Myeloid Growth Factor Support Research Articles

Clinical and Biomarker Findings of Neoadjuvant Pembrolizumab and Carboplatin Plus Docetaxel in Triple-Negative Breast Cancer

Addition of pembrolizumab to anthracycline-based chemotherapy improves pathologic complete response (pCR) and event-free survival (EFS) in triple-negative breast cancer (TNBC). The efficacy of anthracycline-free chemoimmunotherapy in TNBC has not been assessed. To assess the efficacy of the anthracycline-free neoadjuvant regimen of carboplatin and docetaxel plus pembrolizumab in TNBC. This was an open-label phase 2 clinical trial including a single group of patients with stage I to III TNBC enrolled at 2 sites who received neoadjuvant carboplatin and docetaxel plus pembrolizumab every 21 days for 6 cycles. Participants were enrolled from 2018 to 2022. Carboplatin (with an area under the free carboplatin plasma concentration vs time curve of 6) and docetaxel (75 mg/m2) plus pembrolizumab (200 mg) every 21 days for 6 cycles. Myeloid growth factor support was administered with all cycles. Primary end point was pathologic complete response (pCR) defined as no evidence of invasive tumor in breast and axilla. The secondary end points were residual cancer burden, EFS, toxicity, and immune biomarkers. RNA isolated from pretreatment tumor tissue was subjected to next-generation sequencing. Specimens were classified as positive or negative for the 44-gene DNA damage immune response (DDIR) signature and for the 27-gene tumor immune microenvironment (TIM; DetermaIO) signature using predefined cutoffs. Stromal tumor-infiltrating lymphocytes (sTILs) were evaluated using standard criteria. Programmed cell death-ligand 1 (PD-L1) testing was performed using a standard immunohistochemical assay. Among the eligible study population of 115 female patients (median [range] age, 50 [27-70] years) who enrolled from September 2018 to January 2022, 39% had node-positive disease. pCR and residual cancer burden 0 + 1 rates were 58% (95% CI, 48%-67%) and 69% (95% CI, 60%-78%), respectively. Grade 3 or higher immune-mediated adverse events were observed in 3.5% of patients. sTILs, PD-L1, DDIR, and TIM were each predictive of pCR in multivariable analyses. The areas under curve for pCR were 0.719, 0.740, 0.699, and 0.715 for sTILs, PD-L1, DDIR, and TIM, respectively. Estimated 3-year EFS was 86% in all patients; 98% in pCR group and 68% in no-pCR group. The findings of the phase 2 clinical trial indicate that neoadjuvant carboplatin and docetaxel plus pembrolizumab shows encouraging pCR and 3-year EFS. The regimen was well tolerated, and immune enrichment as identified by various biomarkers was independently predictive of pCR. These results provide data on an alternative anthracycline-free chemoimmunotherapy regimen for patients who are not eligible for anthracycline-based regimens and support further evaluation of this regimen as a chemotherapy de-escalation strategy in randomized studies for TNBC. ClinicalTrials.gov Identifier: NCT03639948.

Phase II trial of gemcitabine and nab-paclitaxel for recurrent osteosarcoma: A report from the National Pediatric Cancer Foundation.

10042 Background: The combination of gemcitabine and docetaxel is often used to treat patients with recurrent osteosarcoma. A retrospective study of 35 such patients has reported an objective response rate of 17% and 4-month progression-free survival (PFS) of 56% with this combination (BMC Cancer 2016;16:280). Nab-paclitaxel is a nanoparticle taxane that has activity against osteosarcoma xenografts and may have less myelosuppression than docetaxel. The combination of gemcitabine and nab-paclitaxel is now frontline therapy for pancreatic cancer. We conducted a prospective multi-institutional phase II trial of this drug combination for patients with recurrent osteosarcoma. Methods: Patients with relapsed/refractory osteosarcoma with measurable disease and age ≥ 12 years and adequate organ function were included. A Simon’s two-stage design was used to identify a 4-month progression-free survival (PFS) of > 35%. Patients received nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 weekly x 3 in 4-week cycles. Results: Eighteen patients with a median age 16 years (range 12- 26) received a total of 56 total cycles.(median 2, range 1 - 12). The median number of prior treatment regimens was 3 (range 1-7). Two patients (11%) experienced a partial response, and 6 (33%) received more than 2 cycles. The 4-month PFS was 30% (95% CI 14-62 %). Six patients required dose reductions for neutropenia (n = 4), pleural effusion (1), or neuropathy (1). Two patients were removed from study secondary to neutropenia despite dose reduction and myeloid growth factor support, and one patient came off study due to severe peripheral edema. Conclusions: In this prospective study, the combination of gemcitabine and nab-paclitaxel administered on this schedule showed only limited activity for patients with heavily pretreated recurrent osteosarcoma. Toxicity led to dose modifications in 33% and discontinuation in 17% of patients. When compared to a historical retrospective study, the substitution of nab-paclitaxel for docetaxel did not appear to increase activity or decrease toxicity for this patient population. Clinical trial information: NCT02945800.

