Use Of Hematopoietic Growth Factors Research Articles

Abstract PO1-12-06: Is it appropriate to select patients for primary prophylactic use of pegfilgrastim based on the risk of febrile neutropenia?

Abstract Background: Febrile neutropenia (FN), a major hematologic adverse event in perioperative chemotherapy for breast cancer, is more prevalent among Asians than in Caucasian populations. Four main guidelines, i.e., ASCO, EORTC, NCCN, and ESMO, provide recommendations regarding the appropriate use of hematopoietic growth factors. These guidelines recommend primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) based on the estimated incidence of FN, primarily defined by the chemotherapy regimen. G-CSF administration is recommended when the incidence of FN is ≥20% or 10–20% with risk(s). However, the incidence of FN varies depending on the trial and design, and patient-specific risk factors for FN remain unclear. We previously performed a multicenter prospective cohort study in Japan, the CSPOR-BC FN study, evaluating the incidence of FN during perioperative chemotherapy for breast cancer. Herein, we conducted an additional analysis to explore thresholds of patient-specific risk factors for FN that could be evaluated before chemotherapy. We analyzed the risk factors for FN and verified the appropriateness of patient selection for prophylactic G-CSF administration. Methods: The previously reported CSPOR-BC FN study (PubMed ID=33631458) consecutively enrolled 1005 patients with stage I–III breast cancer between August 2015 and July 2017. In the current additional analysis, we intended to have 477 patients in the visiting group that evaluated true-FN, defined as ≥37.5℃ and grade 4 neutropenia. Multivariate analysis of risk factors for FN was performed, followed by the determination of cutoff values for age and pretreatment absolute neutrophil count (ANC) as risk factors. Results: Chemotherapy regimens administered were FEC (fluorouracil, epirubicin, and cyclophosphamide) in 170 patients (36%), E(A)C (epirubicin (doxorubicin) + cyclophosphamide) in 165 patients (35%), and TC (docetaxel + cyclophosphamide) in 142 patients (30%). The incidence of FN was 28.7% (N = 137). To evaluate the risk factors for FN, we predefined regimens, age, performance status (PS), stage, chemotherapy or radiotherapy history, infectious wounds, open wounds, ANC, and renal and liver dysfunction as potential risk factors. Multivariate analysis of risk factors for FN identified regimen (TC), age (≥65), low pretreatment ANC, treatment setting, and no primary pegfilgrastim prophylaxis as significant risk factors. Two patient-specific risk factors (age and pretreatment ANC) were analyzed. Logistic regression analysis revealed that age≥65 years was a significant risk factor (odds ratio=2.24, 95% confidence interval: 1.34–3.75). Applying a cutoff of 65 years (age) to predict FN, the sensitivity and specificity were 28.4 and 83.8%, respectively, which were inaccurate. Despite applying a cutoff of 67 years optimized from the receiver operating characteristic (ROC) curve, the sensitivity (22.4%), specificity (90.7%), and area under the curve (0.519) indicated low discrimination for predicting FN. The incidence of FN by age group was as follows: < 45 years, 30.8%; 45–55 years, 26.4%; 55–64 years, 20.9%; ≥65 years, 39.6%. Additionally, applying a cutoff of 2436/µL (pretreatment ANC) optimized from the ROC curve, the observed sensitivity (27.6%) and specificity (83.8%), and area under the curve (0.558) also indicated low discrimination for predicting FN. The incidence of FN by stratum of pretreatment ANC was as follows: < 2000, 33.3%; 2000–3000, 30.7%; 3000–4000, 29.9%; and >4000, 24.6. Accordingly, setting a cutoff value to predict FN incidence using age and/or pretreatment ANC was deemed inappropriate. Conclusion: Selecting patients for primary prophylactic G-CSF based on the existing FN risk can be challenging. Primary prophylactic G-CSF would be considered for every patient undergoing perioperative chemotherapy for breast cancer, especially Asians. ROC curve for FN and age. The AUC was 0.519. ROC curve for FN and neutrophil count. The AUC was 0.558. Citation Format: Kazutaka Narui, Takashi Ishikawa, Ikumi Takashima, Kosuke Kashiwabara, Yukari Uemura, Yuichiro Kikawa, Naruto Taira, Hirofumi Mukai. Is it appropriate to select patients for primary prophylactic use of pegfilgrastim based on the risk of febrile neutropenia? [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 PO1-12-06.

