Etoposide-containing Regimens Research Articles

Safety and Efficacy of Anakinra in Haemophagocytic Lymphohistiocytosis Associated with Acute Leukaemia

Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition in which immune hyperactivation and dysregulation results in a cytokine storm. It may be primary or secondary to infection, autoimmune disorders or malignancies (HLH-M). Lymphoma is the most widely described association in HLH-M; there is very limited data linking acute leukaemia and HLH. Current recommended treatments for HLH-M include steroids, IVIG and etoposide-containing regimens. In contrast, the recommended treatment in HLH- Macrophage activation syndrome is anti-IL1 directed therapy such as anakinra. In 2021 NHS England approved the use of anakinra to treat HLH of any cause, but the safety and efficacy data of anakinra in HLH-M is limited. We report a retrospective review of all patients diagnosed with HLH and acute leukaemia (AML) or acute lymphoblastic leukaemia (ALL) in a single London tertiary referral centre (University College London Hospitals NHS Foundation Trust (UCLH)), between 1 January2019 and 31 December 2022. We analysed electronic health records (EHR) of all patients diagnosed with ALL or AML and cross-referenced this with records of all patients referred to the UCLH HLH MDT. This identified 468 patients with acute leukaemia, of whom 13 (2.8%) were diagnosed with HLH. For diagnostic purposes, we utilised H scores (comprising laboratory and clinical parameters providing an HLH probability for each patient) using clinical and laboratory data collected from the EHR. HLH was diagnosed in patients with a clinical suspicion of HLH and an H score of >169. Patients were treated with various types of immunosuppressive therapy (IST). Twelve (92%) received anakinra, three (17%) of whom had anakinra monotherapy whilst the remainder had anakinra with steroids (38%), steroids and IVIG (15%), or steroids, IVIG and etoposide (8%). Anakinra was given intravenously in eleven patients and subcutaneously in one, with a mean daily dose of 4.6mg/kg. All patients required critical care input during their HLH treatment. Eight (62%) were admitted to intensive care unit (ICU) on diagnosis with HLH and required ventilatory and vasopressor support; the remainder were reviewed by critical care outreach. 92% patients had an initial rapid clinicopathological response following IST, becoming afebrile, reduction in oxygen requirement and haemodynamic stability seen within 24-72 hours. One patient (8%) had an initial clinical response to anakinra, methylprednisolone and IVIG triple therapy, but displayed subsequent rapid deterioration in the context of pseudomonal infection and died of multiorgan failure. Nine patients (69%) had no clinicopathological recurrence of HLH following initial treatment. Three (23%) had an initial clinical response to IST but had subsequent biochemical and clinical relapse of HLH. These patients all had relapsed/refractory disease on HLH recurrence. Only one (8%) patient died from HLH. Eight (62%) remain in remission from leukaemia at the end of the study period. Three patients (23%) died of refractory leukaemia, whilst a fourth patient is receiving palliative care for refractory disease. Although the link between HLH and lymphoma is well characterised, there is limited data on HLH in the context of acute leukaemia. In this case series, 2.8% of the patients treated with acute leukaemia developed HLH, which is comparable to the 3% for lymphoma quoted elsewhere. Although 92% of patients had microbiological or radiological evidence of infection on HLH diagnosis, many infections involved organisms not classically associated with HLH e.g. rhinovirus, indicating that the underlying leukaemia may play a central role in HLH-M pathogenesis. This is highlighted by the relapse of HLH which occurred alongside leukaemia relapse in three patients. Treatment responses and outcomes were favourable compared to the existing literature. Tamamyan et al reported an overall survival rate of 15% in 13 patients with HLH-M. Delavigne et al reported a three-month mortality rate of 36% in AML patients presenting with HLH during induction, compared to our figure of 23% for this time period and our overall survival rate of 62%. We believe this is the first case series demonstrating the effectiveness and high overall survival of HLH-M patients with concurrent leukaemia diagnosis using anakinra. Early treatment with anakinra alongside other immunosuppression may explain the trend towards improved outcomes in our cohort.

Successful management of adult hemophagocytic lymphohistiocytosis with an etoposide-containing regimen: Case report and literature review

Objective: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder characterized by a hyperimmune response. Although HLH is well described in the pediatric population, less is known about the appropriate management in adults. Despite the inclusion of etoposide in HLH society protocols, some clinicians refrain from using it due to its cytotoxicity and potential adverse effects. Case: We report here the case of a 43-year-old male presenting with fever and pancytopenia, who was diagnosed with HLH following further evaluation. The patient immediately started the HLH-2004 initial protocol, which consisted of dexamethasone, etoposide, cyclosporine, and IVIG. Symptoms improved after 2 weeks of treatment. Subsequent bone marrow biopsy showed normal results, and the patient achieved complete remission, leading to the termination of treatment in the 12th week of the protocol. At 8 months post-treatment, the patient remained recurrence-free with normal hematological and biochemical test results. Conclusion: This case underscores the importance of considering etoposide-containing regimens, particularly for medically fit patients.

Genome-wide CRISPR/Cas9 screen identifies etoposide response modulators associated with clinical outcomes in pediatric AML.

Etoposide is used to treat a wide range of malignant cancers, including acute myeloid leukemia (AML) in children. Despite the use of intensive chemotherapeutic regimens containing etoposide, a significant proportion of pediatric patients with AML become resistant to treatment and relapse, leading to poor survival. This poses a pressing clinical challenge to identify mechanisms underlying drug resistance to enable effective pharmacologic targeting. We performed a genome-wide CRISPR/Cas9 synthetic-lethal screening to identify functional modulators of etoposide response in leukemic cell line and integrated results from CRISPR-screen with gene expression and clinical outcomes in pediatric patients with AML treated with etoposide-containing regimen. Our results confirmed the involvement of well-characterized genes, including TOP2A and ABCC1, as well as identified novel genes such as RAD54L2, PRKDC, and ZNF451 that have potential to be novel drug targets. This study demonstrates the ability for leveraging CRISPR/Cas9 screening in conjunction with clinically relevant endpoints to make meaningful discoveries for the identification of prognostic biomarkers and novel therapeutic targets to overcome treatment resistance.

Budget impact analysis of trilaciclib for decreasing the incidence of chemotherapy-induced myelosuppression in patients with extensive-stage small cell lung cancer in the United States.

