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Rituximab is a mouse/human chimeric monoclonal antibody targeted toward CD20. It is efficient as first-line therapy of CD20-positive B-cell malignancies. However, a large fraction of treated patients relapse with rituximab-resistant disease. So far, only modest progress has been made in treatment options for rituximab refractory patients. One of the mechanisms for rituximab resistance involves the upregulation of CD46, which is a key cell surface protein that blocks the activation of complement. We have recently developed a technology that depletes CD46 from the cell surface and thereby sensitizes tumor cells to complement-dependent cytotoxicity. This technology is based on a small recombinant protein, Ad35K++ that binds with high affinity to CD46. In preliminary studies using a 6 × histidinyl tagged protein, we had demonstrated that intravenous Ad35K++ injection in combination with rituximab was safe and increased rituximab-mediated killing of CD20-positive target cells in mice and nonhuman primates (NHPs). The presence of the tag, while allowing for easy purification by Ni-NTA chromatography, has the potential to increase the immunogenicity of the recombinant protein. For clinical application, we therefore developed an Ad35K++ protein without His-tag. In the present study, we performed preclinical studies in two animal species (mice and NHPs) with this protein demonstrating its safety and efficacy. These studies estimated the Ad35K++ dose range and treatment regimen to be used in patients. Furthermore, we showed that intravenous Ad35K++ injection triggers the shedding of the CD46 extracellular domain in xenograft mouse tumor models and in macaques. Shed serum CD46 can be measured in the serum and can potentially be used as a pharmacodynamic marker for monitoring Ad35K++ activity in patient undergoing treatment with this agent. These studies create the basis for an investigational new drug application for the use of Ad35K++ in combination with rituximab in the treatment of patients with B-cell malignancies.

Mantle cell lymphoma (MCL) is a high-risk non-Hodgkin lymphoma that is considered incurable with standard chemotherapy. While autologous hematopoietic cell transplantation (autoHCT) can provide lengthy disease-free survival in select patients, cure generally is not an expected outcome with this approach. Allogeneic hematopoietic cell transplantation (alloHCT), which can exploit the potential benefits of graft-versus-lymphoma (GVL) effect, has been shown in multiple studies to yield a small but reproducible portion of patients with long-term remission more suggestive of cure. Historically, alloHCT for MCL was administered after myeloablative conditioning, but this approach was limited by early non-relapse mortality. Development of reduced-intensity (RI)-alloHCT has abrogated some of the early post-transplant risks, allowing this potentially effective therapy to be offered to a larger number of affected individuals. The trends in published data reflect a preference toward using RI-alloHCT for MCL, often because patients in whom alloHCT is being considered have relapsed disease following myeloablative autoHCT. Further efforts to spare the effects of graft-versus-host disease (GVHD) while still evoking GVL remain a focus of investigation in this area. In this review, we will discuss the application of alloHCT in the management of MCL, the factors associated with outcome, the different methods in which it can be performed, and the strategies that can be employed in post-alloHCT relapse.

Overview: Despite advances in chemoimmunotherapy, indolent B-cell non-Hodgkin lymphomas (B-NHLs) are generally not considered curable with this approach. Much attention has been paid to the prospect of hematopoietic cell transplantation (HCT) as a way to improve long-term outcomes for this group of diseases. Autologous (auto) HCT provides intensive conditioning therapy followed by rescue of hematopoiesis, and this has been shown in randomized studies to prolong survival compared with more standard chemotherapy, albeit with increased short-term toxicity and the potential for higher rates of secondary malignancies. Allogeneic (allo) HCT can provide anticancer effects beyond the conditioning therapy through the immune-mediated graft-versus-lymphoma (GVL) effect. It can be administered following myeloablative (MA) conditioning or reduced-intensity (RI) regimens aimed at sufficiently suppressing the patient's immune system to allow engraftment of donor hematopoiesis. However, this same potentially curative alloreactivity of the engrafted immune system can lead to graft-versus-host disease (GVHD), a significant cause of morbidity and mortality following allo HCT. This article will discuss the current role of both auto HCT and allo HCT in the management of indolent lymphoma as well as the relative risks and benefits of each approach such that the reader can place this in context of the multitude of options available for patients with indolent B-NHL.

Hodgkin lymphoma (HL) represents one of the great success stories in hematology going from a uniformly fatal disease, to one that is curable in the vast majority of cases. Despite this success, some patients experience relapse. To address this unmet need a variety of agents, classes of drugs, and strategies have demonstrated activity in HL recurring after autologous hematopoietic stem cell transplantation. These include chemotherapeutics (gemcitabine-based combinations, bendamustine), histone deacetylase (HDAC) inhibitors (panobinostat), immunomodulatory agents (lenalidomide), mTOR inhiobitors (everolimus), monoclonal antibodies (rituximab), and antibody-drug conjugates (brentuximab vedotin) as well the potential of long-term disease control via allogeneic transplantation. Such advances reflect our increased understanding of the biology of HL and hold promise for continued improved outcomes for those suffering with this condition.

Plerixafor enhances CD34(+) cell mobilization, however, its optimal use is unknown. We hypothesized that plerixafor could "rescue" patients in the midst of mobilization when factors indicated a poor CD34(+) yield. Of 295 consecutive autologous peripheral blood mobilization attempts at our center, 39 (13%) used plerixafor as rescue strategy due to a CD34(+) cell concentration

A 71-year-old man was diagnosed with an aggressive mantle cell lymphoma and was started on six cycles of R-CHOP chemotherapy. Approximately two weeks after starting his first cycle of chemotherapy, he complained of severe right lower quadrant abdominal pain, and an abdominal CT scan demonstrated an enlarged appendix with evidence of contained perforation. The man underwent open appendectomy for acute appendicitis and recovered. The appendectomy specimen was submitted for routine pathological analysis. There was histologic evidence of perforation in association with an inflammatory infiltrate with fibrin adhered to the serosal surface; scattered small lymphoid aggregates were present on the mucosal surface. Although the lymphoid aggregates in the submucosa and lamina propria were rather unremarkable by routine histologic examination, immunohistochemistry revealed the lymphocytes to be predominantly Cyclin D1-overexpressing B cells. To our knowledge, this is the first reported case of acute appendicitis in association with appendiceal involvement by mantle cell lymphoma.

Purpose: Pretargeted radioimmunotherapy (PRIT) using streptavidin (SAv)-biotin technology can deliver higher therapeutic doses of radioactivity to tumors than conventional RIT. However, “endogenous” biotin can interfere with the effectiveness of this approach by blocking binding of radiolabeled biotin to SAv. We engineered a series of SAv FPs that downmodulate the affinity of SAv for biotin, while retaining high avidity for divalent DOTA-bis-biotin to circumvent this problem. Experimental Design: The single-chain variable region gene of the murine 1F5 anti-CD20 antibody was fused to the wild-type (WT) SAv gene and to mutant SAv genes, Y43A-SAv and S45A-SAv. FPs were expressed, purified, and compared in studies using athymic mice bearing Ramos lymphoma xenografts. Results: Biodistribution studies showed delivery of more radioactivity to tumors of mice pretargeted with mutant SAv FPs followed by 111In-DOTA-bis-biotin [6.2 ± 1.7% of the injected dose per gram (%ID/gm) of tumor 24 hours after Y43A-SAv FP and 5.6 ± 2.2%ID/g with S45A-SAv FP] than in mice on normal diets pretargeted with WT-SAv FP (2.5 ± 1.6%ID/g; P = 0.01). These superior biodistributions translated into superior antitumor efficacy in mice treated with mutant FPs and 90Y-DOTA-bis-biotin [tumor volumes after 11 days: 237 ± 66 mm3 with Y43A-SAv, 543 ± 320 mm3 with S45A-SAv, 1129 ± 322 mm3 with WT-SAv, and 1435 ± 212 mm3 with control FP (P < 0.0001)]. Conclusions: Genetically engineered mutant-SAv FPs and bis-biotin reagents provide an attractive alternative to current SAv-biotin PRIT methods in settings where endogenous biotin levels are high. Clin Cancer Res; 17(23); 7373–82. ©2011 AACR.

Purpose High-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) are frequently used in an attempt to improve outcome in patients with mantle-cell lymphoma (MCL); however, the importance of intensive induction regimens before transplantation is unknown. Patients and Methods To address this question, we evaluated baseline characteristics, time to treatment, induction regimen, disease status at the time of transplantation, and MIPI score at diagnosis and their associations with survival in 118 consecutive patients with MCL who received HDT and ASCT at our centers. Results The MIPI was independently associated with survival after transplantation in all 118 patients (hazard ratio [HR], 3.5; P < .001) and in the 85 patients who underwent ASCT as initial consolidation (HR, 7.2; P < .001). Overall survival rates were 93%, 60%, and 32% at 2.5 years from ASCT for all patients with low-, intermediate-, and high-risk MIPI, respectively. Low-risk MIPI scores were more common in the intensive induction group than the standard induction group in all patients (64% v 46%, respectively; P = .03) and in the initial consolidation group (66% v 45%, respectively; P = .03). After adjustment for the MIPI, an intensive induction regimen was not associated with improved survival after transplantation in all patients (HR, 0.5; P = .10), the initial consolidation group (HR, 1.1; P = .86), or patients ≤ 60 years old (HR, 0.6; P = .50). Observation of more than 3 months before initiating therapy did not yield inferior survival (HR, 2.1; P = .12) after adjustment for the MIPI in patients receiving ASCT. Conclusion An intensive induction regimen before HDT and ASCT was not associated with improved survival after adjusting for differences in MIPI scores at diagnosis.

Nonmyeloablative allogeneic transplantation (NMAT) infrequently cures active chemoresistant, bulky, or aggressive B-cell lymphoma (B-cell non-Hodgkin lymphoma [B-NHL]). We hypothesized that 90Y-ibritumomab tiuxetan–based NMAT would facilitate early cytoreduction in such patients promoting improved long-term disease control by the allogeneic graft. Forty high-risk B-NHL patients with persistent disease received 0.4 mCi/kg (maximum, 32 mCi/kg) 90Y-ibritumomab tiuxetan, fludarabine, and 2 Gy total body irradiation and matched-related (15) or unrelated (25) transplantation. Baseline features included: median age, 58 years (range, 29-69 years); median prior regimens, 6 (range, 3-12); chemosensitive disease, 6 (15%); bulk > 5 cm, 17 (range, 5.2-18.6 cm, 43%); diffuse large B-cell lymphoma, 14 (35%); and comorbidity score > zero, 34 (85%). Early responses were observed in 24 (60%, 14 complete remission/complete remission unconfirmed, 10 partial response) patients, including 17 of 29 (59%) with chemotherapy-resistant disease and 10 (59%) with bulk > 5 cm. The estimated 30-month survival, progression-free survival, and nonrelapse mortality were 54.1%, 31.1%, and 15.9%, respectively. Early response, baseline platelet counts over 25 000/μL, indolent histology, and related donors were associated with improved survival. The addition of 90Y-ibritumomab tiuxetan to NMAT is safe and yields early responses and prolonged disease control in some of the highest-risk B-NHL patients. This trial was registered at www.clinicaltrials.gov as #NCT00119392.

Purpose Allogeneic hematopoietic cell transplantation (HCT) benefits many patients with acute myeloid leukemia (AML) in first remission. Hitherto, little attention has been given to the prognostic impact of pretransplantation minimal residual disease (MRD). Patients and Methods We retrospectively studied 99 consecutive patients receiving myeloablative HCT for AML in first morphologic remission. Ten-color multiparametric flow cytometry (MFC) was performed on bone marrow aspirates before HCT. MRD was identified as a cell population showing deviation from normal antigen expression patterns compared with normal or regenerating marrow. Any level of residual disease was considered MRD positive. Results Before HCT, 88 patients met morphologic criteria for complete remission (CR), whereas 11 had CR with incomplete blood count recovery (CRi). Twenty-four had MRD before HCT as determined by MFC. Two-year estimates of overall survival were 30.2% (range, 13.1% to 49.3%) and 76.6% (range, 64.4% to 85.1%) for MRD-positive and MRD-negative patients; 2-year estimates of relapse were 64.9% (range, 42.0% to 80.6%) and 17.6% (range, 9.5% to 27.9%). After adjustment for all or a subset of cytogenetic risk, secondary disease, incomplete blood count recovery, and abnormal karyotype pre-HCT, MRD-positive HCT was associated with increased overall mortality (hazard ratio [HR], 4.05; 95% CI, 1.90 to 8.62; P < .001) and relapse (HR, 8.49; 95% CI, 3.67 to 19.65; P < .001) relative to MRD-negative HCT. Conclusion These data suggest that pre-HCT MRD is associated with increased risk of relapse and death after myeloablative HCT for AML in first morphologic CR, even after controlling for other risk factors.