Characterization and Prognosis of Temozolomide-Induced Aplastic Anemia

Introduction: Temozolomide-induced aplastic anemia (TIAA) is a very rare and highly challenging complication of temozolomide (TMZ) chemotherapy. TMZ is a mainstay of therapy in patients with central nervous system (CNS) malignancies. Single-patient case reports and small case series have described variable morbidity and mortality associated with TIAA. However, quantitative evidence describing prognosis, clinical characteristics, and treatment of this entity is absent or very limited.Methods: We performed a 5-center, 22-year observational cohort study of patients with CNS malignancies treated with temozolomide who developed TIAA, retrospectively analyzing prognosis, complications, and recovery. We compared patients who achieved meaningful hematologic recovery [partial hematologic recovery (PHR) or complete hematologic recovery (CHR)] to those who did not recover [refractory disease (RD)]. We used descriptive statistics, T-tests, and chi-square tests to evaluate patient characteristics, outcomes, and laboratory values. Overall time to hematologic recovery and overall survival of patients with PHR, CHR, and RD were estimated using the Kaplan-Meier method and compared using the log-rank test, and a multivariable logistic model evaluated potential predictors of achieving CHR. TIAA was defined using adapted evidence-based severe aplastic anemia criteria incorporating profound cytopenias and a minimum duration (4 weeks) without hematologic recovery (TABLE 1).Results:Study Population and TIAA Prevalence. Of 3,821 patients with CNS malignancies receiving TMZ, 34 patients (0.89%) met criteria for TIAA (FIGURE 1). Onset was rapid, with 29 patients (85.3%) developing TIAA before completing a second TMZ cycle (TABLE 2).Complications and Outcomes of Hematologic Recovery. 23 patients (67.6%) ultimately achieved a hematologic recovery and the remaining 11 patients (32.4%) had refractory disease. Figure 2A illustrates the time from TIAA diagnosis to PHR and CHR for the cohort. In Kaplan-Meier survival analysis, the median time from TIAA diagnosis to PHR was 84 days and the median time to CHR was 134 days. Patients without recovery were more likely to develop serious complications (TABLE 3), including febrile neutropenia (72.7% vs. 30.4%, P=0.03), major infection (45.5% vs. 8.7%, P=0.02), hospitalization (81.8% vs. 43.5%, P=0.04), and death (100.0% vs. 60.9%, P=0.02). This increased risk of complications in patients not achieving hematologic recovery was observed despite a similar median time from TMZ initiation to TIAA diagnosis in the two groups (45 days vs. 40 days). Figure 2B illustrates the overall survival in the entire cohort and by each hematologic recovery subgroup. In Kaplan-Meier survival analysis, median overall survival from the time of TIAA diagnosis was as follows: entire cohort, 355 days; achieved PHR, 752 days; achieved CHR, 1414 days; refractory disease, 28 days (P<0.0001 for comparison of PHR, CHR, and refractory disease). In a multivariable logistic model, none of the evaluated covariates (age, sex, TMZ dose, body surface area, and use of hematopoietic growth factors) were significantly associated with achieving CHR.Treatment of TIAA and Outcomes of Therapy. 29 patients (85.3%) received hematopoietic growth factors (TABLE 3); no patients were treated with immunosuppression or hematopoietic stem cell transplant. Hematologic recovery rates were numerically higher in patients receiving thrombopoietin receptor agonists vs. those who did not (81.8% vs. 54.2%, P=0.15), but were not higher in patients receiving granulocyte colony stimulating factors vs. those who did not (68.0% vs. 66.7%, P=0.99).Conclusions: TIAA occurs in less than 1% of patients receiving temozolomide for CNS malignancies, occurring rapidly after TMZ initiation, but is highly morbid and often fatal when it occurs, precluding further use of cytotoxic therapy in the vast majority of patients. In the one-third who do not recover, risks of febrile neutropenia, infection, and hospitalization are increased, and overall survival greatly diminished. Hematologic recovery is potentially aided by the use of thrombopoietin receptor agonists, as has been demonstrated in classical autoimmune aplastic anemia. Further study of TIAA treatment is needed for this serious complication of TMZ therapy. [Display omitted] DisclosuresForst: Eli Lilly: Current holder of individual stocks in a privately-held company. Al-Samkari: Rigel: Consultancy; Argenx: Consultancy; Moderna: Consultancy; Novartis: Consultancy; Amgen: Research Funding; Dova/Sobi: Consultancy, Research Funding; Agios: Consultancy, Research Funding.