A retrospective comparative cohort study on the routine pre-engraftment use of granulocyte colony-stimulating factor in allogeneic hematopoietic stem cell transplantation

Objective: Myeloid growth factors have been often used in allogeneic hematopoietic stem cell transplantation settings. There are some controversies about increased graft versus host disease, relapse, and delayed platelet engraftment with those growth factors in the pre-engraftment period. In this study, we aimed to compare the transplantation outcomes of allogeneic hematopoietic stem cell transplantation recipients according to their myeloid growth factor support status.
 Materials and Methods: Sixty-seven adult acute myeloid leukemia/myelodysplastic syndrome and acute lymphoblastic leukemia patients who underwent allogeneic peripheral blood stem cell transplantation from HLA-identical matched sibling donors were analyzed retrospectively. All-cause mortality at day 100, day 180, and at 1-year were the primary outcome measures. Secondary outcome measures were the engraftment kinetics, length of hospital stay, and graft-versus-host disease incidences.
 Results: Growth factor supported group was younger (p=0.001), and the first complete remission status at transplantation was seen more compared to the unsupported group (p=0.04). Myeloablative conditioning was used more in growth factor supported group (p=0.004). Faster neutrophil engraftment (p=0.008) and delayed platelet engraftment (p=0.022) were seen in growth factor supported group. Graft-versus-host disease, relapse incidences, and all-cause mortality at day 100, day 180, and at 1-year were not different between groups. Steroid-resistant graft-versus-host disease was the only factor related with relapse (OR: 0.196, p=0.043).
 Conclusion: This real-life study shows colony-stimulating-factors are safe in HLA-identical sibling allogeneic hematopoietic stem cell transplantation. Further prospective randomized controlled studies for different stem cell sources, different donors, and different conditioning and graft-versus-host disease prophylaxis regimens are mandatory.

AML-294: Predictors of Short-Term and Long-Term Mortality in Leukemia Patients with Neutropenic Fever

Context Infections cause substantial morbidity and mortality in acute leukemia patients. Neutropenic fever (NF) frequently complicates leukemia chemotherapy, but the mortality rate of NF and predictors of mortality are not fully defined for adult leukemia patients. We examined factors that influence mortality and type of infection in NF patients admitted to the hematologic malignancy service of a referral hospital. Design Retrospective chart review of NF patients admitted to University of Louisville from April 2016 to July 2018 who had AML, ALL, CML, CLL, or MDS, excluding active transplant patients. We used logistic regression and Cox proportional hazard analysis to evaluate mortality predictors and the Kaplan-Meier method for survival. Median follow-up was 16.6 months. Results Sixty-two patients had 101 episodes of NF. Median age was 56. Frequent primary diagnoses were AML (70%), ALL (24%), CML (2%), and CLL (2%). Infections and bacteremia occurred in 72% and 54% of episodes, respectively. Mean length of stay was 19 +/- 12 days. Refractory/relapsed (R/R) disease (RR 1.53, p=0.034) and ANC nadir of 0 (RR 2.64, p=0.001) correlated with bacteremia. Thirty-day mortality was 14% and increased for R/R disease (OR 3.13, CI=0.99–9.92), bacteremia (OR 3.58, CI=0.94-13.7), and ICU-level care (OR 15.24, CI=4.11-56.5) in univariate analysis. ICU-level care (OR 29.1, CI=5.42–156) and R/R disease (OR 7.30, CI=1.43–37.4) retained significance in multivariate logistic regression. Gram +/- status, resistance pattern, neutropenia severity, age, and neutropenia duration did not influence short-term mortality. Eighty-six episodes had a high-risk MASCC score ( 60 (HR 2.16, CI=1.22–3.84), R/R disease (HR 5.58, CI=2.74–11.4) and ICU-level care (HR 4.96, CI=2.14–11.5) predicted long-term mortality. High-risk MASCC approached significance for OS; median OS 7.8 months (high-risk) versus not reached (low-risk, p = 0.076). Conclusions Bacteremia occurred in the majority of NF episodes we recorded. Thirty-day NF mortality was 14%. Mortality increases for patients with age > 60, R/R disease, and ICU-level care. Identification of high-risk factors in NF may guide the study of interventions such as myeloid growth factor support in appropriate populations.

