ALBERT

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

Description: The majority of patients with relapsed or refractory B-cell, non-Hodgkin’s lymphoma (NHL) are over 60 years of age, yet many are denied potentially curative high-dose regimens due to concerns of excessive toxicity with stem cell transplantation in this age group. Myeloablative anti-CD20 radioimmunotherapy (RIT) can deliver curative radiation doses to tumor sites while limiting exposure to normal organs and may be ideal for older adults requiring high-dose therapy. We have treated 24 patients with relapsed or refractory B-cell NHL aged ≥60 years using high-dose I-131-tositumomab (GlaxoSmithKline) and ASCT on a phase II trial. Patients were required to have a performance status of 0–1, acceptable organ function, ≥2x106 CD34+ cells/kg collected, and 1 extranodal site = 21%, elevated LDH at treatment = 46%, IPI score at transplant 3–5 = 46%, Histology: diffuse large B-cell (DLBCL)=9 pts (with 4/9 transformed from follicular lymphoma [FL]), mantle cell (MCL)=8 pts, FL=6 pts, and marginal zone (MZL) 1 pt. The median I-131 activity administered was 525 mCi (range 328–1154 mCi) with dose limiting organs being lung, liver, and kidney in 12, 8, and 4 patients, respectively. The therapy was well tolerated with no treatment-related deaths, and no grade 3–4 Bearman toxicity. NCI CTC non-hematopoeitic toxicities by day 100 included: Grade 4=2/24 and Grade 3=17/24. The median time after ASCT for recovery of platelets 〉 20K and neutrophils 〉500 was 10 and 15 days, respectively. Sixteen of 24 pts remain alive (67%) and 10 (42%) are alive and progression-free with a median follow up from ASCT of 2.2 yrs (range 1 mo.–4.9 yrs.) for survivors. The estimated 3-year overall and progression-free survival are 56% and 37%, respectively. Surviving patients include 6/8 with MCL, 5/7 with FL/MZL, and 5/9 with DLBCL as well as 9/13 with chemoresistant disease. Myeloablative I-131-tositumomab with ASCT is a well-tolerated and effective transplant option for older adults with high-risk, relapsed B-NHL, though longer follow-up and additional pts will be needed to confirm the reproducibility and durability of these findings.

Description: Reduced intensity allogeneic transplantation offers a potentially curative option to NHL patients with chemorefractory disease or relapse following autologous transplant. The efficacy of this approach relies on the development of a graft-vs-lymphoma (GVL) effect by establishment of donor chimerism. GVL, however, is most effective for NHL in settings of stable, chemoresponsive, and non-bulky disease. Anti-CD20 radioimmunotherapy (RIT) has been shown to be safe and effective in the treatment of B-NHL. This phase II clinical trial was designed to evaluate the safety and efficacy of administering 90Y-Ibritumomab Tiuxetan (Zevalin, Biogen-Idec) as part of reduced intensity allogeneic stem cell transplantation in order to safely provide disease control prior to the establishment of a GVL-effect that could maintain the remissions. Fourteen patients with relapsed or refractory CD20+ NHL and evaluable disease, who had too high-risk lymphoma for a routine non-ablative transplant and were not eligible for a traditional myeloablative transplant were treated with 0.4 mCi/kg 90Y-Ibritumomab Tiuxetan (maximum 32 mCi) on day −14, followed by fludarabine (30mg/m2 on days −7 to −5), 2 Gy TBI on day 0, and HLA-matched related (n=8) or unrelated (n=6) allogeneic PBSC transplantation. Cyclosporine and mycophenolate mofetil were employed for graft-vs-host disease (GVHD) prophylaxis. Patient characteristics included: median age=57y (range 33–69y), median # of prior regimens=6 (range 3–12), prior autologous transplant=5 (36%), chemoresistant=100%, median tumor bulk=3.7cm, elevated LDH=5 (36%), baseline cytopenia (ANC80% donor CD3/CD33 chimerism by 28 days after transplant. No patients developed ≥ grade 3 acute GVHD, though 7 experienced grade 2 GVHD. Three patients died following progressive NHL and 2 died after day 100 from GVHD and infection-related complications. The median platelet and neutrophil nadirs were 9×103/μL and 50/μL, respectively. Responses to date include 3 complete responses (CR), and 4 partial responses (PR), including 1 CR, 6 PR, 3 stable disease by 1 month after transplant. With a median follow up of surviving patients of 6 months (range

