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Background: Despite recent advances in the treatment of HL, an unmet medical need remains, particularly for patients with R/R disease. The alkylating deacetylase inhibitor molecule tinostamustine (EDO-S101) is a novel multi-action therapy designed to improve drug access to DNA strands, induce DNA damage and counteract its repair in cancer cells. Data from a dose-escalation study in patients with R/R haematological malignancies indicate that tinostamustine was well tolerated, with signals of efficacy observed(Zinzani PL, et al. 24 th Congress of the European Hematology Association. 13-16 June 2019. Amsterdam, The Netherlands. Abstract PF300; Pinto A, et al. Hematological Oncology. 2019; 37(S2):Abstract 273). Aims: Here we report findings from the cohort-expansion stage of a Phase I study to evaluate the safety, pharmacokinetics and efficacy of tinostamustine in heavily pre-treated patients with R/R HL (NCT02576496). Methods: Recruitment to the expansion cohort was conducted in two stages, with recruitment continuing only if sufficient response to tinostamustine was observed. Patients received the recommended Phase II dose (RP2D) of tinostamustine as determined in the dose-expansion stage of the study, according to their baseline platelet count: 80mg/m 2 (>100 x 10 9/l to 500 ms, or prolongations that represented an increase >60 ms from baseline, that were not transient or occurred in more than 1 cycle. Results: A total of 14 patients with R/R HL were recruited to the expansion cohort. Patients had a median age of 36.5 (range 25.0-74.0) years, were predominantly male (n/N=10/14, 71.4%) with an ECOG Performance Status of 0 (10/14, 71.4%) and had received a median of 5 (range 3-8) lines of prior therapy; 9/14 (64.3%) had refractory disease. Tinostamustine was well tolerated with no unexpected AEs observed. Treatment-emergent adverse events (TEAEs) were principally haematological (43 events in 7/14 patients; 50%) including thrombocytopenia, neutropenia, anaemia and lymphopenia. In addition, 9/14 patients experienced 23 gastrointestinal disorders, the majority of which were nausea or vomiting. Five patients (35.7%) experienced 6 serious TEAEs that were considered related to tinostamustine, including thrombocytopenia (n=1) and infusion-related reaction (n=1). A total of 4/14 patients (33.3%) discontinued treatment due to TEAEs (thrombocytopenia: n=3), whilst 5/14 patients (41.7%) discontinued due to progressive disease; mean ± SD time to disease progression was 147.5 ± 84.7 days. No fatal TEAEs, or incidences of within-cycle QTc prolongations ≥500 ms, or increases from baseline ≥60 ms, were observed. Patients received a median of 4.5 (range 1-12) cycles of tinostamustine. ORR was 36% (5/14 patients; 95% confidence interval: 13%, 65%); 5/14 patients achieved a PR following a median of 4 (range 3-6) cycles. 7/14 patients experienced stable disease following a median of 6 (range 3-12) cycles. Conclusions: Administration of tinostamustine on Day 1 of a 21-day cycle to patients with R/R HL was well tolerated with no unexpected AEs. Signals of efficacy were observed with an ORR of 36%. Tinostamustine is a promising new agent warranting further investigation in a larger HL patient cohort. Funding: Mundipharma Research Disclosures Ghesquieres: Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Gilead Sciences: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Mundipharma Research Limited: Consultancy, Honoraria; Takeda: Other: Travel, accommodation, expenses; Celgene: Consultancy, Honoraria, Other: Travel, accommodation, expenses. Pinto: Bristol-Myers Squibb, F. Hoffmann-La Roche, Ltd, Janssen, Celgene, Gilead Sciences, and Mundipharma EDO: Honoraria, Speakers Bureau; Bristol-Myers Squibb, F. Hoffmann-La Roche, Ltd, Celgene, Gilead Sciences, and Mundipharma EDO: Membership on an entity's Board of Directors or advisory committees; Mundipharma EDO: Other: intellectual property , Patents & Royalties; F. Hoffmann-La Roche Ltd: Other: travel, accommodations, or expenses . Sureda: GSK: Consultancy, Honoraria, Speakers Bureau; Bluebird: Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Mundipharma: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau. Morschhauser: Janssen: Honoraria; Roche: Consultancy, Speakers Bureau; Chugai: Honoraria; Genmab: Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Janik: