individuals with the non-severe genotype showed an increase in WBC by age. Platelet counts decreased with increasing age for those with the severe genotype while those with non-severe genotypes showed an increase with age.ConclusionSevere SCD genotypes are associated with decreases in HGB, ARC, WBC, and platelet count by age. For HGB and ARC, these declines are significantly attenuated by renal function, suggesting that such declines are largely related to worsening renal function with age. However, an intrinsic bone marrow contribution to this aging process should also be explored in future studies. Decreases in WBC and platelet count with time, observed in the severe genotypes, support the presence of pathological processes of bone marrow dysfunction that may worsen with age. A possible etiology of the increasing bone marrow dysfunction in SCD may be a result of bone marrow exhaustion or cellular senescence. Prospective studies to explore contributors to reduced blood counts during the aging process in individuals with SCD are needed. We are actively exploring potential biomarkers associated with this process. [Display omitted] DisclosuresCarden: Forma Therapeutics: Current Employment. Derebail: Novartis: Consultancy; UpToDate: Patents & Royalties; Travere Therapeutics: Consultancy; Bayer: Consultancy. Ataga: Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy; Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Clinical Features and Cytoreduction Therapy in Children with Newly Diagnosed Acute Myeloid Leukemia and Hyperleukocytosis

Background Hyperleukocytosis is observed in 5% to 20% of patients with newly diagnosed acute myeloid leukemia (AML) and is associated with an increased risk of early complications and mortality. While being used frequently in patients with AML and hyperleukocytosis, the clinical utility of leukapheresis has not been conclusive. Low-dose chemotherapy has also been used recently as a cytoreduction method in these patients, but the data are limited.Objectives: To describe and compare the clinical and laboratory characteristics, early adverse events, and outcomes of children with newly diagnosed AML and hyperleukocytosis according to cytoreductive methods; leukapheresis, low dose chemotherapy (cytarabine), or no intervention.Methods: We studied patients with newly diagnosed AML treated on three multi-institutional St. Jude protocols, AML97, AML02, and AML08, between 1997 and 2017. Hyperleukocytosis was defined as white blood cell (WBC) counts of 100 x 10 9/L or higher at diagnosis. The decision of cytoreductive treatment was made as the discretion of the treating physician. Leukoreduction was used in the AML97 and AML02 studies, and cytarabine (100mg/m 2/dose every 12 hours) was the first choice for AML08 study. We reviewed baseline clinical characteristics and laboratory data (complete blood cell counts [CBC], chemistries, coagulation) and adverse effects (grade 3 or higher on neurologic, renal, respiratory, and hemorrhagic complications based on Common Terminology Criteria for Adverse Events) from diagnosis to day 14 of protocol-based chemotherapy. Cairo-Bishop criteria was used for laboratory/clinical tumor lysis syndrome. The time from the first CBC to administration of protocol-based chemotherapy was calculated.Results: A total of 49 patients were identified: 8 patients in AML97, 19 in AML02, and 22 in AML08) (Table). The age at diagnosis was 10.8 years with a median initial WBC count of 157.6 x 10 9/L; CNS (CNS 2, 3 or traumatic lumbar puncture with blasts) was seen in 29 (59.2%) cases. FAB M4 or M5 subtype was found in 30 patients (61.2%), 11q23 abnormalities in 15 (30.6%) and inv(16) in 8 (16.3%). In regards to leukoreduction method, 16 patients received leukapheresis (14 patients in AML97/02 and 2 in AML08), 18 cytarabine (all in AML08) and 1 hydroxyurea (in AML08); 14 did not receive leukoreduction (13 patients in AML97/02 and 1 in AML08). Leukapheresis was used more often in patients with higher diagnostic WBC counts (218.7 x 10 9/L) than those treated with cytarabine (152.9 x 10 9/L) or without intervention (127.3 x 10 9/L) (P<0.001). The decrease of WBC counts (%) before and after intervention was more pronounced among patients treated with cytarabine than those treated with leukapheresis (75% vs. 48.5%, P=0.03). When decreases in WBC counts were evaluated from the first CBC to the initiation of protocol therapy, cytarabine treatment was associated with more decreases in WBC counts from baseline (84.8%) than leukapheresis (46.7%) or no intervention (1.8%) (P<0.001). Patients who received cytarabine intervention had a longer median time from the first CBC to initiation of protocol therapy (95.2 hours) compared to those who received leukapheresis (28.1 hours) and no intervention (20.4 hours) (P<0.001). No early deaths were observed from the time of diagnosis to two weeks after initiation of protocol chemotherapy, and no statistically significant differences were noted in the incidences of neurologic, pulmonary, renal, hemorrhagic events, or laboratory/clinical tumor lysis syndrome among these three groups.Conclusion: Low-dose cytarabine treatment appears to be a safe and effective mean of cytoreduction for patients with AML and hyperleukocytosis. Further studies are needed to determine if this approach is preferable among patients treated with contemporary treatment. [Display omitted] DisclosuresPui: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Data Monitoring Committee.

