ALBERT

Description: Since NHL is radiosensitive, total body irradiation (TBI) has been used as part of HDT and ASCT for NHL. However, due to short-term and long-term toxicity associated with TBI, alternative regimens have been developed. We have reported that Zevalin at conventional and high doses can be given in combination with HDT and ASCT in patients (pts) with poor-risk or relapsed B-cell NHL without additional toxicity. Given the efficacy of Zevalin in FL and DLBCL, we retrospectively evaluated the outcome of HDT and ASCT in pts with FL and DLBCL who received Zevalin-based HDT regimens (Z-ASCT) and compared to those receiving TBI-based regimen (TBI-ASCT)Between 1/2000 to 1/2006, 187 pts with FL grade I/II (30), FL grade III (20) and DLBCL (137) underwent HDT and ASCT, 62 received Z-ASCT while 125 received TBI-ASCT. For Z-ASCT, pts 〈 60 years old without prior radiotherapy (RT) received high-dose Zevalin in combination with high-dose etoposide and cyclophosphamide while pt 〉 60 yrs or with prior RT received conventional dose Zevalin plus high-dose BEAM. TBI-ASCT was performed during the same period for the following reasons: ineligible for Z-ASCT, pt refusal, physician preference and protocol closure. The pt characteristics between the two groups were similar with respect to histology, disease status, prior regimens, bulky disease, B symptoms and performance status. However, the median age was younger for TBI-ASCT (49 vs. 53, p=0.01) and there were more chemo-resistant pts in the Z-ASCT group (p=0.01). Results: At a median follow-up of 28 months (range 2–64) for Z-ASCT and 38 months (range 1–78) for TBI-ASCT, the 2-year overall survival (OS) and disease-free survival (DFS) were 91% (95% CI, 82–96) and 74% (95% CI, 64–82), respectively for Z-ASCT, and 76% (95% CI, 69–80) and 72% (95% CI, 65–77), respectively for TBI-ASCT(Figure 1). OS remained significantly different when first complete remission pts were excluded from analysis (p=0.019). Multivariate models were generated for the primary endpoints of the study (OS and DFS). The results of these analyses showed that the risk of death and/or relapse was less among the Z-ASCT pts after adjusting for baseline differences (ie. Age, performance status and chemosensitivity status at transplant), and other factors (i.e., disease status at transplant, number of previous chemotherapies) previously shown to be associated with survival/disease free survival post transplant (OS: p

Description: Background: ASCT is an effective treatment for patients with high risk NHL. However, relapse rates remain high. Attempts at further dose intensification are limited by regimen-related toxicity especially in older patients. Zevalin as a single agent has showed activity in aggressive Non-Hodgkin’s Lymphoma (NHL). We therefore, devised a novel conditioning regimen (Z-BEAM) combining standard dose Zevalin (0.4mci/kg) with high dose BEAM (BCNU 150mg/m2 day-7,-6, cytarabine 800mg/m2 and etoposide 800mg/m2 day-5 to day-2, and melphalan 140mg/m2 day-1). Herein, we provide an update on the study and also retrospectively compare this new conditioning regimen with conventional high dose BEAM in older patients (age 〉=50). Between 1995 and 2005, 65 patients (BEAM n=32, Z-BEAM n=33) underwent ASCT utilizing these regimens. Patient selection was similar for Z-BEAM and BEAM. Patients received BEAM prior to the opening of the Z-BEAM protocol and similiarly after the Z-BEAM protocol completed accrual. The groups were well matched for most demographics and disease status. Median age: Z-BEAM - 62 yrs (range 50–78), BEAM - 64 yrs (range 50–77); 1st CR/PR pts comprised 45% in the Z-BEAM arm and 34% in the BEAM, 〉 =1st Relapse 42% vs 50% and induction failure 12% vs 15%. (p=0.7). Median number of prior regimens was 3 in the Z-BEAM group vs 2 in the BEAM arm.(p=0.08) 54 % had bulky disease at diagnosis in the Z-BEAM group vs 41% in the BEAM group (p=0.30). Results: Two-year OS was 78% for all pts (95%CI, 67–86). Two-year OS/PFS in the Z-BEAM group was 88%(95% CI, 70–95)/72 %(95% CI, 57–83) respectively vs 65% (95%CI, 48–77)/ 67%( 95CI, 50–79) in the BEAM group (Figure1). Analysis by histology showed that in patients with diffuse large B-cell lymphoma (DLBCL), there was a significant difference in OS/PFS of Z-BEAM vs BEAM, 95% vs 48% at 2 yrs (p=.009)/ 88% vs 48% ( p=0.015). The OS/PFS difference of Z-BEAM vs BEAM in patients with mantle cell lymphoma did not reach significance. The toxicity profile and transplant related mortality was similar in both regimens. Conclusions: Our study suggests that the addition of Zevalin to the BEAM conditioning regimen is feasible and well tolerated in older patients. The favorable outcome of patients treated with Z-BEAM compared with BEAM alone, especially in patients with DLBCL, suggests that prospective study in a randomized trial is warranted. Overall Survival 