BACKGROUND: Chemotherapy-induced myelosuppression, which commonly manifests as neutropenia, anemia, and/or thrombocytopenia, is a frequent and severe complication of standard treatment regimens for patients with extensive-stage small cell lung cancer (ES-SCLC). Trilaciclib is a first-in-class myeloprotective therapy indicated to decrease the incidence of chemotherapy-induced myelosuppression when administered prior to a platinum-/etoposide-containing regimen or topotecan-containing regimen for ES-SCLC. OBJECTIVE: To estimate the budget impact of administering trilaciclib prior to chemotherapy to manage chemotherapy-induced myelosuppression in adults with ES-SCLC from a US payer perspective. METHODS: A budget impact model was developed to assess the impact of introducing trilaciclib to a hypothetical 1 million-member health insurance plan. The model compared 2 market scenarios: a current scenario of standard treatments for ES-SCLC without trilaciclib, and an alternative scenario of standard treatment plus trilaciclib. Population, clinical, and cost inputs were derived from published literature and trilaciclib clinical trial data. Model outcomes included the number of myelosuppressive adverse events (AEs), costs of treatment, costs of AE management, total cost, and per-member per-month (PMPM) costs. The budget impact of trilaciclib was calculated as the difference in cost (2021 US dollars) between the 2 scenarios over a 1- to 5-year time horizon. Scenario and deterministic sensitivity analyses were conducted to assess uncertainty around key model inputs. RESULTS: An estimated total of 301 patients were eligible for treatment with trilaciclib over a 5-year period. The use of trilaciclib was estimated to reduce the number of myelosuppressive AEs over a 5-year period (events avoided included 108 for neutropenia, 7 for febrile neutropenia, 23 for anemia, and 46 for thrombocytopenia) compared with the scenario without trilaciclib. The adoption of trilaciclib was associated with a cost saving of $801,254 ($0.013 PMPM) over 5 years. The acquisition cost for trilaciclib ($3,704,199) was offset by the reduction in AE management cost ($4,282,748) and reduction in prophylactic granulocyte colony-stimulating factor use ($222,704). The cost savings associated with trilaciclib began in year 1 (total $34,388; $0.003 PMPM) and accrued over time. CONCLUSIONS: The acquisition cost of trilaciclib is projected to be offset by a reduction in the costs of managing AEs related to myelosuppression when added to standard chemotherapy regimens for ES-SCLC. The net budget impact of trilaciclib is estimated to be a cost saving. DISCLOSURES: This research was funded by G1 Therapeutics, Inc., and implemented by ZS Associates, an independent consultancy that collated the model inputs and performed the budget impact analysis. The study sponsor was involved in the study design; collection, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication. The journal open access fee was funded by G1 Therapeutics, Inc. Moran, Chioda, and Huang are employed by G1 Therapeutics, Inc. Chioda and Huang report stocks and stock options for G1 Therapeutics, Inc. Goyal and Deniz are employed by ZS Associates. Goyal reports consulting fees from G1 Therapeutics, Inc. Abraham reports consulting fees from Coherus, G1 Therapeutics, Inc. (unrelated to this study and manuscript), Mylan/Viatris, and Sandoz and participation on a data safety monitoring board or advisory board for G1 Therapeutics, Inc. MacDonald reports consulting fees from Coherus, G1 Therapeutics, Inc. (unrelated to this study and manuscript), Mylan/Viatris, and Sandoz. Deniz reports no disclosures. A synopsis of the current study was presented in poster format at the Virtual AMCP Annual Meeting, April 12-16, 2021.

Dose adjusted R-EPOCH and other etoposide-containing regimens in first-line treatment of diffuse large B-cell lymphoma

Etoposide is a well-known cytotoxic agent effective in the treatment of B-large cell lymphoma (B-LCL). Currently, there is no consensus regarding the place of etoposide-containing regimens (R-CHOEP, R-ACVBP and DA-R-EPOCH) in front-line treatment of B-LCL. This paper summarizes published data and our own experience regarding the activity and toxicity of these regimens, especially DA-R-EPOCH. Most non-randomized, real-life and retrospective studies suggest that, compared to R-CHOP, DA-R-EPOCH, similarly to other etoposide-containing regimens, has superior antitumor efficacy but is also more toxic. The most important severe side-effects are hematological and infectious, making the regimen unfeasible in unfit patients. However, in fit patients with high-risk features, progression-free survival rates seem improved by 15–20% compared to R-CHOP. In our series of high-risk [age-adjusted International Prognostic Index (aaIPI) 2–3] fit [Eastern Cooperative Oncology Group (ECOG) performance status 0–2]) B-LCL patients older than 60 treated with DA-R-EPOCH, PFS at 2 years was 70%, while it was 53% in a comparable historical cohort treated with R-CHOP. DA-R-EPOCH resulted in more hematological and infectious toxicity, but no treatment-related mortality. In our opinion, DA-R-EPOCH should be considered in newly diagnosed, fit, high-risk patients with B-LCL who are older than 60, provided that there is adequate outpatient supervision, supportive care, and prompt hospital admittance in case of neutropenic fever or other severe toxicities.

Clinical study on the effect of etoposide-containing induction regimen for adult-onset Still's disease associated hemophagocytic syndrome

Objective: To investigate the efficacy of an etoposide-containing regimen in the treatment of adult-onset Still's disease related hemophagocytic syndrome(AOSD-HLH). Methods: This study adopted the method of retrospective analysis to collect clinical data of 43 AOSD-HLH patients, including the clinical characteristics, laboratory indexes, treatment regimen and prognosis. There were 7 males and 36 females, aged 24-40 years, with a median age of 30. All of them were diagnosed and treated in Beijing Friendship Hospital of Capital Medical University from December 2014 to December 2019. According to whether or not etoposide (VP-16) was included in the initial therapy, patients were divided into group 1 (VP-16 was not administrated in the initial treatment, n=31) and group 2 (the initial treatment included etoposide, n=12). Patients in group 1 who did not respond to the initial treatment were retreated with VP-16-containing regimen, and the effect of initial treatment was compared between the 2 groups. Similarly, according to whether the VP-16-containing regimen was applied or not, patients achieving remission of HLH were divided into group a (not applied, n=6) and group b (applied, n=33), and the laboratory indicators of the two groups were compared. Results: The overall response rate (ORR, 6/31 vs 11/12) and complete response rate (CRR, 1/31 vs 5/12) of patients in group 1 were significantly lower than those in group 2 (both P<0.05). Patients in group 1 who did not respond to the initial treatment were retreated with a VP-16-containing regimen, and we found that the ORR reached 22/24. Among patients in remission, the natural killer cell activity [16.3(14.2, 17.5)% vs 13.1(12.2, 13.8)%] and granulocyte counts [5.6(3.4, 9.3) ×109/L vs 3.9(2.3, 4.7) ×109/L] of patients was significantly higher in group B than that in group A(both P<0.05). There was no statistically significant difference in haemoglobin [103.0 (97.0, 109.5) g/L vs 91.5 (70.0, 118.0) g/L] and platelet counts [(212.2±74.2)×109/L vs (226.0±114.9)×109/L] between the two groups(both P>0.05). Conclusion: The remission status of HLH has an impact on the prognosis of patients. The use of VP-16 in initial treatment can significantly increase the ORR and CRR of AOSD-HLH patients. The application of VP-16 does not cause bone marrow suppression.