Mundipharma Research Limited: Current Employment. Zinzani: SERVIER: Other: Advisory board, Speakers Bureau; EUSAPHARMA: Consultancy, Other, Speakers Bureau; ROCHE: Other, Speakers Bureau; TAKEDA: Other: Advisory board, Speakers Bureau; TG Therapeutics: Other: Advisory board, Speakers Bureau; MSD: Consultancy, Other: Advisory board, Speakers Bureau; SANDOZ: Other: Advisory board; GILEAD: Other: Advisory board, Speakers Bureau; JANSSEN-CILAG: Other: Advisory board, Speakers Bureau; BMS: Other: Advisory board, Speakers Bureau; CELLTRION: Other: Advisory board, Speakers Bureau; KYOWA KIRIN: Other, Speakers Bureau; NOVARTIS: Consultancy, Other, Speakers Bureau; ADC Therap.: Other; Incyte: Other, Speakers Bureau; Beigene: Other, Speakers Bureau; VERASTEM: Consultancy, Other: Advisory board, Speakers Bureau. OffLabel Disclosure: Tinostamustine is not register for the treatment of Hodgkin Lymphoma

Introduction The kidney is an important target organ in plasma cell dyscrasias, subjected to various mechanisms of injury such as tubular obstruction, hypercalcemia, and pre-existing disease. Preservation of kidney function in newly diagnosed (ND) multiple myeloma (MM) is of concern as treatment-related toxicity (for instance infections and mucositis) is known to increase with renal impairment (RI). However, even severe MM-induced RI may recover with anti-myeloma treatment. We set out to compare three induction regimens in patients (pts) with transplant-eligible NDMM in terms of renal recovery and toxicity, MM response and associated adverse events (AEs). Pts from two prospective trials (NCT00833560, NCT01685814) were analyzed, provided post-induction (PInd) restaging data was available. They received three 3-week induction cycles with bortezomib (btz), cyclophosphamide, and dexamethasone (dex; VCD); btz, lenalidomide (len), and dex (VRD); or three 4-week cycles with len, adriamycin, and dex (RAD). All pts had to have measurable disease, an estimated glomerular filtration rate (eGFR) of >30 ml/min and to be up to 60 (VCD) and 65 years (yrs) of age, respectively. VCD consisted of intravenous (IV) btz 1.3 mg/m² on day (D) 1, 4, 8, 11; IV cyclophosphamide 900 mg/m2D1; dex 20 mg D 1+2, 4+5, 8+9, 11+12. VRD of subcutaneous (SQ) btz 1.3 mg/m² D 1, 4, 8, 11; len 25 mg, D1-14; dex 20 mg D 1+2, 4+5, 8+9, 11+12; and RAD of len 25 mg D1-21; IV adriamycin 9 mg/m² D1-4; dex 40 mg D 1-4 + 17-20. MethodsThis is a secondary analysis of a phase 2 and a phase 3 study. We hypothesized MM disease response (and in turn, renal recovery) would be best with VRD. GFR was estimated by the MDRD IV or CKD-Epi formulas. The increase (and decrease, respectively) of renal function expressed by "GFRpost induction- GFRscreening" was tested for significance (p 50 ml/min and ≤ 70 ml/min (group II) were observed in 11.6 % of VCD pts, 29.9% of VRD and 25.2 % of RAD pts, respectively. 78.2% of VCD pts, 56.1% of VRD and 63.9% of RAD pts had a baseline eGFR of > 70 ml/min (group III; pPR (p=.0387). In the whole cohort, proportion of patients in eGFR group I had decreased from 10.0 to 3.0% (p +2 ml/min(/1.73m²)/month, respectively. 25.7% of VCD, 29.4% of VRD and 23.3% of RAD pts fell into the +2 ml/min was achieved by 55.2% of VCD vs 42.1% of VRD treated pts, respectively (Figure 1; p +2 ml/min(/1.73m²)/month. It is tempting to speculate that either the difference between SQ and IV btz, differential effects of len and cyclophosphamide on kidney function or non-MM related factors account for these unexpected and discordant renal and MM responses. Kidney-specific AEs, urine protein studies and comorbidities will be presented. Disclosures Mügge: Celgene: Research Funding; Celgene, Janssen: Honoraria. Schreder:Janssen, Celgene: Consultancy, Honoraria. Schaefer-Eckart:Pfizer, Janssen, Celgene: Honoraria. Metzler:Bristol-Myers Squibb, Celgene: Consultancy, Honoraria. Hertenstein:RS Media: Research Funding. Maschmeyer:Gilead, Janssen Cilag, Astra Zeneca; BMS, Merk-Serono: Honoraria. Salwender:Janssen Cilag: Consultancy, Honoraria, Other: Travel grants; Celgene: Honoraria, Other: Travel grants; AMGEN: Honoraria, Other: Travel grants; Sanofi: Honoraria, Other: Travel grants; Bristol-Myers Squibb: Honoraria, Other: Travel grants; Takeda: Honoraria, Other: Travel grants; Oncopeptides: Honoraria, Other: Travel Grants. von Lilienfeld-Toal:Celgene, Oncopeptides: Consultancy, Honoraria. Straka:Celgene, Janssen, AMGEN: Consultancy, Research Funding, Speakers Bureau. Knop:Janssen, AMGEN, Bristol-Myers Squibb, Celgene: Consultancy, Honoraria. OffLabel Disclosure: Lenalidomide, adriamycin, dexamethsone in newly diagnosed multiple myeloma

