ALBERT

Description: Randomized trials have demonstrated superior progression free (PFS)and overall survival (OS) with autologous stem cell transplant (ASCT) for patients with relapsed chemosensitive non-Hodgkin lymphoma (NHL) compared with conventional dose salvage chemotherapy. More recent trials have proven that ASCT is also feasible in pts with AIDS associated NHL (ARL). However, the impact of the HIV infection on long term outcome is unknown. We therefore, undertook a retrospective case control analysis of ASCT for high risk B cell NHL in HIV positive (HIV Pos) and HIV negative (HIV Neg) pts. Twenty-nine pts with ARL who underwent ASCT between 1998 and 2007 were matched with HIV Neg controls. Pts were matched for gender, time from NHL dx to ASCT, age at ASCT, dz status at ASCT, number of prior regimens, conditioning regimen (chemo vs. FTBI). Histology was matched as closely as possible with the exception that there were more high-grade NHL pts in the HIV Pos group. Patient HIV Pos HIV Neg P value* (* P value by Fishers exact test or Wilson signed rank sum test) Age at ASCT 42 (11–68) 48(21–65) .06 HISTOLOGY Large cell 19 25 Burkitts 10 0 Follicular gr 3 0 3 Marginal zone 0 1 Disease status 1CR/PR 16 16 IF 2 2 1.0 Relapse 11 11 Prior regimens 2(1–4) 2(1–4) .33 Conditioning - - FTBI 4 4 1.0 Non TBI 25 25 Median followup for HIV Pos pts is 46.7 months and 43.3 months for HIV neg controls (NS). Pts engrafted WBC at a median of 10 days (HIV Pos) and 11 days (HIV Neg) (NS) respectively. Non-relapse mortality (NRM) was 8% (95% CI 2–26) in HIV Pos pts and 4% (95%CI 0.7–25)in HIV Neg controls (NS). Two year PFS for the HIV Pos cohort was 76% (95% CI 62–85) and 56% (95% CI 45–66) for the controls (NS). OS was also similar at 75% (95% CI 61–85) versus 75% (95% CI 60–85)respectively{ see figure }. In conclusion, despite the inclusion of more poor risk pts by histology in the HIV Pos cohort, our series demonstrated matching OS for HIV Pos and HIV Neg pts undergoing ASCT for NHL The equivalent NRM also provides further evidence that HIV status does not affect the outcome of ASCT for NHL and therefore, should be considered a standard approach for select pts with ARL. Figure Figure

Description: Abstract 1417 Poster Board I-440 Gene-modified cellular products (GMCP) hold great promise for the management of numerous disease indications but are considered high-risk biological agents and are derived through extremely complex design and manufacturing processes. Thus, a robust Quality Management System (QMS) is essential for safe production of GMCP for clinical investigation. Development of a QMS that ensures compliance with current Good Manufacturing Practices (cGMP) and current Good Tissue Practices (cGTP) is particularly challenging in an academic setting where basic researchers, clinical investigators, regulatory, administrative, facilities and manufacturing personnel are all involved in the realization of a single GMCP. Following an ISO9001-based gap analysis of the Cellular Therapeutics program at the City of Hope, we implemented Quality Management Reports (QMR) as a tool for capturing data related to GMCP manufacturing. The QMR system was used to document and facilitate corrective and preventative actions (CAPA) as required following protocol deviation and/or Out of Specification (OOS) analyses. QMR data is captured in real-time and includes a detailed description of the event, impact analysis, root cause investigation, action plan and effectiveness analysis for resulting interventions. QMRs are documented using the Labware® (Wilmington, DE) Laboratory Information Management System (LIMS) that is available in real-time to authorized participants in GMCP production. A key aspect in the development of this on-line system was creation of links between the QMRs, OOS and CAPA documentation and investigation. The investigation database contains a series of templates: CAPA, SOP deviations, OOS and QMR that are designed to fully capture any events that impact or have the potential to impact quality, safety or efficient realization of a GMCP. The QMR process was applied to 2 manufacturing campaigns: a lentiviral vector-transfected CD34 GMCP for autologous transplantation in patients with AIDS lymphoma and a Master Cell Bank that was created for the treatment of patients with recurrent