Clinical Profiles, Treatment Characteristics and Outcomes Among Newly Diagnosed Hodgkin Lymphoma Patients Presenting with Unfavorable and Advanced Disease within a US Community Oncology Setting

INTRODUCTIONThe intent of treating newly diagnosed Hodgkin lymphoma (HL) patients is to achieve a complete remission that can eventually translate into a cure. Treatment decisions for HL are guided by several factors, including sub-type, stage, disease symptomatology, laboratory results, radiologic imaging, age and overall health. Understanding patient profiles and treatment characteristics is important as there is a demographic difference between patients treated in community and academic settings. The intent of this study was to improve understanding of the HL patient population and treatment trends among unfavorable-/advanced-stage HL patients receiving care within the US community oncology setting. METHODS: This was a retrospective, observational cohort study of adult HL patients with Stage IIB-IV disease who initiated first-line chemotherapy within the US Oncology Network between 1/1/09 - 6/30/12. Patients were followed until 6/30/16. Most data were captured from structured fields of the electronic healthcare record, with a targeted chart review performed to provide additional detail on select study variables for a subset of the study population. Descriptive analyses were performed to assess patient and treatment characteristics, while the Kaplan Meier method was used to calculate the duration of therapy (DOT), time to next treatment (TTNT) and time to stem cell transplantation (SCT). RESULTS: In total, 565 patients met eligibility criteria and were included in the analysis. The mean age of the patient population was 44.3 years (standard deviation [SD] 18.2), 55.0% were male and 69.2% were Caucasian. Most patients (90.4%) received the ABVD regimen (doxorubicin, bleomycin, vinblastine and dacarbazine) or a variant of the ABVD regimen in the first-line setting (LOT1). Seventy-four (13.1%) patients were as assumed to have relapsed/refractory disease, as evidenced by advancement to second-line (LOT2) therapy. Among these patients, 44.6% received an etoposide-containing regimen, 17.6% received a brentuximab vedotin-containing regimen and 9.5% GVD (gemcitabine, vinorelbine, doxorubicin). Nearly 30% of LOT2 patients received a regimen classified into an “other” category because it was received by less than 5 patients in the study. Following LOT1, the median TTNT was 67.9 weeks (95% confidence interval [CI] 50.8,104.5). Among the 511 patients who received ABVD/ABVD variant regimens in LOT1, the median TTNT was 67.9 weeks (95%CI 49.0,90.9). Compared to LOT1, the median DOT of LOT2 was shorter (22.1 weeks [95%CI not reached] vs. 7.6 [95%CI 6.3, 10.1] weeks). The median DOTs of ABVD/ABVD variants and AVD in LOT1 were 22.1 (95%CI not reached) and 20.1 (95%CI 7.1, 22.1) weeks, respectively. Only 32 patients advanced to LOT3 and 7 to LOT4. Among patients selected for chart review, 31.2% reported symptoms associated with peripheral neuropathy during LOT1. Data pertaining to radiologic imaging and SCT were only available among patients selected for chart review. These results indicated that positron emission tomography (PET) scans were most frequently performed at diagnosis (74.9% of records reviewed) and/or after LOT1 (55.3% of records reviewed). At diagnosis, all PET scan results were positive (Deauville score 4-5); after LOT1 71.7% were negative (Deauville score 1-3). Treatment changes explicitly attributed to PET scan results were infrequently documented. Among the 29 patients observed to have undergone SCT, the median time to SCT was 41.1 weeks (95%CI 32.7, 56.8). CONCLUSIONS: These findings provide insight into the patient profiles and treatment progression in a US community oncology setting. In particular, ABVD/ABVD variant regimens were observed to be the predominate therapy in the front-line setting. Intensive salvage therapy and consolidative SCT were uncommon in the second-line setting, with most patients receiving etoposide- and brentuximab vedotin-containing regimens. Utilization of PET imaging at diagnosis, for interim response assessment and at completion of therapy was not universal. The apparent difference in use of imaging observed in this community oncology setting compared to what is reported by academic centers may be due variation treatment practices across these organizations or underlying differences in their patient populations. Future research should explore how patient profiles influence use of imaging and associated treatment decisions. DisclosuresYasenchak:Seattle Genetics: Consultancy; Bristol-Myers Squibb: Consultancy. Feliciano:Seattle Genetics: Employment, Equity Ownership. Aguilar:McKesson Specialty Health: Employment. Clark:McKesson Specialty Health: Employment, Equity Ownership. Amirian:McKesson Specialty Health: Employment. Richhariya:Seattle Genetics: Employment, Equity Ownership.

Development of Hepatic Steatosis After Chemotherapy for Non‐Hodgkin Lymphoma

Nonalcoholic fatty liver disease is the most common liver disorder in the developed world. Although typically reflecting caloric overload, it can also be secondary to drug toxicity. We aimed to describe the incidence and risk factors for de novo steatosis during chemotherapy for non‐Hodgkin lymphoma (NHL). In this retrospective case‐control study, adult patients with NHL were treated with rituximab, cyclophosphamide, doxorubicin, prednisone, and vincristine (R‐CHOP) or R‐CHOP + etoposide (EPOCH‐R). Patients with liver disease or steatosis were excluded. Abdominal computed tomography was performed pretreatment and at 3‐ to 6‐month intervals and reviewed for steatosis. Patients with de novo steatosis were matched 1:1 to controls by age, sex, and ethnicity. Of 251 treated patients (median follow‐up 53 months), 25 (10%) developed de novo steatosis, with the vast majority (23 of 25; 92%) developing it after chemotherapy. Of those, 14 (61%) developed steatosis within the first 18 months posttreatment and 20 (87%) within 36 months. Cases had higher baseline body mass index (BMI; mean ± SD, 29.0 ± 6.5 versus 26.0 ± 5.2 kg/m2; P = 0.014) and hyperlipidemia (12% versus 2%; P = 0.035). Although their weights did not change during chemotherapy, BMI in cases increased by 2.4 ± 2 kg/m2 (mean ± SD) from end of treatment to steatosis compared to 0.68 ± 1.4 in controls (P = 0.003). Etoposide‐containing regimens were associated with a shorter time to steatosis (median 34 weeks versus 154 weeks; P < 0.001) despite similar baseline risk factors. Conclusion: The recovery period from NHL chemotherapy appears to be a “hot spot” for development of fatty liver, driven by early posttreatment weight gain, especially in subjects with baseline risk factors.