Although HCT offers the best potential for cure for patients with high risk leukemia and MDS, the procedure may not be an option for all patients due to the toxicity of the conditioning regimen. Reduced-intensity conditioning (RIC) allo-HCT regimens are associated with lower non-relapse mortality (NRM), but patients receiving these regimens have a higher risk of relapse. Radioimmunotherapy (RIT) can potentially deliver high doses of targeted radiation while minimizing toxicity to normal tissue. When combined with RIC allo-HCT, RIT may improve responses without increasing toxicity associated with myeloablative conditioning. We evaluated the safety and efficacy of yttrium 90 (90Y)-anti-CD45 antibody (MAb; BC8) followed by a standard RIC regimen with fludarabine (Flu) and 2 Gy total body irradiation (TBI) as a means of developing an improved HCT strategy for high-risk acute leukemia or MDS patients. We used CD45 as a target due to its ubiquitous expression on hematopoietic stem cells including the leukemic blasts. We used the high-energy (2.2 MeVmax) beta-emitter 90Y, which has a relatively short half-life (2.7 days) to eliminate targeted malignant cells. This phase I dose-escalation trial (NCT01300572) was designed to estimate the safety, feasibility and maximum tolerated dose (MTD) of 90Y-BC8-DOTA MAb when combined with Flu and 2 Gy TBI followed by HLA‐matched, related or unrelated allo-HCT for patients with high-risk leukemia or MDS. The MTD was defined as the radiation absorbed dose delivered by 90Y-BC8-DOTA MAb associated with a true dose-limiting toxicity (DLT) rate of 25%, where a DLT is defined as Bearman grade III/IV regimen-related toxicity. Doses of 90Y were escalated in increments of 2 Gy depending on the occurrence of DLT. Inclusion required patients to have advanced leukemia or high-risk MDS (defined as primary refractory or relapsed AML/ALL, secondary AML, MDS expressed as RAEB or CMML). To determine the dose of 90Y-BC8-DOTA, patients first underwent a biodistribution step using a trace-labeled infusion of 111Indium (111In)-BC8-DOTA followed by gamma-camera imaging. On pre-HCT day -12, patients received 90Y-BC8-DOTA at a prescribed radiation dose calculated from the trace-labeled 111In-BC8-DOTA biodistribution, followed by Flu (30 mg/m2/day) on days -4 to -2. TBI (2 Gy) was administered on day 0, prior to G-CSF mobilized donor PBSC infusion. GVHD prophylaxis consisted of mycophenolate mofetil and cyclosporine. Fifteen patients, median age of 62 (range 37-76), were treated (10 with advanced AML, 5 with high-risk MDS). At time of HCT, 9 patients had refractory active disease while 6 were in remission with minimal residual disease (Table 1). The patients received 22.8 to 151.2 mCi of 90Y, delivering an average of 10.5 Gy to marrow, 70 Gy to spleen, and 17 Gy to liver. Although a maximum dose of 28 Gy was delivered to the liver, no DLT was observed. Therefore, the MTD could not be estimated. Treatment led to complete remission in 13 patients (87%), 2 patients had persistent disease after HCT. All patients engrafted with a median donor-derived CD3 and CD33 chimerism both 100% by day 28 after HCT. Ten patients (67%) developed grade II-IV acute GVHD (grade II: n=7; III: n=2; IV: n=1). Five patients (33%) developed chronic GVHD. Six patients relapsed, 5 of whom subsequently died due to progression of disease. The median time to relapse among these 6 patients was 59 days (range, 6- 351 days). One patient died from stage IV steroid-refractory GVHD. One patient died in remission from acute renal failure at 7 months after HCT. Eight patients (53%) are surviving with a median follow-up of 1.8 (range, 0.9-5.9) years. Estimated overall survival at one and two years were 66% and 46%, respectively, with progression-free survival estimated to be 46% at each of these time points. The 1-year estimate of relapse was 41% (Fig. 1). The inclusion of 90Y-BC8-DOTA into a RIC allo-HCT regimen is feasible, tolerable and no DLTs were observed. The efficacy of this approach is promising considering the high-risk leukemia/MDS patients with active disease enrolled. Current studies are evaluating the use of an alpha emitter, astatine-211, which is short-lived (t ½ = 7.2 hours) and provides high-energy radiation, conjugated to anti-CD45 MAb BC8 as part of an HCT conditioning regimen for patients with advanced AML, ALL, or high-risk MDS, in place of 90Y with the goal of continuing to improve outcomes using RIT for allo-HCT (NCT03128034). Disclosures Orozco: Actinium Pharmaceuticals: Research Funding. Green:Juno Therapeutics: Patents & Royalties, Research Funding. Gopal:Incyte: Consultancy; Pfizer: Research Funding; Gilead: Consultancy, Research Funding; Teva: Research Funding; Aptevo: Consultancy; Merck: Research Funding; Janssen: Consultancy, Research Funding; Spectrum: Research Funding; Takeda: Research Funding; BMS: Research Funding; Seattle Genetics: Consultancy, Research Funding; Brim: Consultancy; Asana: Consultancy. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy.

Background Relapsed or refractory (R/R) transformed indolent B-cell non-Hodgkin lymphoma (iB-NHL) is associated with a poor prognosis. Unfortunately, there is little prospective data using novel agents, including kinase inhibitors, since trials tend to specifically exclude transformed disease. To address this question we evaluated single agent ibrutinib in patients with R/R transformed iB-NHL. Methods This was a single-arm, open-label phase II trial for patients with R/R transformed iB-NHL (NCT02207062). Eligibility included no prior treatment with ibrutinib, ECOG 0-2, measurable biopsy-proven transformed iB-NHL, and prior receipt of at least one line of therapy for the transformed disease. Treatment consisted of oral ibrutinib 560 mg daily until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response rate (ORR, per Lugano criteria), with a predefined threshold of success ≥ 30%. Secondary endpoints included clinical benefit rate (CBR, defined as ORR and/or stable disease of ≥ 6 months), progression-free survival (PFS), and safety. Results As of July 1, 2018, 17 patients were treated. The median age was 68 years (range, 36 to 89) and 53% were women. Median number of treatment regimens prior to enrollment was 4 (range 2-9) and 41% had no response to their last prior treatment. Prior therapies included rituximab (100%), anthracycline (100%), platinum (76%), and a novel agent on protocol (36%). Prior autologous hematopoietic stem cell transplantation (HSCT) had been performed in 47% and prior CAR-T in 12%. The most common histologies of the indolent B-NHL included follicular lymphoma (65%), small lymphocytic lymphoma (12%), and lymphoplasmacytic lymphoma (12%). Histology of the transformed disease was diffuse large B cell lymphoma in all cases, and included germinal center B-cell (GCB) subtype by immunohistochemistry in 71% and MYC rearrangement in 12%. Five patients had bulky disease (at least one tumor mass > 5 cm in largest dimension) at the start of treatment. Fifteen patients were evaluable for response at the time of this data cut (Figure 1). The ORR was 40% and CBR was 47% with complete response (CR) seen in 2 patients (13%). Median PFS was 4.1 months and median duration of response was 6.8 months; estimated 12-month PFS was 23%. The 2 patients that achieved CR continue on study in remission at 37 and 15 months, respectively. ORR was associated with disease bulk, with 60% ORR in non-bulky vs 0% ORR in cases of bulky disease (p = 0.04). ORR was not associated with cell of origin (42% in GCB subtype vs 33%) or MYC rearrangement (50% in MYC rearrangement vs 35%). After treatment with ibrutinib, 2 patients proceeded to CAR-T and 1 of these subsequently underwent allogeneic HSCT. No deaths or unexpected toxicities occurred with these therapies. The side effect profile was consistent with other trials with most common adverse events (AEs) for all pts being grade 1-2 and including fatigue (59%), bruising (53%), and diarrhea (24%). Grade ≥ 3 AEs occurred in 8 patients (47%) including neutropenia (6%), lymphopenia (6%), esophagitis (6%), nausea (6%), pneumonia (6%), sepsis (6%), and atrial flutter (6%). Treatment was discontinued due to AE (grade 3 mucositis) in 1 patient after 3 weeks on therapy. One patient died while on treatment due to unknown cause. Conclusions Ibrutinib appears active in patients with R/R transformed iB-NHL that had previously received multiple agents, including rituximab and anthracycline therapy in all cases. Prolonged PFS was observed in some patients, with an estimated 12-month PFS of 23%, with higher efficacy seen in those with lower disease burden. These pilot data indicate that trials in patients with R/R transformed lymphoma can be accomplished and that ibrutinib may be clinically beneficial to a subset of such patients. The final outcome data for full accrual (n = 20) will be reported in December. Figure 1 Waterfall (a) and swimmers (b) plots. In 1a, the best response is noted: CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease. In 1b, the antecedent indolent histology is noted: FL = follicular lymphoma; LPL = lymphoplasmacytic lymphoma; SLL = small lymphocytic lymphoma. Arrowhead = continues on treatment. Disclosures Graf: Beigene: Research Funding; TG Therapeutics: Research Funding; Acerta: Research Funding. Cassaday:Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Seattle Genetics: Other: Spouse Employment, Research Funding; Kite Pharma: Research Funding; Incyte: Research Funding; Jazz Pharmaceuticals: Consultancy; Merck: Research Funding; Adaptive Biotechnologies: Consultancy. Becker:GlycoMimetics: Research Funding. Smith:Incyte Corporation: Research Funding; Portola Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Merck Sharp and Dohme Corp.: Consultancy, Research Funding; Acerta Pharma BV: Research Funding; Genentech: Research Funding; Seattle Genetics: Research Funding. Gopal:Incyte: Consultancy; Teva: Research Funding; Spectrum: Research Funding; Brim: Consultancy; Pfizer: Research Funding; Merck: Research Funding; Aptevo: Consultancy; Asana: Consultancy; Takeda: Research Funding; Seattle Genetics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; BMS: Research Funding.

