Factors Associated with All-Cause 30-Day Mortality in Indonesian Inpatient COVID-19 Patients at Cipto Mangunkusumo National General Hospital.

Introduction: Indonesia, as a developing country, has limited data on the factors associated with 30-day mortality in COVID-19 patients in Indonesia. As a matter of fact, study analyzing factors associated with 30-day mortality of COVID-19 infection in Indonesia has never been conducted. This study aims to fill this gap in the literature by conducting a large-scale analysis of factors associated with 30-day mortality in COVID-19 patients in Indonesia. Method: This study employed a single-center retrospective cohort observational design, and was conducted at Cipto Mangunkusumo National General Hospital between the years 2022 and 2023. Sampling was conducted using the consecutive sampling method. The study included patients aged 18 years and above who had been confirmed to have COVID-19 infection. Survival analysis was conducted using Kaplan-Meier and multivariate Cox regression analysis. Result: Our study included a total of 644 patients, with 120 patients (18.6%) expiring within 30 days. In the multivariate analysis using the backward Wald method, severe COVID-19 (HR: 7.024; 95% CI: 3.971-12.744; p value: <0.0001), moderate COVID-19 infection (HR: 1.660; 95% CI: 1.048-2.629; p value: 0.031), liver cirrhosis (HR: 3.422; 95% CI: 1.208-9.691; p value: 0.021), female sex (HR: 1.738; 95% CI: 1.187-2.545; p value: 0.004), old age (HR: 2.139; 95% CI: 1.279-3.577; p value: 0.004), high leukocyte (HR: 11.502; 95% CI: 1.523-86.874; p value: 0.018), high NLR (HR: 1.720; 95% CI: 1.049-2.819; p value: 0.032), high CRP (HR: 1.906; 95% CI: 1.092-3.329; p value: 0.023), high procalcitonin (HR: 3.281; 95% CI: 1.780-6.049; p value: 0.001), and high creatinine (HR: 1.863; 95% CI: 1.240-2.800; p value: 0.003) were associated with 30-day mortality from COVID-19 infection. Subgroup analysis excluding cancer patients showed that age, D-Dimer, CRP, and PCT were associated with 30-day mortality in COVID-19 patients, while steroid therapy is protective. Conclusions: This study finds that COVID-19 severity, liver cirrhosis, sex, age, leukocyte, NLR, CRP, creatinine, and procalcitonin were associated with COVID-19 mortality within 30 days. These findings underscore the multifactorial nature of COVID-19 infection mortality. It is important, therefore, that patients which exhibit these factors should be treated more aggressively to prevent mortality.

The Association between Anemia and Mortality of Severe Pneumonia COVID-19 Patients in the High Care Unit of a Tertiary Hospital in Jakarta.

BACKGROUND: Numerous studies explored the association between anemia and mortality in patients with severe pneumonia due to COVID-19. However, the findings were inconsistent. Therefore, this study was conducted to investigate the association between anemia at HCU admission and in-hospital mortality in severe pneumonia COVID-19 patients. METHODS: This retrospective cohort study obtained data on 110 COVID-19 patients with severe pneumonia who were admitted to the HCU between January, 1st 2021, and May 31st, 2021. Patients were categorized as anemic and non-anemic based on the World Health Organization (WHO) guidelines. The demographic and clinical characteristics of the subjects were described. The Chi-squared test was carried out followed by a logistic regression test to determine the association of anemia and mortality. RESULTS: Anemia was observed in 31% of 110 patients with severe pneumonia COVID-19. The source population consisted of 60.9% men and 39.1% women with a median age of 58 years. The most prevalent comorbidity was hypertension (38.2%), followed by diabetes mellitus (27.2%), renal diseases (19.1%) and heart diseases (10%). TAnemia on HCU admission was associated with in-hospital mortality in patients with severe pneumonia COVID-19 (RR: 2.794, 95% CI 1.470-5.312). After adjusting comorbidities as confounding factors, anemia was independently associated with mortality (RR: 2.204, 95% CI: 1.124-4.323, P < 0.021). The result also showed anemic patients had longer lengths of stay and higher levels of D-dimer than non-anemic patients. The median duration length of stay among the anemic and non-anemic was 16 (11-22) and 13 (9-17) days, respectively. The median D-dimer among the anemic and non-anemic was 2220 µg/ml and 1010 µg/ml, respectively. CONCLUSION: There is a significant association between anemia at HCU admission and mortality in patients with severe pneumonia COVID-19 during hospitalization.

