Lymphocyte Cytosolic Protein 1 (L-plastin) I232F Mutation Impairs Granulocytic Proliferation and Causes Neutropenia

Neutrophils migrate into inflamed tissue, engage in phagocytosis, and clear pathogens or apoptotic cells. These processes require well-coordinated events involving the actin cytoskeleton. We describe a child with severe neutropenia and episodes of soft tissue infections and pneumonia. Bone marrow examination showed granulocytic hypoplasia with dysplasia. Whole exome sequencing revealed a de novo heterozygous missense mutation in LCP1, which encodes the F-actin binding protein Lymphocyte Cytosolic Protein 1. To determine its pathophysiologic significance, we stably transduced cells with a doxycycline-inducible wild type LCP1 and LCP1 I232F lentiviral constructs. We observed dysplastic granulocytic 32D cells expressing LCP1 I232F cells. These cells showed decreased proliferation without a block in differentiation. Additionally, expression of LCP1 I232F resulted in a cell cycle arrest at G2/M phase, but it did not lead to increased levels of genes involved in apoptosis or the unfolded protein response. Both 32D and HeLa cells expressing mutant LCP1 showed impaired cell motility and invasiveness. Flow cytometry showed increased F-actin. However, mutant LCP1-expressing 32D cells demonstrated normal oxidative burst upon stimulation. Confocal imaging and subcellular fractionation revealed diffuse intracellular localization of LCP1, but only the mutant form was found in the nucleus. We conclude that LCP1 is a new gene involved in granulopoiesis, and the missense variant LCP1 I232F leads to neutropenia and granulocytic dysplasia with aberrant actin dynamics. Our work supports a model of neutropenia due to aberrant actin regulation.

Nutritional Status And Its Impact On The Occurance Of Complications In Children With Acute Lymbhoblastic Leukemia During 1Stinduction Chemotherapy: The Experience At Bp Koirala Memorial Cancer Hospital

Malnutrition is a common problem in cancer patients. It has been recognized as an important component to influence on tolerance to treatment, increased morbidity, poor prognosis, decreased quality of life and increased health care costs. Acute leukemia is the most common malignancy in children of which acute lymphoblastic leukemia accounts for majority of the cases (75%). Chemotherapy is the main treatment modality for acute lymphoblastic leukemia(ALL). Under nutrition can contribute to the incidence and severity of treatment side effects and increases the risk of infection, thereby reducing the chances of survival. Objectives: To evaluate pretreatment nutritional status (BMI) in children with ALL and its effects during first induction chemotherapy. Methodology: This observational study included sixty-two consecutive children with acute lymphoblastic leukemia, admitted in Haemato-Oncology Ward of BPKMCH over a period of 27 months (15thy May, 2015 to 15th July, 2017) were measured for height and weight to calculate BMI for assessing nutritional status at presentation. Children were grouped into 2 group: normal weight and underweight usingCDC BMI percentile chart by World Health Organization(WHO). Day to day observation and documentation were maintained to identify any side effects and complications over a period of first induction chemotherapy. Findings of the study: Among 62 cases, majority were male (66%). Three forth of the cases were B-cell ALL. More than 34 percent of the cases (27) had under- weight (BMI< 5thpercentile). Effects like very severe neutropenia, febrile neutropenia, infections, musculoskeletal problems, severe pancytopenia, G/I problems were noted mostly in children with underweight. Conclusion: Baseline nutritional status negatively influences in the occurrence of complications during induction chemotherapy in children with ALL. The nutritional support has to be personalized according to the nutritional status of the single patient.

Clinical and Prognostic Features in a Young Adult Patient with de novo Myelodysplastic Syndrome presenting t(11;16) (q23; q24)

hematopoietic clonal neoplasms. MDS occurs mainly in elderly patients. KMT2A rearrangements (KMT2A-r) are rare in MDS, so little is known about their prognostic value. The present study describes the clinical characteristics of a young adult patient diagnosed with MDS-EB-2, presenting the t(11;16)(q23;q24). The Decitabine treatment was initiated since no matching donor was found. The patient showed improved anemia and thrombocytopenia. However, he still had severe neutropenia and clonal chromosomal alteration. Two months after the fifth cycle of Decitabine, the patient presented a worsening of the clinical parameters with increased blast and evolution to AML. He was treated with intensification chemotherapy, but despite all efforts, the patient evolved to death. Treatment refractoriness and leukemia transformation suggest that t(11;16)(q23;q24) with KMT2A-r was associated with poor prognosis. This study reinforces the importance of characterizing new chromosomal alterations and their impact on prognosis in MDS.

