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Anthracyclines used in the treatment of acute myelogenous leukemia (AML) inhibit the activity of the mammalian topoisomerase II (topo II) isoforms, topo II α and topo IIβ. In 230 patients with non-M3 AML who received frontline ara-C/daunorubicin we determined expression of topo IIα and topo IIβ by RT-PCR and its relationship to immunophenotype (IP) and outcomes. Treatment outcomes were analyzed by logistic or Cox regression. In 211 patients, available for analysis, topo IIα expression was significantly lower than topo IIβ (P

Effect of measurable (‘minimal’) residual disease (MRD) information on prediction of relapse and survival in adult acute myeloid leukemia

Purpose Younger patients with acute myeloid leukemia (AML) harboring NPM1 mutations without FLT3–internal tandem duplications (ITDs; NPM1-positive/FLT3-ITD–negative genotype) are classified as better risk; however, it remains uncertain whether this favorable classification can be applied to older patients with AML with this genotype. Therefore, we examined the impact of age on the prognostic significance of NPM1-positive/FLT3-ITD–negative status in older patients with AML. Patients and Methods Patients with AML age ≥ 55 years treated with intensive chemotherapy as part of Southwest Oncology Gorup (SWOG) and UK National Cancer Research Institute/Medical Research Council (NCRI/MRC) trials were evaluated. A comprehensive analysis first examined 156 patients treated in SWOG trials. Validation analyses then examined 1,258 patients treated in MRC/NCRI trials. Univariable and multivariable analyses were used to determine the impact of age on the prognostic significance of NPM1 mutations, FLT3-ITDs, and the NPM1-positive/FLT3-ITD–negative genotype. Results Patients with AML age 55 to 65 years with NPM1-positive/FLT3-ITD–negative genotype treated in SWOG trials had a significantly improved 2-year overall survival (OS) as compared with those without this genotype (70% v 32%; P < .001). Moreover, patients age 55 to 65 years with NPM1-positive/FLT3-ITD–negative genotype had a significantly improved 2-year OS as compared with those age > 65 years with this genotype (70% v 27%; P < .001); any potential survival benefit of this genotype in patients age > 65 years was marginal (27% v 16%; P = .33). In multivariable analysis, NPM1-positive/FLT3-ITD–negative genotype remained independently associated with an improved OS in patients age 55 to 65 years (P = .002) but not in those age > 65 years (P = .82). These results were confirmed in validation analyses examining the NCRI/MRC patients. Conclusion NPM1-positive/FLT3-ITD–negative genotype remains a relatively favorable prognostic factor for patients with AML age 55 to 65 years but not in those age > 65 years.

Less-intense remission induction regimens for adults with newly diagnosed acute myeloid leukemia (AML) aim to reduce treatment-related mortality (TRM), here defined as death within 4 weeks after starting induction therapy. This assumes that TRM rates are similar to the 15-20% observed 20 years ago. Herein we test this assumption. We examined TRM rates in 1409 patients treated on SWOG (Southwest Oncology Group) trials and 1942 patients treated at MD Anderson (MDA) from 1991 to 2009. Eighty-eight percent of SWOG patients received '3+7' or regimens of similar intensity while 92% of the MDA patients received ara-C at 1.5-2.0 g/m(2) daily × 3-5 days+other cytotoxic agents. We examined the relationship between time and TRM rates after accounting for other covariates. TRM rates between 1991 and 2009 decreased from 18-3% in SWOG and 16-4% at MDA. Multivariate analyses showed a significant decrease in TRM over time (P=0.001). The decrease in TRM was not limited to younger patients, those with a better performance status or a lower white blood cell count. Though our observations are limited to patients treated with intensive therapy at SWOG institutions and MDA, the decrease in TRM with time emphasizes the problem with historical controls and could be considered when selecting AML induction therapy.

This phase I/II study was conducted to determine the maximum tolerated dose, toxicity, and efficacy of clofarabine in combination with high dose cytarabine and granulocyte colony-stimulating factor (G-CSF) priming (GCLAC), in the treatment of patients with relapsed or refractory acute myeloid leukaemia (AML). Dose escalation of clofarabine occurred without dose-limiting toxicity, so most patients were treated at the maximum dose, 25 mg/m(2) per day with cytarabine 2 g/m(2) per day, each for 5 d, and G-CSF 5 μg/kg, beginning the day before chemotherapy and continuing daily until neutrophil recovery. The complete remission (CR) rate among the 46 evaluable patients was 46% (95% confidence interval [CI] 31-61%) and the CR + CR but with a platelet count

Older acute myeloid leukemia (AML) patients with a chromosome 5q deletion have poor outcomes with conventional chemotherapy. This phase 2 study explored the safety and efficacy of single-agent lenalidomide in previously untreated older AML patients with del(5q) who declined standard chemotherapy. Patients were treated with lenalidomide 50 mg daily for 28 days as induction therapy and 10 mg daily for 21 days of a 28-day cycle as maintenance until disease progression or unacceptable toxicity. Among 37 evaluable patients, the median age was 74 years (range, 60-94), 21 (57%) were female, 19 (51%) had prior myelodysplastic syndrome, and 30 (81%) had pretreatment cytogenetic studies evaluated centrally. Six had isolated del(5q), 1 had del(5q) and +8, 23 had complex cytogenetics, and 7 others had del(5q) identified locally. Fourteen patients (38%) completed induction therapy: 7 patients died during induction therapy, 8 had disease progression, 7 had nonfatal adverse events, and 1 entered hospice. Eight patients started maintenance therapy. Five patients (14%) achieved a partial or complete response, 2 with isolated del(5q) and 3 with complex cytogenetics. Relapse-free survival was 5 months (range, 0-19). Median overall survival was 2 months for the entire population. In conclusion, lenalidomide as a single agent has modest activity in older del(5q) AML patients. Southwest Oncology Group Study S0605 is registered at www.clinicaltrials.gov as NCT00352365.

Purpose This phase II study assessed clofarabine monotherapy in older adults (≥ 60 years of age) with untreated acute myeloid leukemia (AML) and at least one unfavorable baseline prognostic factor. Patients and Methods Clofarabine was administered intravenously for 5 days at 30 mg/m2/d during induction and 20 mg/m2/d during reinduction/consolidation (six cycles maximum). The primary end point was overall remission rate (ORR; ie, complete remission [CR] plus CR with incomplete platelet recovery [CRp]). Results In 112 evaluable patients who were treated (median age, 71 years; range, 60 to 88 years), the ORR was 46% (38% CR, 8% CRp). ORR by unfavorable prognostic factor was 39% for patients ≥ 70 years of age; 32% for Eastern Cooperative Oncology Group (ECOG) performance status 2; 51% for antecedent hematologic disorder; 54% for intermediate karyotype; 42% for unfavorable karyotype; and 48%, 51%, and 38% for one, two, and three risk factors, respectively. The median disease-free survival was 37 weeks (95% CI, 26 to 56 weeks). Median duration of remission was 56 weeks (95% CI, 33 to not estimable). The estimated median overall survival was 41 weeks (95% CI, 28 to 53 weeks) for all patients, 59 weeks for patients with CR/CRp, and 72 weeks for patients with CR. The 30-day all-cause mortality was 9.8%. The most common non-laboratory drug-related toxicities (≥ 20% patients) were nausea, febrile neutropenia, vomiting, diarrhea, rash, and fatigue. Conclusion Clofarabine is an active agent with acceptable toxicity in patients age 60 years or older with untreated AML who have at least one unfavorable prognostic factor. ORR did not seem affected by the presence of multiple unfavorable prognostic factors.

Adhesion of acute myeloid leukemia (AML) blasts in the bone marrow microenvironment confers protection from chemotherapy-induced apoptosis. One mechanism for retention of blasts within the bone marrow is adhesion via very late antigen-4 (VLA-4), the α4β1 integrin heterodimer that binds to its main ligands, fibronectin, and vascular cell adhesion molecule-1 (VCAM-1). To examine the relationship of functional expression of VLA-4 to prognosis in AML, we studied marrow samples from 175 adult AML patients who underwent induction chemotherapy with anthracycline and cytarabine on Southwest Oncology Group trials. The studies included flow cytometry and functional in vitro assays for ligand binding and maximal β1 activation. VLA-4 expression varied widely, with mean expression 60.6% for α4, and was not significantly associated with response to chemotherapy, relapse-free, or overall survival (OS). However, increased binding of soluble VCAM-1 via VLA-4 was significantly associated with longer OS, corrected for age (P = .033). Estimated 5-year OS was 31% (95% confidence interval, 14%-48%) in 30 patients with soluble VCAM-1 binding greater than or equal to 40%, compared with 10% (confidence interval, 3%-17%) in 72 patients with lower binding. Adhesion and migratory properties of AML blasts thus appear to influence chemosensitivity and therefore may be therapeutic targets.

BACKGROUND. The poor prognosis reported for patients with high‒grade glial neoplasms indicates a need for the development of multimodality therapeutic approaches. The addition of chemotherapy has contributed variably to increased survival. The objective of the current study (Southwest Oncology Group [SWOG] 9016) was to determine whether concurrent radiotherapy and chemotherapy with the combination of carmustine and cisplatin could be given safely in a cooperative group setting. Additional objectives included the estimation of response rate, the rate of disease stabilization, and the probability of 1-year survival. METHODS. SWOG 9016 study included 59 eligible patients with grade III or IV astrocytoma who received radiotherapy concurrently with carmustine/cisplatin chemotherapy. Patients were required to have either measurable or evaluable disease. The therapeutic endpoints were comprised of complete response (CR), partial response (PR), or progressive disease (PD). RESULTS. Six patients achieved a CR (CR rate of 10%; 95% confidence interval [95% CI], 4–21%), 4 achieved a PR (PR rate of 7%; 95% CI, 2–16%), and 2 patients (3%) experienced an unconfirmed response. Twenty-four patients (41%; 95% CI, 28–54%) had stable disease and 10 patients (17%) demonstrated PD. The overall disease stabilization rate (CR + PR + stable disease, excluding unconfirmed response) was 58% (95% CI, 44–70%). CONCLUSIONS. Despite the presence of a cohort of long‒term survivors, the results of the current study do not appear to support the additional studyor routine use of concurrent cisplatin and carmustine. Cancer 2008. © 2008 American Cancer Society.

We analysed the outcomes of autologous stem cell transplantation (ASCT) following high-dose therapy with respect to remission status at the time of transplantation and induction regimen used in 56 consecutive patients with mantle cell lymphoma (MCL). Twenty-one patients received induction chemotherapy with HyperCVAD with or without rituximab (+/-R) followed by ASCT in first complete or partial remission (CR1/PR1), 15 received CHOP (+/-R) followed by ASCT in CR1/PR1 and 20 received ASCT following disease progression. Estimates of overall and progression-free survival (PFS) at 3 years among patients transplanted in CR1/PR1 were 93% and 63% compared with 46% and 36% for patients transplanted with relapsed/refractory disease, respectively. The hazard of mortality among patients transplanted with relapsed/refractory disease was 6.09 times that of patients transplanted in CR1/PR1 (P = 0.006). Patients in the CHOP (+/-R) group had a higher risk of failure for PFS compared with patients in the HyperCVAD (+/-R) group, though the difference did not reach statistical significance (hazard ratio 3.67, P = 0.11). These results suggest that ASCT in CR1/PR1 leads to improved survival outcomes for patients with MCL compared to ASCT with relapsed/refractory disease, and a HyperCVAD (+/-R) induction regimen may be associated with an improved PFS among patients transplanted in CR1/PR1.