Human T-cell leukemia virus type 1–associated adult T-cell leukemia/lymphoma (ATL) typically has survivals measured in months with chemotherapy. One prior published series (1983-1991) assessed local radiotherapy for ATL. Ten consecutive patients with pathologically confirmed ATL treated with radiotherapy were reviewed. Subtypes included acute (n = 7), smoldering (n = 2), and lymphomatous (n = 1). Patients received an average of 2.5 systemic therapy regimens before radiotherapy. Twenty lesions (cutaneous = 10, nodal = 8, extranodal = 2) were treated to a mean of 35.4 Gy/2-3 Gy (range, 12-60 Gy). At 9.0-month mean follow-up (range, 0.1-42.0 months), all lesions symptomatically and radiographically responded, with in-field complete responses in 40.0% (nodal 37.5% vs cutaneous 50.0%; P = .62). No patient experienced in-field progression. Nine patients developed new/progressive out-of-field disease. Median survival was 17.0 months (3-year survival, 30.0%). No Radiation Therapy Oncology Group acute grade ≥ 3 or any late toxicity was noted. This report is the first to use modern radiotherapy techniques and finds effective local control across ATL subtypes. Radiotherapy should be considered for symptomatic local progression of ATL.

Despite many therapeutic advances in recent years Multiple Myeloma (MM) still remains incurable in the majority of the patients. In addition, MM patients suffer significantly from co-morbidities including bone pain and renal insufficiency. Therefore, the development of novel treatments is warranted. The TAMR family consists of Tyro3, Axl and Mer which represent evolving targets in cancer. We demonstrated that the role of TAMR is non-redundant in hematologic malignancies, with Axl exerting an important function in AML, but not in MM, where Mer represents a novel target. Therefore, we tested the therapeutic potential of the Mer-inhibitor R992, which has an 8-fold selectivity over Tyro3 and a 13-fold selectivity over Axl in preclinical MM models (Rigel, San Francisco, USA). R992 exerted a dose-dependent growth inhibition of U266, JJN3 and RPMI8226 cells in vitro (n=3, *p Oral administration of 60mg/kg R992 BID to mice significantly reduced tumor burden in the U266 systemic myeloma mouse model. The λ light chain concentration and the CD138+ MM cell load was reduced 2-fold in R992 treated mice compared to placebo-treated mice 8 weeks after injection (n=5/5, *p For further phenotyping of the effects of R992 we performed microcomputed tomography (µCT) and histological analysis of the tibias in the U266 model. µCT analysis of proximal tibia metaphyses revealed, that bone volume and bone mineral density (BMD) were significantly increased by R992 (n=7/7, *p To directly assess the effect of R992 on osteoclasts, we treated osteoclast cultures with R992 and observed an inhibition of osteoclast differentiation by R992 alone and in co-culture with myeloma cells. Western blot analysis confirmed, that Mer phosphorylation was reduced by R992, whereas the phosphorylation of Tyro3 was not altered. Concomitantly, phosphorylation of p38 and activation of non-canonical NFκB pathway showed a dose dependent reduction after Mer blockade. Interestingly, R992 led also to increased osteoblast differentiation and could restore myeloma mediated osteoblast inhibition in co-cultures of MM cells and osteoblasts. In summary, our data suggest that Mer blockade leads to inhibition of MM and its associated bone disease. Furthermore, the function of Mer in bone homeostasis promoting osteoclast and inhibiting osteoblast activity leads to the potential application of Mer inhibitors also in osteolytic bone metastases or osteoporosis. Disclosures Darwish: Rigel Pharmaceuticals: Employment. Bhamidipati:Rigel Pharmaceuticals: Employment. Masuda:Rigel Pharmaceuticals: Employment, Equity Ownership. Loges:BerGenBio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