A comparative study of the COVID-19 vaccine efficacy among cancer patients: mRNA versus non-mRNA.

BACKGROUND: Cancer patients have an increased risk of a severe COVID-19 infection with higher mortality rate. This study aimed to analyze the levels of anti-SARS-CoV-2 S-RBD IgG and NAB among cancer patients who were vaccinated with COVID-19 vaccines, either with BNT162b2, mRNA-1273, AZD1222/ChAdOx1nCoV-19, or Coronavac/BBIBP-CorV vaccines. METHOD: A cross-sectional study was conducted among subjects with either solid or hematological cancers who had received two doses of either mRNA or non-mRNA vaccines within 6 months. The levels of anti-SARS-CoV-2 S-RBD IgG and NAb were analyzed using the Mindray Immunoassay Analyzer CL-900i. Statistical analysis was conducted using mean comparison and regression analysis. RESULT: The mRNA-1273 vaccine had the highest median levels of S-RBD IgG and NAb, followed by BNT162b, ChAdOx1nCoV-19, and BBIBP-CorV/Coronavac. The levels of S-RBD IgG and NAb in subjects vaccinated with mRNA vaccines were significantly higher than those of non-mRNA vaccines when grouped based on their characteristics, including age, type of cancer, chemotherapy regimen, and comorbidity (p<0.05). Furthermore, the S-RBD IgG and NAb levels between the subjects vaccinated with non-mRNA vaccines and the subjects vaccinated with mRNA vaccines were significantly different (p<0.05). However, there was no significant difference between the same types of vaccines. This study demonstrated a very strong correlation between the level of S-RBD IgG and the level of NAb (R = 0.962; p<0.001). The level of anti-SARS-CoV-2 S-RBD IgG was consistently higher compared to the level of NAb. CONCLUSIONS: Generally, mRNA vaccines produced significantly higher anti-SARS-CoV-2 S-RBD IgG and NAb levels than non-mRNA vaccines in cancer subjects.

A Case Series of Aggressive Orbital Plasmacytomas.

Purpose: Orbital plasmacytoma is a tumor of plasma cells located in the orbit, which is uncommon and only accounts for less than 1% of total orbital tumors. Sixty-five percent of orbital plasmacytoma are carrying a diagnosis of multiple myeloma. We hereby present two aggressive orbital plasmacytoma cases, a rare orbital malignancy with unsatisfactory outcomes. Methods: This is a series of two orbital plasmacytoma cases. Both initial complaints were unilateral rapid onset of non-axial proptosis with palpable mass in the superior orbit. The first case was IgA-type multiple myeloma with multiple secondary plasmacytomas diagnosed based on systemic evaluation showing hyperproteinemia, IgA level elevation with free κ-light chains, and multiple destructive osteolytic lesions. The second patient unfortunately died before systemic evaluation was carried out. Results: Both patients died less than 2 months after diagnosis, underscoring a very poor prognosis. It is important to perform systemic evaluation and appropriate treatment immediately once the diagnosis has been established. Conclusions: Orbital plasmacytoma is a rare orbital malignancy and is commonly secondary to systemic multiple myeloma. Ophthalmologists should have a high index of suspicion as it has a nonspecific presentation and consider it as one of the differential diagnoses in orbital tumors.

How to Diagnose, Treat, and Monitor Treatment Response in Patients with Multiple Myeloma.

Multiple myeloma (MM) is a B-cell malignancy characterized by clonal proliferation of malignant plasma cells in the bone marrow, monoclonal protein production in the serum, and organ dysfunction. It is part of a disease spectrum called plasma cell disorders, and to establish the diagnosis, a bone marrow biopsy should be conducted with clinical signs of end-organ damage and/or significantly elevated monoclonal protein (M-protein). MM can also be diagnosed without end-organ damage when certain conditions are met since the International Myeloma Working Group (IMWG) has come up with new diagnostic criteria for multiple myeloma.Treatment for all patients with MM aims to enhance the depth and duration of response while limiting drug toxicity to lengthen survival, improve quality of life, alleviate symptoms and prevent further organ damage. Development of new drugs has improved the survival of patients4 Available tests for monitoring of patients with MM most often include assessments of monoclonal paraprotein and serum-free light chain levels with bone marrow examination, which directly identifies the level of malignant plasma cells.