Glioblastoma Multiforme based upon an oligoclonal allogeneic T-cell product that contained both a chimeric antigen T-cell receptor and a zinc finger disrupted glucocorticoid receptor genomic sequence. Between May 2008-June 2009, 22 QMRs were generated related to product/reagent transfer, reagent quality/storage, equipment malfunction/OOS, product/environmental sterility, biological reagent OOS and Quality Control specifications for product release. Seventeen of 22 QMRs were resolved and closed. The average time to closing a QMR was 82 days (range 4-198 days). QMR findings lead to a revision of the program organizational chart, lead to the development and implementation of a new standard operating procedure (SOP) for Root Cause Analysis (RCA) investigations, development of new forms (GMP Equipment Approval Forms, a Quality Systems Project Proposal Form and Quality Assurance Customer Satisfactions Survey Forms), revisions to the SOP for CAPA and retraining of manufacturing staff as part of the resultant CAPA investigations to prevent repeat occurrences. Based upon QMR findings, 2 multidisciplinary RCAs were performed and resulted in revisions to documentation for CD34-cell selection and a major revision to the use of RODI water and manufacturing flow during GMCP production campaigns. Only 1 of 22 QMR-captured events has recurred (failure of an equipment monitoring system) and no events have re-occurred that might have had an impact upon product quality or safety. User satisfaction surveys performed by QA following the completion of a multidisciplinary RCA investigation indicate that the QMR process was viewed as fair, unbiased and transparent by a majority of the users (86% were either “Extremely Satisfied” or “Satisfied” with the experience). The QMR process is a powerful tool for the safe realization of GMCP and allows for real-time capture and multidisciplinary communication of complex events, including OOS that either individually or in aggregate may impact the purity, potency or safety of manufactured GMCP. These are often events that would not be routinely captured either as part of a batch record or merit CAPA. Because effectiveness analysis is included as part of the QMR process, it provides a key mechanism for continuous process improvement. Disclosures: Alvarnas: Novartis: Speakers Bureau.

Description: Background:The Blood and Marrow Transplant Clinical Trials Network 0803 study confirmed the safety and efficacy of ASCT in HIV-infected patients with lymphoma. Short term toxicity and transplant related mortality was low (5.2%) and engraftment, treatment-related mortality and survival outcomes were not statistically significantly different from that of age and diagnosis matched CIBMTR controls. However, median follow up in that trial was 24 months after ASCT, and the questions of second cancer incidence and other infections in a this population remain (Alvarnas et al, ASH 2014). Herein we report the long term outcomes of ASCT in HIV-infected patients. Methods: Retrospective cohort trial of 52 HIV-infected patients who underwent ASCT for high-risk NHL at City of Hope from January 1, 1998 to December 31, 2011. Two patients were excluded from the analysis due to early post-transplant mortality: one patient died at day 22 due to multiorgan failure, and another died at day 72 due to relapsed lymphoma. Fifty patients with a minimum survival of 100-days post ASCT were evaluated for long-term outcomes. Estimation of event-free survival (EFS) and overall survival (OS) was computed using Kaplan-Meier curves and the cumulative incidence of relapse was estimated with competing risk of mortality. Results: Median follow up was 5.43 years (range 0.30-14.96 years). Median age at the time of transplantation was 45 years (range 26-64 years of age). Prior to transplant, 23 patients (46%) were in complete remission and 27 (54%) were in partial remission. Most patients had aggressive NHL, with diffuse large B-cell lymphoma (48%) and Burkitt lymphoma (24%) being most common histologies. Other subtypes included Burkitt-like (10%), plasmablastic (10%), follicular lymphoma (2%), and T-cell lymphomas (6%). Nine patients relapsed (18%), at a median time of 97 days (range 54-253 days) post ASCT. Fifteen patients (30%) died; 8 out of 15 (53%) died due to relapse. Opportunistic infections (OI) occurred in 8 patients (16%) at a median of 0.68 years (range 0.17-10.82 years). Types of OI included CMV retinitis (1), HSV/Zoster (1), HPV (1), Candida esophagitis (1) and PJP (3). One patient died from OI (PJP). Seven patients (14%) developed a second primary malignancy (SPM) at median time to SPM of 5.63 years (range 1.02-14.35 years). Type of SPM included treatment-related myelodysplastic syndrome (t-MDS) with progression to acute myelogenous leukemia (AML) (2) observed at 3.2 years and 12.6 years, respectively, after ASCT; squamous cell carcinoma of the tongue (1), and skin cancers, including melanoma (1) at 14.3 years post ASCT, basal cell carcinoma (2) at 5.5 and 5.6 years post ASCT, and squamous cell carcinoma in situ (1) at 1.0 year post ASCT. Two patients died from the t-MDS. Conclusions: Thirty-five of 50 patients (70%) were alive at the time of analysis confirming the efficacy of this procedure. EFS/OS at 1 year and 5 years post ASCT was 78% (95% CI:67.3%-90.4%)/82% (95% CI: 71.9%-93.4%) and 71.4% (95% CI:59.8%-85.3%)/73.3% (95% CI: 61.8%-86.9%), respectively. Relapse of NHL tended to occur early post-transplant. Cumulative incidence of relapse was 18% at 1 year post ASCT (95% CI: 8.8%-29.8%). Development of OI was also seen early post-ASCT. While SPM appeared as late as 14.35 years following ASCT, it was no higher than that seen in the non-HIV ASCT setting. This is the largest single institution study reporting long-term follow up of HIV-positive patients post ASCT for NHL and demonstrating that while SPM remain a long term concern neither SPM, OI or HIV infection were major factors in mortality. Disclosures No relevant conflicts of interest to declare.

Description: Tandem cycle high-dose melphalan (Mel) followed by Mel +/− total body radiation therapy improves progression-free (PFS) and overall survival (OS) in comparison to single cycle Mel, but is associated with 3% treatment-related mortality (TRM). We tested a new tandem regimen (THDCT) followed by maintenance therapy in order to lower TRM, while enhancing efficacy. Between 5/94 and 8/04, 114 patients (pts) were enrolled on 2 sequential studies. First, pts received Mel 150 mg/m2 [cycle 1 (C1)], oral busulfan (bu 16 mg/kg; 46 pts), and cyclophosphamide 120 mg/kg (Cy; C2); the next cohort received the same THDCT but bu was given intravenously (i.v. 12.8 mg/kg; 68 pts). All pts were to receive maintenance IF 3 million units/m2 given subcutaneously, 3 times/week. Pts participating on the 2nd study were to receive thal together with IF provided that they were not in CR at 6 months post-THDCT. Peripheral blood progenitor cell mobilization consisted of G-CSF 10 microgram/kg to procure 4 x 106 CD34+ cells/kg without (first 46 pts) or with Cy 1.5 g/m2 (last 68 pts). Pts ≤65 years, with responsive or stable MM, with

Description: Background: Autologous stem cell transplantation (ASCT) has become an accepted treatment option for high risk or relapsed ARL. Treatment related mortality is similar to the HIV negative setting. However, ultimately further improvement in ASCT will depend on both effective anti lymphoma therapy and better control of the HIV infection. Highly active antiretroviral therapy (HAART) can lower HIV viral loads to undetectable levels in the peripheral blood, but reservoirs of HIV are still present in the tissues and acquired resistance to HAART also remains a problem. A treatment strategy that would confer intrinsic resistance to HIV could circumvent theses issues. Herein we report on one such strategy using multiplexed RNA based anti-HIV gene transfer strategies to render autologous peripheral blood progenitor cells resistant to HIV. Patients with high risk ARL deemed candidates for ASCT were eligible. Seven subjects with NHL have been enrolled. (4PR, 2 REL, 1CR2), of whom 2 failed screening phase, 1 failed product release test, 2 are pending transplant, and 2 patients have undergone successful transplantation. Median age was 43 yrs at enrollment. Four pts to date were mobilized with chemotherapy plus GCSF and cells were collected for the clinical product (Fx1) and for CD34-selection (CliniMACSª, Miltenyi) and research treatment (Fx2). (see table ) UPN # Fx1 (CD34+/kg) Fx2 (CD34+/kg) Post Selection and transductionCD34+/kg 301 2.8X106 3.5X106 .26 X106 not infused 304 3.9X106 3.6X106 1.2 