Description: Abstract 33 Purpose: Non-myeloablative allogeneic transplantation (NMAT) can provide prolonged remissions in patients with advanced B-cell lymphoma (B-NHL) via the graft versus lymphoma (GVL) effect, though inferior results are seen in patients with chemoresistant, bulky, or aggressive disease. Radioimmunotherapy (RIT) can safely induce responses in B-NHL with little non-hematologic toxicity. We hypothesized that 90Y-ibritumomab tiuxetan-based NMAT would safely facilitate early cytoreduction in such patients promoting improved long-term disease control by the allogeneic graft which would also abrogate the hematologic toxicity of the RIT. Patients and Methods: Forty patients with relapsed, high-risk B-NHL and persistent disease who were not deemed appropriate for standard NMAT due to disease factors and not considered appropriate for myeloablative transplant due to age, pretreatment, or co-morbidities were enrolled in this phase II trial. Conditioning included 0.4 mCi/kg (max 32mCi) 90Y-ibritumomab tiuxetan (day-14), fludarabine (days -7 to -5) and 2 Gy total body irradiation (day 0) followed by transplantation from matched related (n=15) or unrelated (n=25) donors along with post-grafting immunosuppression with cyclosporine and mycophenolate mofetil. Baseline features included: median age = 58 years (range 29–69 years), median prior regimens = 6 (range 3 to 12), chemosensitive disease = 6 (15%), CR pretransplant = 0 (0%), bulk 〉5 cm = 17 (range 5.2–18.6cm, 43%), 〉25% bone marrow involvement with B-NHL = 10 (25%, range of marrow involvement 40–95%), comorbidity score ≥1 = 35 (85%), median comorbiditiy score 3 (range 0–10), pretransplant IPI ≥3=21 (53%). Histologies included: DLBCL (14, including 6 that had transformed from indolent disease), CLL/SLL (10), mantle cell lymphoma (8), FL (6), hairy cell leukemia (1), and marginal zone lymphoma (1). Results: Early objective responses attributable to the conditioning regimen at 1 and 3 months were observed in 19 (48%, 3 CR/CRU, 16 PR) and 24 (60%, 13 CR/CRU, 11 PR) patients, respectively, including 17 (59%) objective responses in the 29 patients with known chemoresistant disease and 10 (59%) of 17 with bulk 〉 5cm. In total, 33 (83%) patients experienced reduction in the measurable disease burden by day 84. The estimated OS and PFS at 30 months were 54.1%, and 31.1%, respectively. The regimen was well tolerated and all patients experienced sustained engraftment with no graft rejection. The neutrophil and platelet nadirs were 50/μ L and 12,000/μ L and occurred a median of 12 and 8 days after transplant, respectively. The median duration of neutropenia