We hypothesized that incremental improvements in the cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) chemotherapy regimen through optimization of drug selection, schedule, and pharmacokinetics would improve outcome in patients with large B-cell lymphomas. A prospective multi-institutional study of administration of etoposide, vincristine, and doxorubicin for 96 hours with bolus doses of cyclophosphamide and oral prednisone (EPOCH therapy) was done in 50 patients with previously untreated large B-cell lymphomas. The doses of etoposide, doxorubicin, and cyclophosphamide were adjusted 20% each cycle to achieve a nadir absolute neutrophil count below 0.5 × 109/L. The median age of the patients was 46 years (range, 20-88 years); 24% were older than 60 years; and 44% were at high-intermediate or high risk according to International Prognostic Index (IPI) criteria. There was a complete response in 92% of patients, and at the median follow-up time of 62 months, the progression-free survival (PFS) and overall survival (OS) rates were 70% and 73%, respectively. Neither IPI risk factors nor the index itself was associated with response, PFS, or OS. Doses were escalated in 58% of cycles, and toxicity levels were tolerable. Significant inverse correlations were observed between dose intensity and age for all adjusted agents, and drug clearance of doxorubicin and free etoposide was also inversely correlated with age (r = −0.54 andP2 = .08 and r = −0.45 andP2 = .034, respectively). Free-etoposide clearance increased significantly during successive cycles (P2 = .015). Lymphomas with proliferation of at least 80% had somewhat lower progression and those expressing bcl-2 had significantly higher progression (P2 = .04). Expression of bcl-2 may discriminate the recently described activated B-like from germinal-center B-like large-cell lymphomas and provide important pathobiologic and prognostic information. Dose-adjusted EPOCH may produce more cell kill than CHOP-based regimens. Dynamic dose adjustment may overcome inadequate drug concentrations, particularly in younger patients, and compensate for increased drug clearance over time.

In the present study, Hu-Mikβ1, a humanized mAb directed at the shared IL-2/IL-15Rβ subunit (CD122) was evaluated in patients with T-cell large granular lymphocytic (T-LGL) leukemia. Hu-Mikβ1 blocked the trans presentation of IL-15 to T cells expressing IL-2/IL-15Rβ and the common γ-chain (CD132), but did not block IL-15 action in cells that expressed the heterotrimeric IL-15 receptor in cis. There was no significant toxicity associated with Hu-Mikβ1 administration in patients with T-LGL leukemia, but no major clinical responses were observed. One patient who had previously received murine Mikβ1 developed a measurable Ab response to the infused Ab. Nevertheless, the safety profile of this first in-human study of the humanized mAb to IL-2/IL-15Rβ (CD122) supports its evaluation in disorders such as refractory celiac disease, in which IL-15 and its receptor have been proposed to play a critical role in the pathogenesis and maintenance of disease activity. The protocol is registered with www.clinicaltrials.gov as number NCT 00076180.

The occurrence of delayed neutropenia following rituximab is poorly defined and of unknown cause. We hypothesized it may be related to perturbations of stromal derived factor-1 (SDF-1) and granulocyte homeostasis. Late-onset neutropenia (LON) was investigated in 130 patients with untreated aggressive B-cell lymphoma receiving DA-EPOCH (dose-adjusted etoposide, prednisone, Oncovin [vincristine], cyclophosphamide, and hydroxydaunorubicin) chemotherapy with or without rituximab. All patients were in remission and had no known causes for neutropenia. LON occurred in 6 (8%) of 76 patients receiving rituximab and 0 of 54 patients not receiving rituximab (P = .04). The median onset was 175 days (range, 77-204 days) after treatment with a median duration of 14 days (range, 11-16 days). In a subset of 24 patients, a significant correlation was found between rapid B-cell recovery and granulocyte decline over the 6-month recovery period (R = –0.53; P = .04). Rapid B-cell recovery directly correlated with prerecovery SDF-1 levels (R = 0.65; P = .015) and SDF-1 decline (R = –0.67; P = .013) after recovery. Our results suggest that early B-cell lymphopoiesis is important for B-cell recovery following rituximab, and that perturbation of SDF-1 during B-cell recovery retards neutrophil egress from the bone marrow. These findings illustrate the dual role of SDF-1 in human B-cell and granulocyte homeostasis.