We performed a multivariable comparison of 125 consecutive patients with follicular lymphoma (FL) treated at our centers with either high-dose radioimmunotherapy (HD-RIT) using 131I-anti-CD20 (n = 27) or conventional high-dose therapy (C-HDT) (n = 98) and autologous hematopoietic stem cell transplantation. The groups were similar, although more patients treated with HD-RIT had an elevated pretransplantation level of lactate dehydrogenase (41% versus 20%, P = .03) and elevated international prognostic score (41% versus 19%, P = .02). Patients treated with HD-RIT received individualized therapeutic doses of 131I-tositumomab (median, 19.7 GBq [531 mCi]) to deliver 17 to 31 Gy (median, 27 Gy) to critical organs. Patients treated with C-HDT received total body irradiation plus chemotherapy (70%) or chemotherapy alone (30%). Patients treated with HD-RIT experienced improved overall survival (OS) (unadjusted hazard ratio [HR] for death = 0.4 [95% confidence interval (95% CI), 0.2-0.9], P = .02; adjusted HR, 0.3, P = .004) and progression-free survival (PFS) (unadjusted HR = .6 [95% C.I., 0.3-1.0], P = .06; adjusted HR, 0.5, P = .03) versus patients treated with C-HDT. The estimated 5-year OS and PFS were 67% and 48%, respectively, for HD-RIT and 53% and 29%, respectively, for C-HDT. One hundred-day treatment-related mortality was 3.7% in the HD-RIT group and 11% in the C-HDT group. The probability of secondary myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) was estimated to be .076 at 8 years in the HD-RIT group and .086 at 7 years in the C-HDT group. HD-RIT may improve outcomes versus C-HDT in patients with relapsed FL. (Blood. 2003;102:2351-2357)

We evaluated prognostic factors and treatment outcome of patients with relapsed/refractory Hodgkin's disease (HD) receiving autologous stem cell transplantation (ASCT). In total, 92 patients received total body irradiation, cyclophosphamide and etoposide (TBI/CY/E) (n=42) or busulfan, melphalan and thiotepa (Bu/Mel/T) (n=50) supported with ASCT. A total of 33 (66%) patients receiving the Bu/Mel/T regimen had a prior history of dose-limiting irradiation. Mucositis, hepatic and pulmonary toxicities were the main causes of morbidity and mortality, irrespective of the conditioning regimen. The transplant-related mortality was 15%. With a median follow-up of 6 years (range 2.5-11), the cumulative probabilities of survival, event-free survival (EFS) and relapse at 6 years were 55, 51 and 32%. The 6-year Kaplan-Meier (KM) probabilities of EFS for patients with less advanced disease (patients in first chemotherapy-responsive relapse or second remission (n=42)) and more advanced disease (all other patients (n=50)) were 60 and 44%. No differences in toxicities and efficacy between the conditioning regimens were found. ASCT is an effective treatment for patients with refractory/relapsed HD. Female patients and patients with less advanced disease at transplant had a better outcome. Patients with prior irradiation benefited from the Bu/Mel/T regimen.

NUP98/NSD1 has recently been reported in association with poor outcome in acute myeloid leukemia (AML). Previous studies also observed a high overlap between NUP98/NSD1 and FLT3/ITD, raising the question as to whether the reported poor outcome is due to NUP98/NSD1 or caused by the co-occurrence of these 2 genetic lesions. We aimed to determine the prognostic significance of NUP98/NSD1 in the context of FLT3/ITD AML. A total of 1421 patients enrolled in 5 consecutive Children's Oncology Group/Children's Cancer Group and SWOG trials were evaluated. NUP98/NSD1 was found in 15% of FLT3/ITD and 7% of cytogenetically normal (CN)-AML. Those with dual FLT3/ITD and NUP98/NSD1 (82% of NUP98/NSD1 patients) had a complete remission rate of 27% vs 69% in FLT3/ITD without NUP98/NSD1 (P < .001). The corresponding 3-year overall survival was 31% vs 48% (P = .011), respectively. In CN-AML, patients with concomitant NUP98/NSD1 and FLT3/ITD had a worse outcome than those harboring NUP98/NSD1 only. In multivariate analysis, the dual NUP98/NSD1 and FLT3/ITD remained an independent predictor of poor outcome, and NUP98/NSD1 without FLT3/ITD lost its prognostic significance. Our study demonstrates that it is the interaction between NUP98/NSD1 and FLT3/ITD that determines the poor outcome of patients with NUP98/NSD1 disease.

Lymphoproliferative disorders may present in any organ of the body. The mediastinum is an uncommon location for presentation of these heterogeneous disorders, but involvement of the mediastinum may be the sole site of disease for several aggressive lymphomas. Both Hodgkin's disease and non-Hodgkin's lymphoma may present in the mediastinum. The most common types of non-Hodgkin's lymphoma involving the mediastinum include lymphoblastic lymphoma and mediastinal large cell lymphoma. These lymphomas most commonly develop in the anterior mediastinum but may be seen in the middle and posterior mediastinum. Symptoms associated with a mediastinal presentation of a lymphoproliferative disorder are often attributable to compression of mediastinal structures (eg, superior vena cava syndrome) or invasion of thoracic structures such as the pericardium or pleura. Although staging can be performed with routine imaging studies, surgical intervention is often required to ensure accurate histologic diagnosis of these lymphomas. Once a diagnosis has been established, therapeutic modalities usually include chemotherapy and/or radiotherapy.

Older patients with acute myelogenous leukemia (AML) have overexpression of P-glycoprotein (Pgp+), and this has been shown to correlate quantitatively with therapeutic outcome. Since Pgp-mediated efflux of cytotoxic drugs can be inhibited by the cyclosporine analogue, PSC 833, we investigated the use of this agent with a 5-day mitoxantrone/etoposide regimen in patients over age 55 with newly diagnosed AML. Previous studies suggested a 33% incidence of grade IV/V non-hematologic toxicity with the use of mitoxantrone 10 mg/M(2) and etoposide 100 mg/M(2), each for 5 days, in this patient population. Since PSC 833 alters the pharmacokinetic excretion of MDR-related cytotoxins, this phase I dose-finding study was performed to identify doses of mitoxantrone/etoposide associated with a similar 33% incidence of grade IV/V non-hematologic toxicity, when given with PSC 833. Mitoxantrone/etoposide (M/E) doses were escalated in fixed ratio from a starting dose of M: 4 mg/M(2) and E: 40 mg/M(2), to M: 7 mg/M(2) and E: 70 mg/M(2), in successive cohorts of eight patients each. PSC 833 was well tolerated and the MTD of this M/E regimen with PSC 833 in this population was M: 6 mg/M(2) and E: 60 mg/M(2). The complete response (CR) rate for all patients was 50% (15/30) and was considerably higher for de novo than for secondary AML. These data suggest that the addition of PSC 833 to an M/E regimen for older patients with untreated AML is well tolerated but requires a reduction in M/E dosing to avoid increased toxicity.

The success of autologous stem cell transplantation (ASCT) for hematologic malignancy is limited largely by a high relapse rate. It is postulated that IL-2 administered after ASCT may eliminate minimal residual disease and thereby reduce relapses. A phase I/II study was performed to identify a regimen of IL-2 (Chiron) that could be given early after ASCT in phase III trials. In the phase I study, beginning a median of 46 days after ASCT for hematologic malignancy, cohorts of three to four patients received escalating doses of 'induction' IL-2 of 9, 10, or 12 x 10(6) IU/m2/day for 4 or 5 days by continuous i.v. infusion (CIV), followed by a 4-day rest period, and then 1.6 x 10(6) IU/m2/day of maintenance IL-2 by CIV for 10 days. The maximum tolerated dose (MTD) of induction IL-2 was 9 x 10(6) IU/m2/day x 4. In the phase II study, 52 patients received the MTD. Eighty percent of patients completed induction IL-2. Most patients exhibited some degree of capillary leak. One patient died of CMV pneumonia and one died of ARDS. Maintenance IL-2 was well tolerated. In the phase I/II study, 16 of 31 patients with non-Hodgkin lymphoma (NHL), 3/8 with Hodgkin disease (HD), 4/17 with AML, and 4/5 with ALL remain in CR. Two of six multiple myeloma (MM) patients remain in PR. Although the regimen of IL-2 identified had significant side-effects in some patients, it was well tolerated in the majority of patients. Phase III prospectively randomized clinical trials are in progress to determine if this IL-2 regimen will decrease the relapse rate after ASCT for AML and NHL.

The purpose of this study was to determine the outcome of patients with metastatic breast cancer treated with high-dose busulfan (Bu), melphalan (Mel) and thiotepa (TT) followed by peripheral blood stem cell (PBSC) infusion. Fifty-one patients with chemotherapy refractory (n = 32) or responsive (n = 19) metastatic breast cancer received Bu (12 mg/kg), Mel (100 mg/m2) and TT (500 mg/m2) followed by PBSC collected after chemotherapy and growth factor (n = 43) or growth factor alone (n = 8). The 100 day treatment-related mortality was 8% including one death from cytomegalovirus pneumonia, one from aspiration pneumonia and two from regimen-related toxicity (RRT). Seven of 28 refractory (25%) and 5/7 (71%) responsive patients with evaluable disease achieved a complete response of all measurable disease or all soft tissue disease with at least improvement in bone lesions (PR*). Fifteen of 51 patients (29%) are alive and progression-free a median of 423 days (range 353-934) after treatment, 5/32 (16%) with refractory disease and 10/19 (53%) with responsive disease. The probabilities of progression-free survival (PFS) at 1.5 years for the patients with refractory (n = 32) and responsive (n = 19) disease were 0.24 and 0.53, respectively. These preliminary data suggest that high-dose Bu/Mel/TT has significant activity in patients with advanced breast cancer and may be superior to some previously published regimens.

Purpose To determine the frequency of allogeneic hematopoietic cell transplantation (HCT) for patients with acute myeloid leukemia (AML) in first complete remission (CR1). Patients and Methods Between January 1, 2008, and March 1, 2011, 212 newly diagnosed patients with AML received treatment at our center. Ninety-five patients age less than 75 years with intermediate- or high-risk AML achieved a complete remission, and 21 patients achieved a morphologic remission with incomplete blood count recovery. Results Seventy-eight (67%; 95% CI, 58% to 76%) of 116 patients received HCT at a median of 2.8 months (range, 0.5 to 19 months) from their CR1 date. The median age was 57 years in both the HCT patient group (range, 18 to 75 years) and the non-HCT patient group (range, 24 to 70 years; P = .514). Between the HCT patients and the non-HCT patients, the mean Eastern Cooperative Oncology Group performance status was 1.1 compared with 1.5, respectively (P = .005), and the average HCT comorbidity score within 60 days of CR1 was 1.7 and 2.1, respectively (P = .68). Twenty-nine (76%) of 38 non-HCT patients were HLA typed, and matched donors were found for 13 of these 29 patients (34% of all non-HCT patients). The most common causes for patients not receiving transplantation in CR1 were early relapse (within 6 months) in 12 patients (32%), poor performance status in eight patients (21%), and physician decision in five patients (13%). Conclusion HCT can be performed in CR1 in the majority of patients with AML for whom it is currently recommended. The main barriers to HCT were early relapse and poor performance status, highlighting the need for improved therapies for patients with AML of all ages.