Association of leukocyte nadir with complete remission in Indonesian acute myeloid leukemia patients undergoing 7+3 remission induction chemotherapy.

Background: The 7+3 regimen is still the main choice of remission induction chemotherapy in acute myeloid leukemia (AML). Successfully achieving complete remission (CR) and the time required to achieve it determine patient's survival. Hence, bone marrow examination on 14 th day of chemotherapy is recommended to predict CR. However, the examination is invasive and still inaccurate. Methods: A prognostic study with retrospective cohort design was conducted at two central hospitals in Indonesia based on medical record data of AML patients who underwent 7+3 induction chemotherapy from January 1st, 2015, to December 31st, 2019. The association of nadir leukocyte level and the time required to achieve it with CR occurrence was assessed. Results: One hundred and one subjects were recruited with median age 39 years and 55% men. A total of 55.4% subjects achieved CR. Nadir leukocyte level below 200/mcl was the most optimal cut-off point and independently associated with CR (OR 2.48; 95% CI 1.03-5.97) while time required to achieve it was not. Conclusions: The nadir leukocyte level is associated with an increase probability of CR but not for the time required to achieve it in AML patients undergoing 7+3 induction chemotherapy.

The Role of Brentuximab Vedotin (BV) as Second-Line Treatment of Refractory Classical Hodgkin Lymphoma (cHL) in the Era of Pandemic COVID-19.

Background: Salvage conventional chemotherapy followed by high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) is the treatment of choice for most patients with refractory classical Hodgkin lymphoma (cHL). In the era of pandemic COVID-19, there are obstacles to administering salvage chemotherapy followed by HDT and ASCT due to side effects and toxicities which make the patient more susceptible to COVID-19 infection. The toxicities and side effects of BV are different from salvage chemotherapy, but it has clear efficacy as monotherapy. Case Presentation: A 46-year-old female with a history of cHL nodular sclerosis subtype was presented with right cervical lymph node enlargement, after 3 cycles of first-line chemotherapy ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) 3 months ago. She was afraid to undergo second-line chemotherapy in the era of pandemic COVID-19 because of the side effects and toxicities; therefore, she was given 8 cycles of BV as monotherapy. The response of the treatment was complete remission. Conclusion: In this particular case of patient, BV as monotherapy can be an option during the pandemic COVID-19 for refractory cHL ineligible for second-line chemotherapy followed by HDT and ASCT.

Additional Chromosomal Abnormalities in Chronic Myeloid Leukemia Patient Treated with First-Line Tyrosine Kinase Inhibitor Therapy: Good or Poor Prognosis?

A 33-year-old male came to Policlinic of Hematology-Medical Oncology Dr. Cipto Mangunkusumo General Hospital for routine control of chronic myeloid leukemia (CML) treatment. He was treated with Imatinib Mesylate (IM) for two years. At the beginning of therapy, he showed good treatment response. However, after two years of treatment, he lost complete hematological response (CHR) occured and major molecular response (MMR) was not achieved. This demonstrated drug resistance even with good compliance. Evaluation of therapy through cytogenetic karyotype testing showed complex additional chromosomal abnormalities (ACA) in addition to the Philadelphia chromosome (Ph). Tyrosine kinase inhibitor (TKI) therapy in this type of patients should be replaced with other alternative TKIs. A mutation profiling test is needed to determine alternative TKI. Monitoring in the treatment of CML patients is very important. The presence of ACA indicates disease progression and poor prognosis. Time to change therapy in CML patients must be done appropriately based on the results of hematological, molecular, and cytogenetic testing.

Achievement of Pre- and Post-Transfusion Hemoglobin Levels in Adult Transfusion-Dependent Beta Thalassemia: Associated Factors and Relationship to Reduction of Spleen Enlargement.