Levels of serum soluble interleukin 2 receptor (sIL-2R) provide a reliable marker of disease activity in patients with hairy cell leukemia and adult T-cell leukemia/lymphoma. The malignant cells in patients with anaplastic large cell lymphoma (ALCL) express CD30 and are usually positive for expression of CD25. We measured serum sIL-2R and soluble CD30 (sCD30) levels in patients with ALCL treated with EPOCH (etoposide, prednisone, Oncovin, Cytoxan, hydroxydaunorubicin) infusional chemotherapy. Serum sCD30 levels were elevated and decreased in response to therapy as previously reported. Serum sIL-2R levels were elevated in 7 of 9 patients with ALCL and decreased in response to treatment. Baseline serum sIL-2R levels varied but correlated well with serum sCD30 levels (r = 0.97). Patients positive for the anaplastic lymphoma kinase (ALK) gene showed elevated sIL-2R levels, whereas those negative for ALK had normal serum sIL-2R levels and their tumors lacked CD25 expression. Serum sIL-2R levels were elevated in both patients with recurrent disease. (Blood. 2004;104:3355-3357)

This dose-escalation study was performed to evaluate the hematologic activity, biological effects, immunogenicity, and toxicity of PIXY321 (an interleukin-3/granulocyte-macrophage colony-stimulating factor fusion protein) administered after high-dose carboplatin (CBDCA) treatment. Patients with advanced cancers received CBDCA at 800 mg/m2 intravenously on day 0 of repeated 28-day cycles. In part A of the study, patients were treated with CBDCA alone during cycle 1 and then received PIXY321 on days 1 through 18 of cycle 2 and later cycles. In part B, patients received 18 days of PIXY321 beginning on day 1 of all CBDCA cycles, including cycle 1. PIXY321 was administered subcutaneously in 2 divided doses. Total doses of 135, 250, 500, 750, and 1,000 micrograms/m2/d were administered to successive cohorts of 3 to 6 patients in part A. In part B, patient groups received PIXY321 doses of 750, 1,000, and 1,250 micrograms/m2/d. The hematologic effects of PIXY321 were assessed in the first 2 cycles of therapy. Anti-PIXY321 antibody formation was assessed by enzyme-linked immunosorbent assay (ELISA) and neutralization assay. Of the 49 patients enrolled, 31 were fully evaluable for hematologic efficacy. When comparing the first B cycle (cycle B-1; with PIXY321) with the first A cycle (cycle A-1; without PIXY321), the fusion protein had no significant effect on platelet nadirs or duration of platelets less than 20,000/microL but was able to speed the time of recovery of platelet counts to 100,000/microL (15 v 20 days; P =.01). Significant improvements in neutrophil nadir and duration of ANC less than 500 were observed in cycles A-2 and B-1 (with PIXY321) as compared with cycle A-1 (without PIXY321). Initial PIXY321 prophylaxis (cycle A-2 and cycle B-1), enhanced the recovery of ANC to greater than 1,500/microL by an average of at least 8 days as compared with cycle A-1 (without PIXY321; P/=.004). However, positive PIXY321 hematologic effects were lost in the second course of PIXY321 among patients treated in part B. ELISA analysis showed that 92% of patients had developed neutralizing anti-PIXY321 antibodies by the completion of 2 PIXY321-containing cycles. The incidental action of PIXY321 to depress serum cholesterol levels was also abrogated during cycle B-2. We conclude that PIXY321 was active in speeding hematologic recovery but that neutralizing anti-PIXY321 antibody formation suppressed the hematologic and biochemical effects by the second cycle of PIXY321 administration. The immunogenicity of this fusion protein provides a cautionary warning that clinical development of bioengineered human molecules requires thorough testing for immune neutralization.