Mutations in the DNMT3A exon 23 independently predict poor outcome in older patients with acute myeloid leukemia: a SWOG report

The incidence of multiple myeloma (MM) increases with age, and with the aging of the population, the number of adults with MM is expected to double in the next 20 years. Novel agents, including the immunomodulatory agents thalidomide and lenalidomide, and the proteosome inhibitor bortezomib have dramatically changed the treatment of multiple myeloma in the past decade. The purpose of this review was to examine the recent clinical therapeutic trials in older adults with MM. A number of trials have evaluated the addition of novel agents to the traditional backbone of melphalan and prednisone. The combination of thalidomide with melphalan and prednisone has been evaluated in 7 randomized trials. The combination improves response rates and, in meta-analyses, survival, but at the expense of increased toxicity. Other combination regimens which include lenalidomide or bortezomib likewise are associated with higher response rates, but at the expense of greater toxicity. High dose dexamethasone is excessively toxic in older adults and should be avoided. The roles for high-dose therapy with autologous stem cell transplant or intermediate-dose melphalan with autologous stem cell transplant in older adults with MM in the era of modern therapy remain to be defined. In summary, there are a number of new therapeutic options for older adults with MM, allowing an individualized treatment strategy based on the patient's comorbidities and goals of care.

The efficacy of donor lymphocyte infusion (DLI) for treatment of relapsed acute leukemia after allogeneic hematopoietic cell transplantation is limited. We hypothesized that interleukin-2 (IL-2) combined with DLI after chemotherapy might augment graft-versus-leukemia effects. To identify a safe and effective IL-2 regimen, a phase I/II study of DLI plus IL-2 therapy was performed for such patients. After chemotherapy, 17 patients received DLI (1 × 10(8) CD3/kg for patients with related donors, and 0.1 × 10(8) CD3/kg for those with unrelated donors) and an escalating dose of induction IL-2 (1.0, 2.0, or 3.0 × 10(6) IU/m(2)/day representing levels I [n = 7], Ia [n = 9], and II [n = 1]) for 5 days followed by maintenance (1.0 × 10(6) IU/m(2)/day) for 10 days as a continuous intravenous infusion. Unacceptable IL-2-related toxicities developed in 1 patient at level I, 2 at level Ia, and 1 at level II. Grades III-IV acute graft-versus-host disease (aGVHD) developed in 5 patients, and extensive chronic GVHD (cGVHD) developed in 8. Eight patients had a complete remission after chemotherapy prior to DLI, and 2 additional patients had a complete remission after DLI plus IL-2 therapy. In conclusion, the maximal tolerated induction dose of IL-2 combined with DLI appears to be 1.0 × 10(6) IU/m(2)/day. IL-2 administration after DLI might increase the incidence of cGVHD.

We conducted a multi-center phase II trial of gemcitabine (G), carboplatin (C), dexamethasone (D), and rituximab (R) in order to examine its safety and efficacy as an outpatient salvage regimen for lymphoma. Fifty-one patients received 2-4 21-day cycles of G (1000 mg/m(2), days 1 and 8), C (AUC = 5, day 1), D (40 mg, daily days 1-4), and R (375 mg/m(2), day 8 for CD20-positive disease) and were evaluable for response. Characteristics included: median age 58 years (19-79 years), stage III/IV 88%, elevated LDH 33%, median prior therapies 2, prior stem cell transplant 12%, chemoresistant 62%, median prior remission duration 2.5 months. The overall and complete response rates were 67% (95% confidence interval [CI] 54-80%) and 31% (95% CI 19-44%), respectively, with activity seen in a broad variety of histologies. Responses occurred in 16 of 17 (94%, 95% CI 83-100%) transplant-eligible patients and 15 of 28 (54%, 95% CI 34-71%) with chemoresistant disease. The median CD34 yield in patients attempting peripheral blood stem cell (PBSC) collection following this regimen was 10.9 x 10(6) CD34+ cells/kg (range 5.0-24.1 x 10(6)). Hematologic toxicity was common, but febrile neutropenia (2.5%) and grade 4 non-hematologic adverse events (n = 2) were rare, with no treatment-related deaths. GCD(R) is a safe and effective outpatient regimen for relapsed lymphoma, and successfully mobilizes PBSCs.

BACKGROUND. High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the standard treatment for patients with chemosensitive relapsed/refractory Hodgkin lymphoma (HL), but this therapy is commonly denied to patients with resistant disease. We explored the utility of HDT and ASCT for chemoresistant HL because there are few established therapies for these patients. METHODS. Sixty-four chemoresistant HL patients underwent HDT followed by ASCT at our center. Baseline characteristics included median age = 35 years (range, 14-59 years), stage III/IV = 49 (77%), nodular sclerosis histology = 51 (80%), and prior radiation = 32 (50%). Twenty-six patients (41%) received total body irradiation (TBI)-based regimens, and 38 (59%) underwent non-TBI conditioning. RESULTS. The estimated 5-year overall survival (OS) and progression-free survival (PFS) were 31% and 17%, respectively (median follow-up = 4.2 years). Multivariate analysis only identified year of transplant as independently associated with improved OS (P = .008) and PFS (P = .04), with patients receiving transplants in later years having better outcome. The probabilities of 3-year PFS for patients receiving transplants during 1986 to 1989, 1990 to July 1993, August 1993 to 1999, and 2000 to 2005 were 9%, 21%, 33%, and 31%, respectively. CONCLUSIONS. These data suggest that HDT and ASCT may result in prolonged remissions and survival for a subset of chemoresistant HL patients, with improved outcomes in patients receiving transplants more recently. Cancer 2008. © 2008 American Cancer Society.

Udgivelsesdato: 2008-Sep Lonafarnib is an orally bio-available farnesyltransferase inhibitor that prevents farnesylation of specific target proteins including Ras. In a multicenter study, 67 patients with advanced myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) were treated with a continuous oral dose of 200-300 mg of lonafarnib and were evaluated for hematologic, pathologic and pharmacodynamic response. The median age of patients was 70 years (range 44-86). There were 32 patients with MDS (RAEB-20 and RAEB-t-12) and 35 with CMML. Overall 16 (24%) of the patients responded with two patients achieving a complete remission and one a partial response. Responses were seen in 6/32 and 10/35 patients with MDS and CMML, respectively. Of the 19 patients who were platelet transfusion-dependent prior to treatment, 5 (26%) became transfusion-free for a median duration of 185 days. A decrease in the farnesylation of the HDJ-2 protein measured in patient-derived cells was observed in the majority of patients during treatment with lonafarnib, but no clear correlation between changes in farnesylation and clinical effect could be made. Gastrointestinal toxicity was significant with 19% of patients discontinuing therapy due to diarrhea, nausea and/or anorexia. Lonafarnib has demonstrable activity in patients with advanced MDS and CMML.

The impact of the follicular lymphoma (FL) histologic grade on outcomes after high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) is unknown. We evaluated 219 consecutive patients with grades 1-3 FL who underwent HDT and ASCT at our center. Overall survival (OS), progression-free survival (PFS), relapse and non-relapse mortality (NRM) was estimated for each grade after controlling for other predictive factors. The number of patients with grades 1, 2 and 3 FL was 106 (48%), 75 (34%) and 38 (17%), respectively. Five-year outcome estimates for the entire cohort included 60% OS, 39% PFS and 46% relapse (median follow-up=7.8 years). PFS and relapse were nearly identical among patients with grade 3 FL versus grades 1-2 FL after adjusting for other contributing factors (hazard ratio (HR)=0.90, P=0.68; HR=1.07, P=0.80, respectively). The hazard for mortality (HR=0.70, P=0.23) and NRM (HR=0.33, P=0.07) was non-significantly lower among patients with grade 3 FL compared to patients with grades 1-2 disease. Factors associated with inferior PFS included elevated lactate dehydrogenase (HR=1.52, P=0.03), chemoresistance (HR=1.82, P=0.02),or =2 prior therapies (HR=1.8, P=0.03) and prior radiation (HR=1.99, P=0.003). These data suggest that the histologic grade of FL does not impact PFS or relapse following HDT and ASCT.

Purpose The majority of patients with relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL) are older than 60 years, yet they are often denied potentially curative high-dose therapy and autologous stem-cell transplantations (ASCT) because of the risk of excessive treatment-related morbidity and mortality. Myeloablative anti-CD20 radioimmunotherapy (RIT) can deliver curative radiation doses to tumor sites while limiting exposure to normal organs and may be particularly suited for older adults requiring high-dose therapy. Patients and Methods Patients older than 60 years with relapsed B-cell NHL (B-NHL) received infusions of tositumomab anti-CD20 antibody labeled with 185 to 370 Mbq (5 to 10 mCi) [131I]-tracer for dosimetry purposes followed 10 days later by individualized therapeutic infusions of [131I]tositumomab (median, 19.4 Gbq [525 mCi]; range, 12.1 to 42.7 Gbq [328 to 1,154 mCi]) to deliver 25 to 27 Gy to the critical normal organ receiving the highest radiation dose. ASCT was performed approximately 2 weeks after therapy. Results Twenty-four patients with a median age of 64 years (range, 60 to 76 years), who had received a median of four prior regimens (range, two to 14 regimens), were treated. Thirteen patients (54%) had chemotherapy-resistant disease. The estimated 3-year overall and progression-free survival rates were 59% and 51%, respectively, with a median follow-up of 2.9 years (range, 1 to 6 years). All patients experienced expected myeloablation with engraftment of platelets (≥ 20 K/μL) and neutrophils (≥ 500/μL), occurring at a median of 9 and 15 days after ASCT, respectively. There were no treatment-related deaths, and only two patients experienced grade 4 nonhematologic toxicity. Conclusion Myeloablative RIT and ASCT is a safe and effective therapeutic option for older adults with relapsed B-NHL.

Purpose Oncologists in academic cancer centers usually generate professional fees that are insufficient to cover salaries and other expenses, despite significant clinical activity; therefore, supplemental funding is frequently required in order to support competitive levels of physician compensation. Relative value units (RVUs) allow comparisons of productivity across institutions and practice locations and provide a reasonable point of reference on which funding decisions can be based. Methods We reviewed the clinical productivity and other characteristics of oncology physicians practicing in 13 major academic cancer institutions with membership or shared membership in the National Comprehensive Cancer Network (NCCN). The objectives of this study were to develop tools that would lead to better-informed decision making regarding practice management and physician deployment in comprehensive cancer centers and to determine benchmarks of productivity using RVUs accrued by physicians at each institution. Three hundred fifty-three individual physician practices across the 13 NCCN institutions in the survey provided data describing adult hematology/medical oncology and bone marrow/stem-cell transplantation programs. Data from the member institutions participating in the survey included all American Medical Association Current Procedural Terminology (CPT®) codes generated (billed) by each physician during each organization's fiscal year 2003 as a measure of actual clinical productivity. Physician characteristic data included specialty, clinical full-time equivalent (CFTE) status, faculty rank, faculty track, number of years of experience, and total salary by funding source. The average adult hematologist/medical oncologist in our sample would produce 3,745 RVUs if he/she worked full-time as a clinician (100% CFTE), compared with 4,506 RVUs for a 100% CFTE transplant oncologist. Results and Conclusion Our results suggest specific clinical productivity targets for academic oncologists and provide a methodology for analyzing potential factors associated with clinical productivity and developing clinical productivity targets specific for physicians with a mix of research, administrative, teaching, and clinical salary support.