Background: Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) remains standard therapy for previously untreated diffuse large B-cell lymphoma (DLBCL). However, a substantial proportion of patients (pts) will relapse. The anti-PD-1 monoclonal antibody pembrolizumab has shown modest efficacy in previously treated DLBCL. We postulated that the first-line setting, with relatively intact host immunity and coexistence of malignant cells with T-cells in the microenvironment, may represent an opportunity for effective immune checkpoint inhibition. We carried out the first known prospective trial of anti-PD1 therapy with anthracycline chemotherapy in lymphoma, to evaluate the safety of this combination. Methods: Pts age 18 years or older with previously untreated DLBCL, transformed lymphoma and grade 3B follicular lymphoma with a plan for 6-cycle, curative-intent RCHOP were eligible. Steroids within 7 days of treatment, active autoimmune disease, or history of pneumonitis were excluded. This phase I study combined pembrolizumab (200 mg IV q 3 weeks x 6) to RCHOP x 6, with supportive care per standard practice. A 30-pt sample size permitted estimation of the rate of clinically relevant grade 3-5 toxicity, assumed to occur in 40% of pts with RCHOP alone. A stopping rule for more than 3 instances of non-relapse death or inability to complete 6 cycles of RCHOP for any reason was applied. Secondary endpoints included response rates, overall (OS) and progression-free survival (PFS). Baseline PDL1 expression was analyzed centrally (Merck/Qualtek). Peripheral blood flow cytometry for changes in PD1, PDL-1, and PDL-2 subsets were performed. After PET-based response assessment, pts were followed for relapse and survival. Results: Since March 2016, 29 pts were treated on study; 28 have finished all therapy. One is currently on therapy, and 1 remains to be enrolled. Pt characteristics are in Table 1. In 29 pts to date, 18 grade 3-5 clinically significant AE's occurred in 13 unique pts (13/29, 45%). 16 SAE's occurred in 11 pts (11/29, 38%); none qualified as unanticipated events. Two deaths occurred: One in the first accured patient, who had extensive gastric involvement by DLBCL, and died during cycle 1 of bleeding from the responding tumor bed despite maximal inpatient intervention. The other death occurred due to steroid-refractory GVHD after haploidenticial allogeneic transplant for relapsed disease. Four immune-related adverse events (IRAE) occurred: grade 3 rash, resolving with oral steroids and not recurring with further pembrolizumab, grade 1 hyperthyroidism, grade 2 colitis, and 1 episode of grade 3 pneumonitis. This case of pneumonitis was the only immune-related SAE, occurring in a 78 yo with a history of tobacco use and COPD, and resulted in stopping therapy after cycle 3. Among 27 completing treatment (excluding the pt who died during cycle 1), average anthracycline dose was 95% of expected; anthracycline relative dose intensity (RDI: delivered dose intensity/standard dose intensity) was 94%. PET response assessment among 26 evaluable pts showed 18 CR (69%), 7 PR, and 1 primary refractory disease. Among 7 PR, 1 relapsed, 3 had negative biopsies, and 3 remain in remission. Median follow-up of survivors is 13 months and 2 relapses (1 primary progressive disease, 1 after PET PR) occurred. One-year PFS is 87% (Figure 1). Baseline PDL-1 staining available for 19 pts showed a median % tumor cell staining of 30% (moderate 2+ plus strong 3+ staining; range, 0-100%). Tumor PDL1 was ≤5% in 4, 10-29% in 5, 30-49% in 4, and ≥50% in 6 pts. Both EBV+ DLBCL had 60% tumor PDL1 expression. 1 relapsing pt had no detectable tumor PDL1, and the THRLBL failed for technical reasons. Conclusions: RCHOP with pembrolizumab 200 mg q 3 weeks x 6 cycles is safe, with toxicity similar to RCHOP alone and only 4 IRAE's. Anthracycline dose intensity, CR rate, and PFS are favorable. PDL1 tumor cell expression of 10% or more was observed in 15/19 pts. These data support further study of pembrolizumab with chemotherapy in untreated lymphoid malignancies. Final response/progression, correlative studies, and survival data will be presented in December after final accrual. Disclosures Smith: Merck Sharp and Dohme Corp.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Portola Pharmaceuticals: Research Funding; Acerta Pharma BV: Research Funding; Genentech: Research Funding; Seattle Genetics: Research Funding; Incyte Corporation: Research Funding. Lynch:Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Incyte Corporation: Research Funding; Takeda Pharmaceuticals: Research Funding; T.G. Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A.: Research Funding. Till:Mustang Bio: Patents & Royalties, Research Funding. Cowan:Sanofi: Research Funding; Juno Therapeutics: Research Funding; Abbvie: Research Funding; Janssen: Research Funding. Shadman:Acerta Pharma: Research Funding; Genentech: Research Funding; Verastem: Consultancy; Gilead Sciences: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; Celgene: Research Funding; Genentech: Consultancy; Beigene: Research Funding; Pharmacyclics: Research Funding; AbbVie: Consultancy; Mustang Biopharma: Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Consultancy. Shustov:Seattle Genetics: Research Funding. Cassaday:Amgen: Consultancy, Research Funding; Incyte: Research Funding; Seattle Genetics: Other: Spouse Employment, Research Funding; Merck: Research Funding; Jazz Pharmaceuticals: Consultancy; Adaptive Biotechnologies: Consultancy; Pfizer: Consultancy, Research Funding; Kite Pharma: Research Funding. Gopal:Pfizer: Research Funding; Janssen: Consultancy, Research Funding; BMS: Research Funding; Takeda: Research Funding; Incyte: Consultancy; Spectrum: Research Funding; Gilead: Consultancy, Research Funding; Merck: Research Funding; Aptevo: Consultancy; Asana: Consultancy; Seattle Genetics: Consultancy, Research Funding; Brim: Consultancy; Teva: Research Funding.

Background: Autologous stem cell transplantation (ASCT) is the standard of care for eligible patients with newly diagnosed multiple myeloma (MM). Typically, patients receive several cycles of induction therapy to achieve appropriate cytoreduction prior to ASCT. Since the introduction of lenalidomide into induction therapy, there have been conflicting reports about its impact on subsequent autologous peripheral blood stem cell (PBSC) mobilization. Early reports showed a trend of patients failing PBSC mobilization and collection after lenalidomide when granulocyte colony stimulating factor (GCSF) was employed as a single agent. More recent reports suggested that using chemotherapy in combination with growth factors including plerixafor can overcome failures of mobilization. To address these conflicting reports, we evaluated the impact of prior lenalidomide in a large cohort of MM patients undergoing mobilization and collection at a tertiary stem cell transplant center. Methods: The primary aim of this study was to identify the impact of prolonged lenalidomide therapy on mobilization of autologous PBSCs. We examined all patients 18 years of age and older, with a confirmed diagnosis of MM who attempted stem cell mobilization and collection between January 2012 and July 2015 at the Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance. Collected information included: demographics, staging according to the International Staging System, results of cytogenetics by conventional karyotype or FISH, prior treatments, number of cycles of lenalidomide received, mobilization method, receipt of plerixafor, number of stem cells collected, days of collection, and receipt of prior radiation therapy. Patients were also scored as successful or failed mobilization (defined as collecting < 2.5 x 106 CD34+ cells/kg). The patients were categorized into 3 groups (based on our recommendations for induction duration ≤ 6 cycles) for analysis: 1) Those patients with prior receipt of > 6 cycles lenalidomide, 2) Those patients with prior receipt of ≤ 6 cycles of lenalidomide, and 3) Patients without prior lenalidomide exposure. Results: We identified 297 patients with MM who underwent mobilization of PBSCs. Of these, 35 received > 6 cycles of lenalidomide (median of 8 cycles, range of 7 - 25), 156 received ≤ 6 cycles of lenalidomide (median of 4 cycles, range 1 - 6), and 106 received no lenalidomide (Table 1). Similar proportions of patients in each group of lenalidomide exposure received chemotherapy mobilization, chemotherapy with plerixafor, GCSF alone, and GCSF with plerixafor. There was no significant difference in receipt of plerixafor between these groups (p=0.41). A second mobilization attempt was made in 1 patient (2.9%) who received > 6 cycles of lenalidomide, 1.9% of patients who received ≤ 6 cycles of lenalidomide, and 0% of patients with no prior lenalidomide exposure. Only one patient, who had not received lenalidomide previously, failed to collect. In a multivariate linear regression analysis for association between receipt of > 6 cycles of lenalidomide with total number of PBSCs collected, with other covariates including prior radiation therapy, age, and number of prior regimens received, we did not observe a significant effect (regression coefficient of -3.37, p=0.166). We then examined whether receiving > 6 cycles of lenalidomide was associated with days of stem cell collection in a multivariate regression; other covariates included prior radiation therapy, age, mobilization regimen, and number of prior regimens, and did not see any association (regression coefficient -0.053, p=0.697). Discussion: In this retrospective analysis of MM patients undergoing autologous PBSC mobilization at a single center, we show that prior lenalidomide exposure did not meaningfully impact the total number of PBSC collected or the number of days of apheresis after controlling for clinically relevant features in a multivariate model. These data suggest that longer courses of induction therapy with lenalidomide-containing regimens to achieve a maximum response before transplant should not adversely impact the ability to collect PBSC, and that arbitrarily limiting lenalidomide use pre-mobilization does not appear warranted. The extensive use of chemotherapy with G-CSF and plerixafor for mobilization at our center may account in part for these findings. Disclosures Cowan: Abbvie: Research Funding; Janssen: Research Funding; Juno Therapeutics: Research Funding; Sanofi: Research Funding. Becker:GlycoMimetics: Research Funding. Gopal:Incyte: Consultancy; Aptevo: Consultancy; Janssen: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; BMS: Research Funding; Teva: Research Funding; Brim: Consultancy; Asana: Consultancy; Merck: Research Funding; Pfizer: Research Funding; Spectrum: Research Funding; Takeda: Research Funding. Holmberg:Millenium-Takeda: Research Funding; Sanofi-Genzyme: Research Funding; Seattle Genetics: Research Funding; Merck Sharpe: Research Funding; Jazz Pharmaceuticals: Consultancy; NCCN: Consultancy.

Background: Chemorefractory diffuse large B-cell lymphoma (DLBCL) is associated with poor outcomes. Recent Car-T therapy trials, including Zuma-1 which led to the first FDA approval of Car-T for DLBCL (Neelapu NEJM), have shown sustained complete remission, disease control, and long-term survival in a proportion of patients. As with all trials, results must be interepreted in context of study definitions and eligibility parameters. While selection bias is often discussed, little published data regarding specific eligibility requirements on accrual of DLBCL trials exists. To better understand factors influencing Car-T trial eligibility in DLBCL, and context for observed survival rates in Car-T trials, we examined chemorefractory DLBCL patients seen from 2011-2015 at our center, applying key eligibility criteria from Zuma-1 and describing likely reasons for trial exclusion. Methods: Pts with DLBCL seen at our institution from 2011-2015, who had received at least 2 lines of therapy, were reviewed under IRB approval to determine chemorefractory status based on ZUma-1 definition, and potential eligibility for the Zuma-1 trial. Chemorefractory status per Zuma 1 was defined as stable disease (lasting 6 months or less) or progressive disease as best response to most recent chemotherapy, or disease progression within 12 months of autologous stem cell transplant. "Chemorefractory date" was identified by the chart reviewed, based on biopsy or imaging showing progression, and served as the reference date for reviewing potential Zuma-1 eligibility in detail. Specifically, clinical data (ECOG, labs, organ function) within 8 weeks of chemorefractory date was examined to estimate potential Zuma-1 eligibility. On occasion, more remote studies (e.g., an echocardiogram >8 weeks prior) were applied when data appeared relevant. Descriptive statistics and a Kaplan-Meier survival estimate were performed, with a comparison between those potentially Zuma-1 eligible and those not. No attempt was made to compare outcomes among pts receiving specific therapies for chemorefractory DLBCL. The specific eligibility factors examined were: histology (DLBCL, PMBCL and tFL); prior therapy including history of allogeneic SCT; CNS involvement, performance status (ECOG 01- vs 2 or higher), laboratory parameters, cardiac disease, infectious comorbidities; history of second malignancy other than nonmelanoma skin cancer/in situ cance or FL; need for urgent therapy due to tumor mass effect or rapid progression. Results: Of 404 in our DLBCL database from 2011-2015, 163 had received at least 2 therapies and were examined. 36 had inadequate follow up, leaving 127 for detailed analysis. Of these 127, 78 were determined chemorefractory as per Zuma-1. Of these 78 chemorefractory pts, median age was 63 (18-82), 17 had transformed lymphoma, 30 underwent transplant (20 auto, 2 allo, 8 auto-allo), 18 relapsed within 1 year of autologous transplant, and 30 had primary refractory disease. 43 patients (55%) were deemed ineligible for Zuma-1 by retrospective review, for reasons given in Table 1. Figure 1 shows survival. Among "eligible" pts vs not: Median OS was 15 vs 8 months (eligible vs not, p=.04). 1 yr OS was 56% vs 33%, and 2 yrs OS 40% vs 22%. Conclusion: When applied to a historical cohort, about half of chemorefractory DLBCL pts met eligibility criteria for Zuma-1. The survival of "eligible" patients appears significantly better than others. A need for acute therapy (for rapid progression), ECOG performance status 2 or greater, and non-FL transformation (Richter's/CLL history) were the most common reasons for exclusion. Since these three features may not impact safety of Car-T therapy, but are associated with agrgessive disease, broadening eligibility around these criteria could represent a step toward testing Car-T therapies among those with greatest unmet need. Disclosures Lynch: T.G. Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A.: Research Funding; Incyte Corporation: Research Funding; Takeda Pharmaceuticals: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy. Shadman:TG Therapeutics: Research Funding; AstraZeneca: Consultancy; Genentech: Research Funding; Verastem: Consultancy; Mustang Biopharma: Research Funding; Celgene: Research Funding; Gilead Sciences: Research Funding; AbbVie: Consultancy; Qilu Puget Sound Biotherapeutics: Consultancy; Acerta Pharma: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy; Beigene: Research Funding. Till:Mustang Bio: Patents & Royalties, Research Funding. Shustov:SPECTRUM PHARMACEUTICALS: Consultancy, Research Funding. Gopal:Janssen: Consultancy, Research Funding; Asana: Consultancy; Takeda: Research Funding; Merck: Research Funding; BMS: Research Funding; Spectrum: Research Funding; Teva: Research Funding; Pfizer: Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Brim: Consultancy; Aptevo: Consultancy; Incyte: Consultancy. Smith:Pharmacyclics: Research Funding; Genentech: Research Funding; Acerta Pharma BV: Research Funding; Incyte Corporation: Research Funding; Merck Sharp and Dohme Corp.: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding.