 ZBEAM versus BEAM Overall Survival 
 ZBEAM versus BEAM

Description: Background: Peripheral T cell lymphomas (PTCL) have a poor prognosis with current treatment regimens. High-dose chemotherapy followed by autologous stem cell transplant (ASCT) has been used as a consolidation strategy in remission states (CR1 or above) endorsed by the NCCN guidelines in appropriate patients. 5 year DFS is reported at 70% for alk -ve anaplastic large cell lymphoma (ALCL) and 30-40% for most other histologies (D'Amore et al, 2012, JCO). It is also performed in the relapsed settings if no previous ASCT performed and allogeneic transplant is not an option. CD25 is a targetable protein expressed differentially in PTCL and antibody based anti-CD25 therapies are efficacious in PTCL i.e denileukin diftitox (Foss et al Blood 2006, Dang et al , BJH 2006) , monoclonal antibody dacluzimab (Waldman et al 1995 Blood). Yttrium-90 (90Y) labeled chimeric antiCD25 antibody basiliximab emits beta particles and has been shown to inhibit the growth of human ALCL tumors and increase survival in SUDHL-1 xenograft mice (Zhang et al 2009 Cancer Biother Radiopharm). Previous investigations at COH by Raubitschek, Colcher et al established a safe does of Yttrium-90 (90Y) labeled basiliximab at 0.4mCi/kg in combination with BEAM. This is a phase 1 clinical trial of a novel conditioning regimen that includes the use of Yttrium-90 (90Y) labeled basiliximab with BEAM chemotherapy for PTCL patients eligible for ASCT. The trial utilizes a modified version of the rolling 6 design (Skolnik et al) to test 3 dose levels of Yttrium-90 (90Y) Basiliximab i.e 0.4mCi/kg, 0.5miC/kg and 0.6mCi/kg with the primary objective of evaluating the safety and tolerability of this combination and to establish the MTD. Secondary objectives include incidence of relapse, OS, PFS, NRM at day 100, 1 year and 2 years post-transplant. Patients and Methods: Dose limiting toxicity (DLT) is defined according to the Bearman and CTCAE 4.03 scales, the latter for hematologic toxicity. The study/treatment schema is shown in Figure 1. Results: From 07/29/2015 to 05/29/2018, 14 patients underwent ASCT on this trial; n=4 at 0.4mCi/kg n=4 at 0.5mCi/kg and n=6 at 0.6mCi/kg. Median age at ASCT was 51 years (range: 18-76), and histologies included; PTCL-nos (n=7); alk-ve ALCL (n=3); angioimmunoblastic T-cell lymphoma (n=2); and intestinal T-cell lymphoma (n=2). Disease status at ASCT were CR1 in12, CR2 in 2 patients. Median number of prior therapies was 1 (range: 1-2). At a median follow-up of 14.4 months (range: 0.9-26.2), 8 patients remain in remission, 4 have relapsed out of which 2 have died of progressive lymphoma. OS was 100% (95% CI: N/A) at 100-days, and89% (95% CI: 43-98) at 1 year. Non-relapse Mortality was 0% at both100-days and 1-year (95%CI: N/A) (95%CI: N/A). All patients successfully engrafted with the median days to ANC 〉= 500/ul was 11 (range: 10 - 12), and days to PLT 〉= 20,000/ul: 13 (12 - 92). No dose limiting toxicities were experienced. The most common/highest grade toxicity experienced (per Bearman Scale) was grade 2 stomatitis, which was seen in 3 patients at 0.4mCi/kg; 4 patients at 0.5 mCi/kg, and 3 at0.6mCi/kg. The only other toxicities seen were grade 2 GI in 2 patients at 0.4mCi/kg,and grade 2 bladder in one patient at 0.6mCi/kg dose.. Toxicities 〉grade 2 were not seen. Conclusion: aTac- BEAM appears to be safe as an ASCT conditioning regimen for PTCL with no increased toxicity as compared to the historical toxicities seen with BEAM alone in this patient population (D'Amore 2012 J of Clin Onc). The dose level 0.6mCi/kg will likely be the recommended phase II dose. An expanded phase is planned to evaluate the efficacy of this regimen followed by a randomized trial of BEAM alone plus a combination of aTac- BEAM. Figure 1. Figure 1. Disclosures Herrera: Seattle Genetics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Immune Design: Research Funding; KiTE Pharma: Consultancy, Research Funding; Merck, Inc.: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Research Funding; Gilead Sciences: Research Funding. Salhotra:Kadmon Corporation, LLC: Consultancy.