INTRODUCTION: The achievement of blood transfusion hemoglobin targets in transfusion-dependent beta-thalassemia patients is influenced by several factors such as genotype, hypersplenism, blood compatibility, donor blood adequacy, and transfusion interval. Failure to achieve these targets leads to an increase in the size of the spleen. Meanwhile, the post-transfusion hemoglobin of thalassemia patients that is not regularly evaluated has made it difficult to determine donor adequacy. Therefore, this study aims to determine the proportion of patients who achieve optimal pre- and post-transfusion hemoglobin levels, determine the factors involved, and the relationship between achieving hemoglobin levels with spleen enlargement in adult transfusion-dependent beta-thalassemia patients. METHODS: This retrospective cohort study was conducted using total sampling of adult thalassemia transfusion-dependent patients at Cipto Mangunkusumo Hospital. Data were obtained through medical records. RESULTS: A hundred and ten study subjects fulfilled inclusion criteria. The results showed that the blood transfusion deficit <30 mL/kg/year was associated with achieving pre- and post-transfusion hemoglobin targets (p = 0.008). Furthermore, there were significant differences between the groups that achieved the pre- and post-transfusion target hemoglobin levels on the reduction of spleen enlargement in centimeters (p < 0.001). However, thalassemia genotype, blood compatibility, and transfusion interval did not correlate with the achievement of pre- and post-transfusion hemoglobin. CONCLUSION: The achievement of pre- and post-transfusion hemoglobin levels in adult transfusion-dependent beta-thalassemia patients significantly reduced spleen enlargement and contributed to better patient outcomes.

Five-Year Cancer Epidemiology at the National Referral Hospital: Hospital-Based Cancer Registry Data in Indonesia.

PURPOSE: In 2016, there were 1,308,061 cases of cancer being treated in Indonesia, with 2.2 trillion rupiahs spent, amounting to $486,960,633 in US dollars (purchasing power parity 2016). The high burden of cancers in Indonesia requires a valid data collection to inform future cancer-related policies. The purpose of this study is to report cancer epidemiological data from 2008 to 2012 based on Hospital-Based Cancer Registry (HBCR) data from Cipto Mangunkusumo Hospital, Indonesia. METHODS: This was a descriptive study with cross-sectional design. Data were collected from Cipto Mangunkusumo Hospital HBCR 2008-2012. Demographical, diagnostic, stages of cancer, and histopathological types of cancer data were extracted. RESULTS: After screening, 18,216 cases were included. A total of 12,438 patients were older than 39 years of age (68.3%), with a female-to-male ratio of 9:5. Most patients have cancers at advanced stages (stages III and IV, 10.2%). The most common sites of cancer were cervix uteri (2,878 cases, 15.8%), breast (2,459 cases, 13.5%), hematopoietic and reticuloendothelial systems (1,422 cases, 7.8%), nasopharynx (1,338 cases, 7.4%), and lymph nodes (1,104 cases, 6.1%). CONCLUSION: From this HBCR, cancer incidence in female was almost twice the incidence in male, largely because of the burden of cervical and breast cancers. The cervix uteri as one of the top five cancer sites based on this HBCR, 2008-2012, are still approximately consistent with Global Cancer Incidence, Mortality and Prevalence 2018, which portrayed that Indonesia has been severely afflicted by cervical cancer cases more than any other Association of Southeast Asian Nations countries. The HBCR could serve as a robust database of epidemiological data for cancer cases in Indonesia.

Pulmonary Embolism in Hospitalized Patient with Coronavirus Disease 2019 (COVID-19).

Coronavirus disease 2019 (COVID-19) has been a global pandemic for over a year. Meanwhile, thrombosis occurs in up to one-third of hospitalized patients with the disease, while pulmonary embolism has been reported to be the most dangerous thrombosis which greatly increases mortality in COVID-19.Hospitalized patients with COVID-19 are at high risk of thromboembolic complications such as deep vein thrombosis and pulmonary embolism. The hypercoagulable state caused by COVID-19 leads to activation of coagulation cascade, meanwhile, CT pulmonary angiography is used to diagnose or exclude pulmonary embolism. Furthermore, ground-glass opacities are also evaluated using this modality. Low molecular weight heparin is the anticoagulant of choice due to simplicity in administration and low risk of drug-drug interactions.Pulmonary embolism occurs in COVID-19 patients without DVT. Based on the results, parenteral anticoagulant followed by DOAC is the mainstay of treatment in COVID-19 coagulopathy.

Priapismus as Leukostasis Manifestation in Chronic Myeloid Leukemia.

