ALBERT

Description: Despite recent advancements, approximately 50% of patients with acute myeloid leukemia (AML) do not respond to induction therapy (primary induction failure, PIF) or relapse after

Description: Introduction: Filgrastim is widely used for mobilizing CD34+ cells into the peripheral blood that are easily collected by apheresis for allogeneic transplantation. With case reports documenting splenomegaly with life-threatening complications in normal donors, we prospectively evaluated spleen size using ultrasonography and clinical examination during PBPC mobilization and collection in a single-arm trial. Methods: Subjects ≥18 yrs eligible to be PBPC donors per institutional guidelines enrolled. Splenic assessments were done before, during, and after PBPC mobilization. Filgrastim dose and schedule and leukapheresis (LK) procedures were per institutional practice. The primary endpoint was fold change from baseline in splenic volume in post-baseline measurements during mobilization (measured by ultrasound [US]). Spleen size by US was measured in 3 dimensions similarly by all centers: longitudinal (craniocaudal), transverse, and diagonal (perpendicular to transverse in transverse image) diameters. Splenic volume was estimated by taking the cross-product of 3 dimensions and multiplying by 0.52, approximating the volume of an ellipse. Physical examination was performed on US days, assessing spleen palpability. US and palpation results were blinded from each other at assessment times. Timepoints included baseline (before first filgrastim dose), first LK (done before LK, typically day 4 or 5 of filgrastim), 2 and 4 days after first LK, and 7 days after last LK. Timepoints in the post-amendment cohort (n=219) were reduced to facilitate enrollment and were baseline and day of first LK (before LK). Results: 309 donors enrolled, median age 44yrs (range 18 to 74), 56% male. Mean daily filgrastim dose was 11.4mcg/kg (SD=3.0). Median number of LK was 1.5 (range 1 to 4). In all donors, the median increase in each measured dimension on first LK day was 1.4cm, 1.4cm, and 0.6cm (12.8%, 12.6%, and 15.0%), and the median fold volume increase from baseline to first LK was 1.47, resolving to near baseline 1 week after last LK. There was no apparent relationship between volume fold change and filgrastim dose, ANC, or CD34+ yield. Of 861 splenic palpation assessments reported in all donors, 98% were reported as nonpalpable (842 assessments), and 2% were palpable (19 assessments, 2 at baseline). Reporting of palpable spleens did not correlate with increased spleen size. Tenderness or guarding upon splenic palpation was reported in 2 donors with a spleen considered palpable and in 6 donors with nonpalpable spleens. No donor experienced a splenic rupture. Adverse events related to filgrastim were generally mild to moderate. Conclusion: During PBPC mobilization with filgrastim in normal donors, the spleen increased a median of approximately 50% from baseline to day of first LK and returned to near baseline 1 week after last LK. Size change was not associated with significant clinical sequelae. Timepoint Median fold change from baseline in splenic volume (Q1, Q3) *statistically significant (p

Description: Key Points Plasma EBV-DNA is highly concordant with EBV tumor status in Hodgkin lymphoma. Plasma EBV-DNA has prognostic significance in Hodgkin lymphoma, both before therapy and at month 6 of follow-up.