Introduction Axicabtagene citoleucel (axi-cel) is a recently approved, highly effective treatment for relapsed and refractory aggressive B cell lymphomas. It is complicated by the occurrence of cytokine release syndrome (CRS) in > 90% of patients (Neelapu, Locke et al. 2017). CRS is characterized by high fevers and elevation in inflammatory markers such as C-reactive protein (CRP) and ferritin. It can progress to hypotension and end-organ damage. The clinical distinction between CRS and bacterial infections is virtually impossible. Procalcitonin (PCT) is FDA approved to aid in antibiotic management and stopping antibiotics in sepsis. It has been shown in several studies and meta-analyses to reduce antibiotic exposure without affecting mortality, including patients with cancer (Bouadma, Luyt et al. 2010, Schuetz, Chiappa et al. 2011, Sedef, Kose et al. 2015). Methods We sought to evaluate the utility of PCT as an infectious biomarker in patients undergoing commercial treatment with axi-cel. Patient data was collected retrospectively from two institutions and analyzed for clinical and laboratory characteristics, presence of documented infections, and presence and severity of cytokine release syndrome. PCT levels were drawn per the treating team's discretion based on clinical changes (new onset fever, new onset hypotension, requirement of vasopressors, change in level of care). Results A total of 30 patients received axi-cel for relapsed and refractory aggressive B-cell lymphoma and had PCT levels checked during their admission (Table 1). Median age was 61.5 years. Median baseline CRP and ferritin on day of infusion were 22.9 mg/L and 654 ng/mL, respectively. All patients had febrile episodes and evidence of at least grade I CRS by Lee criteria. Median duration of CRS was 6 days. Twenty-two patients (73.3%) had grade 2 or higher CRS. Median maximal temperature was 39.5 0C with a median duration of 5 days. Median number of days till first fever was 1 and median neutrophil count on day of first fever (> 38 0C) was 1475/mm3. Twenty-seven (90%) of the patients were on levofloxacin prophylaxis. Eight patients (26.7%) had an absolute neutrophil count (ANC) of less than 500/mm3 on the day of first fever. All but one patient (97%) were started on intravenous antibiotics during their admission. None of the patients had positive blood cultures. One patient had C. difficile infection and one patient had invasive sinusitis with mucormycosis. The timing of these infections did not correspond to the diagnosis of these infections. Median PCT was 0.86 ng/mL. Twelve patients (40%) had values below the cut-off for bacterial infections. Two of these patients required vasopressors. Three patients expired (10%). Two had progressive disease and one had an invasive fungal infection. Figure 1 shows one patient (panel A) who had normal PCT during their CRS episode and another who had abnormal ones. Discussion Axi-cel is a novel and promising therapy for treatment of relapsed and refractory aggressive B-cell lymphomas. Therapy is complicated by occurrence of CRS in 94% of patients, which can be fatal if not properly identified and managed. CRS can mimic sepsis and patients are frequently placed on broad-spectrum intravenous antibiotics, inducing risk for multi-drug resistant organisms and C. difficile infections. Unlike ferritin and CRP, PCT is typically only elevated in settings of bacterial infections, trauma and surgery and is FDA approved to be utilized in a treatment algorithm for earlier discontinuation of antibiotics in septic patients. It has not been studied in CRS. PCT was checked per the treating team's discretion and the trend was not followed for most of these patients. We herein hypothesize that PCT does not follow the same kinetics of other inflammatory markers frequently interrogated and may serve as a way to distinguish infection from CRS in this population, where 100% of patients experienced CRS and fevers, but 40% had normal PCT levels. The utility of PCT in antibiotic stewardship and the cut-off of 0.5 ng/mL should be further explored to guide antibiotic use in this population. Disclosures Jacobson: Pfizer: Consultancy; Kite: Consultancy; Humanigen: Consultancy; Novartis: Consultancy; Precision Bioscience: Consultancy; Bayer: Consultancy. Abramson:Merck: Consultancy; Juno Therapeutics: Consultancy; Celgene: Consultancy; Humanigen: Consultancy; Seattle Genetics: Consultancy; Gilead: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Karyopharm: Consultancy; Verastem: Consultancy. Kline:Merck: Honoraria, Research Funding; iTeos: Research Funding. Cohen:BioInvent: Consultancy; Janssen: Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Gopal:Teva: Research Funding; Asana: Consultancy; Brim: Consultancy; Aptevo: Consultancy; Merck: Research Funding; Janssen: Consultancy, Research Funding; Spectrum: Research Funding; Takeda: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Incyte: Consultancy. Acharya:Teva: Honoraria; Juno Therapeutics: Research Funding. Jaglowski:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Juno: Consultancy; Kite Pharma: Consultancy, Research Funding.

BACKGROUND: CD19-specific chimeric antigen receptor (CAR) T-cell therapy has proven to be highly effective in patients with relapsed or refractory large B-cell lymphomas, yielding early complete response (CR) rates of ~40%, which are typically sustained. Unfortunately, most patients will not experience prolonged disease control. Despite this fact, little data exist defining the outcomes and impact of subsequent therapies for such individuals. Limited data also exist on the ability for such patients to pursue further clinical trials or allogeneic hematopoietic stem-cell transplant (HSCT). This project details the specific interventions and outcomes of this population to better inform the management of patients who suffer progressive disease (PD) after CD19-specific CAR T-cell therapy. METHODS: Adults with diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (tFL), primary mediastinal B-cell lymphoma (PMBCL), and high-grade B-cell lymphomas (HGBCL) who received CD19-specific CAR T-cells at the University of Washington/Seattle Cancer Care Alliance were included in this analysis. Patients who received CAR T-cell therapy in conjunction with additional protocol-specified therapy were excluded. Those who exhibited PD or persistent lymphoma after CAR T-cell therapy were the focus of this study. We defined initial PD as patients who had evidence of disease progression on the initial response assessment. Delayed PD was defined as achieving a CR, partial response (PR), or stable disease (SD) on the initial response assessment, but eventually progressed or received subsequent anti-lymphoma therapy. Baseline characteristics and all data were retrieved from the electronic medical record up until date of death or date of last contact in our system, including subsequent interventions and outcomes. Primary endpoint of this analysis was overall survival (OS). RESULTS: Between October 2013 and May 2018, we identified 51 patients with PD following CD19-specific CAR T-cell therapy. Baseline characteristics are listed in the Table 1. Histologies included DLBCL (29), HGBCL (11), tFL (8) and PMBCL (3). Median age was 60 years (range 26-75), 65% were male, median prior regimens was 3 (range 1-8). Median time from CAR T infusion to PD was 42 days (range 11-609), with 27 (53%) patients exhibiting initial PD. Median follow up after time of progression was 4.2 months. Initial PD was associated with a higher risk of death (HR 2.376, 95% CI 1.19-4.75, p=0.0143, Figure 1). The median OS for those with initial PD and delayed PD was 5.1 months (95% CI 2.0-9.3) and 13.6 months (4.1-not reached) respectively. 39 (76%) patients received ≥ 1 subsequent therapies after PD. Initial therapies included: 2nd CAR T infusion (14), targeted therapy (10), chemotherapy +/- rituximab (7), other immunotherapy (3), radiotherapy (3), intrathecal chemotherapy (1) and allogeneic HSCT (1). 12 (24%) patients received no further therapy despite PD. Those who received ≥ 1 subsequent therapies after PD had a lower risk of death (HR 0.344, 95% CI 0.149-0.793, P=0.0122) compared to those who did not. There was no difference in survival if 2nd CAR T infusion was the next line therapy compared to others (p=0.449), targeted therapy compared to others (p=0.417), or chemotherapy compared to others (p=0.565). 5 (10%) patients enrolled onto a clinical trial as next line therapy. 4 (8%) patients eventually received an allogeneic HSCT after PD, 2 of whom are still alive. We identified 8 patients who were alive for ≥ 12 months after progression without evidence of lymphoma. Last line of therapy for these patients included allogeneic HSCT (2), subsequent CD19-specific CAR-T cell infusion (2), ibrutinib (2), lenalidomide/rituximab (1), and radiotherapy (1). CONCLUSIONS: Patients with PD post anti-CD19 CAR T-cell therapy, particularly those exhibiting initial PD, have poor long-term outcomes. Patients receiving at least one anti-lymphoma therapy after PD had improved overall survival, although no single approach appeared to confer a survival benefit. Few enrolled onto a clinical trial or received an allogeneic HSCT. These data reinforce the need to both further improve the durable CR rate after CAR T-cell therapy and to develop effective strategies for those not achieving a CR. Figure 1 Figure 1. Disclosures Gopal: Spectrum: Research Funding; Pfizer: Research Funding; BMS: Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding; Takeda: Research Funding; Brim: Consultancy; Janssen: Consultancy, Research Funding; Asana: Consultancy; Gilead: Consultancy, Research Funding; Aptevo: Consultancy; Incyte: Consultancy; Teva: Research Funding. Maloney:Juno Therapeutics: Research Funding; Roche/Genentech: Honoraria; Janssen Scientific Affairs: Honoraria; Seattle Genetics: Honoraria; GlaxoSmithKline: Research Funding. Turtle:Caribou Biosciences: Consultancy; Adaptive Biotechnologies: Consultancy; Nektar Therapeutics: Consultancy, Research Funding; Bluebird Bio: Consultancy; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics / Celgene: Consultancy, Patents & Royalties, Research Funding; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Aptevo: Consultancy; Gilead: Consultancy. Smith:Genentech: Research Funding; Acerta Pharma BV: Research Funding; Incyte Corporation: Research Funding; Merck Sharp and Dohme Corp.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding. Shadman:TG Therapeutics: Research Funding; Mustang Biopharma: Research Funding; Acerta Pharma: Research Funding; AstraZeneca: Consultancy; Verastem: Consultancy; Gilead Sciences: Research Funding; AbbVie: Consultancy; Qilu Puget Sound Biotherapeutics: Consultancy; Beigene: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy; Celgene: Research Funding. Cassaday:Seattle Genetics: Other: Spouse Employment, Research Funding; Incyte: Research Funding; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy, Research Funding; Kite Pharma: Research Funding; Merck: Research Funding; Amgen: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy. Till:Mustang Bio: Patents & Royalties, Research Funding. Shustov:Seattle Genetics: Research Funding. Acharya:Juno Therapeutics: Research Funding; Teva: Honoraria. Lynch:Takeda Pharmaceuticals: Research Funding; T.G. Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A.: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Incyte Corporation: Research Funding.