A Phase III Randomized Study Comparing a Chemotherapy with Cisplatin and Etoposide to a Etoposide Regimen without Cisplatin for Patients with Extensive Small-Cell Lung Cancer.

In a literature meta-analysis, we showed survival benefits for regimens including cisplatin [hazard ratio (HR) 0.61; 95% confidence interval (CI), 0.57-0.66] and for those including etoposide (HR 0.65; 0.61-0.69). That benefit was mainly observed when etoposide alone or in combination with cisplatin was included in the chemotherapy regimens. Our objective was to determine if chemotherapy with both drugs improves survival in comparison to a non-platinum regimen with etoposide. Extensive small-cell lung cancer patients were randomized between cisplatin-etoposide (CE) and ifosfamide + etoposide + epirubicin regimen (IVE) between 2000 and 2013. 176 and 170 eligible patients were allocated to CE and IVE (315 deaths were required before analysis), respectively. Objective response rates were not significantly different: 60% with CE and 59% with IVE. No statistically significant difference in median survival and 1-year and 2-year was observed with rates of 9.6 months, 31 and 5% for CE and 10 months, 39 and 9% for IVE, respectively. HR was 0.84 (95% CI 0.68-1.05, p = 0.16). Only two prognostic factors for survival were retained in multivariate analysis: sex with HR = 0.69 (95% CI 0.49-0.97, p = 0.03) and performance status with HR = 0.53 (95% CI 0.49-0.97, p < 0.0001). After adjustment for these prognostic factors, HR for survival was 0.83 (95% CI 0.65-1.08, p = 0.17). There was more thrombopenia in the CE regimen and more leukopenia with IVE. Combination of CE failed to improve survival in comparison to an etoposide-containing regimen without cisplatin. https://clinicaltrials.gov/ct2/show/NCT00658580?term=ELCWP+01994&rank=1, identifier NCT00658580.

A Case Series of Adult Secondary Hemophagocytic Lymphohistiocytosis Treated at Weill Cornell Medical College

Background: Hemophagocytic Lymphohistiocytosis (HLH) is an often-fatal syndrome of uncontrolled immune activation caused by dysregulation of macrophages and lymphocytes resulting in increased levels of inflammatory cytokines and significant tissue damage. Familial HLH (FHL) is characterized by germline mutations in genes affecting the cytolytic function of Natural Killer (NK) cells and cytotoxic T cells. Secondary HLH is triggered by an infectious, rheumatologic, malignant or autoimmune condition. While FHL is well characterized in the pediatric population, there are currently no available prospective data guiding the diagnosis and treatment of secondary HLH in the adult patient. Here we present 7 cases of adult secondary HLH that were identified and treated at Weill Cornell Medical College in a period of two years. We highlight the presentation and etiology of secondary HLH and the importance of prompt recognition and early treatment. We also explore the relationship of immunosuppressive and antiretroviral therapy with adult secondary HLH. Methods: Between July 2014 and July 2016, 7 adult patients &gt;18 years old were identified at Weill Cornell Medical College, NY that met criteria and were treated for adult secondary HLH. All 7 patients had 5 out of 8 of the following findings established in the HLH-2004 guidelines: fever ≥ 38.5 C°, splenomegaly, cytopenias affecting 2 of 3 lineages in the peripheral blood (hemoglobin &lt;9 g/dL, platelets &lt;100x103/mL, neutrophils &lt;1x103/mL), hypertriglyceridemia (fasting &gt;265 mg/dL) and/or hypofibrinogenemia (&lt;150 mg/dL), hemophagocytosis in the bone marrow, spleen, lymph nodes or liver, low or absent NK cell activity, ferritin &gt;500 ng/mL and elevated sIL2R. Molecular testing was sent to identify pathologic mutations associated with FHL. Patients were treated with chemotherapy and immunotherapy based on the pediatric HLH-94 protocol, as well as treatment targeted at an underlying malignancy or infection. Patient demographics and clinical characteristics, underlying etiology of secondary HLH and treatment modalities were compared. Results: All 7 patients included in this study met criteria for secondary HLH as defined above. The median age at diagnosis was 42 (range 22-68 years) with a male predominance of 6:1. The majority of patients identified as Caucasian (4/7, 57%) and the remaining 3 patients were Hispanic, African American and Haitian. Five out of 7 (71%) patients had been on immunosuppressive therapy prior to diagnosis, 3 patients had Inflammatory Bowel Disease (IBD) and 3 patients were on Emtricitabine and Tenofovir at the time of diagnosis. The median ferritin at diagnosis was 4,589 ng/mL (range 2,127-10,500 ng/mL) with a peak median ferritin of 10,500 ng/mL (range 3,093-306,320 ng/mL). The sIL2R at diagnosis ranged from 1,000-112,200 pg/mL (reference &lt;1,033 pg/mL). Patient clinical manifestations are summarized in Table 2. All patients presented with fevers, elevated ferritin, cytopenias and splenomegaly and 6/7 (86%) patients had evidence of hemophagocytosis in the bone marrow or liver. Four patients (57%) had secondary HLH due to an infection and 3 (43%) had an underlying malignancy. All patients received Etoposide and Dexamethasone and 4 patients received 2ndline treatment either for an underlying malignancy or for refractory HLH. The median time from presentation to initiation of treatment was 4 weeks (range 1-12 weeks). At the time of this report, 3 patients had died (43%) of which 2 had an underlying malignancy, 3 were alive and 1 patient was lost to follow up. Discussion: Diagnosis of adult secondary HLH remains a challenge due to overlap in symptoms and lack of specificity of laboratory findings. Treatment is often postponed due to delayed recognition of this disease. A high degree of medical suspicion in the appropriate clinical context should prompt early treatment with an Etoposide-containing regimen. Interestingly, we found 4 patients with autoimmune conditions on immunosuppressive therapy, 2 of which were also on antiretroviral treatment. Further investigation is needed to elucidate the association of these findings in adult secondary HLH. Molecular mutational testing is of interest in identifying possible underlying genetic predisposition for adult secondary HLH and further studies are warranted in this area. Disclosures Ritchie: Celgene: Consultancy, Other: Travel, Accomodations, Expenses, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Ariad: Speakers Bureau; Pfizer: Consultancy, Research Funding; Astellas Pharma: Research Funding; Bristol-Meyers Squibb: Research Funding; NS Pharma: Research Funding.