Adjuvant FOLFOX + nab-paclitaxel (FOLFOX-A)for pancreatic cancer, BrUOG 278: A Brown University oncology research group phase II study.

e15733 Background: Adjuvant FOLFIRINOX increases survival in pancreatic cancer but is associated with significant toxicity. The Brown University Oncology Research Group (BrUOG) developed the FOLFOX-A regimen in a phase I study in advanced pancreatic cancer (Am J Clin Oncol, 2016). Phase II studies (BrUOG 292 and BrUOG 318) have shown substantial activity in patients with metastatic and locally advanced disease. Highly active regimens have the potential to improve survival in the adjuvant setting. The primary objective of BrUOG 295 was to determine the feasibility of administering 10 cycles of FOLFOX-A. Secondary objectives were toxicity and disease free survival. Methods: Patients received oxaliplatin, 85mg/m2 day 1, nab-paclitaxel, 150mg/m2 and leucovorin 400mg/m2 day 1 and fluorouracil 2400mg/m2 by continuous IV infusion over 46 hours. Myeloid growth factor support was optional. Cycles were repeated every 14 days for up to 10. Oxaliplatin was dose reduced to 68mg/m2 for grade 2 neurotoxicity. CTCAE version 4 toxicity scales were utilized. Results: The study reached its initial accrual goal of 25 patients. The median age was 60 (43-69). Twenty-one patients were node +. Twelve of the first 20 patients have received 10 cycles of FOLFOX-A and 17 of the first 20 patients received > 8 cycles. The most common grade >3 toxicities were neutropenia grade 3 (N = 3), grade 4 (N = 3) and fatigue grade 3 (n = 13). One patient had grade 3 neuropathy. Conclusions: Adjuvant FOLFOX-A is well tolerated with low incidences of grade 3 neuropathy and gastrointestinal toxicity. Toxicity, feasibility and disease free survival will be updated at the May 2019 BrUOG DSMB meeting. Clinical trial information: NCT02022033.

Toxicity of FOLFOX-abraxane (FOLFOX-A) on phase II Brown University Oncology Group (BrUOG) trials.

354 Background: FOLFIRINOX increases survival in pancreatic cancer. The Brown University Oncology Group developed the FOLFOX-A regimen in a phase I study. (Am J Clin Oncol, 2016). We subsequently opened phase II studies of FOLFOX-A in patients with metastatic pancreatic cancer (BrUOG 292), locally advanced/borderline pancreatic cancer (BrUOG 318) and adjuvant disease following resection (BrUOG 295). The BrUOG Data Safety Monitoring Committee met on May 22, 2018. Toxicity of FOLFOX-A reviewed at the May meeting aligned with data lock in April on phase II FOLFOX-A studies and is summarized. Methods: Patients received oxaliplatin, 85mg/m2 day 1, nab-paclitaxel, 150mg/m2 and leucovorin 400mg/m2 day 1 and fluorouracil 2400mg/m2 by continuous IV infusion over 46 hours. Myeloid growth factor support was optional. Cycles were repeated every 14 days for up to 10-12 cycles. Oxaliplatin was dose reduced to 68mg/m2 for grade 2 neurotoxicity. CTCAE version 4 toxicity scales were utilized. Results: A total of 81 patients were accrued, (22 adjuvant, 36 metastatic, 23 locally advanced disease). Cumulative fatigue was the most common toxicity and required dose reduction in 50% of patients. The incidences of grade 2, 3 and 4 neutropenia were 26%, 17% and 6%, respectively. Grade 2,3 and 4 diarrhea were 9%, 15% and 0%. The rates of grade 2,3 and 4 neuropathy were 29%, 2% and 0%. Conclusions: FOLFOX-A is well tolerated with low incidences of grade 3 neuropathy and gastrointestinal toxicity. Toxicities were less frequent in patients treated in the adjuvant setting. Clinical trial information: NCT02080221, NCT02022033, NCT02578732.

Frequency of Infection Source and Predictors of Mortality in Leukemia Patients Diagnosed with Febrile Neutropenia