Introduction: CD19 CAR T cells lead to durable responses in 40% of r/r aggressive B cell NHL patients. We performed a multicenter retrospective study of axicabtagene ciloleucel given in a real world setting where eligibility/management considerations may diverge from clinical trials. We evaluate efficacy and safety, and patient/disease factors associated with response and toxicity. Methods: Patient and treatment characteristics were summarized descriptively. Response and toxicity were reported with 95% exact binomial CIs. CyTOF was performed on frozen PBMCs using 38 metal-tagged mAbs. Multiplex IF was performed on FFPE tissue with standard, primary Abs sequentially, paired with a unique fluorochrome per published protocols. Standard IHC was done on FFPE whole tissue. Results: In total, 76 patients, median age 64, were included (Table 1). The majority had an ECOG PS ≤ 2. Twenty-one percent of patients had double/triple hit cytogenetics. Nearly half had an IPI ≥3 at treatment. Nearly 1/3 had a prior autologous transplant, 25% had prior ibrutinib, and 11% had prior lenalidomide. Twelve percent had bulky disease and 36% received bridging therapy following pheresis. Seventy-three patients were evaluable for response (Table 2). At 4m median f/u, best ORR and CRR was 64% and 41% among those treated. Six patients had 6m f/u, all PRs at 1m: 3 converted to CR and 3 had PD. Eleven patients (13%) were pheresed but not treated due to PD (6), infection (2), or non-conforming cells (3). By ITT analysis, the ORR and CRR were 57% and 36%. OS at 4m among those treated was 84%; PFS will be calculated with longer f/u. In univariate analysis, PS, tumor bulk, IPI, baseline CRP and prior ibrutinib were significantly associated with lack of response (Table 3). There was no association between response and double/triple hit cytogenetics, grade 3+ CRS or NT, or the use of tocilizumab/steroids. Among treated patients, 96% experienced CRS; in 17% this was ≥ grade 3. Two patients died from CRS (3%). Median time to onset was 1d; median duration was 6d (0-14d). NT was seen in 76% of patients; in 38% this was ≥ grade 3. One case of NT was fatal. Median time to onset was 5d; median duration was 8d (0-34d). Tocilizumab and steroids were given to 67% and 78% of patients. ICU care occurred in 30% of patients. Eleven treated patients have died: 6 from PD and 5 from toxicity. In univariate analysis, peak ferritin was associated with grade 3+ CRS and NT; peak ALC was associated with grade 3+ CRS, and peak CRP and prior autologous transplant were associated with grade 3+ NT (Table 4). Three of 4 patients who had a biopsy with CD19 staining after relapse were positive (Fig 1). All 3 patients with PDL1+ tumors were refractory to CAR T cell therapy. Multiplex IF and IHC were performed on 2 primary refractory patients at progression (Fig 1). One was CD19-/PDL1+; multiplex IF showed an abundance of CAR+ T-cells (Fig 1A,B). The second was CD19+/PDL1- and multiplex IF showed no CAR+ T-cells (Fig 1C,D). CyTOF analysis of PBMCs at serial timepoints was performed on 6 patients (4 CRs, 1 PD, 1 PD after CR)(Fig 2, Table 5). Peak CAR T cell levels were seen at day 7 in all patients with increased expression of PD1, 41BB, and Ki67, as well as CC3 indicating apoptosis, followed by a reduction in CAR T cells by day 14. Immune subsets that associate with response will be evaluated and reported. Results from additional patients and longer f/u will be presented. Conclusion: Retrospective analysis of a multicenter cohort treated in the real world with axi-cel reveals important distinctions from ZUMA-1. The ORR and CR rate are lower than the 82% and 54% reported on ZUMA-1. This may reflect inclusion of sicker patients with a poorer PS, and/or with different histologies (ie transformation from non-FL). Outcomes were significantly worse in high risk lymphomas, reflected by IPI, PS, tumor bulk, and baseline CRP. Rates of CRS and NT were similar to ZUMA-1, but toxicity was not associated with tumor bulk or response. It was associated with higher peak inflammatory markers and ALC, which may reflect peak CAR T cell levels, as shown previously. Progression biopsies highlight 3 potential resistance mechanisms: loss of target antigen, an inhibitory tumor/TME, and lack of CAR T cell tumor infiltration. Immunomodulatory molecules on CAR T cells that may affect their activity and survival are upregulated early. This suggests that unique combination approaches are necessary for specific patients/tumors. Disclosures Jacobson: Precision Bioscience: Consultancy; Kite: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Humanigen: Consultancy; Novartis: Consultancy. Rodig:Merck: Research Funding; Affimed: Research Funding; Bristol Myers Squibb: Research Funding; KITE: Research Funding. Maus:novartis: Consultancy; agentus: Consultancy, Research Funding; crispr therapeutics: Consultancy, Research Funding; kite therapeutics: Consultancy, Research Funding; windmil therapeutics: Consultancy; adaptimmune: Consultancy. Chen:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy; REGiMMUNE: Consultancy; Takeda Pharmaceuticals: Consultancy. Abramson:Verastem: Consultancy; Amgen: Consultancy; Merck: Consultancy; Karyopharm: Consultancy; Humanigen: Consultancy; Bayer: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Novartis: Consultancy; Juno Therapeutics: Consultancy. Kline:iTeos: Research Funding; Merck: Honoraria, Research Funding. Cohen:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioInvent: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; BioInvent: Consultancy. Jaglowski:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; Juno: Consultancy. Smith:Merck Sharp and Dohme Corp.: Consultancy, Research Funding; Acerta Pharma BV: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Incyte Corporation: Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding. Maloney:Janssen Scientific Affairs: Honoraria; Seattle Genetics: Honoraria; Juno Therapeutics: Research Funding; Roche/Genentech: Honoraria; GlaxoSmithKline: Research Funding. Gopal:Spectrum: Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding; Gilead: Consultancy, Research Funding; Pfizer: Research Funding; BMS: Research Funding; Brim: Consultancy; Teva: Research Funding; Aptevo: Consultancy; Incyte: Consultancy; Asana: Consultancy. Acharya:Teva: Honoraria; Juno Therapeutics: Research Funding.

Background: Idelalisib (Zydelig®, IDELA), an oral agent, and copanlisib (Aliqopa®, COPA), an intravenous agent, are the only B-cell receptor pathway targeting agents approved for treatment of follicular lymphoma (FL). Both agents target PI3Kδ while COPA also targets PI3Kα. These drugs received accelerated approvals, and overall response rates in their respective phase 2 trials were comparable. Safety profiles may be impacted by distinct kinase inhibitory profiles, delivery method, and dosing. Given similar response rates with these agents, the administration schedule and safety profile become important considerations. A challenge is the appropriate regimen choice to maximize anti-tumor benefit while limiting treatment-emergent adverse events (TEAEs) or exacerbation of pre-existing co-morbidities. Objective: To compare the safety profiles of IDELA and COPA to determine which drug may be more suitable for select patient populations. Methods: We selected key AEs for analysis based on the "Highlights of Prescribing Information" in each drug's United States package insert (USPI) to assess the incidence of TEAEs in patients receiving COPA or IDELA. Using the Safety Analysis Set for patients with iNHL treated with IDELA (N=163, median duration of treatment [mDoT] 27 weeks) and TEAEs reported for patients with FL and other hematological malignancies treated with COPA (Aliqopa® USPI [N=168, mDoT 22 weeks], Dreyling et al., J. Clin. Oncol. 2017; 35:3898 [N=142, mDoT 22 weeks], and Dreyling et al., Blood. 2017; 130:2777 [N=142, mDoT 26 weeks]), we ascertained the most common TEAEs, compared the incidence of specific TEAEs (estimate difference in proportions, Fisher's exact test), and assessed the effect of pre-existing conditions on IDELA- and COPA-mediated AEs. Results: All grade (aGr) and grade 3/4 (Gr3/4) diarrhea and transaminitis were significantly more common in IDELA-treated patients, and aGr and Gr3/4 hyperglycemia (blood glucose >160 mg/dL and >250 mg/dL, respectively) and hypertension (systolic blood pressure [SBP] >120 mmHg; diastolic blood pressure [DBP] > 80 mmHg and SBP > 160 mmHg; DBP > 100 mmHg, respectively) were significantly more common in COPA-treated patients (Figs. 1 and 2). The incidences of aGr and Gr3/4 infection, neutropenia, and pneumonitis were similar in IDELA- and COPA-treated patients. IDELA-treated patients with pre-existing diabetes mellitus or hyperglycemia experienced more Gr3/4 hyperglycemia than IDELA-treated patients without either diagnosis (7.1% vs. 0%, p=0.0286), but at rates lower than in COPA-treated patients (10.7% vs. 53.6%, p Conclusion: Pre-existing co-morbidities and the nature of emergent therapy-associated side effects (including type, severity, and duration [transient vs. chronic]) may impact PI3K inhibitor choice for the treatment of relapsed FL. Findings in this analysis suggest that for patients with pre-existing diabetes mellitus or hypertension, IDELA may be a more appropriate option. For patients at increased risk for diarrhea-related complications, COPA may be a more appropriate option. IDELA-treated patients should be followed closely for diarrhea and should be monitored routinely for hepatotoxicity regardless of hepatic status at treatment initiation. Patients treated with either compound should be followed closely for infection, neutropenia, and pneumonitis. Disclosures Ye: Gilead Sciences, Inc.: Employment, Equity Ownership. Xing:Gilead Sciences: Employment. Roudet:Gilead Sciences, Inc.: Employment. Ruzicka:Gilead Sciences, Inc.: Employment. Dreyling:Bayer: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Acerta: Consultancy; Sandoz: Consultancy. Zinzani:Janssen: Honoraria, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gopal:Teva: Research Funding; Asana: Consultancy; Incyte: Consultancy; Merck: Research Funding; Aptevo: Consultancy; Janssen: Consultancy, Research Funding; Spectrum: Research Funding; Takeda: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Brim: Consultancy.

Introduction Multiple myeloma (MM) is considered incurable but patients achieving minimal-residual disease (MRD) negative status following treatment have significantly better overall and progression-free survival. MM is highly heterogeneous both between and within patients, limiting the curative potential of novel agents targeting specific pathways. However all MM is highly sensitive to radiation. The α-emitter astatine-211 (211At) deposits a very large amount of energy (~100 keV/μm) within a few cell diameters (50-90 μm) resulting in irreparable double strand DNA breaks, making 211At, targeted to MM cells, particularly suited to eliminating MRD. CD38 is expressed on malignant plasma cells regardless of mutational status, and CD38 monoclonal antibodies (mAbs) constitute a proven targeted therapy for MM but do not alone eradicate disease. We proposed that 211At conjugated to an anti-CD38 mAb could effectively eliminate MM MRD, and tested this hypothesis in cellular and murine models. Methods We conjugated the anti-CD38 mAb OKT10 and an isotype matched control mAb, BHV1, to the amine-reactive labeling agent B10-NCS and labeled the final constructs with 211At. To assess in vitro cell binding we incubated each labeled construct with CD38+ cell lines, washed, and then measured cell pellet radioactivity in a gamma counter. To assess cytotoxicity we incubated CD38+ and CD38- cell lines with unlabeled or 211At-labeled OKT10-B10 for 60 hrs, then assayed viability. NOD.Cg-Rag1tm1MomIl2rgtm1Wjl/SzJ (NRG) mice bearing H929luc or OPM-2luc MM xenografts were generated by subcutaneous (SQ) flank injection of 107 cells 7 days prior to treatment. MRD was modeled by intravenous (IV) injection of 2.5 - 5 x 105 cells 5 days prior to treatment. Radioimmunotherapy (RIT) was administered by IV injection of 7.5 - 45 µCi of 211At-OKT10-B10 or 211At-BHV1-B10. For biodistribution studies (n = 5/group) mouse tissues were harvested 24 hrs post RIT and measured in a gamma counter. For therapy studies (n = 8-10/group), all mice received syngeneic bone marrow transplant 3 days post RIT. Disease progression was assessed by tumor dimensions, luminescence imaging and survival. Results 211At-CD38 mAb selectively bound and killed CD38+ but not CD38- MM cells in vitro. In vivo, biodistribution experiments demonstrated that 211At-CD38 RIT delivered 2.4 times more radiation to MM xenografts than did control 211At-BHV1 RIT (p = 0.007), and delivered significantly higher dose to tumor than to healthy tissues including lung (p = 0.04) and kidney (p = 0.015). In murine therapy studies, 211At-CD38 RIT at 15 - 45 µCi at least doubled median survival relative to untreated controls in each of two MM SQ xenograft models (p < 0.003). However, no mice in these models achieved complete remission and all eventually died of disease. In contrast, therapy studies using MRD models showed that 30 µCi 211At-CD38 RIT eliminated detectable disease in 80% of mice at day 21, compared to 20% of mice receiving nontargeted 211At RIT and 0% of untreated mice. At day 130, 50% of the 30 µCi 211At-CD38-RIT mice remained alive and disease-free, while all nontargeted and untreated mice died before day 85 (Fig. 1, survival of 30 µCi > 15 µCi 211At-CD38-RIT [p = 0.016] and all other groups [p < 0.0007]). The impact of therapy on body weight as well as hematopoietic, liver and kidney function was mild and returned to normal within 32 days of treatment. Conclusions The efficacy of CD38 targeted 211At appears to be a function of disease distribution and malignant plasma cell access, as compellingly demonstrated by our models. Bulky tumor geometry reduces mAb penetration. In contrast, the isolated cells and small tumor clusters that define MRD are readily accessible to mAbs, creating optimal conditions for α-emitter cell kill. In an era of highly potent MM therapy, preventing relapse remains frustratingly rare. Our approach is both agnostic to high-risk cytogenetic features and offers the potential to eliminate all residual MM cell clones. These encouraging findings will be explored in a clinical trial of 211At-CD38 RIT. Disclosures Orozco: Actinium Pharmaceuticals: Research Funding. Jones:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Till:Mustang Bio: Patents & Royalties, Research Funding. Gopal:Teva: Research Funding; Spectrum: Research Funding; Janssen: Consultancy, Research Funding; BMS: Research Funding; Incyte: Consultancy; Gilead: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Brim: Consultancy; Pfizer: Research Funding; Aptevo: Consultancy; Takeda: Research Funding; Merck: Research Funding; Asana: Consultancy. Green:Juno Therapeutics: Patents & Royalties, Research Funding.

7541Background: ECHELON-1 is a global, phase 3 study of BV plus doxorubicin, vinblastine, and dacarbazine (A+AVD) vs ABVD as frontline therapy in patients with advanced HL (NCT01712490). The primar...