X106 305 3.4X106 3.8X106 1.4X106 306 5.6X106 8.8X106 pending Three days prior to the completion of CBV (cyclophosphamide 100mg/kg, BCNU 450mg/ m2, VP16 60mg/kg) conditioning, the Fx2 cells were thawed and transduced with a lentivirus vector (LV,rHIV7-ShI-TAR-CCR5Z) encoding 3 RNA elements including short hairpin RNA (shRNA) targeted to HIV tat/rev, a nucleolar localizing TAR decoy sequence, and a ribozyme targeted to CCR5. Cell viability post transduction ranged between 52–64% in three pts. On day 0 Fx2 is given and Fx1 is given 24hrs later (day+1). UPN301 did not receive the transduced Fx2 cells due to a low cell dose. For UPN304 and 305 who received the gene modified Fx2 cells, WBC engraftment occurred at day +11, platelet engraftment at day+16, and there have been no serious adverse events. Results to date at 30 and 60 days post ASCT reveal peripheral blood marking consistent with the ratio of gene modified to unmodified cells infused. Q-PCR analysis demonstrated distribution of genetically modified cells in myeloid and lymphoid lineages, and RT-PCR evidence of shRNA in progeny cells provided further evidence of successful transduction and engraftment of progenitor cells. Follow-up data for these and subsequent patients will be presented at the meeting. Conclusion: Lentiviral vector transduction of autologous peripheral blood progenitor cells with multiplexed RNA is feasible, well tolerated, and led to successful engraftment following high dose chemotherapy for ARL.

Description: Hematopoietic cell transplantation (HCT) has now been shown to be safe and effective for selected HIV-infected patients with hematological malignancies. Autologous HCT is now the standard of care for patients with HIV-related lymphomas who otherwise meet standard transplant criteria. Limited data also support use of allogeneic HCT (alloHCT) in selected HIV-infected patients who meet standard transplant criteria. We recommend enrolling patients in clinical trials that offer access to CCR5Δ32 homozygous donors, if available. HIV-infected patients requiring HCT may also be considered for participation in trials evaluating the activity of gene-modified hematopoietic stem cells in conferring resistance to HIV infection. To be considered for HCT, patients must have HIV infection that is responsive to combination antiretroviral therapy (cART). Careful planning for the peri-HCT management of the cART can avoid risk of significant drug interactions and development of cART-resistant HIV. In general, we recommend against the use of boosted proteasome inhibitors and nonnucleotide reverse transcriptase inhibitors in the cART regimen, in favor of nucleoside reverse transcriptase inhibitors and integrase inhibitors (without cobicistat). After HCT, patients must be closely monitored for development of opportunistic infections (OI), such as cytomegalovirus. Prevention of OI should include prophylactic and pre-emptive antimicrobials.

Description: The treatment of HIV-associated lymphoma has changed since the widespread use of highly active antiretroviral therapy. HIV-infected individuals can tolerate more intensive chemotherapy, as they have better hematologic reserves and fewer infections. This has led to higher response rates in patients with HIV-associated Hodgkin disease (HD) or non-Hodgkin lymphoma (NHL) treated with chemotherapy in conjunction with antiretroviral therapy. However, for patients with refractory or relapsed disease, salvage chemotherapy still offers little chance of long-term survival. In the non-HIV setting, patients with relapsed Hodgkin disease (HD) or non-Hodgkin lymphoma (NHL) have a better chance of long-term remission with high-dose chemotherapy with autologous stem cell rescue (ASCT) compared with conventional salvage chemotherapy. In a prior report we demonstrated that this approach is well tolerated in patients with underlying immunodeficiency from HIV infection. Furthermore, similar engraftment to the non-HIV setting and low infectious risks have been observed. Herein, we expand upon this early experience with the largest single institution series of 20 patients. With long-term follow-up we demonstrate that ASCT can lead to an 85% progression-free survival, which suggests that this approach may be potentially curative in select patients with relapsed HIV-associated HD or NHL.