Introduction:High-risk hematologic malignancies are associated with significant treatment-related morbidity, particularly due to infectious events. Neutropenic fever/Febrile neutropenia (NF) is one of the most common infectious complications of chemotherapy; however, mortality rates associated with NF and the factors predictive of mortality are not well-established in the adult leukemia literature. We sought to examine factors that influence mortality and length of stay in patients admitted with NF to the inpatient hematologic malignancy service of a tertiary care center.Materials and Methods:We performed a retrospective chart review of patients admitted to our hematologic malignancy service between April 2016 and July 2018 who carried a diagnosis of NF, based upon absolute neutrophil count < 500/microL and temperature =>38.3C. We included patients who developed fever during planned admission for treatment or who were admitted for complications. Patients had primary diagnoses of AML, ALL, CML, CLL, and MDS. Patients undergoing autologous or allogenic stem cell transplant were excluded. Our analysis included demographics, primary diagnosis, primary disease status (remission, relapse, refractory), line of therapy prior to admission, duration of neutropenia, and nutritional status. We included infection-specific factors such as the presence of bacteremia, identification of an infection source, gram stain of bacteria isolated, resistance patterns, and need for ICU care. We used linear regression analysis to evaluate potential predictors of length of stay and mortality. Statistical analyses were performed with SAS.Results:We identified 100 episodes of NF that occurred in 63 patients. Median age was 58. Malignancies with the highest representation among NF episodes were AML (69%), ALL (24%), CML (3%), and CLL (2%). Infection sources were identified in 62% of episodes, with bacteremia identified in 54% of cases, accounting for 87% of sources. Mean length of stay was 18.7 (+/- 2.3 days). 14 deaths occurred, with 13 (93%) being AML patients and 11 (79%) having bacteremia. Factors associated with mortality were recurrent or relapsed disease status (RR 3.05, p = 0.034), bacteremia (RR 3.1, p = 0.047), and need for ICU-level care as defined by intubation or pressor requirements (RR 8.2, p <0.001). 8 of 14 episodes requiring ICU-level care resulted in death. Severe malnutrition had a near-significant association with mortality (RR 2.7, p = 0.06). Gram-positive versus gram-negative status, bacterial resistance pattern, degree of neutropenia, type of malignancy, line of therapy, age, and duration of neutropenia were not significantly associated with mortality. There was no association between the presence of bacteremia and length of stay.Conclusion: Infection sources, in particular bacteremia, are identified with high frequency in leukemia patients experiencing NF. This study yielded generalizable outcome estimates for NF patients Risks of morbidity and mortality are high, with a 14% risk of ICU-level therapy and a 14% risk of mortality. Mortality risk increases in the setting of bacteremia, relapsed/refractory disease, and possibly poor nutritional status. The results suggest that early identification of correctable factors and rapid intervention during infections are essential to the management of high-risk hematologic malignancy patients. Early use of myeloid growth factor support may be worthy of study in selected high-risk populations. DisclosuresNo relevant conflicts of interest to declare.

Pralatrexate in Combination with Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) in Previously Untreated Patients with Peripheral T-Cell Lymphoma (PTCL): A Phase 1 Dose-Escalation Study

Background: The prognosis of patients with PTCL remains poor after standard CHOP therapy - the most commonly used combination regimen. Relapses occur in the majority of patients, and curability rates of the relapsed disease are very low. Hence, advances in front-line therapy of PTCL are long overdue. Pralatrexate, a second-generation antifolate, demonstrated a single agent activity in patients with relapsed and refractory PTCL with a response rate of 27%, including complete remissions in 11% of patients (O'Connor et al. J Clin Onc 2011). We conducted a Phase 1 multi-center dose-escalation study of pralatrexate in combination with standard CHOP (Fol-CHOP) in treatment-naïve PTCL patients.Objectives: The primary objective of the study was to determine the maximum tolerated dose (MTD) of pralatrexate when administered with a standard CHOP regimen to patients with newly diagnosed PTCL. The secondary objectives included safety, tolerability, efficacy and pharmacokinetics of pralatrexate in combination with CHOP (Fol-CHOP).Methods: In Part 1 of this 3+3 dose-escalation study, pralatrexate was administered at 10, 15, 20, 25, or 30 mg/m2 as an IV push on days 1 and 8 of a standard 21-day CHOP regimen (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 [maximum 2 mg] on day 1 and oral prednisone 100 mg on days 1-5). In Part 2 of the study patients were treated at the MTD of pralatrexate established in Part 1, with standard CHOP. In both parts of the study patients were treated with up to 6 cycles of therapy, or until toxicity or disease progression. Patients received antimicrobial prophylaxis, myeloid growth factor support, and “leucovorin rescue” throughout 6 cycles of therapy. Dose-limiting toxicities (DLT) were considered during the 1st cycle of Fol-CHOP and included: Grade 4 infections, treatment-related non-hematological toxicity ≥Grade 3, platelet count < 25 X 109/L at any time, or ANC < 0.5 X 109/L for >7 days despite G-CSF administration. Responses were assessed by the investigator per the Revised Response Criteria for Malignant Lymphoma (Cheson 2007).Results: A total of 31 patients have been enrolled (19 in Part 1; 12 in Part 2). MTD was not reached and pralatrexate dose of 30 mg/m2 in combination with CHOP was selected for Part 2 of the study as predefined by the protocol. The majority of patients were male, White, with the median age of 66 yrs (range, 18-78) at the time of enrolment. PTCL diagnoses included: anaplastic large cell lymphoma, anaplastic lymphomakinase-negative (ALCL, ALK-, n=5), peripheral T-cell lymphoma, not-otherwise specified (PTCL-NOS, n=18), and angioimmunoblastic T-cell lymphoma (AITL, n=5). Fol-CHOP was generally well tolerated with median RDI of 98%. Common (≥ 30%) adverse events (AEs) of any grade were fatigue (n=23), constipation (n=20), nausea (n=16), mucositis (n=14), diarrhea (n=12), anemia (n=9), vomiting (n=10) and oral pain (n=10). Most common (≥ 10%) AEs ≥ grade 3 were anemia (n=6), fatigue (n=4) and neutrophil count decreas (n=5). The only Grade >3 treatment-related AEs (≥10%) was neutrophil count decrease (n=4). SAEs were observed in 13 patients, treatment related SAEs were anemia, febrile neutropenia, dehydration, mucositis and nausea. Five patients withdrew from study: 2 due to disease progression, 1 due to AE and 2 due lapse >28 days between doses. In the 27 patients avaluable for response, the investigator assessed objective response (OR) and complete response (CR) rates were 89% wand 67%, respectively.Conclusions: The combination of pralatrexate and CHOP was well tolerated in treatment-naive PTCL patients. MTD of pralatrexate was not reached, and the protocol-defined maximum dose of 30 mg/m2 on days 1 and 8 of a 21-day CHOP cycle was recomended for future studies. The observed OR and CR rates warrant further evaluation of this regimen in newly diagnosed PTCL patients. DisclosuresShustov:Celgene: Other: Publication assistance; Spectrum Pharmaceuticals: Consultancy, Research Funding. Bhat:Spectrum Pharmaceuticals: Employment. Reddy:Spectrum Pharmaceuticals: Employment.