Description: Introduction: 18Fluoro-deoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is one of the most widely used imaging techniques to detect multiple myeloma (MM). Intracellular FDG uptake depicts in vivo metabolic activity, which can be seen in both malignant and non-malignant cells, resulting in limited sensitivity and specificity. Our group showed preclinically that tracing MM dissemination using a CD38-directed human antibody, daratumumab, that is radioconjugated with copper-64 via the chelator DOTA (64Cu-DOTA-Dara), led to improved sensitivity and specificity over that of FDG (Caserta et al, Blood 2018). Herein, we report the results of a Phase 1 trial (NCT#03311828) designed to 1) assess the safety and feasibility of 64Cu-DOTA-Dara PET/CT and 2) to evaluate and characterize the ability of 64Cu-DOTA-Dara to accurately detect or exclude MM lesions compared with FDG PET/CT. Methods: Patients with biopsy-proven MM and/or a plasmacytoma received an FDG PET/CT scan within 60 days of enrollment. On Day 0, patients were infused with unlabeled ("cold") Dara at one of four dose levels (0 mg, 10 mg, 45 mg, 95 mg) to optimize biodistribution of radioconjugated 64Cu-DOTA-Dara, especially in the liver and the spleen. Within 6 hours of unlabeled Dara administration, patients received 64Cu-DOTA-Dara at a dose of 13.63-16.68 mCi (~5 mg). Whole-body PET scans were obtained at 24 hours and at 48 hours (the latter scan encompassing known tumors). 64Cu-DOTA-Dara standardized uptake values (SUV) were evaluated in MM lesions and normal organs, which were then compared with values from standard FDG PET/CT. Biopsies were performed on accessible discordant lesions. Results: A total of 10 Dara-naïve patients were imaged. Patients were treated with 0 (n=3), 10 (n=3), 45 (n=3), or 95 mg (n=1) of unlabeled Dara. Four patients had newly diagnosed disease, one had biochemical relapse, one had a recurrent plasmacytoma by MRI, and four had possible recurrence by standard PET/CT. No significant adverse events were observed from either cold or 64Cu-DOTA-Dara. With the exception of the one patient with a recurrent plasmacytoma, radiolabeled antibody was eliminated from systemic circulation in subjects analyzed at the first three dose levels within 30 min post injection. In the patient with a recurrent plasmacytoma, the radiolabeled antibody was elevated in the blood for over two days. One newly diagnosed patient had extensive disease by FDG PET and had a biopsy-proven target lesion in the sternum, which had an SUVmax of 14.7 on 64Cu-DOTA-Dara PET/CT vs. 3.3 onFDG PET/CT. A second biopsy from the same patient was taken from a discordant iliac crest lesion (positive for 64Cu-DOTA-Dara but negative for FDG PET/CT) that showed 20-30% MM cell infiltration. In another patient, an iliac crest lesion was 64Cu-DOTA-Dara positive and FDG-negative; biopsy revealed 6% plasmacytosis in the bone. A third patient had an FDG PET/CT positive pleural lesion with an SUVmax of 8.98 and negative on 64Cu-DOTA-Dara (Figure 1A). The lesion did not show recurrence upon biopsy. Furthermore, 64Cu-DOTA-Dara PET/CT yielded superior imaging of bone lesions in the calvarium (Figure 1B). Escalating doses of unlabeled Dara decreased liver and spleen uptake by 64Cu-DOTA-Dara. Conclusions: In this ongoing study, 64Cu-DOTA-Dara PET/CT imaging is to date safe and provides whole body imaging of MM. Further dose escalation of cold Dara (145 mg, 195 mg) is planned to optimize background interference. This modality has the potential to improve sensitivity and specificity over FDG PET/CT scanning in early-stage MM as well as in recurrent disease. Disclosures Krishnan: Celgene, Janssen, Sanofi, BMS: Consultancy; Sutro BioPharma, zPredicta: Consultancy; Amgen, Takeda: Speakers Bureau; Celgene, Z Predicta: Other: Stock Ownership; Takeda: Research Funding. Palmer:Gilead Sciences: Consultancy. Rosenzweig:Celgene, Takeda: Speakers Bureau. Wu:ImaginAb, Inc.: Consultancy, Other: Board Member.