Description: Background: Familial MPNs are uncommon disorders that, like sporadic cases, are characterized by clonal hematopoiesis and presence of somatic mutations, e.g. JAK2, CALR, MPL and occasionally TET2. There is little information, however, about germ-line mutations in these families that may explain the low penetrance hereditary predisposition. Methods: We studied five families with MPNs, each with at least 2 affected members. After obtaining an informed consent, clinical data was obtained from the patients’ electronic medical records. Blood and buccal samples were collected from patients and unaffected relatives. Exome sequencing was performed on the blood DNA samples using Agilent SureSelect Human All Exon V5+UTRs exome capture kit followed by massively parallel sequencing with Illumina HiSeq 2000. Sanger sequencing was then done on both the blood and buccal swab DNA samples to validate selected gene variants and to differentiate the nature of those variants (germ line or somatic). Results: The 5 families participating in this study had the following diagnoses: 1. Mother: polycythemia vera (PV); son: essential thrombocythemia (ET), 2. Mother: primary myelofibrosis (MF); daughter: unclassifiable MPN (UMPN), 3. Father: PV; son: PV, 4. Sister: MF; sister: MF, 5. Two aunts: MF; niece; UMPN. Six patients were positive for JAK2, V617F mutation. Blood and buccal samples were collected from 5 patients and 4 relatives. In all 5 families, the pro-band was younger at the time of diagnosis than his/her affected relatives. The clinical course of the MPNs appeared to be similar to the sporadic form. Exome sequencing revealed TET2 mutations in 2 probands. In addition, novel non-synonymous mutations in several candidate genes, KMT2D, KMT2C, NBEAL1, NBEAL2, AHNAK2, RNF213, were identified in the blood samples from the patients but not their unaffected relatives. These include two novel KMT2D mutations in two unrelated families. These 2 mutations were also found in the matching buccal swab samples, indicating that they are germ line mutations. Discussion: KMT2D and KMT2C mutations have been previously identified as somatic mutations in lymphoid malignancies, including non-Hodgkin’s lymphomas (Morin 2011), and as germ line compound heterozygote mutations in infant MLL and ALL (Valentine 2014). About 32% of diffuse large cell lymphoma and 89% of follicular lymphoma have somatic mutations of KMT2D. NBEAL2 germ line mutations are associated with familial gray platelet syndrome, where some patients have myelofibrosis (Gunay-Aygun 2011). To our knowledge, this is the first report describing germ line mutations in familial MPNs. The possible role of these mutations in predisposition to MPN will be discussed. Studies on additional families with MPNs are planned. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 3228 Poster Board III-165 Introduction Using standard dose G-CSF (10 μg/kg) for stem cell mobilization, 25-40% of patients, deemed to be hard to mobilize based on prior therapy, will not collect sufficient HSC (〉 2-2.5 × 106 CD34/kg) to proceed to a prompt autotransplant. Strategies to improve CD34/kg yields have included dose escalating G-CSF up to 30 μg/kg or combining G-CSF and GM-CSF. While dose escalated G-CSF is effective in increasing CD34 yields in normal donors as is the combination of G-CSF and GM-CSF, their comparative value in pre-treated patients has not been tested. To determine the value of these strategies, we performed a randomized comparison of high dose G-CSF (30 μg/kg as 2 doses 12 hours apart), to the combination of simultaneous single daily doses of G-CSF (10 μg/kg) plus GM-CSF (5 μg/kg), to a control group receiving G-CSF at an equivalent total dose of cytokine to the combination arm (15μg/kg) as a single dose. Patients and Methods Patients were eligible if heavily pre-treated, defined as: a minimum of 10 total cycles of combination chemotherapy and two prior regimens, or a total of 6 chemotherapy cycles if the patient also received RT to marrow bearing sites, platinum-based chemotherapy or 2 or more cycles of any BCNU or fludarabine containing regimen. Baseline WBC had to be 〉 3000/μl, ANC 〉 1500/μl and a platelets 〉 100,000/μl. Twelve liter aphereses began on day 5 of mobilization, and continued until ≥ 4 × 106 CD34/kg were collected or a maximum of 5 aphereses. Patients typically proceeded to transplant if they had ≥ 2.5 × 106 CD34/kg collected and were always re-mobilized if they collected 〈 2.0 × 106 CD34/kg. CD34 subsets (CD34+/CD33- and CD34+/CD38-) were also assessed for the 3 groups to determine if more primitive HSC were mobilized by the 2 novel strategies. The sample size was calculated based as follows: 60% of the control group would collect 2.5 × 106 CD34/kg and this would rise to 90% in one or both study arms. The detection of such differences with a power of 80% and a 2-sided alpha level of 0.025 required a total sample of 120 patients. Results A total of 120 patients were randomized; 119 were eligible. Patient demographics, shown in the Table, were matched among the three groups: The % of patients collecting ≥2.5 × 106 CD34/kg was: standard G: 60%, high dose G: 57% (p = 1.0), G + GM: 41% (p = 0.1). Median CD34 collected in first mobilization were, 3.6 × 106/kg, 3.0 × 106/kg (p = 0.22) and 2.0 × 106/kg (p = 0.05) respectively in a median of 4, 4, and 5 aphereses (p = NS). Re-mobilization rates: standard G; 37.5%, high dose G: 35%; G + GM: 50% (p = NS). Total median CD34 collected from first and any second mobilizations were: standard G: 4.8 × 106/kg, high dose G: 3.9 × 106/kg, and G + GM: 3.5 × 106/kg. One patient in the standard G arm and 3 in high dose G did not proceed to transplant due to poor initial mobilization and progression in 2, and one each for progression or poor mobilization alone. There were no significant differences in median engraftment times: for ANC, 10, 11 and 15 days respectively for the standard G-, high dose G- and G + GM arms and for platelets, 11, 13 and 14 days respectively. The overall survivals @ the median f/u time of 37 months were 59.8%, 61.8% and 48.1% respectively (p = 0.272) for the three groups. The % primitive HSC (CD34+/CD33- and CD34+/CD38-) from the first mobilization were identical in the 3 patient groups. Conclusions We found no advantage to dose escalated G-CSF nor to the combination of G-CSF and GM-CSF to mobilize HSC for autotransplantation in heavily pre-treated patients. We also did not find higher numbers of more primitive CD34 subsets mobilized by these newer strategies. Alternative approaches, e.g. the combination of plerixifor + standard dose G-CSF (Stiff et al: BBMT; 15:249-56, 2009) would appear to be the preferred method of initial HSC mobilization for heavily pre-treated patients. Disclosures Stiff: Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Abstract 33 Background: Circulating levels of peripheral blood (PB) CD34+ cells/μl are a strong predictor of hematopoietic stem cell (HSC) yields in patients with non-Hodgkin's lymphoma (NHL) undergoing autologous HSC transplantation (auto-HSCT), and are routinely monitored to optimize the timing and success of HSC collection after cytokine ± chemotherapy mobilization. The threshold PB CD34+ cell count to initiate apheresis varies from 5-20 cells/μl, depending on the institution. This analysis compared the efficacy of plerixafor + G-CSF to placebo + G-CSF for HSC mobilization in NHL patients with pre-apheresis PB CD34+ cells/μl