TET2 Inhibitory Effects of Eltrombopag Contribute Its Hematopoietic Activity

Severe aplastic anemia (sAA) is bone marrow (BM) failure syndrome characterized by immune mediated BM hypoplasia and pancytopenia usually treated with immunosuppressive therapy (IST) or allogeneic BM transplant. Despite the successes of IST in treating acquired, idiopathic sAA, most of the available treatment options only convert severe into non-severe forms of disease. Recently, eltrombopag (Epag), a small molecule thrombopoietin receptor (TPOR) agonist has been introduced into the routine treatment of de-novo and refractory AA with robust clinical response. Epag treatment showed remarkable tri-lineage responses in AA, suggesting an effect on hematopoietic stem and progenitor cells (HSPCs) amplification. The use of hematopoietic growth factors in AA that increases HSPCs has been associated with justified fears of facilitating AA evolution to MDS. Similarly, Epag has parallel effects on the amplification of HSPCs and there has been recent signals that long term treatment of Epag may increase the MDS risk. Using an in-house developed highly stable cell free high throughput screening of bioactive small molecule chemical library, we identified Epag as one of the most potent inhibitor of TET2. TET2 is the most abundant DNA dioxygenase in HSPCs. The loss-of-function mutations of TET2 frequently occurs in myeloid neoplasia. Here using in vitro and in vivo model system we report that effect of Epag, in part, is mediated by its ability to inhibit TET-dioxygenase activity. We demonstrate that Epag directly binds to TET2 in the presence of Fe2+ and inhibits its dioxygenase function in cell free system. In cell culture model we observed that nearly 40% of Epag partitioned into to nucleus suggesting its potential TET2 inhibitory role in cells. To test if TPOR signaling activation by Epag has any impact on TET activity we engineered murine cell lines BaF3 and 32D by introducing human TPOR. Irrespective of the status of TPOR-JAK-STAT pathway activation, as reflected in STAT5 phosphorylation, Epag demonstrated a robust TET-inhibition activity. However, in similar experiments peptide agonist of TPOR or another small molecule TPOR agonist Avotrombopag did not have any TET inhibitory effects. Consistent with these observations, Epag but not TPO or Avotrombopag inhibited TET activity in murine BM. Thus, Epag mediated TET2 inhibition in these cells are specific and independent of TPOR signaling. Consistent with previous reports, we observed that Epag treatment can significantly expand murine HSPCs even in the absence of TPOR signaling activation. The hematopoietic activity of Epag in murine system is dependent on its ability to inhibit TET2 as confirmed by the lack of Epag effects on Tet2-/- HSPCs. We further confirmed that TET-inhibition by Epag is central for its ability to expand HSPCs in murine model under in vivo settings using BM transplant experiments. We transplanted a mixture of cells derived from Tet2+/+ Pep Boy (CD45.1, 95%) and Tet2-/- C57BL/6 (CD45.2, 5%) into lethally irradiated recipient PepBoy mice. Epag treatment of mice reconstituted with the mixture of BM cells increases the fraction of Tet2+/+ BM cells only. Interestingly, Epag mimic loss of Tet2 in vivo as observed in the expansion of myeloid compartments of Tet2+/+ fractions reflected in CD11b-CD11c+, CD11b+CD11c-, CD11b+CD11c-Ly6C+Ly6G- (monocytes) and CD11b+CD11c-Ly6ClowLy6G+ (neutrophils). We did not observe any significant change in B220+, CD4+ or CD8+ lymphoid populations. On the contrary, we observed a growth restrictive effect of Epag treatment on Tet2-/- myeloid cells. Consistent with our hypothesis that Epag inhibits TET-dioxygenase activity, we observed hypermethylation in the mononuclear cells derived AA patients (n= 16) after Epag treatment. This was further confirmed in ex vivo Epag treatment of BM cells derived from healthy donor. Epag treatment significant increase clonogenic expansion of normal BM cells but not TET2 mutant myeloid cells. In summary, here we demonstrate that Epag is a potent inhibitor of TET-dioxygenase and its biological consequences are independent of TPOR-JAK-STAT activation. Epag treatment mimics TET2 loss of function in AA cells, however it restricts clonal expansion of TET2 mutant myeloid cells. Disclosures Patel: Alexion: Other: educational speaker. Nazha:Jazz: Research Funding; Incyte: Speakers Bureau; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau. Saunthararajah:EpiDestiny: Consultancy, Current equity holder in private company, Patents &amp; Royalties: University of Illinois at Chicago. Sekeres:Pfizer: Consultancy; BMS: Consultancy; Takeda/Millenium: Consultancy. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria.

Considerations for Use of Hematopoietic Growth Factors in Patients With Cancer Related to the COVID-19 Pandemic.

Hematopoietic growth factors, including erythrocyte stimulating agents (ESAs), granulocyte colony-stimulating factors, and thrombopoietin mimetics, can mitigate anemia, neutropenia, and thrombocytopenia resulting from chemotherapy for the treatment of cancer. In the context of pandemic SARS-CoV-2 infection, patients with cancer have been identified as a group at high risk of morbidity and mortality from this infection. Our subcommittee of the NCCN Hematopoietic Growth Factors Panel convened a voluntary group to review the potential value of expanded use of such growth factors in the current high-risk environment. Although recommendations are available on the NCCN website in the COVID-19 Resources Section (https://www.nccn.org/covid-19/), these suggestions are provided without substantial context or reference. Herein we review the rationale and data underlying the suggested alterations to the use of hematopoietic growth factors for patients with cancer in the COVID-19 era.