Description: PURPOSE: Autologous stem cell transplantation (ASCT) is the standard of care for patients with chemosensitive relapsed or refractory diffuse large B-cell lymphoma (DLBCL). However, even with this aggressive approach, 40-70% of patients will still relapse. Many conventional conditioning regimens employ a combination of chemotherapy +/- total body irradiation (TBI), with further dose escalation limited by non-hematological toxicities. CD20-targeted radioimmunotherapy (RIT) delivers high doses of tumor-localized radiation with relative sparing of vital organs and has been successfully utilized to improve the efficacy and reduce the normal organ toxicity of ASCT. Based on the radiosensitivity of DLBCL and the reduced cross-resistance with chemotherapy, we hypothesized that RIT-based ASCT would improve survival outcomes for patients with relapsed/refractory DLBCL. PATIENTS AND METHODS: We performed a prospective phase II trial utilizing RIT-based myeloablative conditioning with high-dose I-131 tositumomab (to deliver ≤25 Gy to critical normal organs), cyclophosphamide (100mg/kg) and etoposide (60mg/kg) followed by ASCT in patients with relapsed/refractory DLBCL. Additionally, based on retrospective chart review, we identified and evaluated 61 eligibility-matched control patients who underwent myeloablative conditioning with TBI (12Gy), cyclophosphamide (100mg/kg), and etoposide (60mg/kg) at our Center during the trial enrollment period. RESULTS: From October 1999 to May 2011, we treated 27 DLBCL patients on this phase II trial. Baseline patient characteristics included advanced disease (89%), IPI≥2 (52%), and a median age of 51.4 years (range 31.9-59.1). The vast majority of patients had received prior rituximab (89%), with 59% considered rituximab refractory (defined as less than partial remission (PR) following or relapse within 6 months of rituximab therapy) and 55% experiencing relapse within 12 months of rituximab-based immunochemotherapy (R-chemo). Fifteen percent of patients achieved complete remission (CR) with their last chemotherapy regimen, 37% achieved PR, 26% had stable disease (SD) and 22% had progressive disease (PD). Patients received a median I-131 activity of 540 mCi (range 285 to 797), with lung (n=21), liver (n=4), and kidney (n=2) as the critical normal organs receiving the highest absorbed dose. Engraftment of neutrophilsand platelets occurred at a median of 13 (range 9-17) and 11 (range 7-38) days after ASCT, respectively. The 100-day non-relapse mortality was 7% (n=2), with one death due to cardiac failure and one due to respiratory failure. With a median follow up of 6.6 years (range 0.2-15.5), median overall survival (OS) was not reached and median progression free survival (PFS) was 3.5 years. Median PFS in the highest-risk patients, as defined by recurrent disease within 12 months of R-chemo (n=15) or chemorefractory relapse (n=13), was 22.6 and 10.8 months, respectively. Serial annual bone marrow evaluations did not identify any cases of treatment-associated myelodysplastic syndrome or acute myeloid leukemia. In comparison to the RIT group, the 61 eligibility-matched, TBI-conditioned control group patients were less heavily pretreated (2 vs 3 average prior regimens [p=

Description: 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.

Description: The poor survival of elderly patients with advanced AML or high-risk MDS following conventional chemotherapy, as well as their poor tolerance for high-dose regimens used in conventional myeloablative hematopoietic cell transplantation (HCT) demands innovative therapeutic approaches. Recent success achieving stable donor chimerism following infusion of allogeneic peripheral blood stem cells (PBSC) after reduced intensity (non-myeloablative) conditioning regimens affords an opportunity to safely induce a graft-vs-leukemia (GVL) effect with minimal acute morbidity. GVL effects, however, appear to be most potent in patients with low tumor burdens at the time of transplantation. We have therefore conducted a Phase I clinical trial of targeted hematopoietic irradiation delivered by an 131I-labeled anti-CD45 antibody (BC8) to determine the feasibility, safety and efficacy of this approach toward reducing the burden of disease before an established non-myeloablative regimen. In this dose escalation study designed to estimate the maximum tolerated dose of 131I-BC8 antibody that can be combined with fludarabine (FLU) and low dose total body irradiation (TBI), 33 patients over 50 years of age with advanced AML or high-risk MDS (〉 5% blasts) were treated with 246 to 932 mCi 131I delivering an estimated 5.2 to 45.9 (mean 27.5) Gy to bone marrow, 17.3 to 155 (mean 81.2) Gy to spleen, and 12–24 Gy to the liver (dose-limiting organ). Patients then received FLU (30 mg/m2 daily for 3 days), 2 Gy TBI, and HLA-matched related (n = 10) or unrelated (n = 23) PBSC grafts with graft-vs-host disease prophylaxis provided by cyclosporine and mycophenolate mofetil. The median age of patients was 61 (50–71) years. Twenty-four patients had AML, with 6 (13%) patients in second or third complete remission, 2 (4%) with primary refractory disease, and 16 (35%) in relapse. Nine (20%) patients had MDS with 〉5% blasts. Treatment with the 131I-BC8 Ab/FLU/TBI regimen produced a remission in all patients, and all had 100% donor CD3+ and CD33+ cell engraftment by day 28 post-transplant. The absolute neutrophil count surpassed 500/uL at a median of 14 (range, 10–19) days, and the self-sustained platelet count surpassed 20,000/uL at a median of 17 days (range, 15–43). Eighteen patients (55%) are surviving disease-free 2 to 16 months (median 9.5 months) post-transplant. In 9 (27%) patients, the disease relapsed 3 to 38 months after HCT. The day-100 non-relapse mortality was 12%. This study demonstrates that at least an average of 27 Gy of targeted radiotherapy can be delivered to bone marrow and an average of 81 Gy to the spleen, in addition to a standard reduced intensity transplant regimen, without a marked increase in day 100 mortality. Whether this approach will reduce post-transplant relapse rates for older patients with high-risk AML/MDS remains to be determined.