Patient Characteristics and Initial Treatment Patterns in the United States for the Most Common Subtypes of Peripheral T-Cell Lymphoma (PTCL)

Background: Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE) is the largest registry of prospectively treated PTCL patients in the United States. Patients are enrolled at the initial diagnosis of PTCL and within 30 days of starting treatment. Data on demographics, clinical characteristics, diagnosis, therapy delivered as induction or salvage, and outcomes are collected.Methods: For this report, we examined baseline characteristics and induction treatment patterns for patients with the 3 most common subtypes of PTCL: PTCL not otherwise specified (NOS), anaplastic large cell lymphoma (ALCL) and angioimmunoblastic T-cell lymphoma (AITL). Only data from locked records are reported. Locked records are those that have been reviewed and digitally signed by the treating investigator.Results: Five hundred patients were enrolled from February 2010 until January 2014. As of July 2014, there were 257 locked baseline records and 188 locked treatment records for patients with a diagnosis of PTCL-NOS, ALCL or AITL. The mean age of these patients was 60 (range: 51-70). Most were male (66%) and white (78%). At study entry, 234 (91%) had an ECOG performance status of 0-1, 190 (74%) had Ann Arbor stage of III/IV, and 120 (47%) had one or more B symptoms. Half of the patients had extranodal disease. Mean international prognostic index (IPI) score was 2 (range 0-5). For staging, a PET/CT was the most common radiographic method used (58% of patients), and for pathologic diagnosis, on average, 10 phenotypic and ~1 genetic markers were assessed. For baseline characteristics reported here, patients treated at academic centers had more extranodal disease, a higher IPI score and tended to have more advanced disease compared to patients treated in the community. The primary intent of initial therapy was a cure for 89% of patients and 60% received an anthracycline or anthracycline plus etoposide-containing regimen. A minority of patients (21%) participated in a clinical trial for PTCL. Further details on induction therapy can be found in the table below.TableInitial Treatment CharacteristicsTotalAcademicCommunityInitial Treatment Approach*N=188n=158n=30Induction chemotherapy (CT) alone125 (66%)102 (65%)23 (77%)Induction CT + consolidation or maintenance11 (6%)10 (6%)1 (3%)Stem cell transplant36 (19%)33 (21%)3 (10%)Local radiotherapy +/- chemotherapy10 (5%)7 (4%)3 (10%)Observation/best supportive care6 (3%)6 (4%)0 (0%)Induction RegimensN=186n=154n=32CHOP/CHOP-like76 (41%)56 (36%)20 (63%)CHOP/CHOP-like + etoposide37 (20%)30 (20%)7 (22%)Gemcitabine-based regimen6 (3%)6 (4%)0 (0%)Platinum-based regimen5 (3%)5 (3%)0 (0%)Other62 (33%)57 (37%)5 (15%)Number of Cycles of Induction CTMedian, Inter-Quartile Range (Cycles)5 (2-6)5 (2-6)5 (1-6)Type of Transplant PerformedN=36n=33n=3Autologous34 (94%)31 (94%)3 (100%)Allogeneic2 (6%)2 (6%)0 (0%)*5 patients received CNS prophylaxis with selected treatments shown aboveCHOP=cyclophosphamide, doxorubicin, prednisone, and vincristineConclusions: Early results from the first prospective US-based registry of newly diagnosed patients with PTCL-NOS, ALCL and AITL show that beyond CHOP-based therapy, there is little consensus on initial management of these patients. These data strongly support the need to develop evidence-based approaches for this rare and heterogeneous group of patients. DisclosuresPinter-Brown:Spectrum: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Foss:spectrum: Research Funding; seattle genetics: Research Funding; Merck: Research Funding; Celgene: Honoraria, Research Funding; Millenium: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Carson:Spectrum: Consultancy; Celgene: Consultancy, Speakers Bureau. Horwitz:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Research Funding; Infinity: Research Funding; Kiowa-Kirin: Research Funding; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy. Rosen:Allos: Consultancy, Honoraria. Gisselbrecht:Spectrum: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Hsi:Daiichi-Sankyo: Consultancy; Allos: Research Funding; Seattle Genetics: Speakers Bureau; Eli Lilly: Research Funding; Abbott: Research Funding; Cellerant Therapeutics: Research Funding; BD Biosciences: Research Funding; Millennium: Research Funding. Advani:Seattle Genetics: Research Funding. Lechowicz:Spectrum: Consultancy; Seattle Genetics: Consultancy; Janssen: Consultancy; Millennium: Consultancy. Smith:Allos/Spectrum: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Kahl:Allos : Research Funding. Park:Teva: Research Funding; Seattle Genetics: Research Funding; Janssen: Travel funding, Travel funding Other.

Clinical Study Of Dose-Adjusted EPOCH Regimen For Non-Hodgkin's Lymphoma With Hemophagocytic Lymphohistiocytosis: Preliminary Results Of An Ongoing Phase II Study