Evaluation of weekly paclitaxel plus carboplatin followed by anthracycline chemotherapy on the neoadjuvant treatment of patients with triple-negative breast cancer

ObjectiveTo evaluate the effectiveness and tolerability of neoadjuvant chemotherapy with weekly paclitaxel in combination with weekly carboplatin area under curve 2 followed by anthracycline chemotherapy. Patients and methodsThis is a retrospective review of electronic medical records of patients (N = 32) with stage 1c–III triple-negative breast cancer. Patients received neoadjuvant chemotherapy with paclitaxel 80 mg/m2 once per week for 12 weeks in combination with carboplatin area under curve 2 once per week for 12 weeks (wP + wCb), followed by a standard anthracycline regimen including either doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 2 or 3 weeks, or epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks for four cycles with myeloid growth factor support. ResultsMost patients (91%) received all 12 cycles of wP + wCb, and 88% received all four planned cycles of anthracycline chemotherapy. Of the patients, 84% completed all planned therapies. The complete pathologic response rate was 60%. In terms of hematologic toxicity, 96% of the patients experienced grade ≥3 leucopenia, 40% grade ≥3 anemia, and 15% grade ≥3 thrombocytopenia, and neutropenic fever was seen in 22% of the patients. ConclusionThe combination of neoadjuvant chemotherapy with wP + wCb before anthracycline chemotherapy can be tolerated by patients with triple-negative breast cancer. Complete pathologic response rates were comparable with those historically seen. Careful selection of patients is fundamental as this regimen is associated with a high incidence of hematologic toxicity.

Growth factor use and costs in breast cancer patients undergoing adjuvant therapy.

e18277Background: Myeloid growth factor support (GFs) reduces the incidence/duration of neutropenia and facilitates dose intensity. GFs is recommended by ASCO guidelines when the risk of chemothera...

Prediction of adverse events during intensive induction chemotherapy for acute myeloid leukemia or high‐grade myelodysplastic syndromes