Chronic Myeloid Leukemia (CML) is a myeloproliferative disease characterized by the presence of Philadelphia chromosome or BCR-ABL oncogene fusion. Patients with CML commonly present in the chronic phase with chief complaint of abdominal pain or early satiety. Priapism as the first manifestation of CML is a rare phenomenon. Priapism as a consequence of leukostasis is a urological emergency that requires immediate intracavernosus therapy followed by systemic therapy. We report a 44-year-old male patient presenting with priapism as the first manifestation of CML.

Primary CD20-positive mediastinal diffuse large B-cell lymphoma.

Primary mediastinal B-cell lymphoma (PMBCL) is a rare tumour with different characteristics from other type of lymphomas. Clinical manifestations may vary and cause delay in diagnosis and management. We present a 22-year-old patient with symptoms of shortness of breath, weight loss, and night sweats. Laboratory studies only showed a markedly high lactate dehydrogenase (LDH) level and thoracic computed tomography (CT)scan revealed a large mediastinal mass. Core biopsy-guided CT scan was performed and the pathological and immunohistochemistry established a PMBCL diagnosis. We administered Rituximab Dose-Adjusted Etoposide Prednisolone Vincristine Cyclophosphamide Doxorubicin (R-DA-EPOCH) chemotherapy regimen and the patient responded well to treatment. This is an example of rare case of mediastinal lymphoma with challenges to overcome to achieve diagnostic and therapeutic success. Failure to differentiate PMBCL with other systemic diffuse large B-cell lymphoma (DLBCL) could skew treatment algorithm and prevent optimal response. Administration of proper systemic therapy, especially in young, low-risk patients could yield excellent outcome.

Extra-Nodal Marginal Zone Lymphoma (MZL) of MALT CD20+ of the Ocular Adnexa: Case Report.

Even though rare in the orbital region, lymphomas are reported as the third most common malignancies of the conjunctiva, following squamous cell carcinoma and melanoma. It is estimated that more than 95% lymphomas in periocular tissues are B cell in origin. We present a case of extra-nodal marginal zone lymphoma (MZL) of MALT type of the ocular adnexa, successfully treated with chemoimmunotherapy R-CVP.

Recent Management of Patients with Advanced Epidermal Growth Factor Receptor Mutation Non-small Cell Lung Cancer: Role of Afatinib and Lesson Learned for Developing Countries.

Lung cancer is a devastating disease with a high incidence, mortality and morbidity rate, especially in developing countries. Conventional treatment with cytotoxic chemotherapy has some limitations attributed to chemoresistance and toxicity. Recent advances have shown that first generation Tyrosine Kinase Inhibitor (TKI), Gefitinib and Erlotinib, and the newest available second generation Tyrosine Kinase Inhibitor (TKI), Afatinib, have the potential to be an option in the management of patients with epidermal growth factor receptor/ EGFR mutation positive advanced/ metastatic non-small cell lung cancer. Afatinib works by binding to EGFR irreversibly, thus inactivating the tyrosine kinase receptor. Some studies demostrated that Afatinib first-line may result in longer progression free survival (PFS) and better disease control, and as an alternative for patients who intolerance to Gefitinib or Erlotinib. In Indonesia, the era of National Health Insurance has been implemented and National Health Insurance has covered treatment for cancer, including first generation TKIs, Gefitinib dan erlotinib, for patients with EGFR mutation positive advanced/ metastatic non-small cell lung cancer at Cipto Mangunkusumo National Hospital. Afatinib, as one of the newest available second generation TKI, may be given free of charge too as an alternative if the National Health Insurance will be covered in the future. Further research is needed to know the efficacy and adverse effects that may occur in patients from developing countries.

Clinical Outcome and Survival of Osteosarcoma Patients in Cipto Mangunkusumo Hospital: Limb Salvage Surgery versus Amputation.