Abstract 3706 Despite the success of treatment of patients with refractory and relapsed Hodgkin's lymphoma with combination chemotherapy, radiation and hematopoietic stem cell transplantation, a significant fraction of patients will not respond to treatment or will subsequently relapse and succumb to Hodgkin's lymphoma (HL). We have focused on CD25, the IL-2 receptor alpha subunit, as a target for systemic radioimmunotherapy of HL. The scientific basis for this choice is that with the exception of T regs, CD25 is not expressed by normal resting lymphoid cells whereas it is expressed on both a minority of Reed-Sternberg cells and also on regulatory T cells rosetting around the Reed-Sternberg cells. We have utilized the humanized monoclonal antibody, daclizumab that targets CD25 (IL-2R alpha) armed with yttrium-90 a radionuclide that provides strong beta emissions that kill tumor cells at a distance via a crossfire effect. Patients with histologically confirmed HL and expression of CD25 in at least 10% of the cells in the lymphomatous mass were eligible. Thirty consecutive patients with HL were entered. The patients had received a median of 4 prior chemotherapy regimens and were required to have had an autologous and/or allogeneic stem cell transplant or had refused a transplant. Patients were treated with an initial dose of 10 or 15 mCi of 90Y-daclizumab depending on transplant status. After the first cycle, patients could receive 90Y-daclizumab 15 mCi per cycle every 6 to 10 weeks to complete up to a maximum of 7 doses if tolerated. A total of 98 cycles of treatment were administered to 30 patients with a median aggregate radiation dose of 40 mCi. In 30 HL patients treated with 90Y-daclizumab there were 7 partial responses and 12 complete responses. Toxicities were limited to transient bone marrow suppression and the myelodysplastic syndrome (3 cases). Responses were seen among the 5 patients whose Reed-Sternberg cells expressed CD25 as well as in those whose neoplastic cells were CD25 negative provided that the associated rosetting T regs expressed CD25. The increased efficacy compared to alternative radioimmunotherapy strategies for HL appears to reflect the increase in the target antigen, CD25, in lymphomatous masses provided by the overexpression of CD25 by associated rosetting T cells, and the use of a high energy, beta-emitting radionuclide Yttrium-90 to arm the antibody that thereby does not have to come in contact with each tumor cell but can kill cells by crossfire at a distance. In conclusion, repeated 90Y-daclizumab infusions predominantly directed toward non-malignant T cells rosetting around Reed-Sternberg cells provided effective therapy for select HL patients. Disclosures: No relevant conflicts of interest to declare.

Abstract 2865 T cells can be genetically modified to express chimeric antigen receptors (CARs) that specifically recognize the B-cell antigen CD19. Adoptive transfer of autologous T cells expressing anti-CD19 CARs is an attractive new approach for treating B-cell malignancies. We have constructed a CAR that consists of the variable regions of a mouse-anti-human-CD19 antibody coupled to the signaling domains of CD28 and CD3-zeta. We have treated 5 patients with 2 doses of 60 mg/kg of cyclophosphamide and 5 doses of 25 mg/m2 of fludarabine followed by infusions of anti-CD19-CAR-transduced T cells and administration of high-dose IL-2. All of the patients received infusions of cells that produced cytokines in a CD19-specific manner. The percentage of the infused cells that expressed the anti-CD19 CAR as measured by flow cytometry ranged from 45% to 65%. The first patient enrolled on our trial has follicular lymphoma. He was treated twice. The patient obtained a partial remission (PR) from his first course of chemotherapy, 0.4×109 anti-CD19-CAR-transduced T cells, and IL-2 (reported in Kochenderfer et al. Blood First Edition); however, he subsequently developed progressive disease, and 40 weeks after his first CAR-transduced T cell infusion he received a second course of chemotherapy followed by 2×109 CAR-transduced T cells and IL-2. The second course of treatment resulted in an additional PR and was not associated with any toxicity that could be attributed to the CAR-transduced T cells. At last follow-up, a small amount residual disease detected only by positron emission tomography remained. In this first patient, the initial treatment course resulted in eradication of blood and bone marrow B-lineage cells for 39 weeks. In contrast to the prolonged eradication of B-lineage cells after the initial treatment course, the number of polyclonal blood B cells normalized 9 weeks after the second CAR-transduced T cell infusion. CAR-transduced T cells were present at a level of 0.1% of total peripheral blood mononuclear cells (PBMCs) one month after the first CAR-transduced T cell infusion. Despite the five-fold higher dose of CAR-transduced T cells administered with the second treatment, CAR-transduced T cells were not detected in the blood one month after the second CAR-transduced T cell infusion. The second patient treated on our protocol had follicular lymphoma and had received extensive prior therapy including autologous stem