Intensive chemotherapy for newly diagnosed acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) is associated with significant treatment-related morbidity and mortality. Herein, we investigate how pretreatment characteristics relate to early adverse outcomes in such patients, studying 205 consecutive individuals receiving curative-intent induction chemotherapy with cytarabine and an anthracycline ("7 + 3"; n = 175) or a "7 + 3"-like regimen (n = 30). Among the entire cohort, baseline grade 4 neutropenia (i.e., absolute neutrophil count <500 cells/µL) was associated with development of fever (P = 0.04), documented infection (P < 0.0001), and bacteremia (P = 0.002) but not requirement for intensive care unit-level care; after exclusion of the 30 patients who received "7 + 3"-like induction, baseline grade 4 neutropenia remained associated with documented infection (P < 0.0001) and bacteremia (P = 0.0005). Among patients achieving a complete remission with the initial treatment cycle, grade 4 neutropenia was associated with delayed neutrophil count recovery (P < 0.0001). Low monocyte and lymphocyte counts at baseline were similarly associated with increased risk of documented infection or bacteremia. After adjustment for age, gender, disease type, cytogenetic/molecular risk, and performance status, the risk of fever, documented infection, or bacteremia was 1.87 (95% confidence interval: 1.04-3.34; P=0.04)-fold, 4.95 (2.20-11.16; P<0.001)-fold, and 3.14 (0.99-9.98; P=0.05)-fold higher in patients with initial grade 4 neutropenia. Together, our studies identify severe baseline neutropenia as a risk factor for infection-associated adverse events after induction chemotherapy and may provide the rationale for the risk-adapted testing of myeloid growth factor support in this high-risk AML/MDS patient subset.

131I-Tositumomab Consolidation Radioimmunotherapy (RIT) In Patients With B-Cell Chronic Lymphocytic Leukemia (CLL) Or Small Lymphocytic Lymphoma (SLL) In First Remission

BackgroundDespite the initial response to combination chemotherapy in CLL/SLL patients, disease relapse and minimal residual disease (MRD) remain major issues in treatment of these diseases. Therefore, developing more effective treatments for CLL/SLL patients is a necessity. One strategy is to eliminate persistent disease using radioimmunotherapy (RIT), such as 131I-tositumomab (Bexxar®), as consolidation after an objective complete (CR) or partial response (PR) after an induction regimen. In this study we investigated the tolerability and efficacy of standard non-myeloablative doses of 131I-tositumomab following primary induction chemotherapy in CLL/SLL patients in first remission. Patients and MethodsPatients older than 18 with CLL/SLL with indication for treatment were included if they were in first CR or PR from prior treatments and had <25% bone marrow involvement and acceptable peripheral counts. 131I-tositumomab (75 cGy total-body dose) was delivered between days 90 and 180 from the first day of the last chemotherapy treatment. The dose was reduced to 65 cGy in cases of thrombocytopenia (between 100,000-150,000/µL). Three months after the treatment dose, efficacy and response criteria were specified per NCI working group guidelines and toxicity assessments were recorded based on the CTCAEv3.0. Rituximab levels were determined using ELISA with a monoclonal anti-rituximab idiotype antibody. Results16 patients (CLL11, SLL 5) received consolidative 131I-tositumomab in first remission between 2005-2012. The median age was 61 (38-78). Seven patients (43.7%) had high-risk disease based on cytogenetics or molecular profile. Two patients (12.5%) had 11q deletion and one had mutated TP53 (6.25%). Increased CD38 and ZAP-70 expression was present in 3 of 11 and 6 of 7 patients who were tested and unmutated IgVH was detected in 1 of 3 patients. Twelve patients (75%) were in PR when entered the study while 4 (25%) were in CR. Eight patients (50%) had minimal residual disease (MRD) assessed by multiparametric flow cytometry (MFC). Prior chemotherapy consisted of FR in 9 patients (56.2%), FCR in 4 patients (25%), BR in 2 patients (12.5%) and R-CHOP in 1 patient (6.2%). The median time from the first day of the last treatment cycle to the RIT dose was 15.4 weeks (10 - 29). 7 patients (43.7%) needed dose reduction. At 3 months, CR was achieved or sustained in 12 patients (80%). Conversion from PR to CR following RIT occurred in 4 of 8 patients (50%). Likewise, 131I-tositumomab eliminated MRD in 4 of 8 patients (50%) by negative MFC at 3 months. One patient (6.6%) had PR, one (6.6%) had nodular PR and one had disease progression (6.6%) after administration of 131I-tositumomab. Lymphadenopathy was improved in 83% (5 of 6) of the patients with measureable disease prior to 131I-tositumomab. Overall, the patients with CR at 3 months had significantly higher levels of pre-treatment Rituximab levels (11.0 vs. 2.32 µg/ml, p = 0.01. There was no difference in the pre-treatment levels in patients with pre-treatment MRD who had a negative MFC analysis at 3 months compared to the ones to had residual MRD (12.5 vs. 7.6 µg/ml, p = 0.50) or in patients with PR before receiving 131I-tositumomab who achieved CR at 3 months compared to the ones who did not (11.7 vs. 5.8 µg/ml, p = 0.19). These Results suggest that the levels of Rituximab may be blocking CD20 sites at the lymph node and/or marrow level. The median follow-up was 9.4 months (2.7-54.3). Hematologic toxicities at 3 months were grade 3 anemia in 1 patient (6.2%), grade 3 or 4 neutropenia in 13 (81%), and grade 3 or 4 thrombocytopenia in 8 (50%). Six patients (37.5%) required blood or platelet transfusions. Two patients (12.5%) needed myeloid growth factor support. One patient was hospitalized within 3 months of RIT for neutropenia-related sepsis/typhlitis. Two patients (12.5%) had disease progression and dysplastic changes were found in one. One patient died 3 years after treatment for an unrelated medical reason. Persistent cytopenias were reported in 4 patients (25%) during the follow-up period. ConclusionOverall, consolidation RIT with 131I-tositumomab after first remission appears to be a feasible approach and may provide the potential benefit of converting PR to CR or eliminating MRD in CLL/SLL patients. Further long–term follow-up to assess possible prolonged side effects and clinical effectiveness of this approach remain on-going. [Display omitted] Disclosures:Off Label Use: Bexxar is not FDA approved for consolidation of CLL. Gopal:GSK : Research Funding. Becker:Pfizer: Consultancy. Maloney:GSK: Consultancy. Press:Roche/Genentech: Consultancy.