▪ IntroductionHemophagocytic lymphohistiocytosis (HLH), also known as hemophagocytic syndrome (HPS) is characterized by cytokines storm and uncontrolled activation of macrophages. Secondary HLH in adults may occur in different occasions, including infections, autoimmune diseases, carcinomas and hematologic malignancies, in which Lymphoma-associated hemophagocytic lymphohistiocytosis(LA-HLH) has a high fatality rate and the worst outcome. The major cause of LA-HLH is aggressive non-Hodgkin's lymphoma (NHL), especially T/NKT cell lymphomas. Until now, there is no recommended therapeutic schedule for this fatal disease. Because of promising results of etoposide-containing regimen for HLH and high effective of continuous infusion chemotherapy regimen for aggressive NHL .The investigators therefore employed an intensive chemotherapy regimen--DA-EPOCH regimen (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) to treat non-Hodgkin's lymphoma with hemophagocytic lymphohistiocytosis and we have performed a preliminary analysis of this ongoing Phase 2 study and evaluated safety and efficacy of this regimen. MethodsThe clinical trial was designed as a prospective, multicenter, single-arm phase 2 clinical trial (NCT01818908). Enrolled patients included those with previously untreated NHL, and met the diagnostic criteria of either HLH2004 or ASH 2009 of HLH, patients with primary HLH and secondary HLH other than NHL were excluded. Therapeutic protocol of DA-EPOCH regimen was as follows: etoposide 50 mg/m2 CI 24h d1-d4, doxorubicin 10 mg/m2 CI 24h d1-d4, vincristine 0.4 mg/m2 CI 24h d1-d4, cyclophosphamide 750 mg/m2 IV d5, prednisone 60 mg/m2 oral d1-d5, If enrolled patient was histologically confirmed CD20+ B cell lymphoma, standard dose of rituximab will be recommended to combine with DA-EPOCH regimen. Drug dose was adjusted as previously described (Wyndham H. et al, 2002), each cycle of treatment was administered every 21 to 28 days according to recovery of toxicities. For patients who responded to the treatment and did not have disease progression, interim evaluation was conducted after 3 cycles of treatment. ResultsAt the time of analysis 26 patients were enrolled and 20 patients were eligible to evaluate. Patients were 60.0% (12/20) male with median age 44(range: 14-60), the age-adjusted international prognostic score (aaIPI) enrolled to study was high/intermediate (2 score) 10/20, high risk group (3 score) 10/20. Histologies were four B-NHL, ten T-NHL and six NK-NHL. The median number of cycles of therapy was 3, patients who had discontinued study were mainly due to rapid disease progression. The overall response rate (ORR) among treated pts was 50.0%, with 35.0% (7/20) of patients achieving CR/CRu and 15.0% (3/20) achieving PR, and 50.0% of patients (10/20) had PD. With the median follow-up of 8 months, progression-free survival (PFS) rate was 46.3% and in subgroup analysis, PFS of B-NHL, T-NHL and NK-NHL was 75%, 45.7% and 25% respectively (Fig. 1); Overall survival (OS) rate was 52.4%(Fig. 2) and 75.0%, 58.3%, 22.2% in subgroup of B-NHL, T-NHL and NK-NHL(Fig. 3). The most common grade ≥3 treatment-related side effects were hematologic toxicities including neutropenia and thrombocytopenia. [Display omitted] [Display omitted] [Display omitted] ConclusionsLymphoma-associated hemophagocytic lymphohistiocytosis progresses rapidly and has a high mortality rate, our preliminary results suggest DA-EPOCH regimen has acceptable toxicities and promising activity in NHL with HLH, especially for B-NHL and T-NHL, but prognosis of NK-NHL with HLH remains dismal, urgent need for novel therapeutic strategies may benefit the survival of patients with this disease. Disclosures:No relevant conflicts of interest to declare.

Phase II Study of Induction Cisplatin and Irinotecan Followed by Concurrent Carboplatin, Etoposide, and Thoracic Radiotherapy for Limited-Stage Small-Cell Lung Cancer, CALGB 30206

We sought to determine the efficacy of using both irinotecan- and etoposide-containing regimens sequentially for patients with untreated limited-stage small-cell lung cancer. Patients with untreated, measurable, limited-stage small-cell lung cancer with performance status 0 to 2, and adequate organ function were eligible. Treatment consisted of induction with cisplatin 30 mg/m and irinotecan 65 mg/m intravenously on day 1 and 8, every 21 days for two cycles. Beginning day 43, daily chest irradiation to 70 Gy was administered concurrently with carboplatin area under curve 5 on day 1, and etoposide 100 mg/m on days 1 to 3, every 21 days for three cycles. The primary objective was to differentiate between 45% and 60% 2-year survival. Two induction cycles were delivered to 72 of 75 eligible patients (96%) and all planned treatment was delivered to 59 patients (79%). Cisplatin and irinotecan induction chemotherapy resulted in complete responses in 7% and partial responses in 64% (response rate 71%, 95% confidence interval [CI], 59%-81%). The best response to all therapy included 88% complete or partial responses (95% CI, 78%-94%). With median follow-up of 57 months, the median progression-free survival and overall survival are 12.6 (95% CI, 9.4-14.7) and 18.1 months (15.8-22.9), respectively. The 1- and 2-year survival was 69% and 31%, respectively. Frequent (>20%) grade 3 and 4 toxicities were neutropenia in 84%, hemoglobin in 36%, platelets in 51%, esophagitis in 22%, and dehydration in 24%. There were no fatal toxicities. This treatment regimen of irinotecan-cisplatin induction chemotherapy followed by 70 Gy concurrent radiation and etoposide-carboplatin had tolerable toxicity but did not meet the preplanned 2-year survival target for further development.

A Comparative Retrospective Survey of Reinduction Chemotherapy Regimens for Acute Myeloid Leukemia (AML) in First Relapse: A Single-Institution Experience

Abstract 4273 Introduction:Relapsed acute myeloid leukemia (AML) carries a poor prognosis. Although most newly diagnosed patients with AML achieve a complete remission after initial induction (CR1) using standard chemotherapy regimens, relapse follows in the majority of cases. The optimal reinduction chemotherapy regimen for patients following relapse remains unknown, and there is little comparative data to guide selection between various available reinduction regimens. The current study is a single-institution retrospective review over a 10 year period, which seeks to compare rates of response, disease-free survival (DFS) and overall survival (OS) between different reinduction regimens among patients with AML in first relapse. Methods:We performed a retrospective chart review of patients with AML who relapsed following CR1, and who were treated with reinduction chemotherapy at our institution between January 1, 2000, and December 31, 2010. Our patients were categorized into four groups based upon the type of reinduction chemotherapy they received: MEC (mitoxantrone, etoposide, cytarabine) or similar etoposide-containing regimens, 7+3 (infusional cytarabine and anthracycline) or 7+3-based regimens, HiDAC (high-dose cytarabine)-based regimens, and “other” combinations (less frequently used regimens including cytarabine and topotecan; decitabine; gemtuzumab; mitoxantrone and etoposide). Patients were identified using medical billing diagnosis codes, and included if they were above age 18 at diagnosis, obtained CR1 but experienced subsequent relapse, and were treated during first relapse with reinduction with intent to achieve remission. Exclusion criteria included patients with acute promyelocytic leukemia, primary refractory disease, and patients who were given chemotherapy for persistent disease on a mid-treatment bone marrow biopsy. Information about date of diagnosis, treatment regimens, tumor cytopathology and histology, comorbidities at diagnosis, and presenting laboratory data were collected. Statistical analysis was performed using the Kaplan-Meier method, and log rank tests where appropriate, to analyze DFS and OS. Fisher's exact test was used to assess the associations between categorical variables. Results:We identified 66 patients who were treated with reinduction chemotherapy for AML in first relapse; of these, 28 (42%) achieved CR2. The type of reinduction chemotherapy received was not associated with any difference in the rates of CR2 (p=0.19). Patients who achieved CR2 had a median DFS of 5.1 months. For all patients, including those who failed to achieve CR2, the median OS following reinduction was 4.9 months. There was no significant difference in OS between re-induction regimens (p=0.09). However, there was a statistically significant difference in median DFS depending on regimen (p=0.006). Patients who received 7+3-based regimens, and to a lesser degree MEC, had longer median DFS than HiDAC-based regimens (8.9, 3.4, and 2.0 months, respectively). Patients who received 7+3-based re-induction regimens had a longer duration of preceding CR1 (p=0.006). Longer duration of CR1 (≥7.4 months, the median in our data) was associated with higher rate of CR2 (61% vs 22%, p=0.03) and OS (8.9 vs 2.9 months, p=0.0006) compared to duration of CR1 <7.4 months. Patients who were given “other” regimens (including demethylating therapies) were on average older (62 years old compared to 50, 52, and 54 years old in other groups); however, they had CR2 rates and OS similar to patients receiving 7+3, MEC, or HiDAC-based regimens. Conclusion:According to this retrospective analysis, patients treated with MEC or 7+3-based reinduction chemotherapy regimens had improved DFS compared to patients given HiDAC-based regimens. However, as expected, patients treated with 7+3-based reinduction chemotherapy were also more likely to have experienced a longer duration of CR1. Longer CR1 (≥7.4 months) was associated with improved DFS and OS following reinduction chemotherapy. It remains unclear whether the improved DFS seen in those AML patients who received 7+3-based regimens is due to the type of chemotherapy, or if this is related to the characteristics of their underlying disease, as manifested by the longer duration of CR1 seen in this treatment group. Our data does suggest that MEC may be preferable to HiDAC-based regimens for patients with early relapse following CR1. Disclosures:No relevant conflicts of interest to declare.