A Phase II, Multicenter, Single-Arm, Open-Label Study of Parsaclisib, a PI3Kδ Inhibitor, in Relapsed or Refractory Follicular Lymphoma in China

Background: Follicular lymphoma (FL) is a common subtype of indolent lymphomas, and accounts for about 10% of all non-Hodgkin lymphoma(NHL) cases. FL patients generally respond well to the 1 st line therapy, but most patients would then relapse, and duration of response gradually decreases as treatment line escalates. For FL patients of 3 rd line and beyond, treatment options are limited, and recurrent chemotherapy also greatly impact their quality of life. Four PI3Kδ inhibitors have been approved in the US for adult patients with relapsed or refractory FL. Currently, multiple trials investigating PI3K inhibitors in R/R FL are on-going in China, yet none has been approved. Parsaclisib, a potent, highly-selective, next-generation PI3Kδ inhibitor, has shown promising efficacy and tolerance in patients with previously treated B-cell malignancies. Here, we report interim result of CIBI376A201 (NCT04298879), a multicenter, open-label phase 2 study of parsaclisib in 3 rd line FL patients in China.Methods: Key eligibility included, age ≥18 years, histologically confirmed FL grade 1, 2, or 3a, ≥2 prior systemic therapies, Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, and ineligible for hematopoietic stem cell transplantation (HSCT). Patients were allocated to receive parsaclisib 20 mg once daily (QD) for 8 weeks followed by 2.5 mg QD, till disease progression, intolerable AE or withdrawal from study due to other reasons. Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was required. Primary end point was objective response rate (ORR) evaluated by independent review committee (IRC), secondary end points included: ORR by investigator, duration of response (DOR), progression-free survival (PFS), overall survival (OS), pharmacokinetic characteristics and safety and tolerability.Results: From April, 2020 to 11 th, April 2021 (data cut-off), 36 patients were treated. Enrollment is ongoing. At cut-off date, 5 (13.9%) patients had discontinued treatment due to PD (progressive disease)/PMD (progressive metabolic disease). The median exposure (range) was 104 days (5-354 days). The median age was 51 years, and 52.8% of the patients were male. The median time since initial diagnosis was 3.3 years. At enrollment, most patients (88.9%) had an ECOG PS ≤1, and 55.6% had a Follicular Lymphoma International Prognostic Index score ≥3 (high risk). All patients had ≥2 lines of prior systemic therapy, in which 22.2% had 3 or more prior lines.At the data cut-off date, 24 patients were evaluable for response. According to the investigator's evaluation, the ORR and CRR were 91.7% (95% confidence interval [CI]: 73%−99%) and 16.7% (95% confidence interval [CI]: 4.7%-37.4%) respectively, in all evaluable patients. The median DOR was not reached among responders overall.Among the 36 patients evaluable for safety, the most common treatment-emergent adverse events (TEAE) were neutrophil count decrease (36.1%), white blood cell count decrease (16.7%), platelet count decrease (16.7%), anemia (13.9%), upper respiratory tract infection (11.1%), ALT elevation (11.1%) and diarrhea (11.1%). The most common grade ≥3 TEAEs were neutrophil count decrease (8.3%), platelet count decrease (2.8%), upper respiratory tract infection (2.8%) and anemia (2.8%). 22.2% of patients had dose interruption due to TEAE, no dose reduction occurred due to TEAE. No treatment discontinuation occurred due to TEAE. Serious TEAEs included upper respiratory tract infection (2.8%), organ dysfunction (2.8%), dizziness (2.8%) and nasal cavity mass (2.8%), all unrelated to the study drug. One patient (2.2%) died during the trial, considered unrelated to studied drug by investigator.Conclusion: Parsaclisib demonstrated promising efficacy, and was generally well tolerated. These results demonstrate parsaclisib could bring substantial benefit for 3 rd line FL patient. Updated data will be presented in the future. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