Necrotizing Bacterial Myositis as the Initial Presentation of Severe Aplastic Anaemia

Introduction. Necrotizing soft tissue infections are rapidly progressing infections associated with severe inflammation and cytokine release. Early recognition and surgical intervention are key factors to secure survival. The current case presents a patient with multifocal necrotizing soft tissue infection as the initial presentation of severe aplastic anaemia. Case Presentation. A man in his fifties was admitted with septic shock with multiorgan failure and severe pancytopenia, after two days of malaise with high fever and right flank pain. The diagnosis streptococcal necrotizing myositis was significantly delayed due to atypical clinical findings. After initial surgical exploration, the decision was made to defer from surgical debridement due to extensive involvement of several muscle groups, grave pancytopenia, and suspected dismal prognosis. Surprisingly, the patient stabilized after antibiotics and intensive care treatment. Based on severe pancytopenia and hypocellular bone marrow, with no evidence of other bone marrow disorders, the patient was diagnosed with aplastic anaemia. Treatment for aplastic anaemia with antithymocyte globulin, cyclosporine, and eltrombopaq was started, and 2 months later, a partial haematological recovery was observed. The patient could be discharged from hospital without antibiotic treatment. Conclusions. This case illustrates the crucial role of a multidisciplinary approach on admission and further during the clinical course. Clinical improvement despite severe neutropenia and stabilization during immunosuppressive therapy suggest that immunological factors modulate clinical course in necrotizing soft tissue infections.

Risk Factors for Neutropenia after the First Cycle of Chemotherapy for Non-Hodgkin Lymphoma

Background and Objective: Neutropenia that occurs after the first cycle of chemotherapy for non-Hodgkin’s Lymphoma (NHL) may predict its recurrence in the subsequent cycles. Moreover, it has also been reported to be a poor prognostic factor for the treatment outcome. Therefore, we aimed to observe the incidence of first cycle neutropenia and identify the potential risk factors for its occurrence among patients with NHL underwent chemotherapy. Methods: A retrospective cohort was conducted in Sardjito General Hospital, Yogyakarta, Indonesia to analyze 466 subjects during 2012-2018, confirmed NHL, age 17 or older, treatment-naïve, underwent first-line chemotherapy without any previous primary GCSF prophylaxis. Relevant clinical conditions, pre-treatment laboratory parameters and treatment factors were obtained from medical records. Univariate and multivariate analysis were done using logistic regression to determine the significant factors. Results: Among 466 NHL subjects, 241 (51.7%) received rituximab-containing regiment, with DLBCL as predominant subtype in 196 subjects (41.8%). Neutropenia occurred in 119 (25.5%; 95% CI 21.7-29.6%) of the cases, with 87 (73.2%) of them had moderate-severe neutropenia. Age older than 50 years old, use of rituximab-containing regiment, ANC ≤ 4.83×103 cells/mm3, and WBC ≤ 7.26×103 cells/mm3 were significant predisposing factors for first cycle neutropenia. A multivariate analysis showed two significant prognostic factors i.e., rituximab-containing regiment and ANC level ≤ 4.83×103 cells/mm3 with OR 2.18 (95% CI 1.38–3.43) and 2.30 (95%CI 1.49–3.57), respectively. Conclusion: The administration of rituximab-based regimen and pre-treatment ANC ≤ 4.83×103 cells/mm3 in NHL require more attention to anticipate the occurrence of neutropenia after the first chemotherapy cycle. Further investigation is required to validate risk model and identify subgroup who benefits from early use of growth factor.

All You Need to Know About UGT1A1 Genetic Testing for Patients Treated With Irinotecan: A Practitioner-Friendly Guide

Irinotecan is an anticancer agent widely used for the treatment of solid tumors, including colorectal and pancreatic cancers. Severe neutropenia and diarrhea are common dose-limiting toxicities of irinotecan-based therapy, and UGT1A1 polymorphisms are one of the major risk factors of these toxicities. In 2005, the US Food and Drug Administration revised the drug label to indicate that patients with UGT1A1*28 homozygous genotype should receive a decreased dose of irinotecan. However, UGT1A1*28 testing is not routinely used in the clinic, and specific reasons include lack of access to concise information on this wide issue as well as mixed recommendations by regulatory and professional entities. To assist oncologists in assessing whether and when to use UGT1A1 genetic testing in patients receiving irinotecan-based therapies, this article provided (1) essential knowledge of UGT1A1 polymorphisms; (2) an update on the impact of UGT1A1 polymorphisms on efficacy and toxicity of contemporary irinotecan-based regimens; (3) dosing adjustments based upon the UGT1A1 genotypes, and (4) recommendations from currently available guidelines from the US and international scientific consortia and major oncology societies.

Myelodysplastic syndromes (MDS)

MDS in children is a rare group of hematopoietic stem cell clonal disorder. Allogeneic HSCT is the only curative treatment. HLA typing and the search for a compatible donor must be carried out upon diagnosis, for all patients. However, patients with refractory cytopenia of childhood without an unfavorable karyotype can keep the disease stable for a long time. Thus, in the absence of transfusion dependence or severe neutropenia, a careful observation strategy without treatment is recommended. The treatment of children diagnosed with MDS with excess blasts remains a major challenge. Allogeneic HSCT is the only curative treatment, although the data published in the literature generally include a small number of patients, heterogeneously transplanted. For children with MDS secondary to therapy, despite HSCT, the evolution is generally unfavorable.