Adverse Events During Intensive Induction Chemotherapy For Acute Myeloid Leukemia (AML) Or High-Grade Myelodysplastic Syndromes (MDS)

BackgroundIntensive chemotherapy for adults with newly diagnosed acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) is associated with a considerable risk of morbidity and mortality, commonly due to infections and bleeding. Little information is available on pre-treatment risk factors that predispose to these complications. Here, we investigated the relationship between baseline peripheral blood counts and (a) subsequent adverse events and (b) duration of neutropenia following administration of induction chemotherapy at our institution over the last decade for newly diagnosed AML/MDS undergoing curative-intent induction chemotherapy. Patients and MethodsWe retrospectively analyzed 205 consecutive adults receiving 7 + 3-like treatment regimens. Daily blood counts were recorded from initiation of chemotherapy until the day of neutrophil recovery (defined as an absolute neutrophil count [ANC] greater than or equal to 500 cells/µL). Adverse events (fever, infection, bacteremia, transfer to the intensive care unit, and death) were recorded until day 35 or administration of additional chemotherapy, whichever came first. Cytogenetic risk was classified based on revised MRC/NCRI criteria. Associations between baseline patient characteristics and adverse events were assessed using Kaplan-Meier survival curves with a log-rank test (for two groups) or log-rank test for trend (for three or more groups); patients requiring salvage therapy for persistent disease were censored on the day such therapy was initiated. Cox proportional hazards models were used to estimate the hazard ratio (HR) for the associations between age, gender, disease type, cytogenetic risk and adverse outcomes in univariate and multivariate analyses. ResultsThe median age of our study cohort was 53 (range: 18 to 81) years. Sixty-six percent of the patients had de novo AML. Cytogenetic risk was favorable in 14%, intermediate in 60%, and adverse in 24%. Among all patients, the complete remission (CR) rate was 75%, while 2% died before response could be assessed (range: day 13 to 28) and 23% were refractory. When analyzed as a continuous variable, the baseline neutrophil count was statistically significantly associated with fever (HR=0.97 [95% confidence interval: 0.95-0.999] for each increase of 1000 cells/µL, P=0.04) and infection (HR=0.92 [0.87-0.98], P=0.01), but not bacteremia (HR=0.95 [0.89-1.01], P=0.10) or requirement for intensive care unit (ICU) care (HR=1.00 [0.93-1.07], P=0.99). For subsequent analyses, we dichotomized the study cohort based on pre-treatment ANC and compared patients with baseline ANC<500/µL (n=75) with those with ANC greater than or equal to 500/µL (n=130). As shown in Figure 1, baseline ANC<500/µL was associated with the development of fever (P=0.022), documented infection (P<0.001), bacteremia (P<0.001), and death (P=0.035) [Figure 1] but not requirement for ICU care (P=0.39). In patients who achieved CR with 1 course of therapy without myeloid growth factor support, baseline ANC<500/µL was associated with delayed neutrophil count recovery (P<0.0001). In addition to low baseline ANC, we also found that low baseline monocyte and lymphocyte counts were associated with increased risk of documented infection or bacteremia. After adjustment for age, gender, disease type, and cytogenetic risk, the risk of documented infection or bacteremia was 2.71 (1.78-4.12)-fold and 2.11 (1.26-3.55)-fold higher in patients with baseline ANC<500/µL. Having demonstrated that baseline ANC<500/µL was associated with both duration of neutropenia and the development of adverse events and death, we wondered whether this patient subset could be suitable for the targeted use of myeloid growth factors. To investigate this, we evaluated whether those with 0% bone marrow blasts at first post-treatment assessment were also more susceptible to adverse events after day 14. Indeed, this was the case for infection (P=0.0140) and bacteremia (P=0.0023). ConclusionOur studies identify pre-treatment ANC<500/µL as a risk factor for both infection-associated adverse events, including death, and longer duration of neutropenia. If validated, these results would provide the rationale for the risk-adapted testing of myeloid growth factor support in patients with AML/MDS with pre-treatment ANC< 500/µL when undergoing curative-intent induction chemotherapy. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Phase II Trial of Combined Modality Therapy with Myeloid Growth Factor Support in Patients with Locally Advanced Non-small Cell Lung Cancer