TIME-DEPENDENT, LIFE-SAVING SUPPORTIVE TREATMENT IN AN UNORDINARY PULMONARY LEUKOSTASIS PRESENTATION: A CASE REPORT

TOPIC: Pulmonary Manifestations of Systemic Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Pulmonary leukostasis (PL) is a medical emergency defined by an extremely high white blood cell count (WBC) with pulmonary symptoms with or without imaging findings. This condition is seen more frequently in acute myeloid leukemia or chronic myeloid leukemia during a blast crisis and confers up to 30% mortality. Symptoms usually do not occur unless WBC exceeds 400x10ˆ3 / µL in patients with chronic lymphocytic leukemia (CLL). Here we present an atypical presentation of this dreaded disease. CASE PRESENTATION: An 80-year-old man with a history of atrial fibrillation, benign prostatic hyperplasia, diabetes mellitus, and a recent diagnosis of chronic lymphocytic leukemia came to the emergency room with tachypnea, hypoxia, headache, slurred speech, drowsiness, and confusion. Days before his arrival, he began with bradyphrenia, subjective fever, and dry cough. Vital signs with tachypnea and peripheral oxygen saturation of 90%. Routine laboratories stood out for 95.2 x10ˆ3 / µL white blood cells, with 65% immature blood cells, 17% lymphocytes, 10% neutrophils, and arterial blood gas with metabolic alkalosis and hypoxemia. Supportive therapy began with respiratory therapies every four hours, aggressive intravenous hydration, and empirical antibiotics. Chest radiography and chest computed tomography failed to show effusions, infiltrates, or consolidations. Brain studies negative for intracranial pathology. Debulking and leukoreduction therapies were discussed with the patient who decided to continue with supportive therapy, even with the risk of tumor lysis. After observation and aggressive hydration, there was a significant clinical improvement that correlated with the decrease in WBC from 95.2x10ˆ3 / µL to 69.9x10ˆ3 / µL. Noteworthy, cultures and respiratory panel were negatives. The following days the antibiotics were suspended and the patient was discharged with scheduled chemotherapy. DISCUSSION: Leukostasis is an emergency condition that, if overlooked or misdiagnosed, could be fatal if left untreated. In case of clinical suspicion, expeditious treatment is indicated since the mortality rate is approximately 20 to 40 percent regardless of the leukocytosis. CONCLUSIONS: Although it is less common in CLL and almost unthinkable with WBC less than 100x10ˆ3 / µL; L This case highlights the important role of high clinical suspicion of PL even if not all medical criteria are met and its response to supportive and symptomatic therapy when implemented in a rapid timely manner. REFERENCE #1: Kacar, D., Yarali, N., Candir, M. O., Kara, A., Ozbek, N., & Tunc, B. (2017). Pulmonary Leukostasis. Journal of Pediatric Hematology/Oncology, 39(2), 156–158. doi:10.1097/mph.0000000000000731 REFERENCE #2: Soares, F. A., Landell, G. A. M., & Cardoso, M. C. de M. (1992). Pulmonary leukostasis without hyperleukocytosis: A clinicopathologic study of 16 cases. American Journal of Hematology, 40(1), 28–32. doi:10.1002/ajh.2830400106 REFERENCE #3: Baer, M. R., Stein, R. S., & Dessypris, E. N. (1985). Chronic lymphocytic leukemia with hyperleukocytosis the hyperviscosity syndrome. Cancer, 56(12), 2865–2869. doi:10.1002/1097-0142(19851215)56:12<2865::aid-cncr2820561225>3.0.co;2-6 DISCLOSURES: No relevant relationships by Ian Da Silva Lugo, source=Web Response No relevant relationships by Arelis Febles, source=Web Response No relevant relationships by Juan Feliciano-FIgueroa, source=Web Response No relevant relationships by Heydee Fournier, source=Web Response No relevant relationships by Joel Gonzalez Chaple, source=Web Response No relevant relationships by Juan Santiago, source=Web Response

Overnight Immune Regulation and Subjective Measures of Sleep: A Three Night Observational Study in Adolescent Track and Field Athletes.

To ensure health maintenance of young athletes, immunological stress due to physical exercise has to be balanced for performance development and health maintenance. Sleep is an important influencing factor for immune regulation because of its regenerating effect. In an attempt to assess overnight immune regulation, this observational study aimed to examine associations between changes in capillary immunological blood markers and measures of sleep in adolescent athletes. Over a period of three nights, 12 male (n = 6) and female (n = 6) adolescent track and field athletes aged 16.4 ± 1.1 years were monitored for their sleep behavior (e.g., sleep duration, sleep depth) and immune regulation by using subjective (e.g., sleep) and objective (capillary blood markers) measurement tools. Over the 4 day (three nights), athletes followed their daily routines (school, homework, free time activities, and training). Training was performed for different disciplines (sprint, hurdles, and long-jump) following their daily training routines. Training included dynamic core stability training, coordination training, speed training, resistance training, and endurance training. Capillary blood samples were taken 30–45 min after the last training session (10:00–12:00 a.m. or 5:00–6:00 p.m.) and every morning between 7:00 and 10:00 a.m. Changes in capillary blood markers from post-training to the next morning and morning-to-morning fluctuations in capillary blood markers were analyzed over a three-night period using a generalized estimating equations (GEE) statistical approach. Associations of overnight changes with measures of sleep were analyzed using GEE. We found significant decreases in white blood cell count (WBC), granulocytes (GRAN), granulocytes% (GRAN%), monocytes (MID), and granulocyte-lymphocyte-ratio. In contrast, lymphocytes% (LYM%) increased significantly and systemic inflammation index showed no difference from post-training to the next morning. Furthermore, there was a significant decrease in WBC and GRAN between morning 1 and morning 3. At morning 4, values returned to baseline (morning 1), irrespective if athletes performed a training session or rested on day 3. Furthermore, sleep duration was significantly and negatively associated with changes in WBC (βz = −0.491) and lymphocytes (βz = −0.451). Our results indicate that overnight sleep duration is an important parameter of immunological overnight regulation for adolescent athletes.