A Phase III, Randomized, Multi-Center, Open-Label, Fixed Dose, Neulasta Active-Controlled Clinical Trial of F-627, a Novel G-CSF, in Women with Breast Cancer Receiving Myelotoxic Chemotherapy

Background - Chemotherapy-induced neutropenia (CIN) is the primary dose-limiting toxicity in patients receiving myelotoxic chemotherapy which is associated with increased morbidity and early mortality. Ryzneuta TM (F-627), a recombinant fusion protein containing human granulocyte-colony stimulating factor (G-CSF) and IgG2-Fc fragment, is intended to reduce CIN by utilizing the neutrophilic proliferating and activating properties of G-CSF. F-627 was designed as a novel, non-pegylated molecule with dimeric G-CSF, which may possess stronger G-CSF receptor activating properties and improved efficacy compared to filgrastim and pegfilgrastim. The primary objective of this study was to evaluate the safety and efficacy of F-627 given as a single fixed dose (20 mg) pre-filled syringe (PFS) as compared to Neulasta® (6 mg) in the first chemotherapy cycle. Methods - This was a phase III, multi-center, randomized, open-label, two-arm, active-controlled study that randomized female patients with Stage I to III invasive breast cancer who received 4 cycles of myelotoxic taxane + cyclophosphamide chemotherapy treatment. Forty-one (41) sites across 5 countries participated in the trial, including Bulgaria, Hungary, Russia, Ukraine, and US. Patients were randomized to F-627 or Neulasta® in a 1:1 ratio on the day of chemotherapy and administered study drug 24 hours after chemotherapy administration in each cycle. A total of 393 patients were randomized and analyzed for efficacy and safety. Clinical assessments were cycle-specific and included physical examination, serum samples for immunogenicity before each chemotherapy cycle, laboratory assessments, hematology and CBC with differentials, urinalysis, body weight, vital signs, adverse event (AE) collection, and concomitant medications. The pharmacokinetics (PK) and the pharmacodynamics (PD) of F-627 were also assessed. The primary efficacy endpoint was the duration in days of Grade 4 (severe) neutropenia (ANC &lt;0.5 × 10 9/L) during cycle 1 of chemotherapy. Results - The mean duration of Grade 4 neutropenia in chemotherapy cycle 1 was 0.2 days for both F-627 and Neulasta®. F-627 was non-inferior compared to Neulasta® for the duration of Grade 4 neutropenia in chemotherapy cycle 1 with a mean difference of 0.0 days (95% CI: -0.1, 0.1), utilizing a non-inferiority margin of 0.6 days. The incidence of Grade 4 neutropenia in chemotherapy cycle 1 was comparable between F-627 and Neulasta®, 11.7% for both treatment groups. For chemotherapy cycles 2, 3, and 4, the incidence and duration of Grade 4 neutropenia was generally lower than in chemotherapy cycle 1. The mean durations of Grade 4 neutropenia were 0.1, 0.0, and 0.0 days for F-627 and 0.1, 0.1, and 0.1 days for Neulasta® in chemotherapy cycles 2,3,4, respectively. The incidence of Grade 4 neutropenia was 4.6%, 2.6%, and 1.6% for F-627 and 5.1%, 6.3%, and 5.3% for Neulasta® in chemotherapy cycles 2, 3, and 4, respectively. Across all chemotherapy cycles and for each chemotherapy cycle, the mean duration and the incidence of IV antibiotic use and hospitalization due to febrile neutropenia or any infection were low and comparable between F-627 and Neulasta®. The depth of ANC nadir was comparable in each chemotherapy cycle between F-627 and Neulasta®. For each chemotherapy cycle, time to ANC nadir was slightly longer for patients treated with F-627 than those with Neulasta®; the mean time to ANC nadir was 6.4, 6.1, 6.2, and 6.2 days for F-627, compared to 6.1,5.3, 5.7, and 5.5 days for Neulasta® in cycles 1, 2, 3, and 4, respectively. F-627 was well tolerated, with a low incidence of serious AEs and AEs leading to discontinuation, comparable to the profile for Neulasta®. There were 3 deaths during the study (1 for F-627 and 2 for Neulasta®). None of the deaths were related to study drug treatment. Clinical laboratory abnormalities were observed to be similar between the two treatment groups. Conclusion - Once-per-cycle F-627, given as a fixed 20 mg dose, was non-inferior to Neulasta® in reducing the duration of severe neutropenia following TC chemotherapy. F-627 was well tolerated during the study with an overall safety profile comparable to that for Neulasta®. F-627 is a safe, effective, and easy to use alternative to current CIN therapy. Disclosures Daley: Evive: Current Employment, Current holder of stock options in a privately-held company. Chen: Evive: Current Employment.