Biochemical Markers of Colorectal Cancer - Present and Future.

According to a report by the National Cancer Institute, colorectal cancer (CRC) is one of the most common types of cancer worldwide. CRC is often recognized too late for successful therapy. Tumor markers have been sought for a number of years to detect the transformation of malignant cells at the earliest possible stage. They are usually proteins associated with a malignancy and might be clinically useful in patients with cancer. Several classical markers have been used to recognize colorectal cancer, including carcinoembryonic antigen (CEA), carbohydrate antigen (CA 19.9), tissue polypeptide specific antigen (TPS) and tumor-associated glycoprotein-72 (TAG-72). None of these tests, however, have excellent diagnostic accuracy. Recent studies have been conducted on the use of hematopoietic growth factors (HGFs) and various enzymes in the diagnosis and prognosis of colorectal cancer. These include macrophage-colony stimulating factor (M-CSF) and granulocyte-macrophage-colony stimulating factor (GM-CSF), interleukin-3, interleukin-6 and enzymes (alcohol dehydrogenase and lysosomal exoglycosidases). Significantly, most cancer deaths are not caused by the primary tumor itself but by its spread. Analysis of circulating cancer cells (CTCs), ie, factors responsible for metastasis, may be a source of information useful in the treatment of patients with colorectal cancer. Currently available markers have significant limitations.

Management of the toxicity of chemotherapy and targeted therapies in elderly cancer patients.

The elderly form a very heterogeneous group in relation to their general health state, degree of dependence, comorbidities, performance status, physical reserve and geriatric situation, so cancer treatment in the older patient remains a therapeutic challenge. The physiological changes associated with aging increase the risk of developing a serious toxicity induced by chemotherapy treatment, as well as other undesirable consequences as hospitalizations, dependence and non-compliance with treatment, that can negatively affect survival, quality of life and treatment efficacy. The use of hematopoietic growth factors and other active supportive interventions in the elderly can help prevent and/or alleviate these toxicities. However, we have little data on the efficacy and tolerance of support treatments in the older patient. The objective of this work is to review the most frequent toxicities of oncological treatments in the elderly and their management.

Use of Hematopoietic Growth Factors in Elderly Lung Cancer Patients Receiving Chemotherapy: A SEER-Medicare-based Study.

Hematopoietic growth factors (HGFs) are essential for successful completion of chemotherapy in lung cancer patients. However, because of their adverse effects, clinical guidelines recommend their use in only selective clinical scenarios. This study, for the first time, explores patient characteristics and temporal trends associated with HGF utilization among elderly lung cancer patients receiving chemotherapy. This is a retrospective analysis of the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data containing 80,940 patients, aged 65 years and older, diagnosed with stage I to IV lung cancer between 1992 and 2009, and who received chemotherapy. Descriptive statistics and logistic regressions were used to examine the characteristics associated with 2 types of HGFs-colony stimulating factors (CSFs) and erythropoiesis-stimulating agents (ESAs). Twenty-five percent of the patients received CSFs and 42% received ESAs. Temporal variations were most predictive of HGF utilization, with an increase from 2.6% in 1992 to 47.3% in 2009 for CSFs and 1.3% to 30.5% for ESAs. Higher chemotherapy-based risk profiles increased the odds of HGF receipt 2 to 3 times (P<0.0001). Even after controlling for relevant clinical characteristics, unexplained sociodemographic associations persisted, suggesting lack of compliance with HGF guidelines. There has been a significant increase in the use of HGFs over time. Although chemotherapy-based risk profiles were significant predictors of HGF receipt, the study results suggest possible lack of compliance with treatment guidelines, which should be investigated. Given the high cost of HGFs, future studies are also needed to determine cost-effectiveness of these drugs among lung cancer patients.

Supportive (Maintenance) Therapy in Hematopoietic Stem Cell Transplantation: Main Principles and New Perspectives

Supportive (maintenance) therapy (ST) for hematopoietic stem cell transplantation (HSCT) is undergoing significant changes and development. The aim of the review was to summarise the basic data on methods and perspective of ST for HSCT and to analyse new opportunities and alternative approaches to enhance the antitumor potential of HSCT. The need for ST is constantly growing as a result of significant increase in the number of performed HSCT and an increase in patient survival. The review highlights traditional methods of ST which allowed to boost the success of HSCT: antibacterial, antifungal, and antiviral preventive treatment. The authors discuss preventing toxicity of dimethyl sulfoxide (cryopreserving agent); understudied aspects of vaccination of HSCT recipients, and effects on microbiota. The study demonstrates that many of the classic recommendations of ST are being constantly updated given the wide variability of approaches not only to post-transplant monitoring, but also to empirical antibiotic therapy and the use of hematopoietic growth factors and the appropriateness of the correction of the microbiota, constraints of the external environment and social contacts. Currently, HSCT is becoming more available, in conditions close to the out-patient clinics, which leads to improved outcomes and significantly decreases the cost of hospital stay. The future improvement of the cost effectiveness and quality of ST will be possible due to health information technologies, and digital infrastructure between doctor and patient. We report our own experience of ST for allo-HSCT in 19 patients and for auto-HSCT in 82 patients, and implementation of auto-HSCT in non-insulated wards without HEPA-filtration. The literature review shows both the increased demand for the various methods of ST at HSCT and its increasing efficiency. Despite the lack of uniform standards, introduction of new approaches of ST should significantly improve HSCT outcomes.