Description: More than 56,000 new cases of non-Hodgkin’s lymphoma (NHL) will be diagnosed this year in the United States. Despite advances in treatment modalities such as radiation, biologic agents, and cytotoxic chemotherapeutic regimens, only 25–30% of these patients will be cured of their disease. Standard salvage regimens such as DHAP, ESHAP, ICE and EPOCH have proven efficacy at the cost of increasing toxicity and hospitalization costs. The reported response rates for these are on the order of 50–75% as first-line salvage regimens. However, as our aging patient population develops worsening performance status and co-morbidities, it seems appropriate to develop effective lymphoma treatments, which have fewer toxicities and lower costs for administration. One approach is to combine non-myelosuppressive therapies. One non-myelosuppressive agent, which has efficacy in lymphoma, is gallium nitrate. Investigation of gallium nitrate for cancer treatment dates back to the 1970’s. While it is currently approved for the treatment of bisphosphonate resistant hypercalcemia of malignancy, it has also been shown to inhibit ribonucleotide reductase and bind transferrin and potentially complex with the transferrin receptor, which is highly expressed in intermediate and aggressive histology lymphomas. It appears that the binding of the transferrin receptor on the lymphocyte as well as its inhibition of ribonucleotide reductase, eventually impairs iron metabolism, which is a necessary component of the intracellular cytochrome systems/mitochondrial function and ultimately oxidative phosphorylation. The current study is a phase II clinical trial investigating the combination of gallium nitrate, rituximab and dexamethasone (GaRD) for relapsed or refractory DLBCL, MCL or transformed follicular lymphomas. The gallium nitrate is given at 200mg/m2 CIV days 1–7, rituximab 375mg/m2 IVPB day 1 and dexamethasone 40 mg po days 1–4. Eligible patients must have proven relapsed or refractory disease and have a SWOG PS