We conducted a retrospective analysis of 968 adults with acute myeloid leukemia (AML) on 5 recent Southwest Oncology Group trials to understand how the nature of AML changes with age. Older study patients with AML presented with poorer performance status, lower white blood cell counts, and a lower percentage of marrow blasts. Multidrug resistance was found in 33% of AMLs in patients younger than age 56 compared with 57% in patients older than 75. The percentage of patients with favorable cytogenetics dropped from 17% in those younger than age 56 to 4% in those older than 75. In contrast, the proportion of patients with unfavorable cytogenetics increased from 35% in those younger than age 56 to 51% in patients older than 75. Particularly striking were the increases in abnormalities of chromosomes 5, 7, and 17 among the elderly. The increased incidence of unfavorable cytogenetics contributed to their poorer outcome, and, within each cytogenetic risk group, treatment outcome deteriorated markedly with age. Finally, the combination of a poor performance status and advanced age identified a group of patients with a very high likelihood of dying within 30 days of initiating induction therapy. The distinct biology and clinical responses seen argue for age-specific assessments when evaluating therapies for AML.

The effectiveness of amphotericin B oral suspension versus nystatin oral suspension for the prevention of oral colonization by Candida in hematopoietic cell transplant (HCT) patients was examined.Prior to hematopoietic cell infusion, 40 patients receiving systemic fluconazole for prophylaxis were randomized to receive either amphotericin B oral suspension or nystatin oral suspension, q.i.d. The study continued to day 21 or until the patient was discharge from the hospital or withdrawn from the study. Oral examinations were conducted twice weekly, and adverse events and compliance were recorded. Cultures were taken for quantitative counts and species identification. Candida isolates were assessed for resistance to the oral antifungal agents. Blood was collected for assessment of amphotericin B levels.Ulcerative mucositis occurred in 84.6% of patients undergoing HCT, and no correlation was observed between the severity of mucositis and the presence of oral Candida and the severity of mucositis. Systemic and topical antifungal treatment resulted in a decrease in the number of colonized patients (54.8% before treatment; 23.1% during treatment); however, oral colonization was not eliminated. Tolerability of the oral rinse products was limited, with greater noncompliance in the amphotericin B than the nystatin group. Reports of altered taste appeared to be greater in the amphotericin B group. Minimal absorption of amphotericin B was seen following oral rinsing (serum levels 0.12-0.50 microg/ml), and no consistent changes in organism susceptibility to polyenes were seen. The results suggest that topical antifungal rinses may further control oropharyngeal colonization by Candida in patients on systemic antifungals receiving HCT, but the effect is limited by tolerability and reformulation and should be considered in order to increase compliance.

Relapsed mantle cell lymphoma is a radiation-sensitive malignancy that is unlikely to be cured by treatment with conventional high-dose therapy and autologous stem cell transplantation. We tested the safety and efficacy of using a CD20-specific monoclonal antibody conjugated with 131I to deliver high-dose radiation selectively to all lymphoma sites. Patients with relapsed or refractory mantle cell lymphoma received infusions of 131I-labeled CD20-specific monoclonal antibody (Tositumomab). The antibody dose was 1.7 mg/kg body weight, and the amount of 131I was calibrated to deliver 20 to 25 Gy to vital normal organs. This treatment was followed 10 days later by administration of high-dose etoposide (30-60 mg/kg), cyclophosphamide (60-100 mg/kg), and infusion of cryopreserved autologous stem cells. The 16 patients in this study had received a median of 3 prior treatments, and 7 had chemotherapy-resistant disease. The median dose of 131I was 510 mCi (18.87 GBq). There were no therapy-related deaths. Among the 11 patients with conventionally measurable disease at the time of treatment, the respective complete and overall response rates were 91% and 100%. Fifteen patients remain alive, and 12 have had no progression of lymphoma at 6 to 57 months from transplantation and 16 to 97 months from diagnosis. Overall survival at 3 years from transplantation is estimated at 93%, and progression-free survival is estimated at 61%. High-dose treatment with 131I-Tositumomab, etoposide, and cyclophosphamide results in a high remission rate and may provide long-term disease-free survival for patients with relapsed or refractory mantle cell lymphoma.

The effectiveness of intensive post-remission chemotherapy regimens for adult patients with acute lymphoblastic leukemia (ALL) is limited by both a high rate of disease recurrence and a substantial incidence of treatment toxicity. To evaluate a potentially more effective and less toxic approach, we conducted a multicenter phase III trial of consolidation therapies comparing the standard L10M regimen with one combining the brief, intensive L17M regimen and escalating methotrexate (MTX) and L-asparaginase (L-asp). Patients over age 15 with previously untreated ALL were eligible. Induction therapy included vincristine, prednisone, doxorubicin, cyclophosphamide and intrathecal methotrexate administered over 36 days. Patients who achieved complete remission (CR) were randomized to receive consolidation with either the L10M regimen or with DAT (daunomycin, cytosine arabinoside, 6-thioguanine) and escalating MTX and L-asp. The randomization was stratified by age, WBC and Ph chromosome status. Maintenance therapy was the same in both arms. Of 353 eligible patients, 218 (62%) achieved CR and 195 were randomized. The treatment arms did not differ significantly with respect to disease-free survival (DFS; P= 0.46) or overall survival (P= 0.39). Estimated DFS at 5 years was 32% (95% confidence interval (CI) 23-42%) in the L10M arm and 25% (95% CI 16-33%) in the DAT/MTX/L-asp arm. In each arm, 4% of patients died of toxicities (infection in all but one case). Infections and nausea/vomiting were somewhat more common in the L10M arm (occurring in 68% and 53% of patients respectively) than the DAT/MTX/L-asp arm (56% and 33%). The DAT/MTX/L-asp consolidation regimen was associated with some reduction in nonfatal toxicities, but no significant improvement in DFS, overall survival or non-relapse mortality when compared to the standard L10M regimen.

Background The limitations of current CLL/SLL treatments include suboptimal response rates, variable remission durations, toxicities, and few cures. Vorinostat is a histone deacetylase inhibitor that regulates gene transcription and possibly CD20 expression, leading to its investigative use in the treatment of B-cell malignancies. For this reason, we studied the addition of vorinostat to fludarabine, cyclophosphamide and rituximab (FCR+V) followed by maintenance therapy with rituximab and vorinostat. Methods Patients over age 18 with previously untreated Rai stage I-IV CLL or SLL and ECOG 0-2 were eligible. They received 4-6 cycles of FCR+V followed by up to eight cycles of maintenance with rituximab and vorinostat. Each cycle of FCR used cyclophosphamide 250 mg/m2 IV on days 1-3 and fludarabine 25 mg/m2 IV days 1-3 of each cycle given every 28 days; with rituximab 375 mg/m2 IV once with cycle 1 followed by 500 mg/m2IV once per cycle for cycles 2-6. Rituximab 500 mg/m2 IV was given day 1 of each 3 month cycle of maintenance for up to 8 cycles. Vorinostat was given on days 1-5 and 8-12 of each treatment cycle and days 1-14 of each 3-month maintenance cycle. The Phase I vorinostat starting dose was 200 mg/day and escalated by 100 mg/day to a maximum pre-determined dose of 400 mg/day in a 3 x 3 design. Since no dose limiting toxicity was seen during Phase I, the previously designated maximum dose of 400 mg/day vorinostat was chosen for the Phase II portion of the trial. Results Ten patients were treated on the Phase I portion of the study, and 26 patients have been enrolled in the Phase II portion at the maximum vorinostat dose of 400 mg/day combined with FCR and rituximab maintenance. The median age of patients on study was 58 (range, 36-72); with 6 patients enrolled with Stage I, 15 with Stage II, 5 with Stage III and 10 with Stage IV disease. Nine patients (25%) had >30% CD38 expression, 13 patients (36%) had >20% ZAP70 expression, and 4 patients (11%) had 17p deletions detected by FISH of marrow samples. Median follow-up on study is 15 months (range, 0.9-38.6). Of the 36 patients enrolled, 22 patients are evaluable after completing 4-6 cycles of FCR+V, 1 patient progressed after cycle 2 (del17p), 9 patients are currently receiving FCR+V and 4 patients are unevaluable. Of these 4 patients, one withdrew voluntarily, one was taken off study due to non-compliance, one went off study after cycle 3 due to cytopenias, and one patient with multiple co-morbidities died of sepsis after cycle 5. Of the 22 patients who have completed 4-6 cycles of FCR+V, 16 (73%) obtained a complete response (CR), 5 (22.5%) obtained a partial response (PR), and 1 (4.5%) has stable disease. Of these 22 patients, 4 (18%) have completed 8 cycles of maintenance with rituximab and vorinostat, 5 (23%) were taken off study due to cytopenias, 1 (4.5%) went off study due to insurance issues, 1 (4.5%) went off study due to recurrent infections, 2 (9%) voluntarily withdrew from study, and 9 (41%) are still receiving maintenance therapy. The most common grade 3-4 non-hematologic toxicities during FCR+V were gastrointestinal symptoms in 10 patients and fatigue in 3 patients. However, there were no grade 3-4 non-hematologic toxicities that resulted in patient withdrawal from study during treatment with FCR+V. No grade 3-4 non-hematologic toxicities have been observed in patients who have completed or are undergoing maintenance with rituximab and vorinostat. Conclusion Treatment of CLL/SLL with fludarabine, cyclophosphamide, rituximab and 400mg/day vorinostat (FCR +V) followed by maintenance with rituximab and vorinostat appears feasible and tolerable, and may warrant further study. Disclosures: Gopal: Merck: Research Funding. Press:Roche/Genentech: Consultancy.

Introduction Gemtuzumab ozogamicin (GO, Mylotarg) in AML treatment remains controversial: some studies report significant survival benefits either overall or in patient subgroups, but one study showed no, with an excess of early mortality in the GO arm. The five trials so far reported had the common aim of augmenting standard induction chemotherapy which lends itself to a meta-analysis, to determine whether the totality of the evidence demonstrates any benefit for GO, and/or in which specific subgroups of patients. We therefore performed an individual patient data (IPD) meta-analysis of these trials. An IPD meta-analysis has considerable advantages over a published data meta-analysis. Analyses can take into account updated data, unpublished trials, and also look at stratified analyses to identify subgroups of patients. Methods and Materials The 5 trials combining GO with the first course of standard induction chemotherapy were identified, the SWOG-0106 study (ClinicalTrials.gov Identifier: NCT00085709), the ALFA-0701 trial, the UK MRC/NCRI AML15 & 16 trials, and the GOELAMS AML2006IR trial. The last of these is so far unpublished. Updated datasets were requested from all trialists. A total of 3339 patients, ranging in age from 0 to 84 were recruited. Information was requested on age, sex, de Novo/Secondary disease, performance status, cytogenetics, FLT-3 ITD, NPM1 status, survival, relapse, remission, and stem cell transplant. Outcomes were assessed using standard meta-analytic techniques, where patients within the same trial were compared and then summary statistics combined to obtain overall estimates. Heterogeneity between trials, and interactions between treatment and baseline covariates were explored using standard heterogeneity and trend statistics. Results The addition of GO did not change remission rate (OR 0.91, 95% CI 0.77-1.07, p=0.3). However, there was a suggestion of slightly greater early mortality (30-day mortality HR 1.28 (0.97-1.70) p=0.08. Overall survival was improved (HR 0.89 (0.82-0.97) p=0.01), due to a significant reduction is relapse (HR 0.80 (0.72-0.89) p=0.00006), leading to significantly improved survival from remission (HR 0.84 (0.76-0.94). p=0.001). In all cases there was no significant heterogeneity between trials, although there was a suggestion that the excess early mortality was greater in patients given higher dose of GO. In analyses stratified by baseline covariates, there was no evidence of significant interaction between either age or FLT-3 ITD status and the effect of GO on survival (p=0.9 for trend by age, p=0.9 for heterogeneity by ITD mutation status). However, there was a highly significant interaction between cytogenetic risk group, as defined by each cooperative group, and treatment (p=0.003 for trend, p=0.006 for heterogeneity). There was highly significant benefit for patients with favourable (HR 0.50 (0.33-0.77) p=0.001) and intermediate (HR 0.85 (0.76-0.96) p=0.007) risk patients, but no evidence of benefit for patients with adverse risk cytogenetics (HR 1.04 (0.86-1.25) p=0.7). Conclusions The combined evidence from 5 randomised trials of GO given with course 1 of induction chemotherapy shows a significant benefit in survival which more than outweighs any possible increase in early mortality. However, the benefit appears to be restricted to patients who have favourable or intermediate risk cytogenetics, with the greatest benefit in patients with a core binding factor leukaemia, although survival is still highly significantly improved in intermediate risk patients. On the basis of this IPD meta-analysis, adding GO to induction improves survival in the majority of patients with AML with no restriction by age of FLT3 ITD mutation status. On behalf of the GO trialists collaborative group. The SWOG-0106 Study was supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA32102, CA38926 and in part by Pfizer Pharmaceuticals. Disclosures: Off Label Use: Gemtuzumab Ozogamicin in AML.