Description: The treatment of high-risk MCL remains a challenge. High dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has been used for some of these patients (pts). However, relapse rates remain high. RIT with single agent 90Yttrium(90Y) ibritumomab tiuxetan (Zevalin®) has demonstrated activity in pts with relapsed MCL. Therefore, we postulated that the combination of 90Y with HDC and ASCT may reduce relapse rates of pts with high- risk MCL. Between 5/00 and 9/04 eighteen pts with MCL were enrolled on one of two RIT ASCT trials. The first was a phase I/II dose escalation trial of high-dose 90Y + cyclophosphamide 100mg/kg (day -4) and etoposide 60mg/kg(day-2). Pts underwent dosimetry day-21 with 5mCi Indium111 followed a week later by 90Y to deliver a maximum target dose of 1000cGy to normal organs. The second study was a phase I/II trial of standard dose 90Y (0.4mCi/kg) administered day-14 and BEAM (day-8 to day-2, BCNU300mg/m2, cytarabine 800mg/m2, etoposide 800mg/m2, melphalan 140mg/m2). Ten pts who were〉60yrs or had received prior dose-limiting radiation were placed on the 90Y BEAM trial while the other 8 received high-dose 90Y. The median age at ASCT was 58 years (range 44–72). Disease status at ASCT included 1st CR -9(high or high intermediate IPI score), 1st PR-4, 1st relapse -4, 2nd CR-1. Fifty percent had received HyperCEVAD chemotherapy and 56% had Rituximab prior to ASCT. Thirteen pts had stage IV disease, 5 had stage III disease. The median 90Y dose administered was 40mCi (range 27–100). Treatment was well tolerated. Engraftment to anc〉500 occurred at a median of 10 days (range 9–26). Reversible grade 3 pulmonary toxicity occurred in 5 pts. This included steroid responsive pneumonitis in four and acute respiratory distress related to sepsis in one. One pt with a prior history of heavy alcohol use died of liver failure at four months post ASCT. Four pts have relapsed and two have died of disease progression. With a median follow up of 19 months (range 6–60), the estimated overall survival and disease free survival at two years are 79% (CI 55–91) and 59% (CI 43–73) respectively. By univariate analysis 90Y dose did not correlate with risk of relapse. To date, no relapses were seen beyond the first twelve months (see figure). In conclusion 90Y based transplant conditioning regimens are well tolerated, even in older pts. The apparent plateau in the relapse rate is encouraging and suggests that this approach may lead to durable remissions in pts with high-risk MCL. Figure Figure

Description: Background: Peripheral T cell lymphomas (PTCL) have a poor prognosis with current treatment regimens. High-dose chemotherapy followed by autologous stem cell transplant (ASCT) has been used as a consolidation strategy in remission states (CR1 or above) endorsed by the NCCN guidelines in appropriate patients. 5-year DFS is reported at 70% for alk -ve anaplastic large cell lymphoma (ALCL) and 30-40% for most other histologies (D'Amore et al, 2012, JCO). It is also performed in the relapsed settings if no previous ASCT performed and allogeneic transplant is not an option. CD25 is a targetable protein expressed differentially in PTCL and antibody based anti-CD25 therapies are efficacious in PTCL i.e denileukin diftitox (Foss et al Blood 2006, Dang et al, BJH 2006) , monoclonal antibody dacluzimab (Waldman et al 1995 Blood). Yttrium-90 (90Y) labeled chimeric antiCD25 antibody basiliximab emits beta particles and has been shown to inhibit the growth of human ALCL tumors and increase survival in SUDHL-1 xenograft