Use of Hematopoietic Growth Factors and Risk of Thromboembolic and Pulmonary Toxicities in Elderly Patients with Advanced Ovarian Cancer

ObjectiveTo evaluate the risk of thromboembolic and pulmonary toxicities associated with hematopoietic growth factor (HGF) use (i.e., erythropoietin-stimulating agent [ESA] and/or colony-stimulating factor [CSF]) in a community-dwelling cohort of elderly patients with advanced ovarian cancer. MethodsWe studied 8,188 women, 65 years and older from the Surveillance, Epidemiology and End Results-Medicare linked database, diagnosed from January 1, 2000 to December 31, 2009. Patients were categorized into five groups: no chemotherapy and no ESA/CSF (n = 2,616), chemotherapy but no ESA/CSF (n = 1,854), ESA only (n = 1,313), CSF only (n = 743), and ESA + CSF (n = 1,662). We reported the cumulative incidence of toxicities for 2, 6, and greater than 6 months, and the incidence density for the overall follow-up. Cox-proportional hazards regression was performed to determine risk of toxicities. ResultsOf the 5,572 patients receiving chemotherapy, 66.7% (n = 3,718) received HGF supportive treatment, 29.8% received ESA + CSF, 23.6% received ESA only, and 13.3% received CSF only. Patients who received chemotherapy and also ESA + CSF had a 14.1% cumulative incidence of thromboembolic event (TEE) at 6 months of follow-up compared with 8.0% in those who received chemotherapy without growth factor and 3.2% in those with neither chemotherapy nor growth factor. Those with chemotherapy who received ESA + CSF had a significantly higher risk of TEE (adjusted hazard ratio, 1.22; 95% confidence interval, 1.01–1.47) as compared with patients with chemotherapy and no ESA/CSF, although patients aged 85 years and older may experience up to a five-fold increased risk. The risk of pulmonary toxicities did not significantly differ by HGF use. ConclusionsAn increased risk of TEEs was observed in elderly patients with ovarian cancer who received ESA + CSF. The risk–benefit ratio for administering HGF should be carefully evaluated, especially among those 85 years and older.

How to approach drug-induced agranulocytosis in ICU

Many drugs can cause agranulocytosis and neutropenia by bone marrow suppression. Drug-induced agranulocytosis (DIA) is a relatively rare, but life-threatening disorder that frequently occurs as an adverse reaction to drugs. The overall incidence of DIA ranges from 2.4 to 15.4 cases/million patients exposed to drugs per year. DIA remains a serious adverse event because of the occurrence of severe sepsis with severe deep infections (such as pneumonia), septicemia, and septic shock in around two thirds of patients. In this setting, older age (>65 years), septicemia or shock, metabolic disorders such as renal failure, and a neutrophil count below 0.1×10 9 /l are poor prognostic factors. The severity of neutropenia ( 10 days) may also impact negatively on the outcome. Commonly used drugs such as antibiotics (b-lactam and cotrimoxazole), antiplatelet agents (ticlopidine), antithyroid drugs, sulfasalazine, neuroleptics (clozapine), antiepileptic agents (carbamazepine), nonsteroidal anti-inflammatory agents, and dipyrone are the most common causes of neutropenia and agranulocytosis. Recent investigations suggest that there are at least three mechanisms by which it can be produced, namely, differences in drug pharmacokinetics, abnormal sensitivity of myeloid precursors, and adverse immune responses to drug administration. Genetic factors are important and could act by any of the above mechanism. In management, use of hematopoietic growth factors, such as granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor, reduced mortality rate from 21.5 to 5%. Now a days, physicians use many drugs to increased life expectancy, as well as the development of new agents, should be aware of this complication and its management.

Filgrastim for the treatment of hematopoietic acute radiation syndrome.

The U.S. Food and Drug Administration (FDA) recently approved Neupogen(®) (filgrastim) for the treatment of patients with radiation-induced myelosuppression following a radiological/nuclear incident. It is the first medical countermeasure currently approved by the FDA for this indication under the criteria of the FDA "animal rule". This article summarizes the consequences of high-dose radiation exposure, a description of the hematopoietic acute radiation syndrome (H-ARS), the use of hematopoietic growth factors in radiation accident victims and current available treatments for H-ARS with an emphasis on the use of Neupogen in this scenario.