High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the optimal treatment for patients with relapsed aggressive non-Hodgkin's lymphoma (NHL). HDT, however, is often reserved for relatively younger patients due to limited data in older adults. We treated 53 patients aged 60 years and older (median age 62 years, range 60.3–67.7 years) with HDT and ASCT for NHL at our centers. Forty-four patients (83%) had aggressive histology, 75% had chemosensitive disease and all had failed anthracycline therapy. Conditioning regimens included busulfan, melphalan, and thiotepa (45%); cyclophosphamide (CY), etoposide (VP-16), and total body irradiation (TBI) (30%); CY and TBI (15%); and other regimens (10%). Estimated 4-year overall survival (OS), progression-free survival, and treatment-related mortality (TRM) were 33%, 24% and 22%, respectively. A multivariable analysis demonstrated that patients with chemosensitive disease (P = 0.03) and ⩽3 prior regimens (P = 0.03) had superior survival. Four-year OS in patients with chemosensitive disease was 39% vs15% in patients with chemoresistant disease. Reduced TRM was associated with the CY, VP-16 and TBI regimen (P = 0.02). HDT therapy with ASCT may result in prolonged survival and potential cure for about a quarter of elderly patients, and for almost 40% with chemosensitive disease. Optimal conditioning regimen selection may further improve outcome by reducing TRM. Age alone should not be used to exclude patients from receiving myeloablative therapy with ASCT. Bone Marrow Transplantation (2001) 27, 593–599.

Objective To evaluate the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of a humanized anti-CD11/CD18 monoclonal antibody (Hu23F2G) in patients with multiple sclerosis. Methods In this phase I uncontrolled dose escalation study, patients (n = 24) with primary or secondary progressive multiple sclerosis received single intravenous infusions of Hu23F2G (0.01 to 4.0 mg/kg). Study parameters included safety, pharmacology, immunogenicity, and brain magnetic resonance imaging (MRI). Results Hu23F2G had few adverse effects, but 2 cases of urinary tract infection and 2 cases of gingivitis did occur. Transient leukocytosis developed in some subjects receiving ≥1.0 mg/kg. The pharmacokinetic response was nonlinear, with the area under the curve increasing out of proportion to the increase in dose. The mean terminal half-life increased with dose and was 21.9 (SD, 12.8) hours at the 4.0 mg/kg dose. High saturation (>80%) of CD11/CD18 on circulating leukocytes was achieved with doses ≥0.2 mg/kg. The duration of high leukocyte saturation was dose-dependent, persisting for more than a week at the 4.0 mg/kg dose. A marked decrease in leukocyte migration in response to cutaneous inflammation was observed. Antibodies against Hu23F2G were not detected. The neurologic examinations were stable except for 1 subject who had worsening weakness associated with an infection. No significant changes were noted on brain MRI scans. Conclusions Hu23F2G was tolerated at doses that achieved high degrees of leukocyte CD11/CD18 saturation with in vivo inhibition of leukocyte migration. Because this phase I study was not designed to determine the clinical efficacy of Hu23F2G, further studies are needed. Clinical Pharmacology & Therapeutics (1998) 64, 339–346; doi

OBJECTIVES: A phase II trial of high-dose cyclophosphamide, etoposide, and cisplatin was done. STUDY DESIGN: Forty-eight patients with progressive or persistent disease and previous cisplatin-based chemotherapy and no paclitaxel therapy were entered for treatment on the basis of two cycles of cyclophosphamide (4500 mg/m 2 ), etoposide (750 mg/m 2 ), and cisplatin (120 mg/m 2 ). RESULT: Seventy-four cycles were delivered. Six patients died during treatment (12.5%). Of 28 with measurable disease, there was a 25% response rate and 32% had stable disease. Median time to recurrence and survival were significantly different for minimal versus bulky disease ( p = 0.0089, p = 0.0008, log-rank) and for platinum-sensitive versus platinum-resistant disease ( p = 0.18, p = 0.0012, log-rank). The number of prior regimens was not correlated with time to progression or survival. CONCLUSION: This study shows little advantage for high-dose protocols except for patients with a response to platinating agents and minimal residual disease. (Am J Obstet Gynecol 1996;174:1688-94.)

Abstract 129 Background Recent emphasis has been placed on administration of induction regimens less intense than standard 3+7 for patients with newly diagnosed AML. A primary goal is to reduce the presumed average treatment related mortality (TRM) rate of 10% occurring within the first 28 days after start of 3+7 or higher intensity therapies; TRM rates have been > 30% in patients who are older and/or have poor performance status (PS]. (Walter et al. JCO 2012). This practice presupposes that TRM rates with higher intensity induction regimens are static, a notion seemingly difficult to reconcile with advances in supportive care (e.g. newer anti-aspergillosis drugs) that have sharply reduced rates of non-relapse mortality after allogeneic hematopoietic cell transplant (Gooley et al. NEJM 2010). Methods We thus addressed rates of TRM from 1991–2009 in 1,409 patients given 3+7 induction regimens on SWOG protocols (cytarabine dose 100 mg/m2 daily × 7) and 1,933 patients given induction regimens containing higher cytarabine doses (at least 1.0 g/m2 daily × 4–5 days) at MDA, variably combined with idarubicin, fludarabine or other agents. Multivariate analyses were used to account for confounding factors. Results TRM rates declined both in SWOG and at MDA. However this reduction must account for the declining ages of patient given 3+7 or more intense induction (p Conclusion There has been a reduction over time in TRM after “intensive” induction possibly due to better supportive care. Although various selection biases cannot be excluded, this decline is not due to younger age or better performance status and needs to be considered when choosing AML induction therapy. Disclosures: No relevant conflicts of interest to declare.

Abstract 3082 Background: High-dose therapy (HDT) and autologous hematopoietic cell transplantation (auto HCT) has been shown to improve outcomes in mantle cell lymphoma (MCL) when used in first remission. In contrast, most series evaluating HDT and auto HCT when used for relapsed/refractory (rel/ref) disease suggest that the outcomes are typically poor. Such data have broadly limited the use of HDT and auto HCT in this setting, though the question of a potential benefit of this approach in a subset of these patients has never been addressed. We, thus, hypothesized that certain factors could be identified to predict which patents with rel/ref MCL would experience a favorable outcome after auto HCT. Methods: Records from consecutive pts older than 18 years with a confirmed diagnosis (dx) of MCL receiving HDT and auto HCT between April 1996 and February 2011 at our center were reviewed. Pts who received auto HCT for either second or later remission or for primary refractory disease were identified while excluding those who received a planned tandem auto-allogeneic HCT. Characteristics both at dx and at the time of pre-HCT work-up were recorded. The statistical significance of differences in event rates was evaluated with the proportional hazards regression model. Reported p-values are based on the Wald statistic, and two-sided p-values less than 0.05 were considered statistically significant. Kaplan-Meier (K-M) curves were used to estimate the probabilities of overall and progression-free survival (OS and PFS, respectively). Results: From a cohort of 165 pts, 68 (41%) met the prespecified definition of rel/ref MCL. In this subgroup, the median PFS was 14 months and the median OS was 36 months. The median age at the time of auto HCT was 58 years (range 41–70), and the median number of treatments pre-HDT was 2 (range 1–6). There were 9 pts (13%) with blastoid histology, and 18 patients (26%) had B symptoms (sx) at the time of dx. The median time from dx to auto HCT was 25 months (range 4–183). Pretransplant disease status included CR = 15 (22%), PR = 42 (62%), and chemorefractory or untested relapse = 11 (16%). Pretransplant simplified MIPI scores based on data obtained prior to HDT (sMIPI-Auto) were as follows: ≤ 2 in 26 pts (38%), 3 in 28 pts (41%), and ≥ 4 in 14 pts (21%). Three factors were identified as independent predictors of worse OS and PFS in multivariable models: 1. higher sMIPI-Auto (HR 2.0 for OS, p = 0.001; HR 3.1 for PFS, p < 0.001), 2. presence of B sx (HR 2.5 for OS, p = 0.009; HR 2.6 for PFS, p = 0.005), and 3. lower remission quotient (RQ), calculated by dividing the time in months from diagnosis to auto HCT by the number of prior treatments (HR 1.8 for OS, p = 0.002; HR 1.4 for PFS, p = 0.01). The estimated linear predictors from this multivariable model allowed formulation of a predictive score for OS and PFS, which defined a subset of 23 pts (34%) with relatively low risk of death and/or progression having at least 2 favorable features from the above analysis (see Figure, Score 1). Favorable groups specifically included: 1) sMIPI-Auto of ≤ 2 and no B sx, with a RQ ≥ 5, 2) sMIPI-Auto of ≤ 2, presence of B sx, and a RQ of ≥ 14, and 3) sMIPI-Auto of 3, no B sx, and a RQ of ≥ 14. Pts not meeting one of these sets of criteria, particularly those with either a sMIPI-Auto of ≥ 4 or a RQ of < 5 (independent of the other factors), were predicted to do poorly (see Figure, Scores 2 and 3). The K-M 3-yr estimates for PFS were 66% (95% CI 41 – 82%) for Score 1, 23% (95% CI 9 – 40%) for Score 2, and 24% (95% CI 8 – 45%) for Score 3; the K-M 3-yr estimates for OS were 80% (95% CI 54 – 92%) for Score 1, 43% (95% CI 22 – 62%) for Score 2, and 29% (95% CI 11 – 49%) for Score 3. Conclusions: These data identify 3 simple factors (sMIPI-Auto, B symptoms, and high RQ) that can be used to distinguish MCL patients who may experience prolonged OS and PFS after auto HCT used for the treatment of rel/ref disease. In contrast to studies to date, our detailed analysis of this specific population could be used to provide another effective therapeutic option for up to one third of patients with rel/ref MCL, though independent validation of these results is required. Disclosures: Holmberg: Sanofi: Research Funding; Seattle Genetics: Research Funding; Merck: Research Funding; Otsuka: Research Funding; Millenium: Research Funding.