Introduction: Thrombotic microangiopathy (TMA) is a clinical syndrome that can develop after hematopoietic cell transplantation (HCT). Previous studies have been limited to small case series with conflicting results. In this large, single-center longitudinal TA-TMA database, we describe the incidence, etiology, treatment, and outcome of this rare but challenging clinical presentation. Methods: We performed a retrospective cohort analysis of consecutive allogeneic HCT recipient during 2006-2015 at Fred Hutchinson Cancer Research Center. TA-TMA was defined as persistent microangiopathic hemolytic anemia (MAHA) composed of red cell fragmentation, elevated lactate dehydrogenase (LDH), thrombocytopenia, anemia, and lack of coagulopathy (Table 1). We performed a primary search algorithm using "consecutive MAHA" followed by a secondary search algorithm using "suspected hemolysis" to identify all cases from date of transplant until date of death or last follow-up (Table 1). For each suspected case, we further reviewed available patient records to confirm the diagnosis, determine the etiology, treatment, and complication. The most likely etiology was determined by reviewing the clinical events in the 2-week window before the TMA onset. Since 96% of patients were receiving calcineurin inhibitor (CNI), we chose idiopathic/drug as a diagnosis of exclusion if all other causes were excluded. TMA resolution was defined as LDH Results: Among 2241 consecutive adult allogeneic HCT recipients, 209 patients (9%) met the laboratory criteria of TA-TMA (Table 2) with a median onset time of 62d (35d-93d). One hundred and nine patients (52%) had end-organ damage with either acute kidney injury (AKI) or neurologic deficit. The median follow-up was 181d (92d-478d) and 53 patients (25%) achieved hematologic resolution. Diagnostically, acute GVHD (n=96) represented the largest category and those with GVHD refractory to high dose steroid (n=61) had poor prognosis. Diffuse alveolar hemorrhage (DAH) and idiopathic pneumonia syndrome (IPS) (n=30) also frequently preceded the TMA onset. Finally, despite excluding patients with coagulopathy, non-specific causes of TMA such as disease recurrence (n=20) and systemic infection (n=33) were frequently evident. Overall survival, separated by TMA etiology is shown in Figure 1. Whereas the idiopathic/drug and non-refractory acute GVHD categories approached the survival of non-TMA post-HCT recipients, the other groups had worse prognosis. Regardless of cause, the most common treatment (32%) was CNI cessation or CNI switch (in no particular pattern). We did not observe an association between changes to CNI therapy and TMA resolution (24% vs. 26%, Fisher P 0.80) or overall survival at 6 months (37% vs. 34%, Wald P 0.75). This remained true when each diagnostic category and each CNI drug was separately analyzed. Plasma exchange was rarely performed at our center. Finally, TMA resolution often correlated with improvement of the underlying disorder. The achievement of TMA resolution was associated with significantly improved survival (HR 0.35, P Conclusion: Despite meeting the same laboratory definition for persistent MAHA, clinical review revealed heterogeneous disease groups with dissimilar prognostic implications. Our data suggest that TA-TMA is not one disease entity but rather a "final common pathway" for several disorders that likely have different pathophysiologic mechanisms. Instead of empiric treatment with CNI adjustment, we need to identify and understand the underlying causal pathway towards TA-TMA, and to determine if earlier recognition and successful treatment improves patient outcomes. Disclosures Lee: Kadmon: Other: One-time advisory board member; Amgen: Other: One-time advisory board member; Bristol-Myers-Squibb: Other: One-time advisory board member; Mallinckrodt: Honoraria. Gopal: Seattle Genetics: Consultancy, Research Funding.

Introduction: Novel agents and autologous stem cell transplant (auto-SCT) have resulted in a survival benefit among patients with multiple myeloma (MM), but almost all ultimately relapse. Allogeneic transplant (allo-SCT) provides a tumor-free graft and graft-versus-myeloma (GVM) effect, but myeloablative conditioning regimens are associated with high rates of treatment-related mortality (TRM). In contrast, reduced intensity allo-SCT conditioning regimens are associated with lower TRM, but patients receiving these regimens tend to have a higher risk of relapse. Radioimmunotherapy (RIT) offers the potential to deliver high doses of targeted radiation while minimizing toxicity to normal tissue. When incorporated into reduced intensity allo-SCT, RIT may improve responses without the associated toxicity historically associated with myeloablative conditioning. We studied 90Yttrium conjugated to an IgG1 murine anti-CD45 monoclonal antibody (MAb) (BC8), in conjunction with a reduced intensity-conditioning regimen prior to allogeneic SCT. We used CD45 as a target due to its ubiquitous expression in hematopoietic stem cells. We used the high-energy (2.8 MeVmax) beta-emitter, 90Y to facilitate a bystander crossfire effect and eliminate malignant plasma cells. Methods: This is a single-arm, open label, dose-escalation, phase I trial designed to estimate the safety, feasibility and maximum tolerated dose (MTD) of 90Y-BC8-DOTA MAb when combined with fludarabine (flu) and low dose total body irradiation (TBI) followed by HLA-matched, related or unrelated allo-SCT for patients with high risk MM. Inclusion required patients to have at least one high risk MM-associated disease characteristic at diagnosis (del13 or hypodiploidy by conventional cytogenetics, t(4;14), t(14;16), del 17 by FISH, beta-2 microglobulin >3.5 mcg/mL, LDH >1.5 times upper limit of normal, plasma cell leukemia or progressive disease following primary therapy), and/or disease progression after auto-SCT. To determine the dose of 90Y-BC8-DOTA, patients first underwent a biodistribution step using a trace-labeled infusion of 111Indium-BC8-DOTA followed by gamma camera imaging and bone marrow biopsy. On pre-transplant day -12, patients received 90Y-BC8-DOTA at a dose calculated from the trace-labeled 111Indium-BC8-DOTA biodistribution, followed by Flu (30 mg/m2/day) on days -4 to -2. TBI (2 Gy) was administered on day 0, prior to growth factor mobilized donor peripheral blood stem cell infusion. GVHD prophylaxis consisted of mycophenolate mofetil and cyclosporine initiated on day 0 and day -3, respectively. The MTD was defined as the dose of 90Y-BC8-DOTA MAb associated with a true dose-limiting toxicity (DLT) rate of 25%, where a DLT is defined as Bearman grade III/IV regimen-related toxicity. Doses of 90Y were escalated in increments of 2 Gy depending on the occurrence of DLT. Results: A total of 15 patients were enrolled. Patient characteristics and outcomes are summarized in Table 1. One patient was withdrawn from the study prior to receiving the therapy dose after testing positive for human anti-mouse antibodies. The remaining 14 patients went on to receive 90Y-BC8-DOTA (0.5 mg/kg antibody) at escalating 90Y dose levels of 6 to 32 Gy to the liver, which is the normal critical organ. Six patients (43%) experienced grade 3-4 toxicity, predominantly GI and metabolic/electrolyte disturbances. No DLTs were observed. Because no DLTs were seen, the MTD could not be estimated. All patients achieved platelet and neutrophil engraftment, and 13 patients (93%) were >95% donor in the CD3, CD33 and CD56 compartments at day +28. Estimates of overall and progression-free survival at 2 years were 77% and 78%, respectively (Figure 1). Eleven patients who completed the study regimen are alive at 2.6 months to 4.1 years. Of these, 6 patients are in complete remission, 2 have persistent disease, and 3 have relapsed at 4 months, 6 months, and 3 years post-transplant. Three patients died: 2 due to progressive disease and 1 due to respiratory failure in the setting of liver GVHD. Conclusion: The inclusion of 90Y-BC8-DOTA into a reduced intensity allo-SCT conditioning regimen is feasible and no dose-limiting toxicities have been observed. The efficacy of this regimen is promising compared with historical control rates of conventional allo-SCT for MM and should be explored in a phase II trial. Disclosures Orozco: Actinium Pharmaceuticals: Other: Research Funding to Institution for sponsored Clinical Trials. Gopal: Seattle Genetics: Consultancy, Research Funding. Becker: GlycoMimetics, Inc.: Research Funding. Press: Roche: Honoraria, Research Funding; BMS: Honoraria; Bayer: Consultancy. Bensinger: Janssen: Membership on an entity's Board of Directors or advisory committees.

P>SGN-30, a chimeric anti-CD30 monoclonal antibody, has demonstrated potent preclinical antitumour activity in both Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL). We conducted an open-label, Phase II study to determine the safety and objective response rate of SGN-30 in 79 patients with refractory/recurrent HL (n = 38) or systemic ALCL (n = 41). Each course of SGN-30 comprised 6 weekly intravenous infusions, followed by a 2-week treatment-free period. Patients had received a median of 3 (range 1-5) prior regimens of chemotherapy or systemic therapy. The initial 40 patients received 6 mg/kg weekly; the latter 39 patients received 12 mg/kg weekly. In the ALCL group, two patients achieved a complete response and five additional patients achieved a partial response, with response durations ranging from 27 to 1460+ d. No objective responses were observed in the HL group; however, 11 patients (29%) had stable disease (duration 62-242 days). Although adverse events were common, most were mild or moderate, and no specific pattern of adverse events was observed in either disease group. These results demonstrate that weekly administration of SGN-30 is safe, with modest clinical activity in patients with ALCL.

Relapsed B-cell lymphomas are currently incurable with conventional chemotherapy and radiation treatments. Radiolabeled antibodies directed against B-cell surface antigens have emerged as effective and safe therapies for relapsed lymphomas. We therefore investigated the potential utility of both directly radiolabeled 1F5 (anti-CD20), HD39 (anti-CD22), and Lym-1 (anti-DR) antibodies (Abs) and of pretargeted radioimmunotherapy (RIT) using Ab-streptavidin (SA) conjugates, followed by an N-acetylgalactosamine dendrimeric clearing agent and radiometal-labeled DOTA-biotin, for treatment of lymphomas in mouse models using Ramos, Raji, and FL-18 human lymphoma xenografts. This study demonstrates the marked superiority of pretargeted RIT for each of the antigenic targets with more complete tumor regressions and longer mouse survival compared with conventional one-step RIT. The Ab-SA conjugate yielding the best tumor regression and progression-free survival after pretargeted RIT varied depending upon the lymphoma cell line used, with 1F5 Ab-SA and Lym-1 Ab-SA conjugates yielding the most promising results overall. Contrary to expectations, the best rates of mouse survival were obtained using optimal single Ab-SA conjugates rather than combinations of conjugates targeting different antigens. We hypothesize that clinical implementation of pretargeted RIT methods will provide a meaningful prolongation of survival for patients with relapsed lymphomas compared with currently available treatment strategies.

Anthracycline-based chemotherapy is the cornerstone of modern curative regimens for aggressive lymphomas; however, these drugs cannot be safely administered in the setting of severe hepatic dysfunction. Alternative regimens for this setting are required. We describe 2 patients with newly diagnosed advanced aggressive lymphoma (diffuse large B-cell lymphoma [DLBCL] and classic Hodgkin lymphoma [HL]) presenting with severe hepatic dysfunction with hyperbilirubinemia (4.3-13.2 mg/dL). Because of the inability to safely administer unattenuated doses of anthracycline-based regimens, dexamethasone, high-dose cytarabine, and cisplatin (DHAP) was used at full doses (along with rituximab for the DLBCL patient) until hepatic function normalized (1-5 cycles). The treatment was then converted to R-CHOP (rituximab/cyclophosphamide/ doxorubicin/vincristine/prednisone) and ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) for the DLBCL and HL patient, respectively, to complete therapy. The patients had a partial remission and complete remission, respectively. These data suggest that DHAP is a safe and effective regimen that can be used without dose modification as part of initial therapy in the setting of aggressive lymphoma and hepatic failure. The literature on the use of treatment regimens for aggressive lymphoma in the setting of hepatic dysfunction is reviewed.

Radioimmunotherapy (RIT) for treatment of hematologic malignancies frequently fails because of disease recurrence. We therefore conducted pretargeted (P)RIT studies to augment the efficacy in mice of therapy using a pretargeted anti-human (h)CD45 antibody (Ab)-streptavidin (SA) conjugate followed by a biotinylated clearing agent and radiolabeled 1,4,7,10-tetraazacylodode cane N,N′,N″,N‴-tetraacetic (DOTA)-biotin. Tumor-to-blood ratios at 24 hours were 20:1 using pretargeted anti-hCD45 RIT and

Myeloablative radioimmunotherapy using 131I-tositumomab (anti-CD20) monoclonal antibodies is an effective therapy for B-cell non-Hodgkin9s lymphoma. The amount of radioactivity for radioimmunotherapy may be determined by several methods, including those based on whole-body retention and on dose to a limiting normal organ. The goal of each approach is to deliver maximal myeloablative amounts of radioactivity within the tolerance of critical normal organs. Methods: Records of 100 consecutive patients who underwent biodistribution and dosimetry evaluation after tracer infusion of 131I-tositumomab before radioimmunotherapy were reviewed. We assessed organ and tissue activities over time by serial γ-camera imaging to calculate radiation-absorbed doses. Organ volumes were determined from CT scans for organ-specific dosimetry. These dose estimates helped us to determine therapy on the basis of projected dose to the critical normal organ receiving a maximum tolerable radiation dose. We compared organ-specific dosimetry for treatment planning with the whole-body dose-assessment method by retrospectively analyzing the differences in projected organ-absorbed doses and their ratios. Results: Mean organ doses per unit of administered activity (mGy/MBq) estimated by both methods were 0.33 for liver and 0.33 for lungs by the whole-body method and 1.52 for liver and 1.74 for lungs by the organ-specific method (P = 0.0001). The median differences between methods were 0.92 mGy/MBq (range, 0.36–2.2 mGy/MBq) for lungs, 0.82 mGy/MBq (range, 0.28–1.67 mGy/MBq) for liver, and −0.01 mGy/MBq (range, −0.18–0.16 mGy/MBq) for whole body. The median ratios of the treatment activities based on limiting normal-organ dose were 5.12 (range, 2.33–10.01) for lungs, 4.14 (range, 2.16–6.67) for liver, and 0.94 (range, 0.79–1.22) for whole body. We found substantial differences between the dose estimated by the 2 methods for liver and lungs (P = 0.0001). Conclusion: Dosimetry based on whole-body retention will underestimate the organ doses, and a preferable approach is to evaluate organ-specific doses by accounting for actual radionuclide biodistribution. Myeloablative treatments based on the latter approach allow administration of the maximum amount of radioactivity while minimizing toxicity.