Increasing utilization and predictors of hematopoietic growth factors in patients diagnosed with colorectal cancer: findings from a large national population-based cohort in the USA, 1992–2009

None of previous studies has provided the detailed pattern, variation, and temporal trend in the use of growth factors for patients with colorectal cancer. The aim of the study was to examine the temporal trend and predictors of receiving hematopoietic growth factors in a large nationwide and population-based cohort of patients with colorectal cancer in the USA from 1992 to 2009. We studied 50,768 patients diagnosed with colorectal cancer at age 65-89 years in 1992-2009 in the Surveillance, Epidemiology and End Results areas who received chemotherapy as part of initial therapy within 12 months of diagnosis according to Medicare data. Growth factors were identified for colony-stimulating factors (CSFs) and for erythropoiesis-stimulating agents (ESAs). Overall, 16.3% received CSFs and 26.5% received ESAs with an increase from 0.8 and 1.5% in 1992 to 29.4 and 14.1% in 2009, respectively. Compared with patients diagnosed in 1992-1994, those diagnosed in 1995-1997 were >2 times more likely to receive CSFs and ESAs, whereas patients diagnosed recently in 2007-2009 were >22 times and 4 times to receive CSFs and ESAs, respectively. Gender, marital status, comorbidity scores, geographic area, year of diagnosis, tumor stage, number of lymph nodes, and risk profile for febrile neutropenia were statistically significant predictors of using CSFs and ESAs. There were substantial temporal and geographic variations in the use of hematopoietic growth factors in patients with colorectal cancer following chemotherapy. More studies would be needed to explore the effectiveness of hematopoietic growth factors in preventing and treating neutropenia, anemia, and infection.

Sustained Virologic Response After 6 Weeks of Therapy With a First-Generation Hepatitis C Virus Protease Inhibitor

To the Editor—Patients with hepatitis C virus (HCV) genotype 1 infection should receive 12 weeks of triple combination therapy with the first-generation HCV protease inhibitor telaprevir, pegylated interferon (peg-IFN) alfa-2a or alfa-2b, and ribavirin (RBV), followed by 12 or 36 weeks of double therapy with peg-IFN and RBV [1]. We report a case of sustained virologic response (SVR) achieved after only 6 weeks of triple combination treatment. A 53-year-old white woman with history of breast cancer was treated with surgery, adjuvant chemotherapy, and radiation in 2010, followed by hormonal therapy with letrozole. During a routine follow-up at another facility, elevated transaminases were detected and further investigation led to the diagnosis of chronic HCV infection that was probably acquired 30 years before current presentation. She was infected with HCV genotype 1b, and host genotyping revealed the IL28B CC allele. Liver biopsy showed bridging fibrosis. The patient was initiated on telaprevir, peg-IFN alfa-2a, and RBV. Concurrent medications included hydrochlorothiazide and lisinopril for hypertension. Letrozole was discontinued a few weeks before antiviral treatment initiation, to avoid potential drug interactions. On week 4 of treatment, the HCV load was undetectable (rapid virological response [RVR]). Two weeks later, the patient presented with shortness of breath, anemia, thrombocytopenia, rash, and acute renal failure. HCV treatment was discontinued because of severe renal dysfunction. During the first 2 weeks off therapy, the hematologic toxic effects worsened, necessitating hospital admission, use of hematopoietic growth factors, and red blood cell transfusion (Figure ​(Figure11). Figure 1. Outcome and laboratory abnormalities in a patient successfully treated with 6 weeks of telaprevir-based therapy. aHepatitis C virus was measured with the transcription-mediated amplification method. Abbreviations: HCV, hepatitis C virus; Rx, treatment; ... The patient was referred to our institution for investigation of possible myelodysplastic syndrome. Bone marrow biopsy revealed no evidence of malignancy, and the abnormal laboratory parameters were attributed to HCV treatment. In the following weeks, the patient improved and all laboratory parameters normalized. The HCV load remained undetectable at 24 weeks after cessation of HCV treatment (SVR24). Telaprevir-containing therapy is very effective, but is often associated with the development of severe side effects [1]. This treatment combination is also associated with renal impairment, which leads to more pronounced anemia from decreased RBV elimination [2]. The half-life of RBV ranges from 100 hours normally to 500 hours in patients with decreased renal function [3]. The renal impairment our patient developed might have contributed to her severe anemia by prolonging RBV exposure after treatment cessation. The fact that the anemia worsened even after treatment discontinuation supports this hypothesis. On the other hand, extended RBV exposure might have led to the patient's favorable virologic outcome. In regard to positive predictors of response to HCV treatment, our patient had several: female sex, white race, HCV-1b genotype infection, IL28B CC allele, low baseline viral load, no cirrhosis or steatosis, and RVR [4]. We found 2 reports of patients with SVR after shortened duration of telaprevir-based therapy (Table ​(Table1)1) [5, 6]. The common characteristics of these patients and our patient include non–African American race, HCV-1b genotype, and absence of cirrhosis. Table 1. Reported Cases of Sustained Virologic Response After Short-Duration Telaprevir-Based Therapy The interim analysis of an exploratory multicenter study designed to evaluate the efficacy of 12-week-total telaprevir-based therapy in patients with HCV genotype 1, either treatment-naive or with relapse after treatment, showed an SVR of 87% (74 of 85 subjects) among noncirrhotic patients with the IL28B CC genotype who had achieved RVR [7]. In conclusion, the addition of first-generation protease inhibitors to the anti-HCV treatment armamentarium has improved outcomes of patients infected with genotype 1 HCV [1]. Unfortunately, these regimens are frequently associated with serious adverse events. The present report describes the common characteristics of patients successfully treated after short-duration telaprevir-based therapy.