Abstract 3594 Background: Several regimens composed of clofarabine and cytarabine have exhibited efficacy for both newly diagnosed and relapsed/refractory acute myeloid leukemia (AML) (Faderl et al Blood 2005, 2006, 2008). Clofarabine's ability to increase araCTP formation and inhibit ribonucleotide reductase confer potent anti-leukemic effect. We previously reported the results of an induction regimen consisting of G-CSF priming, clofarabine, and high dose cytarabine for relapsed/refractory AML (GCLAC) (Becker et al Br J Haematol 2011), which resulted in a complete remission (CR) rate of 46% overall, and a CR rate of 50% in patients with poor risk cytogenetics. Furthermore, we demonstrated that GCLAC is superior to fludarabine/cytarabine combinations in the relapsed/refractory setting (retrospective comparison; Becker et al Haematologica Epub ahead of print, 2012). Because of its activity as a salvage regimen, we examined the response rate and toxicity of GCLAC in the upfront setting. Methods: A multicenter clinical trial (NCT01101880) of G-CSF priming, clofarabine, and high dose cytarabine enrolled newly diagnosed patients < 65 years old with acute myeloid leukemia (AML), advanced myelodysplastic syndrome (MDS) or advanced myeloproliferative neoplasm (MPN) from September 2010 through May 2012. The GCLAC regimen consists of G-CSF 5 mcg/kg/day by subcutaneous injection beginning the day prior to chemotherapy until neutrophil recovery, clofarabine 30 mg/m2/day × 5, and cytarabine 2 gm/m2/day × 5. A second induction with the same regimen was permissible if marrow blasts over 5% persisted on day 21 or thereafter. Consolidation courses were administered for up to 3 cycles, with clofarabine 25 mg/m2/day days 1–4, cytarabine 2 gm/m2/day days 1–4, and G-CSF days 0–4. Results: Fifty patients with non-APL AML, RAEB2, or myelofibrosis with >10% blasts were treated. The median age was 53, range 22–64. Twenty-one of the patients (42%) had antecedent hematologic disorders or proliferative/dysplastic disorders with ≥10% blasts or secondary leukemia. Twelve patients (24%) had unfavorable, 32 patients (64%) intermediate, and 4 (8%) favorable cytogenetics. Overall, 37 patients (74%) achieved complete remission (CR; 95% CI 62–86%), 40 (80%) CR + CRp (CR with incomplete platelet recovery). Of these remissions, 5CRs and 1 CRp had been attained after a second induction course in 11 patients. Thirty-four patients received one, 20 two, and 11 three cycles of consolidation treatment. The CR rate was 83% for patients without antecedent hematological disorder (AHD), and 57% for those with AHD. The CR rate was 100% for patients with favorable risk, 84% for those with intermediate risk, and 46% for those with unfavorable risk cytogenetics. The median time to neutrophil recovery (>500/μl) was 19 days (13–35 range) and to platelet recovery >100,000/μl 24 days (16–63 range) after induction. The most significant grade 4 toxicity occurring in 3 patients, was a constellation of pulmonary infiltrates, hypoxia, and diffuse alveolar hemorrhage that responded to steroids, and was rarely seen when patients were premedicated with steroids. Out of the 125 cycles of chemotherapy administered, the most frequent grade 3 adverse events (AEs) were pulmonary (11), bacteremia (22), and transaminase elevation (10). There were 11 grade 4 AEs including pulmonary (5), hyperglycemia (2), transaminase elevation (1), acute cholecystits (1), and septic shock (2). The 30 day mortality was 0%. Conclusion: GCLAC is a well tolerated induction regimen and a comparison with 7+3 is in progress, using data from Southwest Oncology Group (SWOG) and the Fred Hutchinson Cancer Research Center (FHCRC). Disclosures: Becker: Sanofi: Research Funding. Off Label Use: Clofarabine is indicated for the treatment of pediatric patients with relapsed or refractory acute lymphoblastic leukemia.

Conventional treatment of malignant high grade gliomas includes maximal resection followed by external beam radiotherapy. The addition of adjuvant chemotherapy has provided little improvement in the median duration of survival for these patients, particularly those patients with glioblastoma multiforme. The failure of conventional dose chemotherapy to improve the outcome of patients with high grade brain tumors has led several investigators to utilize high dose chemotherapy in order to overcome the limited benefit seen with conventional dose therapy which is due to intrinsic drug resistance as well as the impermeability of blood brain barrier. The majority of published studies utilizing this approach suggest that the addition of high dose chemotherapy with bone marrow transplant is of marginal benefit. However, most of these trials include small numbers of patients with advanced, refractory disease. A few trials have been reported utilizing high dose therapy in an adjuvant setting and the data from these studies are somewhat more promising. This review will analyze these studies and also discuss possible modifications of this approach in order to improve this aggressive treatment for patients who otherwise would have a dismal prognosis.

Abstract 3617 Clofarabine and cytarabine combinations have been effective in the treatment of adult acute myeloid leukemia (AML) in both the relapsed/refractory and upfront settings. Based on our results with GCLAC (G-CSF priming, clofarabine, and high dose cytarabine) in a trial for relapsed/refractory AML (Becker et al. Br J Haematol in press), we are currently testing this regimen in newly diagnosed patients age < 65. The G-CSF dose is 5 mcg/kg/day by subcutaneous injection beginning the day prior to chemotherapy, clofarabine 30 mg/m2/day × 5 and cytarabine 2 gm/m2/day × 5. Second induction with the same regimen was permissible if marrow blasts over 5% persisted on day 21 or thereafter. Consolidation courses were administered for up to 3 cycles, with clofarabine at a dose of 25 mg/m2/day × 4 days and cytarabine 2 gm/m2/day × 4 days. The primary objectives of this trial are to estimate rates of CR (complete remission) and EFS (event free survival). A stopping rule would be imposed if there was reasonable evidence that the CR rate was inferior to that obtained with standard induction 7+3, 70% (Fernandez et al. NEJM 2009; 361:1249–59). Absent early stopping, 50 patients will be treated. Twenty-five patients with non-APL AML, RAEB2, CMML2, or myelofibrosis with >10% blasts have been treated thus far; their median age is 52, range 22–63. Eleven patients had antecedent hematologic disorders(AHD). Four patients had poor risk cytogenetics, four patients had normal cytogenetics with Flt3+, and 5 patients had good risk cytogenetics. The most significant grade 3/4 toxicity occurring in 2 patients, was a constellation of pulmonary infiltrates, hypoxia, and diffuse alveolar hemorrhage that responded to steroids. This incidence is not dissimilar to the pulmonary toxicity described with single-agent high-dose cytarabine (Andersson et al. Cancer 1990; 65:1079–84). Pulmonary toxicity has not occurred in 8 subsequent patients given steroid premedication. The other grade 3 adverse events (AEs) included pneumonia (8), viral respiratory infection (6), abscess (4), bacteremia (13), and one additional grade 4 AE was septic shock. There has been no treatment related mortality. Fifteen of 17 currently evaluable patients have achieved CR, all but one with a single course, and 1 additional patient attained CRp (complete remission with incomplete platelet recovery). Using a model that accounts for cytogenetics, age, AHD, and organ function, the observed CR rate of 88% (95% CI 64%to 95%) exceeds the expected rate of 61% had the same patients received other high-dose cytarabine containing regimens but without clofarabine. Given the recent shortage of daunorubicin and the lack of assurance that an idarubicin dose (18mg/m2) that would be the nominal equivalent of 90mg/m2 daunorubicin is safe (Garcia-Manero et al. Haematologica 2002; 87:804–7), GCLAC may be a suitable alternative induction regimen for newly diagnosed AML and advanced myelodysplastic syndrome or myeloproliferative neoplasm. Disclosures: Becker: Sanofi-Oncology: Research Funding. Off Label Use: Clofarabine is FDA approved for treatment of relapsed pediatric acute lymphoblastic leukemia.

Abstract 2026 Background: High-dose therapy (HDT) and autologous stem cell transplantation (ASCT) is frequently employed to improve outcomes in patients with mantle cell lymphoma (MCL), yet results after transplant vary widely. We and others have shown that the Mantle Cell International Prognostic Index (MIPI) measured at diagnosis can predict overall survival (OS) after HDT and ASCT (Geisler, Blood 2010; Budde JCO 2011). Unfortunately, this approach is often limited at the time of transplant by the lack of available MIPI data from the time of diagnosis. Furthermore, the MIPI at diagnosis does not take into account other disease-related data that may be present at transplant. We hypothesized that the MIPI measured immediately before initiation of HDT could be attainable and predictive of outcomes after ASCT and explored the contribution of this measure along with other clinical factors to OS and progression-free survival (PFS). Methods: Records of consecutive MCL patients undergoing HDT and ASCT at our centers were reviewed under an IRB approved minimal risk protocol. Patients undergoing planned tandem autologus-allogenic transplants were excluded. MIPI elements, simplified MIPI score, and other clinical data were collected from the period immediately prior to initiation of conditioning and evaluated for their independent association with OS and PFS. Results: Between November 1995 and May 2011 190 MCL pts meeting the above criteria underwent HDT and ASCT at our centers, of these 186 (98%) had all available pretransplant MIPI data and were included in the analysis. Pretransplant MIPI scores of 0–1, 2, 3, 4, and 5–7 were seen in 27 (15%), 61 (33%), 60 (32%), 21 (11%), and 17 (9%) patients, respectively. Other baseline pretransplant characteristics included: median age 57 years (range 35–71years), elevated LDH = 48 (26%), median WBC = 4.51/μL (range 0.7 –42.43/μL), performance score 0 = 103 (55%), median prior regimens = 2 (range 1–9), blastoid variant = 16 (8%), leukemic variant = 6 (3%), chemosensitive disease = 157 (86%), and administration of rituximab (R) within 3 months prior to transplant = 139 (75%). The 8-year estimates of OS and PFS for the entire cohort were 43% (95% CI 27 – 57%) and 31% (95% CI 16 – 48%), respectively with 3 years median follow up for survivors. The pretransplant MIPI was highly associated with OS when modeled as a continuous (p=0.008) or categorical variable (p=0.002). Survival at 2 years was 88% (95% CI 78 – 93%) for MIPI 0–2, 73% (61 – 82%) for MIPI 3 or 4, and 65% (34 – 84%) for MIPI 5 or greater (Figure). Of the MIPI elements, age (hazard ratio [HR] for death 1.5 for every 10 yrs, p=0.03) and performance score (HR 1.6 for score >1, p=0.08) had the greatest independent impact on OS. In addition, chemosensitive disease (HR 0.3, p The pretranplant MIPI score was also predictive of PFS, but less so than with OS (global and categorical p=0.02) with age providing the greatest independent association (HR for death or progression 1.3 for every 10 years, p=0.08). Again, non-MIPI factors including number of prior regimens (p Conclusions: Our data suggest that the simplified MIPI score measured immediately prior to HDT and ASCT is a readily available and robust predictive tool for OS and PFS in MCL pts undergoing transplant. This score along with other clinical factors can be utilized to counsel patients and to compare results between various treatment options. The independent association of pretransplant R with improved outcomes supports its use in this setting. Disclosures: No relevant conflicts of interest to declare.