Description: Abstract 415 Background: The ability to cure patients (pts) with advanced Hodgkin's Lymphoma (HL) with combination chemotherapy (CC) (MOPP and variants, ABVD and variants) represented a major milestone in oncology research, and CC became a paradigm for other malignancies. Further, the rationale for combined modality therapy (CMT) (radiation (RT) and CC) in HL evolved based on the high frequency of relapse in initially involved sites. As response rates and survival improved, newer treatments such as the combined modality Stanford V regimen were developed to shorten the duration of chemotherapy, add RT to sites of disease and reduce toxicity while maintaining or improving the cure rate. Indeed, the Stanford V regimen was tested and validated in a Phase II co-operative group trial (E1492) (J Clin Oncol 2000; 18:972). In order to investigate this approach against “standard” therapy, we conducted a randomized Phase III Intergroup trial of ABVD vs. the Stanford V regimen for patients with locally extensive or advanced HL. Objectives: The trial was designed to detect a 33% reduction in the failure free survival (FFS) hazard rate with Stanford V compared with ABVD, which corresponds to a difference in five-year FFS of 64% vs. 74%. Method: Patients with locally extensive (defined as clinical Ann Arbor Stage I-IIA/B and bulky mediastinal disease (BMD) (mass 〉 1/3 maximum intrathoracic diameter on standing postero-anterior chest x-ray or 〉/−10 cm on computerized tomography) or advanced (Ann Arbor Stage III or IV) HL were randomized to receive either ABVD × 6–8 cycles (C) (51% had 6 C, 35% had 8 C, 14% had 5cm or for macroscopic splenic disease). The log-rank test was used to compare FFS for all eligible patients stratified on extent of disease (locally extensive vs. advanced), and number of International Prognostic Factor Project (IPFP) risk factors (0–2 vs. 3–7). An extended Cox model was also used to address non-proportional hazard between the two arms. Results: 854 pts enrolled from April, 1999 to June, 2006 and 812 were eligible for analysis. 404 pts were randomized to ABVD and 408 to Stanford V. Median age was 33 yrs in both arms (range 16–83). 53% were men and 47% women; 4% had Stage I, 31% had Stage II, 39% had Stage III and 25% had Stage IV disease by Ann Arbor criteria. 35% of pts on ABVD and 35% on Stanford V had BMD. Three % of pts had nodular lymphocyte predominant HL, 77% of pts had nodular sclerosis HL, 14% had mixed cell HL. Age, stage, pathology and risk factors (0–2 vs. 3–7) were similar in both arms. In total, 65% were IPFP score 0–2 and 33% were 3–6. Response rate. There was no difference in response rates (RR) between the two arms (ABVD=72% CR+ CCR, 7.7% PR, 7.9% SD; Stanford V= 69 % CR +CCR, 7% PR and 10 % SD. 8% were not evaluable for response on ABVD and 9% on Stanford V. Toxicity was similar in both groups. The most frequent Grade 3 + 4 toxicity was neutropenia, and was similar between the 2 groups (76% Grade 3 + 4 in ABVD and 70% Grade 3+ 4 in Stanford V). Grade 5 toxicity was 5 cm and macroscopic splenic disease). There was more Grade 3 lymphopenia (p〈 0.0001) and more Grade 3 + 4 sensory neuropathy (p〈 0.0001) on Stanford V. Thus ABVD (plus RT for BMD) remains the standard of care because Stanford V did not meet the objective of 33% improvement in FFS. For some patients, Stanford V, when given as described with RT, remains an acceptable alternative. Disclosures: Friedberg: Genentech: Honoraria. Blum:Seattle Genetics: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Horning:Genentech: Employment.

Description: Background The international prognostic score (IPS) (Hasenclever et al., NEJM 1988) uses 7 factors (age〉 45, male sex, hemoglobin 15,000, and lymphopenia〈 600) to predict a 5 year freedom from progression (FFP) of 42%-84% and overall survival (OS) of 56%-89% for patients with advanced HL. Constructed from a retrospective analysis of patients treated before 1992, the IPS continues to be the most commonly used risk stratification index for advanced HL. Recent studies suggest that the predictive range of the IPS has narrowed due to improved outcomes of patients treated with current therapy (Moccia et al. JCO 2012). In this report we prospectively evaluated the ability of the individual components of the IPS to predict outcome in patients enrolled on the US Intergroup trial E2496. Methods All seven IPS (IPS-7) variables were recorded for all patients at study entry. FFP was defined as the time from study entry to disease progression or relapse; deaths that occurred during remission that were not preceded by disease progression/relapse were censored. OS was defined as the time from study entry to death from any cause. Kaplan-Meier methodology was used to construct survival curves. Univariate and multivariate analysis (MVA) was performed using Cox proportional-hazards models. We subsequently constructed an alternative prognostic score utilizing the factors which were significant on MVA (PS-3). Results From 1996-2006, 854 patients with advanced HL, were randomized to treatment with either ABVD or Stanford V, with no significant differences in outcome (Gordon et al, JCO 2013). While the IPS-7 remained prognostic it did not stratify the lowest risk patients (0-1 risk factor) or patients with 3-5 risk factors, as its predictive range was narrowed due to improved clinical outcomes (Fig 1a and 2a). Table 1 shows the univariate and multivariate analysis for IPS-7 and outcomes. In contrast to the original IPS-7, on MVA, only two factors, hemoglobin and stage were significant for FFP, and three factors for OS: hemoglobin, stage, and age. We then evaluated a new 3 factor score (PS-3) utilizing variables significant on the MVA. The PS-3 was significant for both FFP (p=0.0001) and OS (p