Diagnosis and treatment of pediatric acquired aplastic anemia (AAA): An initial survey of the North American Pediatric Aplastic Anemia Consortium (NAPAAC)

Randomized clinical trials in pediatric aplastic anemia (AA) are rare and data to guide standards of care are scarce. Eighteen pediatric institutions formed the North American Pediatric Aplastic Anemia Consortium to foster collaborative studies in AA. The initial goal of NAPAAC was to survey the diagnostic studies and therapies utilized in AA. Our survey indicates considerable variability among institutions in the diagnosis and treatment of AA. There were areas of general consensus, including the need for a bone marrow evaluation, cytogenetic and specific fluorescent in situ hybridization assays to establish diagnosis and exclude genetic etiologies with many institutions requiring results prior to initiation of immunosuppressive therapy (IST); uniform referral for hematopoietic stem cell transplantation as first line therapy if an HLA-identical sibling is identified; the use of first-line IST containing horse anti-thymocyte globulin and cyclosporine A (CSA) if an HLA-identical sibling donor is not identified; supportive care measures; and slow taper of CSA after response. Areas of controversy included the need for telomere length results prior to IST, the time after IST initiation defining a treatment failure; use of hematopoietic growth factors; the preferred rescue therapy after failure of IST; the use of specific hemoglobin and platelet levels as triggers for transfusion support; the use of prophylactic antibiotics; and follow-up monitoring after completion of treatment. These initial survey results reflect heterogeneity in diagnosis and care amongst pediatric centers and emphasize the need to develop evidence-based diagnosis and treatment approaches in this rare disease.

Multiple Myeloma: An Update

Multiple myeloma is a rare, largely incurable malignant disease of plasma cells. Patients usually present with hypercalcemia, renal insufficiency, anemia and/or lytic bony lesions along with a monoclonal protein in the serum and/or urine in addition to an increase in the number of clonal plasma cells in the bone marrow. Patients with myeloma live on an average for five to seven years, with their survival dependent on the presence or absence of different prognostic markers. Treatment of younger fit patients is with induction therapy consisting of steroids with one or more novel anti-myeloma agents followed by high dose melphalan and autologous stem cell transplantation, while older and less fit patients are treated with melphalan-based combination chemotherapy. Supportive care is of paramount importance and includes the use of bisphosphonates, prophylactic antibiotics, thrombosis prophylaxis and the use of hematopoietic growth factors along with the treatment of complications of disease and its therapy. As more progress is being made and deeper responses are being attained, the disease might turn into a potentially curable one in the near future.

Granulocyte-colony stimulating factor for hematopoietic stem cell donation from healthy female donors during pregnancy and lactation: what do we know?