Abstract 332 Background: Older patients (pts, ≥60 years [yrs]) with AML have a dismal prognosis; the majority are not treated with any type of chemotherapy. Many have antecedent myelodysplastic syndromes (MDS), and 20–30% harbor chromosome 5 abnormalities. Lenalidomide (LEN) yields hematologic responses in 67% of lower-risk MDS pts with the del(5q) cytogenetic lesion, and complete responses (CRs) in 20% of higher-risk del(5q) MDS pts, all with isolated lesions. This Phase II study explores the safety and efficacy of single agent LEN in previously untreated older pts with AML and the del(5q) abnormality. Method: Untreated older pts with AML defined by 2001 World Health Organization criteria (without t(15;17)) who harbored a del(5q) cytogenetic abnormality (alone or in combination with other abnormalities) and who declined or were felt to be poor candidates for intensive induction chemotherapy were eligible. Pts were treated with LEN 50mg daily for up to 28 days as induction therapy. Concomitant cytotoxic or growth factor therapies were not allowed. Pts achieving stable disease or better per day 28 bone marrow assessment received post-remission LEN 10mg daily for 21 days of a 28-day cycle until disease progression or unacceptable toxicities. Enrollment from October 2006 through June 2010 was in 2 stages: 20 pts were registered; if at least 1 CR/CRi was observed using International Working Group response criteria, another 20 pts were to be enrolled. The study was designed with a critical level of 4.7% (erroneously concluding the regimen warrants further study if the true response rate is 5% or less) and power of 92% (probability of concluding that a response rate of 20% warrants further study). Result: Of 41 patients enrolled, 4 were excluded (2 without AML, 1 without del(5q), and 1 died prior to receiving therapy), leaving 37 for toxicity and efficacy analyses. Median age was 74 yrs (range, 60–94), 21 (57%) were female, 33 (89%) white, and 19 (51%) had prior MDS. Median presenting white blood cell count was 2,600 mcl (range, 600–658,000), and 30 (81%) had a performance status of 1. Of the 37 evaluable pts, 29 had pretreatment cytogenetic studies evaluated centrally. Two pts displayed no demonstrable abnormalities (but had del(5q) by fluorescence in situ hybridization); 5 had isolated del (5q); and 22 (76%) had complex karyotypes (≥3 abnormalities). Seven patients were removed from protocol therapy due to toxicities (infection, renal, respiratory, gastrointestinal, and rash), and 4 deaths occurred that were at least possibly related to therapy: 2 respiratory, 1 cardiac, and 1 febrile neutropenia. Five additional patients had grade 4 non-hematologic toxicities: hypocalcemia (2), fatigue (2), infection (1). Fourteen pts (38%) completed protocol induction therapy. Four pts (11%) of the 37 evaluable pts achieved CR/CRi following induction therapy, all of whom had complex karyotypes; 3 of the 4 relapsed after 1, 2, and 4 months, and the 4th died 13 months after CR without a report of relapse. Thirteen (35%) pts had stable disease following induction therapy; 8 went on to protocol post-remission therapy. Thirty-three of the 37 pts have died and the median overall survival was 2 months (95% CI, 1 to 4 months). The follow-up time of the 4 survivors was between 6 and 23 months. Conclusion: LEN as a single agent has modest activity and expected toxicity in older del(5q) AML pts, particularly when compared to other single-agent molecularly-targeted approaches, such as FLT3 inhibitors. Future trials will combine LEN with cytoxic or hypomethylator therapies in older del(5q) AML pts. Disclosures: Sekeres: Celgene: Honoraria. Off Label Use: Lenalidomide in (del)5q AML. Lancet:Celgene: Research Funding. List:Celgene: Research Funding.

Abstract 2737 Synonymous SNPs may directly impact gene function through various translational or post-translational mechanisms. Further, such “silent” SNPs in the mutational hotspots of AML-associated genes have recently been reported to carry prognostic impact. We aimed to determine the prevalence, clinical associations, and prognostic significance of a known SNP in exon 4 of IDH1, near the location of the frequently-mutated R132 codon. Diagnostic marrow specimens from 253 pediatric AML patients (treated on the COG trial AAML03P1) and 274 adult AML patients (treated on SWOG trials S9031, S9333, or S9500) were analyzed for the presence of SNP rs11554137 via direct sequencing. In the pediatric cohort (median age 9.8 years), SNP rs11554137 was present in 27 of 253 (10.7%) patients. SNP+ pediatric patients did not differ significantly from wild-type patients in terms of sex, racial distribution (African American patients accounted for 23% of SNP+ patients vs. 14% of wild-type patients, P=0.24), bone marrow blast percentage, or age distribution, except in patients aged 0–2 years, who accounted for 44% of SNP+ patients vs. 23% of wild- type patients (P=0.013). Recurrent cytogenetic abnormalities occurred with similar frequencies in both the SNP+ and wild-type pediatric populations, as did FLT3/ITD, NPMc, and CEBPA mutations. Miscellaneous cytogenetic abnormalities accounted for 33% of SNP+ patients vs. 14% of wild-type patients, P=0.033. IDH1 SNP status had no prognostic impact on survival in the pediatric cohort, as SNP+ and wild-type patients had similar rates of five-year overall survival (OS, 76% vs. 63%, P=0.50), disease-free survival (DFS, 48% vs. 53%, P=0.97), and relapse rate (RR, 39% vs. 39%, P=0.94). In the adult cohort (median age 63 years), the IDH1 SNP was present in 30 of 274 (10.9%) patients. A slight female predominance for the SNP (63% vs. 37%, P=0.052) occurred among adult patients. The SNP was more prevalent in African American patients, who accounted for 30% of the SNP+ patients vs. 7% of wild-type patients, P=0.0046. SNP+ patients also had somewhat higher diagnostic bone marrow blast percentages (medians 80% vs. 70%, P=0.025). The normal karyotype subset accounted for similar proportions of SNP+ vs. wild-type patients (42% vs. 46%, P=0.83). Notably, SNP rs11554137 was not present in adult core-binding factor AML. Miscellaneous cytogenetic abnormalities were significantly more common in SNP+ patients (46% vs. 22%, P=0.022). SNP status was not significantly associated with FLT3/ITD status when all adult patients were considered (P=0.14). However, within the normal karyotype subset, FLT3/ITD was present in 90% of SNP+ patients vs. 59% of wild-type patients (P=0.0053). SNP+ patients had somewhat poorer 5 year OS (10% vs. 18%, hazard ratio [HR]=1.17) though this difference was not statistically significant (P=0.44). Among the 142 patients who achieved complete remission (CR), however, 5-year relapse-free survival (RFS) was significantly worse for SNP+ patients (0% vs. 25%, HR = 2.89, P=0.0014). Of the 14 SNP+ patients who achieved CR, 13 relapsed and the 14th patient died of sepsis in remission after 61 days. In multivariate analysis, after adjusting for the effects of age and cytogenetic group, SNP rs11554137 retained an independent prognostic effect (P=0.0062) regarding RFS. Notably, when FLT3/ITD status is included in multivariate analysis, SNP positivity loses independent prognostic significance (HR=1.72, P=0.18). Genome-wide expression profiling was performed on 134 pediatric AML specimens in whom IDH1 SNP status was known. By comparing SNP+ patients with wild-type patients, we derived a distinct gene-expression signature for patients with SNP rs11554137. Among the most upregulated probe sets in the SNP+ cohort were those representing PEX6 and NFYA, both of which interact with the TGF-beta/SMAD signaling network; the retinoid × receptor beta gene RXRB; and the FER gene, a tyrosine kinase critical to FLT3 signaling. The IDH1 SNP rs11554137 is present in approximately 11% of pediatric and adult AML patients, and gene expression profiling data suggests that leukemia in SNP+ patients may have unique biologic features. The SNP was an independent predictor of decreased RFS in adult AML in univariate analysis, but not in multivariate analysis when adjusting for FLT3/ITD status. Disclosures: No relevant conflicts of interest to declare.

Abstract 3806 Background: Hospital admission for neutropenic fever in patients with AML is standard practice. However, discharge practices vary once patients become afebrile, with many patients hospitalized until rise in the absolute neutrophil count (ANC) to > 500/μL (ANC recovery). Data to support this practice are sparse. We hypothesized that patients admitted for neutropenic fever, particularly if in complete remission (CR) or about to enter CR following the chemotherapy course associated with neutropenic fever, might be safely discharged earlier (ED). Benefits of ED are less exposure to hospital pathogens, reduced cost, increased availability of beds for patients more in need of urgent care, and potentially, enhanced psychological well-being. Methods: We identified patients age 18–70 with newly diagnosed AML who were admitted to the University of Washington Medical Center with neutropenic fever between January 2008 and May 2010. We compared subsequent (within 30 days of discharge) deaths, intensive care unit (ICU) admissions, and readmissions for neutropenic fever according to discharge ANC, regarded as a numerical variable using the Mann-Whitney U test and as < 500/μL vs. > 500/μL using the Fisher Exact test. We used the Mann-Whitney U or Spearman correlation to analyze the relation between ANC at discharge and other covariates that might have affected outcome: age, ECOG performance status at admission for neutropenic fever, days inpatient, remission status, and type of infection (pneumonia, gram negative bacteremia, other). Results: We evaluated 49 patients discharged after admission for neutropenic fever, 26 of whom were discharged with an ANC < 500/μL. 35 of the patients were in CR or entered CR following the chemotherapy course associated with their neutropenic fever admission. Patients who were discharged with lower ANC were more likely to be readmitted with neutropenic fever (Mann-Whitney U p = 0.03), although this was not true using ANC categorized as < vs. > 500/μL (Fisher Exact p = 0.24, 95% confidence interval -0.47, 0.11). There was no relation between ANC at discharge and subsequent admission to an ICU (Mann-Whitney U p = 0.50, Fisher Exact p = 0.64, 95% confidence interval 0.2, 0.34 using the 500/μL ANC cut off). One patient died: a 55 year old discharged with ANC 0/μL after successful treatment of neutropenic fever died 19 days after hospital readmission with fever of unknown origin. Stenotrophomonas maltophilia pneumonia and sepsis were discovered 14 days after readmission. Assuming a beta distribution and rates of death of 1/26 for discharge with ANC < 500/μL and 0/23 for discharge with ANC > 500/μL, the probability that a discharge ANC with < 500/μL is associated with a higher death rate is 0.019. The number of events was too small for a multivariate analysis. However, patients with better performance status (< ECOG 2) or who spent a shorter time in hospital after admission for neutropenic fever were more likely to be discharged with lower ANC (Fisher exact p = 0.09 and Spearman p = 0.02 respectively), while the likelihood of discharge with ANC < 500/μL was unrelated to age, remission status, or type of infection. Thus we examined the relation between ANC and readmission for neutropenic fever separately in patients with better or worse performance status and in patients who spent more or less than the median time (8 days) in hospital after admission for neutropenic fever. This analysis indicated that patients discharged with lower ANC were more likely to be readmitted only if they had spent more than 8 days in hospital or if they were performance status < 2. Conclusions: Our results suggest that an ANC of 500/μL is an excessively high cut off for discharge following hospitalization for neutropenic fever. The rate of rise of the ANC, as well as its absolute value, may also play a role. Disclosures: No relevant conflicts of interest to declare.

Abstract 790 Study S0106 is an open-label randomized phase III trial to evaluate the benefit and toxicity of adding Gemtuzumab ozogamicin [GO] to standard induction therapy, followed by a post-consolidation randomization to receive either 3 additional doses of GO or no additional therapy [OBS]. Eligible patients were adults (age 18-60) with previously untreated de novo nonM3 AML. Patients were randomized (stratified by age 627 patients were registered on study S0106 from May 15, 2004 though July 23, 2009, the cutoff for the second interim analysis of induction outcomes (which by protocol plan was based on the first 456 eligible patients) and first planned interim analysis of disease-free survival measured from the post-consolidation randomization [DFS] (based on the first 64 relapses or deaths). Complete response [CR] rates were 150/277=66% (AD+GO) and 159/229=69% (AD), ruling out the originally hypothesized 12% increase with AD+GO at the prespecified significance level (P In this study, the addition of GO to induction therapy or as post-consolidation therapy did not improve the CR rate, RFS, post-consolidation DFS, or overall survival, but was associated with a significantly higher risk of fatal induction adverse events. Disclosures: No relevant conflicts of interest to declare.