cell transplantation. After an initially uncomplicated course, this patient developed pneumonia caused by culture-proven influenza A virus and died 18 days after CAR-transduced T cell infusion. Quantitative PCR was used to measure the level of CAR-transduced cells in multiple tissues obtained from this patient at autopsy. CAR-transduced cells were widely distributed with the highest levels in the spleen and bone marrow. The third patient treated on our trial obtained a complete remission of advanced chronic lymphocytic leukemia (CLL) after treatment with chemotherapy, infusion of 2×109 anti-CD19-CAR-transduced T cells, and IL-2. At the time of last follow-up, three months after treatment, adenopathy had resolved, CLL cells were not detected by flow cytometry analysis of the blood and bone marrow, and the number of normal polyclonal B cells in the blood was below normal levels. This patient had a period of fever and hypotension 7 days after cell infusion that was associated with an elevated serum interferon-gamma level of 1532 pg/mL. At the time of the hypotensive episode 7 days after cell infusion, anti-CD19-CAR-transduced cells made up 2.1% of PBMCs. The fourth patient treated on our study obtained a PR of splenic marginal zone lymphoma that continues 2 months after treatment with chemotherapy, 2×109 CAR-transduced T cells, and IL-2. This patient did not have prolonged depletion of normal B cells after treatment, and he did not have any toxicity that could be attributed to the anti-CD19 CAR-transduced T cells. We recently treated a fifth patient who has CLL. Follow-up on this patient is too short to evaluate toxicity or response. In conclusion, we have shown that adoptive transfer of anti-CD19-CAR-transduced T cells with in vivo activity is feasible. The promising results obtained on this trial raise important questions for future research aimed at optimizing therapy with anti-CD19-CAR-transduced T cells. Disclosures: No relevant conflicts of interest to declare.

Conjugation of radionuclides to monoclonal antibodies provides a strategy to target radiation therapy directly to cells expressing the antigen of interest, also known as radio-immunotherapy (RIT). This modality has emerged as an effective targeted anti-neoplastic strategy in patients with B cell lymphoma. Certain hematologic malignancies express abnormally high levels of interleukin (IL)-2Rα (CD25, Tac) including cutaneous T cell lymphoma, peripheral T cell lymphoma, anaplastic large cell lymphoma, Hodgkin’s lymphoma (HL) and chronic lymphocytic leukemia. In this study 90Y-labeled daclizumab in CD25 positive malignancies, other than adult T cell leukemia, was investigated. We determined that 15 millicuries (mCi) was the maximum tolerated dose (MTD) in patients without a history of stem cell transplantation. As objective responses were only seen in HL, the phase II component of the study has focused on patients (pts) with relapsed and refractory HL. Eligibility criteria include: Karnofsky performance status (KPS) >50%, AGC >1,500/mm3, platelet >100,000/mm3, adequate hepatic/renal function and informed consent. As an added safety measure pts with a prior history of peripheral stem cell transplantation received an initial dose of 10mCi; in the absence of hematologic toxicity subsequent cycles were administered at 15mCi. All other pts received 15 mi 90Y-daclizumab every 6 weeks until disease progression, DLT or completion of 7 cycles. Ca-DTPA was used to reduce bone marrow exposure to free 90Y. 111In-labeled daclizumab was used for tumor imaging. Thirty pts with Hodgkin’s lymphoma have been treated, median age of 35 years (range, 20 to 67 years). The majority are heavily pre-treated, median of 4 prior chemotherapy regimens, range 1–8. Twenty pts had received a prior autologous transplantation; while 4 patients had received both autologous and allogeneic transplantation. One hundred cycles have been administered, median cycles per patient is 3 (range 1–7 cycles). Of 30 pts treated with 90Y-daclizumab, 12 achieved a complete response (CR), 7 had a partial response (PR), 5 had stable disease and 6 progressed. The response rate in pts who had undergone a transplant was 80%. Interestingly, many of the responses were seen in pts with CD25 negative malignant cells but with surrounding CD25 positive T cells within the tumor microenvironment. The median response duration was 129 days (range 28 to 720 days). The freedom from progression for the pts with a CR ranged from 28 to 788 days with a median of 222 days. There were no infusional reactions, however 5 pts developed non-symptomatic human anti-human antibody (HAHA) titers to daclizumab after one or more treatments. Seven pts failed to recover platelet count to the protocol mandated limit of 75,000, resulting in halting therapy, and 3 pts developed myelodysplastic syndrome (MDS) after 90Y-daclizumab, however one of those patients in retrospect had evidence of the same cytogenetic abnormalities predating therapy. 90Y-daclizumab produces objective responses in relapsed and refractory HL but as with other RIT strategies is not a curative approach. The role for 90Y-daclizumab in patients with relapsed HL with stem cell transplantation will be investigated.