To evaluate the efficacy and safety of myeloid growth factors in patients with locally advanced non-small cell lung cancer treated with combined modality therapy (CMT). Patients with stage IIIA/B non-small cell lung cancer, performance status 0 to 1, and forced expiratory volume in 1 second > or =1.5, received cisplatin 75 mg/m(2) on day 1 + etoposide 80 mg/m(2) on days 1 to 3 every 3 weeks for 2 cycles concurrent with thoracic radiotherapy to 61 Gy. filgrastim 5 mcg/kg/d was administered for 10 days beginning on day 4 of each chemotherapy cycle. Patients without progression received docetaxel 75 mg/m(2) every 21 days for 3 cycles with peg-filgrastim 6 mg on day 2. The primary end point was a 50% reduction in the incidence of grade (3/4) neutropenia compared with historical controls. A total of 26 eligible patients were enrolled. Median age was 67, 76% were men, and 58% had stage IIIA. Gr3/4 neutropenia during CMT was 19.2% and 3.8%, respectively. There were no episodes of febrile neutropenia. Gr4 thrombocytopenia was 15.4% with 2 patients requiring transfusions. Gr3 esophagitis was noted in 7.7% and Gr (3/4) pneumonitis in 21.6% of patients. No patients died of treatment-related toxicities. Dose reductions/delays occurred in 3.8% of patients during CMT. Median progression-free survival and median survival were 10.7 and 27.6 months, respectively. The 1- and 2-year survival rates were 61.5% and 46.2%, respectively. Our data suggest that the addition of filgrastim to CMT is safe and effective. The rate of grade (3/4) toxicities, including febrile neutropenia, compares favorably to previous trials using a similar regimen. Dose intensity is maintained. This strategy merits further evaluation.

TOP-M Chemotherapy (Thiotepa, Oncovin [Vincristine], Prednisone, Mitoxantrone) Plus Rituximab for Marginal Zone Lymphoma.

Although considered an indolent disease, marginal zone lymphoma (MZL) often requires treatment. No standard therapy has been clearly established. Mitoxantrone has been effective in combination for indolent lymphomas, and is associated with considerably less cardiotoxicity and alopecia than doxorubicin. Thiotepa likewise does not induce alopecia, and does not display the immunosuppressive properties of fludarabine, which is also frequently employed as therapy for indolent lymphoma. The combination of thiotepa, vincristine, prednisone and mitoxantrone chemotherapy, with a scope similar to CHOP, has been demonstrated to be useful in elderly patients with diffuse large cell lymphoma (Lichtman, et al, Am J Clin Oncol , 24(4):360–2, 2001). The TOP-M regimen consists of thiotepa 7.5 mg/m2, mitoxantrone 7.5 mg/m2, vincristine and prednisone as per the CHOP regimen, with rituximab 375 mg/m2 all given on day 1 with a 21–28 day cycle (in accordance with resolution of cytopenias). Thiotepa and mitoxantrone doses were escalated by a total of 2.5 mg/m2 to a maximum of 20 mg/m2, respectively, based on nadir blood counts. We have retrospectively reviewed data on 12 patients with disseminated MZL treated with TOP-M either alone (n=4) or with rituximab (n=8). All subjects had advanced stage disease (4 with stage III, 8 with stage IV), 4 had B symptoms, and all patients clinically required treatment. Median age was 69, and 4 (33%) had an elevated LDH. Myeloid growth factor support was routinely applied, and anti-emetics were generally unnecessary. Central venous access was not required since neither thiotepa nor mitoxantrone are associated with tissue injury in the event of extravasation. Treatment was well tolerated, with only two episodes of hospitalization for fever. There was no cardiac toxicity. Eleven of 12 patients (92%) demonstrated clinical responses, with 9 CR/CRu (75%) and 3 PR (17%). Median duration of response has not been reached at with a range of 11 to 40 months of followup. TOP-M with rituximab is an easily administered, well tolerated and active regimen for disseminated marginal zone lymphoma, and may have utility for other indolent lymphomas.