Abstract 3327 Poster Board III-215 Mantle cell lymphoma (MCL) exhibits short remission durations and a poor prognosis. To improve outcomes, many have advocated the use of high-dose therapy (HDT) and autologous hematopoietic stem cell transplantation (ASCT). However, most data indicate that ASCT is not curative with nearly all patients eventually relapsing. Since little is known regarding the outcomes of these individuals, we retrospectively evaluated MCL patients relapsing after HDT and ASCT and described the association of factors with survival. A total of 134 consecutive MCL patients received HDT and ASCT at our center from 1996 to 2009. Among them, 51 has relapsed so far (38%). Their baseline characteristics included: median age at diagnosis = 57 years (range, 35-70), median age at transplant = 59 years (range, 35 – 70), stage III-IV at diagnosis=98%, median LDH/upper limit of normal (ULN) at diagnosis = 1.14 (range, 0.56 -5.65), median LDH/ULN at transplant = 0.92 (range, 0.58-3.00), median white blood cell (WBC) count at diagnosis = 9.70 × 109 /liter (range, 1.40 – 48.00), mean WBC count at transplant = 5.30 × 109 /liter (range, 0.10 – 17.60), median number of prior chemotherapy regimens = 2 (range, 1-5). The median time to relapse following ASCT was 0.97 years (range: 0.08 – 5.61). Seven patients (14%) received a non-ablative allogeneic transplant (NMAT) for the treatment of relapse after ASCT. Of the 51 patients who relapsed, 40 (78%) have died. Overall survival at 3 years after relapse was 13.2% (95% CI, 4.9-25.5) (Fig.1). The MCL international prognostic index (MIPI) at diagnosis (MIPI-Dx) was a predictor of OS when evaluated either as a categorical variable (0-3 vs. 4 vs. 5-9, p=0.05, global test) or continuous linear variable (p=0.005). When compared to patients with a MIPI-Dx of 0-3, those with a score of 5-9 had a 3.5 (95% CI 1.3-9.7) fold higher risk of mortality after relapse. Similarly the MIPI at autologous transplant (MIPI-Trx) was also a significant predictor of OS after relapse when evaluated as a continuous linear variable (p=0.01). A multivariable model of all factors collected at ASCT identified ECOG performance status (PS)>0 (HR 2.1, 95% CI 1.0-4.2), TBI-based conditioning regimen (HR 4.3, 95% CI 1.8-10.0) and transplant beyond 1st remission (HR 3.5, 95% CI 1.5-8.0) as associated with a significantly higher risk of mortality after relapse; whereas time to relapse from transplant >1 year (HR 0.1, 95% CI 0.04 -0.5) was associated with lower risk of mortality. For example, patients relapsing one year or later after transplant had an estimated 1-year survival after relapse of 76% compared to 17% for those who relapsed earlier (Fig.2); patients transplanted in CR/PR1 had an estimated 1-year survival of 75% after relapse compared to 28% transplanted beyond first remission. These results indicate that OS following relapse of MCL after HDT and ASCT is poor, with the worst outcomes in those with early relapse, transplant later in the disease course, poor PS, TBI-based HDT, and high MIPI score. Only a small minority of patients attempted salvage with NMAT after relapse. These data can be used to better counsel patients and optimize treatment strategies based on the identified mortality risk factors, as improved outcomes are clearly needed in this population. Fig.1. OS of all MCL patients after relapse Fig.1. OS of all MCL patients after relapse Fig.2. OS of MCL patients who relapsed < 1 year after ASCT and those relapsed ≥ 1 year after ASCT Fig.2. OS of MCL patients who relapsed < 1 year after ASCT and those relapsed ≥ 1 year after ASCT Disclosures No relevant conflicts of interest to declare.

Abstract 1204 Poster Board I-226 Non-myeloablative allogeneic transplantation (NMAT) has provided the potential benefit of allogeneic hematopoietic stem cell transplantation (allo-SCT) to a broader cohort of lymphoma patients via lowered non-relapse mortality (NRM). NMAT also provides a post-transplant platform of a chemotherapy-naïve graft for both myelosuppressive and immune-mediated anti-tumor therapies, though the lack of high-dose conditioning may also heighten the risk for early relapse. Herein, we describe the survival as well as factors associated with outcomes for lymphoma patients experiencing relapse within 200 days of NMAT. Between December, 1997 and April, 2009, 267 lymphoma/CLL patients underwent NMAT at our center, of which 70 (35%) relapsed within 200 days from transplant. Histologies were categorized as aggressive (n= 36) including diffuse large-B-cell (n=22), blastic mantle cell lymphoma (n=10) and T-lymphoblastic lymphoma (n=4), and indolent (n=21) with chronic lymphocytic leukemia (n=15), follicular lymphoma (n=3) and classic mantle cell lymphoma (n=3). We also evaluated patients with Hodgkin Lymphoma (n=13). Conditioning regimens included 2 Gy total body irradiation (TBI), fludarabine 30 mg/m2 daily x 3 days + 2 Gy TBI, and Y-90-Ibritumomab-tiuxetan+ fludarabine 30 mg/m2 daily x 3 days + 2 Gy TBI in 13, 41, and 16 patients, respectively. Grafts were from HLA-matched related (n=34) or unrelated (n=31), HLA-mismatched unrelated (n=3) and HLA-haploidentical related (n=2) donors. Interventions to treat relapse included chemotherapy and/or radiation therapy in 43 (61%) patients and no therapy or withdrawal of immunosuppression in the remaining 27 (39%). Donor lymphocyte infusion (DLI) was attempted in 9 patients. Overall survival (OS) from time of relapse at 3 and 5 years among all 70 patients was 28% (95% CI 16-41%) and 19% (95% CI 9-32), respectively. Aggressive histology was associated with increased mortality relative to indolent histology (HR for death=2.57 [1.28-5.14, p=0.008]), while Hodgkin Lymphoma had similar outcome to the indolent group (HR=1.04 [0.42-2.53, p=.94]). The 3-year OS among patients with aggressive and indolent histologies was 14% (95% CI 3-33%), and 43% (95% CI 21-64%), respectively (Figure). Later relapse was associated with improved survival (p=.01) with patients relapsing between 31 and 100 days and those relapsing between 101 and 200 days having a reduced hazard of mortality relative to those relapsing less within 30 days (HR=0.36 [0.17-0.75, p=.006]; HR=0.30 [0.13-0.69, p=.005], respectively). When both histology and time to relapse were included in one model, these associations were somewhat reduced but the qualitative conclusions remained. In particular, patients with aggressive disease had a 2.16-fold (1.10-4.23, p=.03) increase in mortality compared to patients with Hodgkin or indolent lymphoma; the group that relapsed from 31 to 100 days was 0.41 (0.19-0.88, p=.02) times as likely to die compared to the group that relapsed within 30 days and the group that relapsed 101-200 days was 0.43 (0.17-1.04, p=.06) times as likely to die compared to the early-relapse group. Patients with chemoresistant disease pre-transplant were 1.46 times more likely to die than those with responding disease, but this difference was not statistically significant (95% CI, 0.82-2.62, p=.20). Fifty-nine patients relapsed with measurable disease and had a higher risk of mortality compared to 11 patients with only blood or marrow evidence of relapse, but the difference in mortality was not statistically significant (HR=1.53 [0.71-3.29, p=.28]). Pre-relapse graft-versus-host disease, bone marrow involvement, remission status at transplant, number of prior therapies, comorbidity score, and disease bulk were not statistically significantly associated with survival. These data indicate that despite early relapse of lymphoma after NMAT, some patients can experience prolonged survival with the best outcomes in patients with indolent histology and later relapse, though further improvement in disease control for patients with aggressive lymphoma and very early relapse is needed. Disclosures: No relevant conflicts of interest to declare.

Combination chemotherapy remains the cornerstone of treatment for most patients with relapsed lymphoma. Unfortunately, the most frequently used salvage regimens such as ICE or DHAP often require inpatient hospitalization for administration and must be used with caution in the elderly, frail, or those with comorbidities. In order to develop a safe, effective, outpatient salvage therapy for the treatment of lymphoma, PSOC prospectively evaluated 2–4 cycles of the novel regimen GCD±R. Eligibility criteria included: age ≥18 yrs, measurable relapsed/refractory disease, no active CNS disease, PS 22, ANC ≥1500/μl, platelets ≥100k/μl, bili/Cr 70% ORR) and can successfully mobilize PBSC. These results provide an additional, outpatient-based therapeutic option for such patients and set the stage for future randomized trials directly comparing salvage regimens for lymphoma. Table: Response rates by histology Histology n Overall Response (%) CR/CRu (%) HL 14 12 (86) 7 (50) FL 11 9 (82) 4 (36) DLBCL 8 5 (63) 1 (13) MCL 7 5 (71) 3 (43) MZL 4 3 (75) 1 (25) PTCL 3 0 (0) 0 (0) SLL 3 0 (0) 0(0) LPL 1 0 (0) 0(0) Total 51 34 (67) 16 (31)

Mantle Cell Lymphoma (MCL) exhibits short remission durations and a poor prognosis. To improve on these outcomes, many have advocated the use of high-dose therapy (HDT) and ASCT. The MIPI predicts overall survival (OS) from diagnosis, yet it remains unknown if the MIPI assessed at diagnosis (MIPI-Dx) or prior to transplant (MIPI-Tx) can be used to predict OS from ASCT. To address this question we retrospectively evaluated the association of the MIPI-Dx and MIPI-Tx, and other characteristics with OS following HDT and ASCT in 87 consecutive MCL patients transplanted at our center. Baseline characteristics included: median age at diagnosis=56 years (range, 35–70), median age at transplant=57 years (range, 35 – 70), stage III-IV=97%, median LDH/upper limit of normal (ULN) at diagnosis=0.91 (range, 0.46–5.65), median LDH/ULN at transplant= 0.88 (range, 0.39–3.00), median white blood cell (WBC) count at diagnosis=7.50 x 109 / liter (range, 1.40 – 54.70), mean WBC count at transplant=4.66 x 109 /liter (range, 0.07 – 17.60), median number of prior chemotherapy regimens=2 (range, 1–5). The estimated 5-year OS and PFS for the entire cohort were 56% (95% CI, 39–73%) and 45% (95% CI, 30 – 60%), respectively with a median follow up among surviving patients of 2.0 years (range 0.1 – 10.1 years). The MIPI-Dx was a better predictor of OS (p0 (hazard ratio (HR) of 3.0, p=0.03), number of prior regimens >2 (HR 5.2, p=0.01), lack of complete remission (CR) (HR 3.4, p=0.04), and elevated LDH (HR 4.4, p=0.01) as associated with higher risk of death after transplant. These results indicate that the MIPI-Dx is a robust prognostic tool that can even be used to predict outcomes after a later transplant, suggesting that it may continue to reflect the biology of an individual patient’s disease over time. Further assessment of survival predictions after ASCT can be made independently by examining pre-transplant factors including performance status, number of prior regimens, attainment of CR, and LDH. Though these data require prospective validation, our results can be used to counsel patients about outcomes and account for potential differences in results from clinical trials of HDT and ASCT for MCL. Figure Figure