Description: Key PointsAutologous hematopoietic cell transplantation is safe and effective in patients with HIV-related lymphoma who meet standard transplant criteria. Patients with HIV-related lymphomas should not be precluded from participating in AHCT clinical trials.

Description: Total body irradiation (TBI)-based conditioning regimens are considered the standard of care for patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic cell transplantation (HCT). However, due to concerns regarding acute and long-term toxicities, non-TBI regimens, commonly including busulfan (BU), have been increasingly explored. We performed a retrospective cohort analysis with the hypothesis that there would be equivalence of these two myeloablative approaches by reviewing outcomes for adult patients (pts), aged 18-60 years, undergoing a first, well-matched sibling, related or unrelated donor HCT in CR1 or CR2 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 2005-2014. Eight hundred nineteen pts received TBI (63% 9-12 Gy, 37% ≥13 Gy) combined with etoposide (25%) or cyclophosphamide (Cy) (75%) and 299 pts received intravenous BU combined with a second alkylator Cy (15%) or melphalan (Mel) (13%), or a nucleoside analogue fludarabine (Flu) (41%) or clofarabine (Clo)(30%). The majority of the BU-based pts were treated at the Moffitt or MD Anderson Cancer Center. The BU-based regimens were grouped together for analyses since no significant differences in basic outcomes among the different chemotherapy-only regimens were noted. Patients in the BU-containing group were older but had better performance status, took longer to achieve CR1 and longer to receive HCT; more received peripheral blood than marrow grafts, peri-HCT ATG, pre- and post HCT tyrosine kinase inhibitors ( TKI), and were treated more recently than pts in the TBI-based group (Table 1). With median follow-up of 3.6 years for the BU-based group and 5.3 years for the TBI-based group, adjusted 3 year outcomes showed treatment-related mortality (TRM) BU 19% vs. TBI 25% (p=.04); relapse BU 37% vs. TBI 28% (p=.007); disease-free survival (DFS) Bu 45% vs. TBI 48% (p=.35); and overall survival (OS) BU 57% vs. TBI 53% (p=.35) (Figures A-B). Patients in the BU group had significantly more grade II-IV acute GVHD (47% vs. 40%, p=.025), but marginally less chronic GVHD (49% vs. 55% at 3 years, p=.073). In multivariate analysis, the BU group had a significantly higher rate of acute GVHD after day 50 (RR 1.75, 95% CI 1.19-2.58, p=.004), but marginally less chronic GVHD (RR 0.83, 95% CI 0.68-1.01 p=.059) and higher risk of relapse (RR 1.46, 95% CI 1.15-1.85 p=.002) compared with TBI-based regimens. Despite the observed higher risks of acute GVHD and relapse, BU-based conditioning led to similar TRM, OS, and DFS following HCT for ALL. Table 1 Table 1. Figure Figure. Disclosures Ciurea: Spectrum Pharmaceuticals: Other: Advisory Board; Cyto-Sen Therapeutics: Equity Ownership. Seftel:Otsuka: Research Funding. Pulsipher:Medac: Other: Housing support for conference; Chimerix: Consultancy; Jazz Pharmaceutical: Consultancy; Novartis: Consultancy, Other: Study Steering Committee. Champlin:Ziopharm Oncology: Equity Ownership, Patents & Royalties; Intrexon: Equity Ownership, Patents & Royalties.