This study investigated the antitumor activity of alemtuzumab (Campath 1-H) with regard to response rate, time to progression, overall survival and adverse events in patients with human T-cell lymphotrophic virus-1 (HTLV-1)-associated adult T-cell leukemia/ lymphoma (ATL). In a single institution non-randomized open-label phase II trial, 24 patients with chronic (n=2), acute (n=13) and lymphomatous (n=9) ATL were treated with intravenous alemtuzumab 30 mg three times weekly for a maximum of 12 weeks. Patients received antimicrobial prophylaxis from the initiation of treatment continuing for a minimum of 2 months after treatment, or until the peripheral blood CD4+ T-cells were ≥ 200 cells/μL. Tumor responses were assessed at the end of 4, 8, and 12 weeks. All patients were evaluable for toxicity and one patient was not evaluable for response due to early withdrawal. The overall objective response rate was 10 out of 23 patients (95% CI: 23 to 66%). Based on the 10 patients who responded, median time to response was 1.1 months (range, 1.0 to 3.0 months). The median response duration was 3.9 months. Median progression free survival of patients with chronic subtype was 2.0 months, 1.0 month for lymphomatous subtype and 2.4 months for acute subtype. Median time to treatment failure was 1.7 months. At data cut-off, (April 24, 2008), 6 (25%) patients were alive. Overall median survival was 5.9 months. Median overall survival by subtypes was 3.9 months for chronic, 4.8 months for lymphomatous, and 7.6 months for acute. Median survival for all responders from on study date was 8.4 months. Clinical benefit was observed both in responders and in patients with stable disease. The most common adverse events were related to infusion and were generally grade 1 or 2, occurring mainly in the first week of alemtuzumab administration. All patients developed CMV antigenemia; however, only 3 (12.5%) were symptomatic. Grade 3 or 4 infections were reported in 6 (25%) patients. Median time to recovery of ALC to >200 cells/μL was 1.9 months.

Gray zone lymphomas (GZL) are diseases with transitional morphology and immunophenotypic features between Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Their pathological and clinical characteristics are not well studied and the best treatment strategy (using HL or DLBCL regimens) has not been defined. Small previous series of HL-like ALCL, which would include GZL, suggest they have a poor outcome with HL treatments. We present GZL’s treated on studies of DA-EPOCH-R at the National Cancer Institute and describe their clinical and histological features and outcome. Overall, 14 patients with GZL were identified. Characteristics included median (range) age 30 (12–51) years; male sex 10 (71%); stage III/IV 2 (14%) and; elevated LDH 7 (50%). These cases could be divided into three Gray zone groups: classical HL (cHL) and primary mediastinal B-cell lymphoma (PMBL) in 9 (64%) patients; cHL and DLBCL in 2 (14%) and; lymphocyte predominant HL (LPHL) and T-cell histiocyte-rich large cell lymphoma (TCRBCL) in 2 (14%). Pathological characteristics are shown below. All but one case was CD 10 negative. Markers of cHL included CD15 in 33–50% and CD30 in 66–100% of cases. Morphologically, Reed-Sternberg like cells were typically seen in GZL with cHL features. Thirteen newly diagnosed patients received DA-EPOCH-R. Of 11 patients evaluable for response (2TE), 10 (91%) achieved CR and 1 PR. At a median follow-up time of 4 years, OS and PFS are is 86% and 57%, respectively. Of 9 patients with GZL between cHL and PMBL, 4 (44%) also required radiation therapy compared to only 3/31 (10%) patients with PMBL to achieve durable remissions. Gray zone lymphomas represent a biological and clinical continuum between HL and B-cell lymphomas. Clinically, they appear to be more resistant to treatment than either HL or DLBCL and may require aggressive treatment strategies including radiation. Accrual continues. Gray Zone Total 14 CD 20 CD 15 CD 30 cHL- PMBL 9 8 (89%) 7 (50%) 9 (100%) cHL-DLBCL 2 2 (100%) 1 (50%) 2(100%) LPHL-TCRBCL 3 3 (100%) 1 (33%) 2 (66%)