Primary Epstein-Barr Virus Infection Associated with Kikuchi's Disease and Hemophagocytic Lymphohistiocytosis: A Case Report and Review of the Literature

An association between hemophagocytic lymphohistiocytosis (HLH) and Kikuchi's disease is rarely seen in children. Here, we present the case of a male adolescent (age 16 years and 3 months) who suffered from spiking fever for more than 1 week, and multiple nodules over the neck and bilateral axilla for 2 months. A skin rash also developed over all four limbs, abdomen and face. Laboratory data and skin biopsy gave results compatible with a diagnosis of Kikuchi's disease. Hemophagocytosis in the bone marrow, hyper-triglyceridemia, elevated ferritin, and splenomegaly were also found, fulfilling the criteria for HLH. A recent primary Epstein-Barr virus infection was also diagnosed by serology. The patient ran a relatively benign course. Intravenous immunoglobulins, steroids or etoposide-containing regimens were not used, and his recovery was uneventful. A review of the literature showed that up to February 2009, 11 additional cases of Kikuchi's disease presenting simultaneously with, or mimicking, HLH had been reported. Complete resolution within several weeks, with no recurrence, was seen in all but one patient (a pregnant woman).

Peripheral Stem Cell Mobilization with Chemotherapy + G-CSF Priming in a Large Series of Patients with Lymphoma Candidates to Autologous Transplantation. An Analysis of Baseline and Ongoing Predictors of Failure or Suboptimal Stem Cell Collection.

Abstract 2149Poster Board II-126 BackgroundAutologous stem cell transplantation (ASCT) is a potentially curative treatment for lymphoma. Adequate stem cell (SC) collection is possible in the majority of cases but poor mobilization remains a major issue in some patients (pts). New agents were recently developed which may improve the rate of SC mobilization. AimsA retrospective analysis was conducted on a large series of lymphoma pts candidates to ASCT in order to identify factors influencing SC mobilization outcome. Potential early markers of poor mobilization were also evaluated. Patients and methodsA total of 415 attempts of PBSC collection consecutively performed at 7 Italian centres in 388 pts affected by lymphoma were analyzed. Their median age was 52. A collection of less than 2×106 CD34+ cells/kg was defined as “mobilization failure” and of more than 5×106 CD34+ cells/kg as “good mobilization”. The following parameters were analysed for correlation with mobilization outcome: lymphoma diagnosis, disease status at mobilization, type of mobilizing chemotherapy, bone marrow infiltration at collection, n° of previous lines of therapy, prior use of fludarabine, alkylating agents or radiotherapy. The ratio between circulating CD34+cells/nL and total WBC/μL on the first day of CD34+ count (SCratio) was also analysed, trying to predict mobilization failure. Both univariate and multivariate statistical analyses were performed with SPSS package 13.0. ResultsLymphoma diagnosis was diffuse large B cell/Burkitt in 38%, follicular in 10%, mantle in 13%, Hodgkin in 26%, T or NK/T in 6%, and other in 7% of cases. Disease status at apheresis was CR in 25%, chemosensitive in 49% and refractory in 26%. Mobilization was attempted during first-line therapy in 14%, in 37% during second-line and in 26% at third- or subsequent lines of therapy. Fludarabine, alkylating agents and extended-fields radiotherapy had been used prior to mobilization in 5%, 73% and 13% of cases respectively. Marrow infiltration by lymphoma was present in 17,7% and 7,7% of patients had failed a prior mobilization attempt.In 99% of cases (411/415) mobilizing therapy included chemotherapy and G-CSF. Two pts received AMD3100 and 2 G-CSF. Several chemotherapy programs were used for mobilization. For analysis purposes they were grouped as follows: single-agent cyclophosphamide (CTX) in 62 (15,1%); high-dose cytarabine, either single agent or in combination (HD-ARAC) in 143 (34,8%), etoposide-containing regimens in 119 (30,0%), and platinum containing regimens in 108 cases (26,3%).Mobilization failure occurred in 14% (59/415) whereas a good mobilization was obtained in 72% of cases. At univariate analysis mobilization failure was significantly associated with the use of single-agent CTX as mobilizer (p=0.000), with the n° of prior lines of treatment (p=0.006) and with failure of a previous mobilization attempt (p=0.000) whereas a diagnosis of follicular lymphoma (FL) was associated with a reduced risk of mobilization failure (p=0.007). Multivariate analysis confirmed FL as protective factor for mobilization failure (p=0.008) and single agent CTX and a higher n° of prior treatment lines as negative predictive factors (p=0.000 and 0.033 respectively).A “good mobilization” was significantly predicted at univariate analysis by HD-ARAC use as mobilizer (p=0,004) whereas single-agent CTX (p=0.000), n° of prior lines of therapy (p=0.005), prior fludarabine (p=0.035) or alkylating agents (p=0.003) were adverse predictors. Multivariate analysis confirmed HD-ARAC as independent predictive factor for good mobilization (p=0.031) and single-agent CTX and n° of prior lines of therapy as independent negative predictive factors (p=0.000 and 0.003 respectively). A SCratio of less than 10 on the first day of CD34+ count was associated with an increased risk of poor mobilization (p=0.000 risk estimate 0.638). ConclusionsIn this large series of pts with lymphoma the standard policy of SC mobilization was the use of chemotherapy + G-CSF. Nevertheless collection failed in a significant proportion of cases (14 %) and only 72% of cases reached an optimal SC collection. Predictive factors for mobilization outcome included disease and treatment history, type of lymphoma and type of mobilizing chemotherapy. These data provide the framework to rationally explore the use of new mobilizing agents in patients with lymphoma undergoing SC mobilization with chemotherapy and G-CSF. Disclosures:No relevant conflicts of interest to declare.