Description: Background: Value is defined as health outcomes achieved per dollar spent. While risk-stratified AL HCT survival estimates are made possible by the Stem Cell Therapeutic Outcomes Database (SCTOD), an assessment of healthcare value is not possible as they do not include cost adjustments based upon clinical risk. We report a risk-based cost analysis, modeled on AL pts undergoing HCT at our institution that can potentially serve as a simple, statistically significant risk-based comparison tool. Methods: All AL pts who underwent HCT at City of Hope between 1/1/2010 and 12/31/2014 were included. Detailed data were captured from multiple electronic record sources in our database. Total direct costs were assessed for each pt from 14 days prior to 100 days post HCT. Categorical data were tested for associations by Chi-square; continuous data that were normally distributed were tested by T-test, while non-normal data were tested by Wilcoxon rank sum test. Univariate and multivariable logistic regression models were used to identify predictors associated with HCT costs ≥ median and ≥ 80th percentile. Univariate and multivariable Cox proportional hazards regression were used to identify predictors of overall survival (OS). All p-values were 2-sided with alpha level of 0.05. Results: This analysis included 389 pts (AML 352; ALL 37); median age was 52.5 years (yr) [range 1-74; 107 (27.5%) age ≥ 60]; 48% were female. At the time of HCT 204 (52%) were in 1st complete remission [CR], 87 (22%) in 1st relapse (rel)/2nd CR, and 98 (25%) 〉2nd CR/Induction Failure [IF]; ECOG performance status was ≥1 in 29.5% and Sorrer comorbidity score ≥1 in 56%. 214 (55%) and 175 (45%) received myeloablative (MAC) or reduced intensity (RIC) conditioning regimen, respectively; 231 (59%) had matched unrelated donor [MUD] or mismatched related donor (MRD) HCT. Graft-versus-host prophylactic (GVHD) regimen consisted of tacrolimus/sirolimus for 80% pts. 207 pts were enrolled on a therapeutic intervention trials and 121 had Medicare and/or Medicaid (Medi-Cal) as payer. Median follow-up was 12.9 months. The estimated 1- yr unadjusted OS for the entire group post-HCT was 71% (95% CI 66%-75%), 80% (74%-85%) for pts in 1st CR, 68% (57%-77%) for pts in 1st rel/2nd CR, and 56% (45%-65%) for pts 〉2nd CR/ IF. OS was similar for sibling matched and MUD/MRD transplants (1-yr OS 73% vs. 70%). In a multivariable analyses, disease status, MUD/MRD donor, MAC regimen, GVHD prophylaxis other than tacrolimus/sirolimus, ECOG ≥1, and Medicare and/or Medicaid as payer significantly predicted for cost ≥ median (Figure1A). Using Akaike Information Criterion (AIC) scores, donor type and disease status at HCT were found to be more informative variables with regard to higher cost of HCT. Disease status, MUD/MRD, MAC regimen, Medicare and/or Medicaid as payer and ECOG ≥1 also significantly predicted cost ≥ 80th percentile (Figure1B). In a multivariable analysis for OS (Figure 1C) , only 〉2nd CR/IF and HCT cost exceeding median had significantly higher hazard of death. Of note, despite reaching statistical significance in univariate analysis age, cytogenetics, treatment on protocol, and Sorrer score lost significance in adjusted higher costs and OS multivariable models. Conclusions: Our data suggest that: 1. Higher levels of care complexity drive higher costs, 2. Patients with more advanced disease status and inferior performance status have higher costs, 3. Statistically significant drivers of higher care costs are predictable prior to HCT. These risk factors are easily abstractable from medical records and provide prospective, equitably comparisons of risk-based costs between transplant centers. These data compliment the outcomes data available from the SCTOD and may enable providers and payers to make meaningful value comparisons between transplant centers. They may also help establish alternative models for payer contracting that include consideration of clinical risk-stratification. Of note, given the favorable survival outcomes of pts with higher cost-risk features (i.e., advanced disease status at HCT and MUD/MRD), the higher care costs associated with effective care of higher complexity pts are justified. While validation of this model is necessary using large payer or multi-institutional databases, we propose that similar clinical-economic models can be created for pts with other blood cancers requiring high complexity care. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Forman: Mustang Therpapeutics: Other: Construct licensed by City of Hope.