BACKGROUND Hematopoietic growth factors (HGFs) are mostly used as supportive measures to reduce infectious complications associated with neutropenia. Over the past decade, the use of HGFs became a common method for mobilizing human CD34+ stem cells, either for autologous or allogeneic transplantation. However, since their introduction the long-term safety of the procedure has become a major focus of discussion and research. Most information refers to healthy normal donors and data concerning pregnant and lactating women are scarce. The clinical question, which is the core of this review, is whether stem cell donation, preceded by administration of granulocyte-colony stimulating factor (G-CSF) for mobilization, is a safe procedure for pregnant donors. METHODS Literature searches were performed in Pubmed for English language articles published before the end of May 2012, focusing on G-CSF administration during pregnancy, lactation and hematopoietic stem cell donation. Searches included animal and human studies. RESULTS Data from animals (n = 15 studies) and women (n = 46 studies) indicate that G-CSF crosses the placenta, stimulates fetal granulopoiesis, improves neonatal survival mostly for very immature infants, promotes trophoblast growth and placental metabolism and has an anti-abortive role. Granulocyte macrophage-CSF is a key cytokine in the maternal immune tolerance towards the implanted embryo and exerts protective long-term programming effects to preimplantation embryos. The available data suggest that probably CSFs should not be administered during the time of most active organogenesis (first trimester), except perhaps for the first week during which implantation takes place. Provided CSF is administered during the second and third trimesters, it appears to be safe, and pregnant women receiving the CSF treatment can become hematopoietic stem cell donors. There are also risks related to the anesthesia, which is required for the bone marrow aspiration. During lactation, there should be a period of at least 3 days to allow for clearance of CSF from milk before resuming breast feeding. With regard to teratogenicity or leukaemogenity, in non-pregnant or non-lactating women reports show that CSF administration is associated with a risk for leukemia; however, this risk is not higher compared with the control population. CONCLUSIONS The information available to date indicates that administration of CSF in general, and G-CSF in particular, is safe and healthy pregnant women can serve as donors of either bone marrow or peripheral blood stem cells. However, the clinical experience is rather limited and therefore until more data become available, G-CSF should not be used during pregnancy and lactation when other therapeutic options, instead of stem cell transplantation, are available.

Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Effect of obesity on toxicity in women treated with adjuvant chemotherapy for early-stage breast cancer: a systematic review

The purpose of this study is to provide more definite evidence regarding the role of dose modification of chemotherapy in obese women with breast cancer by systematically reviewing current literature regarding chemotherapy-induced toxicity rates in obese and non-obese women with early-stage breast cancer. A systematic search of Pubmed and EMBASE was conducted to identify original studies investigating chemotherapy-induced toxicity in obese women receiving adjuvant chemotherapy treatment for breast cancer. Ten studies were identified. We noted low rates of adjustment for confounders such as prophylactic hematopoietic growth factor use and empirical dose reductions. Seven studies found reduced toxicity in obese compared to non-obese women. Of four studies, where dose capping was precluded or statistically adjusted for, three found reduced toxicity in obese women. These outcomes include less febrile neutropenia (body mass index (BMI) >23.6; odds ratio (OR) 4.4; 95 % confidence interval (CI) 1.65-12.01), fewer hospital admissions (BMI >35; OR 0.61, 95 % CI 0.38-0.97), and fewer neutropenic events (BMI >25; OR 0.49; 95 % CI 0.37-0.66). Only a single study reported higher rates of toxicity in obese women, but this study had significant methodological issues. As a conclusion, we observed that obese patients tolerate chemotherapy better than lean patients. However, this may be confounded by poorly specified dose capping practices and the use of hematopoietic growth factors. Further research should focus on improved documentation of body size, of dose, and of use of growth factors, and analysis of how these affect recurrence rates, toxicity, and survival.

Hodgkin Lymphoma in Patients with HIV Infection: A Review

Hodgkin lymphoma (HL) is one of the most common types of non-AIDS-defining tumors in the HIV-infected. Its incidence however seems to have increased under highly active anti-retroviral therapy (HAART). HIV-HL is a different entity from HL in HIV-negative subjects with a poorer prognosis that is associated with tumor-subtype, EBV-infection, and "B" symptoms. Despite the aggressive nature of the disease, clinical outcome has improved with combination therapies including appropriately timed antiretroviral strategies and the quality of supportive care-notably the use of hematopoietic growth factors. More intensive chemotherapy regimens with or without autologous stem cell transplantation appear to improve survival. Functional imaging such as positron emission tomography and computed tomography (FDG-PET) may help guide treatment strategy and minimize long-term toxicity.

Current treatment for chronic hepatitis C virus/HIV-infected individuals

Liver disease is an important cause of morbidity and mortality in the era of combination antiretroviral therapy in HIV/hepatitis C virus (HCV) co-infected patients. This review highlights the role of pegylated interferon-alpha (peg-IFN) and ribavirin (RBV) therapy and examines factors associated with response and strategies to maximize responses. HCV viral clearance is lower in HIV co-infected patients than in HCV mono-infected patients. However, in patients who attain sustained response there is clinical benefit in terms of liver disease associated morbidity and mortality and treatment is costeffective. Predictors of response appear similar, although there are a number of modifiable patient-associated and HIV-associated factors that could be addressed. Moreover, the use of weight-based RBV and treatment length guided by early viral responses improve response rate. Avoidance of drug-drug interactions and use of haematopoietic growth factors reduce adverse events and dose reductions and ultimately increase response rates. Very early prediction of treatment futility is promising. Induction dosing strategies have not yielded positive results, though twice weekly peg-IFN-alpha-2a induction therapy merits further investigation. Peg-IFN/RBV therapy plays an important role in the management of HCV in HIV-infected patients. Efforts to maximize response to current therapy need to continue while we await new therapies.