CALGB 30206: Phase II study of induction cisplatin (P) and irinotecan (I) followed by combination carboplatin (C), etoposide (E), and thoracic radiotherapy for limited stage small cell lung cancer

7565 Background: We sought to determine the efficacy of using both irinotecan- and etoposide-containing regimens for patients with untreated LS-SCLC. Methods: Eligibility: measurable disease, performance status (PS) 0–2, no prior therapy, and adequate organ function. Treatment: Induction with P 30 mg/m2 and I 65 mg/m2 both IV day 1 and 8 q21 days ×2 cycles. Beginning day 43 daily chest irradiation (200 cGy/fraction) to 70 Gy concurrent with C AUC=5 IV day 1 and E 100 mg/m2 days 1–3 q 21 days x3 cycles (5 chemotherapy cycles total). Endpoints: Primary - to differentiate a 45% and 60% 2-year survival rate (&gt;39 pts alive/75 pts; a=0.091, β=0.098); secondary-response rates to induction and overall therapy, overall and progression-free survival, and toxicity. Results: Characteristics: Between 11/03 and 9/05, 78 patients were enrolled (2 ineligible): male/female, 43/33; white/black, 74/2; median age 61 (range, 41–79); PS 0/1, 50/26; wt loss &gt;5% in 10 (2 missing data). Two full induction cycles were delivered to 73 (96%) patients; all planned treatment was delivered to 50 pts (66%). Efficacy: To date, 41 (54%) pts have died before 2 yrs. P+I induction chemotherapy resulted in 4 (5 %) CR, 45 (59 %) PR; Overall RR 64% (95% CI 53–74%). Best response to therapy among 76 evaluable pts was 23 (30%) CR and 40 (53%) PR. The 95% CI for ORR is 73–90%. With median follow-up of 18 m, median PFS and OS are 12.6 m (95% CI 10.1–14.7) and 16.1 m (14.1–23.9). Toxicity: Frequent (&gt;20%) grade 3/4 toxicities over all therapy in 77 patients were: neutropenia 25%/58%, hemoglobin 35%/1%, platelets 26%/26%. Maximum hematological toxicity was grade 3/4 in 16%/70% of patients. Maximum non-hematological toxicity was grade 3/4 in 47%/12% including: esophagitis in 27%/3% and dehydration in 21%/1%. No fatal toxicities. Conclusions: This treatment regimen, employing irinotecan doublet induction therapy followed by 70 Gy concurrent radiation and “standard” etoposide carboplatin has tolerable toxicity but did not produce a 2 year survival rate of &gt;50%. New strategies for augmenting median and overall survival among patients with LS-SCLC are needed. [Table: see text]

Modern management of children with haemophagocytic lymphohistiocytosis.

Modern management of children with haemophagocytic lymphohistiocytosis.

Salvage combination chemotherapy with 5-fluorouracil and actinomycin D for patients with refractory, high-risk gestational trophoblastic tumors.

The objective of this study was to evaluate the efficacy and toxicity of a high-dose 5-fluorouracil and actinomycin D regimen (the FA regimen) as salvage chemotherapy for patients with high-risk gestational trophoblastic tumors (GTTs). From 1985 to 1997, 10 patients with refractory, high-risk GTTs were treated with the FA regimen at Chiba University Hospital. Of those 10 patients, 7 patients developed drug resistance to methotrexate, etoposide, and actinomycin D combination chemotherapy (the MEA regimen); 1 patient developed recurrent disease after receiving the MEA regimen; and 2 patients developed recurrent disease after receiving combination chemotherapy with etoposide, methotrexate, and actinomycin D alternating with cyclophosphamide and vincristine (the EMA/CO regimen). The hematologic toxicity of the FA regimen was graded at every chemotherapy course. With the FA regimen, the survival rate was 80.0% (8 of 10 patients) for a mean follow-up of 10 years. Two patients died due to multidrug resistance, and two patients subsequently developed recurrent disease. The two patients with recurrent disease were successfully salvaged again with the MEA regimen. The toxicity of the FA regimen was evaluated in 78 cycles. Myelosuppression seemed to be the dose-limiting toxicity, and the incidences of World Health Organization Grade 4 leukocytopenia and thrombocytopenia were 6.4% and 3.8%, respectively, of 78 cycles. Although etoposide-containing chemotherapy is currently the most effective and well-tolerated regimen for patients with high-risk GTTs, 20-30% of patients develop resistance to etoposide-containing regimens. Salvage combination chemotherapy with FA is effective for these patients with refractory disease, and the toxicity is predictable and manageable.

Requirement for etoposide in the treatment of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis.

We sought to identify the clinical variables most critical to successful treatment of Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH). Among the factors tested were age at diagnosis (< 2 years or > or = 2 years), time from diagnosis to initiation of treatment with or without etoposide-containing regimens, timing of cyclosporin A (CSA) administration during induction therapy, and the presence or absence of etoposide. By Kaplan-Meier analysis, the overall survival rate for the entire cohort of 47 patients, most of whom had moderately severe to severe disease, was 78.3% +/- 6.7% (SE) at 4 years. The probability of long-term survival was significantly higher when etoposide treatment was begun less than 4 weeks from diagnosis (90.2% +/- 6.9% v 56.5% +/- 12.6% for patients receiving this agent later or not at all; P <.01, log-rank test). Multivariate analysis with the Cox proportional hazards model demonstrated the independent prognostic significance of a short interval from EBV-HLH diagnosis to etoposide administration (relative risk of death for patients lacking this feature, 14.1; 95% confidence interval, 1.16 to 166.7; P =.04). None of the competing variables analyzed had significant predictive strength in the Cox model. However, concomitant use of CSA with etoposide in a subset of patients appears to have prevented serious complications from neutropenia during the first year of treatment. We conclude that early administration of etoposide, preferably with CSA, is the treatment of choice for patients with EBV-HLH.