Radioimmunotherapy (RIT) combines the mechanism of action and targeting capability of monoclonal antibodies with the tumoricidal effect of radiation and has shown promising results in the treatment of various hematologic malignancies. Based on RIT's efficacy and safety profile, many investigators have evaluated its use in transplant conditioning regimens with the goal of improving long-term disease control with limited toxicity. In lymphoma, two basic transplant approaches targeting CD20 have emerged: (1) myeloablative doses of RIT with or without chemotherapy, and (2) standard nonmyeloablative doses of RIT combined with high-dose chemotherapy. Myeloablative RIT has been shown to be feasible and efficacious using escalated doses of iodine 131-tositumomab, yttrium 90-ibritumomab tiuxetan, and (131)I-rituximab with or without chemotherapy followed by autologous stem cell transplant (ASCT). The second approach predominantly has used standard doses of (90)Y-ibritumomab tiuxetan or (131)I-tositumomab plus BEAM chemotherapy (carmustine [BCNU], etoposide, cytarabine, melphalan) followed by ASCT. RIT targeting CD45, CD33, and CD66 prior to allogeneic transplantation also has been evaluated for the treatment of acute leukemia. Overall RIT-based transplant conditioning for lymphoma and leukemia has been shown to be safe, effective, and feasible with ongoing randomized trials currently underway to definitively establish its place in the treatment of hematologic malignancies.

Radiolabeled anti-CD20 antibodies have demonstrated impressive efficacy in the treatment of relapsed non-Hodgkin's lymphoma. However, the amount of radiation that can be delivered to eradicate the malignancy is limited by toxicity to normal organs. We examined an "extracorporeal adsorption therapy" (ECAT) method to remove circulating unbound radioimmunoconjugate and improve the ratios of radiation delivered to B-cells in a macaque model.ECAT was applied with an avidin-agarose column 24 hours after an injection of (111)In- or (177)Lu-DOTA-biotin-rituximab (anti-CD20 antibody) to normal macaques. Two (2) animals were studied in initial blood clearance studies, and 6 additional animals were evaluated in subsequent detailed biodistribution experiments. After the injection of (111)In- or (177)Lu-antibody, 3 animals underwent ECAT circulating one volume/hour while 3 served as controls. Serial blood, marrow, and lymph node samples, gamma-camera images, and necropsy tissues were obtained to estimate radiation-absorbed doses in organs of interest.Optimal blood clearance (98%) was achieved by performing ECAT at a flow rate of one blood volume/hour. Radiation doses to normal organs were reduced with ECAT in kidney (49% +/- 12%), liver (42% +/- 10%), lungs (60% +/- 6%), total body (51% +/- 16%), marrow (50% +/- 15%), spleen (38% +/- 10%), and lymph nodes (19% +/- 3%). Despite dose reduction in both target and nontarget tissues, therapeutic ratios were significantly higher in animals treated with ECAT (20% higher for spleen:kidney and 60% for lymph node:kidney), compared to controls.ECAT is a safe, feasible, and effective method to remove unbound radioimmunoconjugates from the bloodstream and reduce the nonspecific radiation exposure of normal tissues.

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 analysed treatment results of two high-dose regimens: BEAM (carmustine, etoposide, cytarabine, melphalan) and BuMelTT (busulphan, melphalan, thiotepa) in autologous transplant patients with non-Hodgkin lymphoma. Patients received BEAM (n=48) or BuMelTT (n=59) from 1998 to 2005. BEAM group patients were older (mean 59.7 vs 50.1 years), more advanced (stage>or=III 88 vs 61%), had higher IPI/FLIPI scores (score>or=3, 65 vs 19%), and a higher comorbidity index (HCT-CI) (score>or=2, 40 vs 19%). Grade 3-4 complications occurred in 10 patients (17%), with six deaths in the BuMelTT group versus none in the BEAM group. CR was achieved in 20 of 36 (56%) BuMelTT versus 12 of 39 (31%) BEAM patients. After adjusting for IPI/FLIPI, HCT-CI, age and stage of disease, the hazards of death, relapse and treatment failure were similar in both groups. In this retrospective comparison, BEAM regimen appeared to be equally effective but less toxic than BuMelTT.

Relapsed or treatment refractory B-cell lymphomas are currently incurable with conventional chemotherapy and radiation treatments. High-dose chemoradiotherapy and stem cell transplantation can cure some patients with relapsed or refractory lymphoma, but the majority of such patients die of progressive disease. We have investigated the potential utility of pretargeted radioimmunotherapy using monoclonal antibody-streptavidin, immunoconjugates, and fusion proteins in combination with N-acetylgalactosamine dendrimeric clearing agent and radiometal-labeled 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid biotin for treatment of lymphomas using mouse and primate models. We have targeted a variety of cell surface antigens, including CD20, CD22, CD45, and HLA-DR, using conventional and pretargeted radioimmunotherapy. These studies showed the marked superiority of pretargeted radioimmunotherapy for each of the antigenic targets in terms of superior biodistributions, more complete tumor regressions, and longer survival. We are optimistic that this novel approach will provide a meaningful prolongation of survival for patients with relapsed or refractory lymphomas.

Despite the promise of radioimmunotherapy using anti-CD20 antibodies (Ab) for the treatment of relapsed patients with indolent non-Hodgkin lymphoma (NHL), most patients treated with conventional doses of 131I-tositumomab or 90Y-ibritumomab eventually relapse. We did comparative assessments using conventional radioimmunotherapy targeting CD20, CD22, and HLA-DR on human Ramos, Raji, and FL-18 lymphoma xenografts in athymic mice to assess the potential for improving the efficacy of radioimmunotherapy by targeting other NHL cell surface antigens. Results of biodistribution studies showed significant differences in tumor localization consistent with variable antigenic expression on the different lymphoma cell lines. Interestingly, the radioimmunoconjugate that yielded the best tumor-to-normal organ ratios differed in each tumor model. We also explored administering all three 111In-1,4,7,10-tetra-azacylododecane N,N′,N″,N‴-tetraacetic acid antibodies in combination, but discovered, surprisingly, that this approach did not augment the localization of radioactivity to tumors compared with the administration of the best single radiolabeled Ab alone. These data suggest that conventional radioimmunotherapy using anti-CD20, anti–HLA-DR, or anti-CD22 Abs is effective when used singly and provides targeted uptake of radiolabel into the tumor that is dependent on the levels of antigen expression. Improvements in tumor-to-normal organ ratios of radioactivity cannot be achieved using directly labeled Abs in combination but may be afforded by novel pretargeting methods. [Cancer Res 2007;67(12):5921–8]

Pretargeted radioimmunotherapy (PRIT) using streptavidin (SA)–conjugated antibodies (Abs), followed by clearing agent and radiolabeled biotin is a promising method that can increase the effectiveness of RIT, while decreasing the toxicities associated with directly labeled Abs. Although CD20 has been the traditional target antigen for RIT of non-Hodgkin lymphoma (NHL), studies targeting HLA DR and CD22 have yielded promising results. Targeting all 3 antigens at once may further augment the effect of PRIT. This study compares the targeting of Ramos, Raji, and FL-18 lymphoma xenografts with either anti-CD20 Ab/SA (1F5/SA), anti-HLA DR Ab/SA (Lym-1/SA), anti-CD22 Ab/SA (HD39/SA), or all 3 conjugates in combination, followed 24 hours later by a biotin-N-acetyl-galactosamine clearing agent, and 3 hours after that by 111In-DOTA-biotin. The Ab/SA conjugate yielding the best tumor uptake and tumor-to–normal organ ratios of radioactivity varied depending on the target antigen expression on the cell line used, with 1F5/SA and Lym-1/SA yielding the most promising results overall. Also, the best tumor-to–normal organ ratios of absorbed radioactivity were obtained using single conjugates optimized for target tumor antigen expression rather than the combination therapy. This study highlights the importance of screening the antigenic expression on lymphomas to select the optimal reagent for PRIT.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces programmed cell death (apoptosis) preferentially in tumor cells. However, not all cancer cells are sensitive to TRAIL. We determined whether ligation of the retinoid receptor, RXR, would sensitize cells to TRAIL-mediated apoptosis. The leukemic cell lines KG1a (apoptosis-resistant) and ML-1 (apoptosis-sensitive) were treated with the RXR-specific retinoid bexarotene, TRAIL, or both, and apoptosis was determined. In KG1a cells, bexarotene downregulated FLIP(Long) and activated caspase-8, thereby allowing for TRAIL-triggered apoptosis. Overexpression of FLIP(Long) in ML-1 cells abrogated apoptosis. In unmodified ML-1 cells bexarotene enhanced programmed cell death via truncation of Bid and release of cytochrome C. Blockade of caspase-8 prevented enhancement in both cell lines; blockade of caspase-9 had a significant effect only in ML-1 cells. Thus, the effect of bexarotene on TRAIL-mediated programmed cell death involved proximal events of the extrinsic pathway; however, downstream signals involved the intrinsic pathway in ML-1 but not in KG1a cells. These studies add further information to the regulation of programmed cell death in leukemic cells that have to be considered when designing therapeutic strategies.

Chemotherapeutic agents without cross-resistance to prior therapies may enhance PBSC collection and improve patient outcomes by exacting a more potent direct antitumor effect before autologous stem cell transplant. Bendamustine has broad clinical activity in transplantable lymphoid malignancies, but concern remains over the potential adverse impact of this combined alkylator–nucleoside analog on stem cell mobilization. We performed a prospective, nonrandomized phase II study including 34 patients with multiple myeloma (MM) (n=34; International Staging System (ISS) stages I (35%), II (29%) and III (24%); not scored (13%)) to evaluate bendamustine’s efficacy and safety as a stem cell mobilizing agent. Patients received bendamustine (120 mg/m2 IV days 1, 2), etoposide (200 mg/m2 IV days 1–3) and dexamethasone (40 mg PO days 1– 4) (bendamustine, etoposide and dexamethasone (BED)) followed by filgrastim (10 μg/kg/day SC; through collection). All patients (100%) successfully yielded stem cells (median of 21.60 × 106/kg of body weight; range 9.24–55.5 × 106/kg), and 88% required a single apheresis. Six nonhematologic serious adverse events were observed in 6 patients including: neutropenic fever (1, grade 3), bone pain (1, grade 3) and renal insufficiency (1, grade 1). In conclusion, BED safely and effectively mobilizes hematopoietic stem cells.

Autologous stem cell transplant (ASCT) can improve outcomes for mantle cell lymphoma (MCL) patients, yet relapses are frequent. We hypothesized that high-dose anti-CD20 radioimmunotherapy (RIT)-based conditioning could improve results in this setting. We thus assessed 162 consecutive patients with MCL at our centre undergoing ASCT following high-dose RIT-based (n = 61) or standard (n = 101) conditioning. RIT patients were less likely to be in first remission (48% vs. 72%; P = 0·002), be in complete remission (CR) (26% vs. 61%; P < 0·001) and have chemosensitive disease (84% vs. 96%; P = 0·006). RIT-based conditioning was associated with a reduced risk of treatment failure [hazard ratio (HR) 0·40; P = 0·001] and mortality (HR 0·49; P = 0·01) after adjusting for these imbalances. This difference increased as disease status worsened (from CR to partial remission to stable/progressive disease), with respective HRs of 1·14, 0·53 and 0·04 for mortality, and 0·66, 0·36 and 0·14 for treatment failure. RIT-based conditioning appears to improve outcome following ASCT for MCL patients unable to achieve CR after controlling for imbalances in important risk factors. These data support the further study of RIT and radiation-based strategies in a risk-adapted approach to ASCT for persistent MCL.