mice (Zhang et al 2009 Cancer Biother Radiopharm). Previous investigations at COH by Raubitschek, Colcher et al established a safe does of Yttrium-90 (90Y) labeled basiliximab at 0.4mCi/kg in combination with BEAM. This is a phase 1 clinical trial of a novel conditioning regimen that includes the use of Yttrium-90 (90Y) labeled basiliximab with BEAM chemotherapy for PTCL patients eligible for ASCT. The trial utilizes a modified version of the rolling 6 design (Skolnik et al) to test 3 dose levels of Yttrium-90 (90Y) Basiliximab i.e 0.4mCi/kg, 0.5miC/kg and 0.6mCi/kg with the primary objective of evaluating the safety and tolerability of this combination and to establish the MTD. Secondary objectives include estimating incidence of relapse, OS, PFS, NRM at day 100, 1 year and 2 years post-transplant. Patients and Methods: Dose limiting toxicity (DLT) is defined according to the Bearman and CTCAE 4.03 scales, the latter for hematologic toxicity. The study/treatment schema is shown in Figure 1. Results: From 07/29/2015 to 06/10/2020, 20 patients underwent ASCT on this trial; n=4 at 0.4mCi/kg n=4 at 0.5mCi/kg and n=12 at 0.6mCi/kg. Median age at ASCT was 51 years (range: 18-76), and histologies included; PTCL-nos (n=10); alk-ve ALCL (n=5); angioimmunoblastic T-cell lymphoma (n=3); and intestinal T-cell lymphoma (n=2). Disease status at ASCT were CR1 in18, CR2 in 2 patients. Median number of prior therapies was 1 (range: 1-4). At a median follow-up of 17.1 months (range: 0.9-26.2), 12 patients remain in remission, 8 have relapsed out of which 5 have died of progressive lymphoma. OS was 100% (95% CI: N/A) at 100-days, and 83% (95% CI: 57-94) at 1 year. Non-relapse Mortality was 0% at both 100-days and 1-year. All patients successfully engrafted with the median days to ANC 〉= 500/ul was 10 (range: 10 - 21), and days to PLT 〉= 20,000/ul: 13 (12 - 92). Overall, no dose limiting toxicities were experienced. The most common/highest grade toxicity experienced (per Bearman Scale) was grade 2 stomatitis, which was seen in 3 patients at 0.4mCi/kg; 4 patients at 0.5 mCi/kg, and 7 at0.6mCi/kg. The only other toxicities seen were grade 2 GI in 2 patients at 0.4mCi/kg, and grade 2 bladder in one patient at 0.6mCi/kg dose.. Toxicities 〉grade 2 were not seen. Conclusion: aTac- BEAM appears to be safe as an ASCT conditioning regimen for PTCL with no increased toxicity as compared to the historical toxicities seen with BEAM alone in this patient population (D'Amore 2012 J of Clin Onc). The dose level 0.6mCi/kg will likely be the recommended phase II dose. An expanded phase is planned to evaluate the efficacy of this regimen followed by a randomized trial of BEAM alone plus a combination of aTac- BEAM. Figure 1 Disclosures Zain: Mundi Pharma: Research Funding; Seattle Genetics: Research Funding; Kyowa Kirin: Research Funding. Herrera:Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Immune Design: Research Funding; AstraZeneca: Research Funding; Karyopharm: Consultancy; Pharmacyclics: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Merck: Consultancy, Research Funding. Salhotra:Kadmon: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Nakamura:NapaJen Pharma: Consultancy; Celgene: Other: Support on seminar; Magenta Therapeutics: Other: Advisory board meeting; Viracor: Consultancy; Merck: Other: advisory board meeting; Alexion: Other: Support on a meeting presentation; Kyowa-Kirin: Other: Support on a meeting presentation; Kadmon Corporation: Other: Advisory board meeting. OffLabel Disclosure: Yittrium labelled Basiliximab