Description: Pretargeted radioimmunotherapy (PRIT) is designed to enhance the directed delivery of radionuclides to malignant cells. Through a series of studies in 19 nonhuman primates (Macaca fascicularis), the potential therapeutic advantage of anti-CD45 PRIT was evaluated. Anti-CD45 PRIT demonstrated a significant improvement in target-to-normal organ ratios of absorbed radiation compared with directly radiolabeled bivalent antibody (conventional radioimmunotherapy [RIT]). Radio-DOTA-biotin administered 48 hours after anti-CD45 streptavidin fusion protein (FP) [BC8 (scFv)4SA] produced markedly lower concentrations of radiation in nontarget tissues compared with conventional RIT. PRIT generated superior target:normal organ ratios in the blood, lung, and liver (10.3:1, 18.9:1, and 9.9:1, respectively) compared with the conventional RIT controls (2.6:1, 6.4:1, and 2.9:1, respectively). The FP demonstrated superior retention in target tissues relative to comparable directly radiolabeled bivalent anti-CD45 RIT. The time point of administration of the second step radiolabeled ligand (radio-DOTA-biotin) significantly impacted the biodistribution of radioactivity in target tissues. Rapid clearance of the FP from the circulation rendered unnecessary the addition of a synthetic clearing agent in this model. These results support proceeding to anti-CD45 PRIT clinical trials for patients with both leukemia and lymphoma.

Description: We conducted a study to estimate the maximum tolerated dose (MTD) of 131I–anti-CD45 antibody (Ab; BC8) that can be combined with a standard reduced-intensity conditioning regimen before allogeneic hematopoietic cell transplantation. Fifty-eight patients older than 50 years with advanced acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) were treated with 131I-BC8 Ab and fludarabine plus 2 Gy total body irradiation. Eighty-six percent of patients had AML or MDS with greater than 5% marrow blasts at the time of transplantation. Treatment produced a complete remission in all patients, and all had 100% donor-derived CD3+ and CD33+ cells in the blood by day 28 after the transplantation. The MTD of 131I-BC8 Ab delivered to liver was estimated to be 24 Gy. Seven patients (12%) died of nonrelapse causes by day 100. The estimated probability of recurrent malignancy at 1 year is 40%, and the 1-year survival estimate is 41%. These results show that CD45-targeted radiotherapy can be safely combined with a reduced-intensity conditioning regimen to yield encouraging overall survival for older, high-risk patients with AML or MDS. This study was registered at www.clinicaltrials.gov as #NCT00008177.

Description: 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.