AIM: to analyze the outcome and survival rate of osteosarcoma patients in our hospital as well as the factors affecting prognosis and functional outcome. METHODS: this is a retrospective cohort study of osteosarcoma patients in Cipto Mangunkusumo Hospital underwent limb salvage surgery (LSS), amputation, LSS + amputation, and refused surgery from year 1995 to 2014. The surgical decision was based on patient's age, staging, location, neurovascular involvement, Huvos type, functional demand, patient preference, and general condition. Functional outcome was assessed using the Musculoskeletal Tumor Society (MSTS) score with the maximum score of 30. RESULTS: subjects consisted of 80 male and 52 female aged 4 to 61 year-old. They underwent limb salvage surgery (LSS) (n=37), amputation (n=42), LSS + amputation (n=2), and refused surgery (n=51). Overall 5-year cumulative survival rate was 14.6%. The 5-year survival rate for each group; LSS, amputation, combined LSS and amputation, and refused surgery was 34.8%; 15.9%; 0%; and 0%, respectively. Patients with tumor size <8 cm tend to underwent LSS compared to amputations (60.7% vs 39.3%, p=0.046). Local recurrence-free survival for LSS and amputation was 96.2% and 86.5% respectively (p=0.586). MSTS score was higher in LSS than amputation group (25.0 vs 18.5, p=0.011). CONCLUSION: LSS had higher survival rate than amputation in osteosarcoma patients who were treated in Cipto Mangunkusumo Hospital. MSTS functional score in the LSS group was higher than amputation group.

Underutilization of anticoagulant for venous thromboembolism prophylaxis in three hospitals in Jakarta.

AIM: to assess the current use of anticoagulants and implementation of International Guidelines in venous thromboembolism (VTE) prophylaxis in hospitalized patients with acute medical illnesses in Jakarta, Indonesia. METHODS: a multicenter, prospective, disease registry, recruiting patients diagnosed as acutely ill medical diseases and other medical conditions at risk of VTE, with in-hospital immobilization for at least 3 days. RESULTS: of 401 patients, 46.9% received anticoagulants which included unfractionated heparin (64.4%), fondaparinux (11.7%), enoxaparin (9.6%), warfarin (3.7%), and combination of anticoagulants (10.6%). VTE prophylaxis using physical and mechanical method was used in 81.3% of patients, either as a single modality or in combination with anticoagulants. During hospitalization, VTE were found in 3.2% patients; 10 patients (2.5%) had lower limb events and 3 patients (0.75%) had a suspected pulmonary embolism. The main reference international guidelines used were AHA/ASA 2007 (47.4%), followed by ACCP 2008 (21.7%). CONCLUSION: the study showed underutilization of prophylaxis anticoagulants in which mechanical thromboprophylaxis either alone or combination with anticoagulants was the most commonly used. Unfractionated heparin was the preferable choice. The most commonly used guideline was AHA/ASA 2007. VTE thromboprophylaxis in medically ill patients needs to be encouraged.

Clinical characteristics and hematologic responses to Imatinib in patients with chronic phase myeloid leukemia (CML) at Cipto Mangunkusumo Hospital.

AIM: To analyze the clinical characteristics of patients with chronic phase CML and evaluate complete hematologic responses (CHR) and overall survival (OS) after treatment with Imatinib. METHODS: This is a cross sectional study using retrospective medical record of patients with chromosome Philadelphia positive and/or BCR-ABL positive chronic phase CML at the polyclinic of Teratai Department of Internal Medicine Cipto Mangunkusumo National Hospital during 2003-2008. In a period of 6 years, we included 53 patients with chromosome Philadelphia positive and/or BCR-ABL positive chronic phase CML. Patients were administered Imatinib 400 mg daily and then evaluation of clinical characteristics and complete blood count + differential count were performed every 2 weeks until CHR achieved at 3 months as defined by white cells count < 10,000/mm3, platelet count > 450,000/mm3, and non palpable spleen. RESULTS: The median age was 37 years (16-67 years). Males were slightly more frequent than females (29 v.s. 24) with ratio of 1.2:1. Thirty three percent of patients had splenomegaly. The vast majority (60%) of patients had previous treatment with Hydroxyurea. The laboratory features were: median of hemoglobin level was 10.0 g/dL (6.3-16.6 g/dL), median of white-cell count was 13,300/uL (1900-621,000/uL), and median of platelet count was 424,000/uL (108,000-4,400,000/uL). Median of basophils was 1.6% (0%-20%) and 88% of patients had <5% blasts in bone marrow. CONCLUSION: A CHR was achieved in 74% of patients and overall survival during the study was 66%. The most common adverse events were: nausea, myalgia, hypopigmentation of the skin, anemia, thrombocytopenia, and neutropenia.