Aims Brentuximab vedotin, an antibody–drug conjugate (ADC), selectively delivers the microtubule-disrupting agent monomethyl auristatin E (MMAE) into CD30-expressing cells. The pharmacokinetics of brentuximab vedotin have been characterized in patients with CD30-positive haematologic malignancies. The primary objective of this phase 1 open label evaluation was to assess the pharmacokinetics of brentuximab vedotin in patients with hepatic or renal impairment. Methods Systemic exposures were evaluated following intravenous administration of 1.2 mg kg–1 brentuximab vedotin in patients with CD30-positive haematologic malignancies and hepatic (n = 7) or renal (n = 10) impairment and compared with those of unimpaired patients (n = 8) who received 1.2 mg kg–1 brentuximab vedotin in another arm of the study. Results For any hepatic impairment, the ratios of geometric means (90% confidence interval) for AUC(0,∞) were 0.67 (0.48, 0.93) for ADC and 2.29 (1.27, 4.12) for MMAE. Mild or moderate renal impairment caused no apparent change in ADC or MMAE exposures. Severe renal impairment (creatinine clearance

Background High-dose therapy and autologous stem cell transplantation (ASCT) improves outcomes for patients with mantle cell lymphoma (MCL), but relapse ultimately occurs in most patients. Recently presented interim results from a phase III prospective trial suggest maintenance rituximab (MR) after ASCT for MCL improves progression-free survival (PFS). The maturation of these data and any benefit of MR on overall survival (OS) remain to be defined. Patients and methods In this retrospective study, we examined a cohort of consecutive patients with MCL that underwent ASCT for MCL at our center and evaluated their outcomes according to whether they received MR after ASCT (n = 50) or did not (n = 107). MR was treated as a time-dependent covariate to account for variation in timing of its initiation. Results MR was associated with an improved PFS [hazard ratio (HR) 0.44; confidence interval (CI) (0.24–0.80), P = 0.007] and overall survival (OS; HR 0.46; CI 0.23–0.93, P = 0.03) following a multivariate adjustment for confounding factors with a median follow-up of ∼5 years. Grade 4 neutropenia was increased (34% versus 18%, P = 0.04) in the MR group, but no effect on the rate of mortality unrelated to relapse was observed. Conclusions These data support that MR after ASCT for MCL confers a benefit in PFS and additionally suggest it may improve OS. General application of this strategy will require confirmation of benefit in prospective randomized trials.

Molecularly targeted agents have become an established component of the treatment of indolent B-cell malignancies (iNHL). iNHL disproportionately affects older adults, so treatments that have excellent tolerability and efficacy across multiple lines of therapy are in demand. The numbers and classes of targeted therapies for iNHL have proliferated rapidly in recent years; classes of agents that show promise for older patients with iNHL include anti-CD20 antibodies, phosphatidyl-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway inhibitors, immunomodulators, proteasome inhibitors, epigenetic modulators, and immunotherapies. Here, we review the proposed mechanisms of action, efficacy, and tolerability of novel agents for iNHL, with an emphasis on their applicability to older patients.

Introduction Overexpression of cyclin D1 is a hallmark feature of mantle cell lymphoma (MCL). Many of the oncogenic effects of cyclin D1 are mediated through cyclin-dependent kinases (CDKs). P276-00 is a potent small molecule inhibitor of CDK4-D1, CDK1-B, and CDK9-T, with promising activity in preclinical models. In phase I studies of P276-00 in patients with refractory solid neoplasms, it was well-tolerated with a mild trend toward single-agent efficacy. Patients and Methods A phase II study of P276-00 was conducted in patients with relapsed or refractory MCL at the recommended dose of 185 mg/m 2 /day from days 1 to 5 of a 21-day cycle. Thirteen patients were enrolled in the present study. Results Of the 13 patients, 11 experienced disease progression, 1 patient was withdrawn because of an adverse event (AE), and 1 patient died. Also, 11 patients (84.6%) experienced a treatment-emergent AE deemed related to P276-00. Of the 13 patients, 9 (69.2%) received ≥ 2 cycles of treatment, which was the predefined threshold to be evaluable for efficacy. Treatment was discontinued early in 2 patients because of AEs (1 of which was attributed to P276-00 administration) and in 2 patients because of disease progression. Finally, 2 patients experienced stable disease for an estimated median duration of 60.5 days (range, 58-63 days). The estimated median time to progression for the predefined efficacy population was 43 days (range, 38-58 days). Conclusion Given the results observed in the present study, if evaluation of CDK inhibition in MCL continues, it should be considered earlier in the disease course or as a part of combination strategies for relapsed or refractory disease.

We present response and survival outcomes of a pivotal phase 2 trial of the antibody-drug conjugate brentuximab vedotin in patients with relapsed/refractory Hodgkin lymphoma following autologous stem cell transplant (N = 102) after a median observation period of approximately 3 years. Median overall survival and progression-free survival were estimated at 40.5 months and 9.3 months, respectively. Improved outcomes were observed in patients who achieved a complete remission (CR) on brentuximab vedotin, with estimated 3-year overall survival and progression-free survival rates of 73% (95% confidence interval [CI]: 57%, 88%) and 58% (95% CI: 41%, 76%), respectively, in this group (medians not reached). Of the 34 patients who obtained CR, 16 (47%) remain progression-free after a median of 53.3 months (range, 29.0 to 56.2 months) of observation; 12 patients remain progression-free without a consolidative allogeneic stem cell transplant. Younger age, good performance status, and lower disease burden at baseline were characteristic of patients who achieved a CR and were favorable prognostic factors for overall survival. These results suggest that a significant proportion of patients who respond to brentuximab vedotin can achieve prolonged disease control. The trial was registered at www.clinicaltrials.gov as #NCT00848926.

Purpose Pretargeted radioimmunotherapy (PRIT) is a multi-step method of selectively delivering high doses of radiotherapy to tumor cells while minimizing exposure to surrounding tissues. Yttrium-90 (90Y) and lutetium-177 (177Lu) are two of the most promising beta-particle emitting radionuclides used for radioimmunotherapy, which despite having similar chemistries differ distinctly in terms of radiophysical features. These differences may have important consequences for the absorbed dose to tumors and normal organs. Whereas 90Y has been successfully applied in a number of preclinical and clinical radioimmunotherapy settings, there have been few published pretargeting studies with 177Lu. We therefore compared the therapeutic potential of targeting either 90Y or 177Lu to human B-cell lymphoma xenografts in mice. Methods Parallel experiments evaluating the biodistribution, imaging, dosimetry, therapeutic efficacy, and toxicity were performed in female athymic nude mice bearing either Ramos (Burkitt lymphoma) or Granta (mantle cell lymphoma) xenografts, utilizing an anti-CD20 antibodystreptavidin conjugate (1F5-SA) and an 90Y- or 177Lu-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-biotin second step reagent. Results The two radionuclides displayed comparable biodistributions in tumors and normal organs; however, the absorbed radiation dose delivered to tumor was more than twice as high for 90Y (1.3 Gy/MBq) as for 177Lu (0.6 Gy/MBq). More importantly, therapy with 90Y-DOTAbiotin was dramatically more effective than with more » 177Lu-DOTA-biotin, with 100% of Ramos xenograft-bearing mice cured with 37 MBq 90Y, whereas 0% were cured using identical amounts of 177Lu-DOTA-biotin. Similar results were observed in mice bearing Granta xenografts, with 80% of the mice cured with 90Y-PRIT and 0% cured with 177Lu-PRIT. Toxicities were comparable with both isotopes. Conclusion 90Y was therapeutically superior to 177Lu for streptavidin-biotin PRIT approaches in these human lymphoma xenograft models. « less

Nonmyeloablative allogeneic transplantation provides a valuable therapeutic option for patients with relapsed non-Hodgkin lymphomas, particularly those that have recurred after autologous transplantation. However, the absence of an intensive conditioning regimen renders this approach less effective for patients with aggressive or bulky lymphoma because rapid tumor growth may outpace the evolution of the graft-versus-lymphoma effect. Radioimmunotherapy provides an attractive, minimally toxic modality to safely prevent early progression of B-cell lymphomas and induce remissions without incurring the risks of traditional intensive therapy. This approach provides a time window during which a robust graft-versus-lymphoma effect may be established before tumor progression, thereby providing more effective long-term disease control. The rationale for incorporation of radioimmunotherapy into reduced intensity allogeneic transplantation regimens for non-Hodgkin lymphoma is discussed, as are current study designs, preliminary results, and future directions.

In an attempt to improve outcomes for patients with acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (HCT), we conducted a phase 1/2 study in which targeted irradiation delivered by 131I–anti-CD45 antibody was combined with targeted busulfan (BU; area-under-curve, 600-900 ng/mL) and cyclophosphamide (CY; 120 mg/kg). Fifty-two (88%) of 59 patients receiving a trace 131I-labeled dose of 0.5 mg/kg anti-CD45 murine antibody had higher estimated absorbed radiation in bone marrow and spleen than in any other organ. Forty-six patients were treated with 102 to 298 mCi (3774-11 026 MBq) 131I, delivering an estimated 5.3 to 19 (mean, 11.3) Gy to marrow, 17-72 (mean, 29.7) Gy to spleen, and 3.5 Gy (n = 4) to 5.25 Gy (n = 42) to the liver. The estimated 3-year nonrelapse mortality and disease-free survival (DFS) were 21% and 61%, respectively. These results were compared with those from 509 similar International Bone Marrow Transplant Registry patients who underwent transplantation using BU/CY alone. After adjusting for differences in age and cytogenetics risk, the hazard of mortality among all antibody-treated patients was 0.65 times that of the Registry patients (95% CI 0.39-1.08; P = .09). The addition of targeted hematopoietic irradiation to conventional BU/CY is feasible and well tolerated, and phase 2 results are sufficiently encouraging to warrant further study.

Radioimmunotherapy (RIT) for treatment of hematologic malignancies has primarily employed monoclonal antibodies (Ab) labeled with 131I or 90Y which have limitations, and alternative radionuclides are needed to facilitate wider adoption of RIT. We therefore compared the relative therapeutic efficacy and toxicity of anti-CD45 RIT employing 90Y and 177Lu in a syngeneic, disseminated murine myeloid leukemia (B6SJLF1/J) model. Biodistribution studies showed that both 90Y- and 177Lu-anti-murine CD45 Ab conjugates (DOTA-30F11) targeted hematologic tissues, as at 24 hours 48.8 ± 21.2 and 156 ± 14.6% injected dose per gram of tissue (% ID/g) of 90Y-DOTA-30F11 and 54.2 ± 9.5 and 199 ± 11.7% ID/g of 177Lu-DOTA-30F11 accumulated in bone marrow (BM) and spleen, respectively. However, 90Y-DOTA-30F11 RIT demonstrated a dose-dependent survival benefit: 60% of mice treated with 300 µCi 90Y-DOTA-30F11 lived over 180 days after therapy, and mice treated with 100 µCi 90Y-DOTA-30F11 had a median survival 66 days. 90Y-anti-CD45 RIT was associated with transient, mild myelotoxicity without hepatic or renal toxicity. Conversely, 177Lu- anti-CD45 RIT yielded no long-term survivors. Thus, 90Y was more effective than 177Lu for anti-CD45 RIT of AML in this murine leukemia model.

The anti-CD20 monoclonal antibody rituximab induces remission in 40% to 60% of patients with indolent B-cell lymphoma, but virtually all patients have relapses. We evaluated the efficacy of concurrent administration of another biologic agent, N-(4-hydroxyphenyl) retinamide (4HPR, fenretinide) with rituximab against a variety of human B-cell lymphoma cell lines (Ramos, DHL-4, and FL-18) in vivo. Concurrent 4HPR and rituximab administration prevented tumor progression of lymphoma-bearing mice in a minimal disease model (rituximab + 4HPR, 100% progression free; rituximab alone, 37.5% progression free, P = .01; 4HPR alone, 12.5% progression free, P < .01; controls, 0% progression free, P < .01). Combinations of 4HPR + rituximab exceeded the predicted 50% additive rate of disease control from each agent alone (P = .038). Administering 4HPR and rituximab to mice with established tumors induced complete responses (CRs) in 80% of animals compared with 20% to 40% CRs using either agent alone (P = .07), resulting in significantly improved survival. Tumors harvested from 4HPR + rituximab-treated mice displayed elevated caspase activation compared with untreated controls (P = .02). Adding a broad-spectrum caspase inhibitor in vivo fully abrogated the antitumor effects of 4HPR + rituximab (P = .05). These results establish the efficacy of 4HPR/rituximab combinations, confirm their caspase-mediated mechanism of action, and offer the potential for disease control with minimal toxicity for patients with B-cell malignancies. (Blood. 2004;103:3516-3520)