Abstract: Introduction: Multiple Myeloma (MM) is a clonal plasma cell malignancy, accounting for 10% of all hematological malignancies. Genetic analyses of large populations revealed that blood-specific somatic mutations in hematopoietic stem cells (HSCs) are commonly acquired during aging, a new entity labeled: clonal hematopoiesis of indeterminate potential (CHIP). We sought to determine the role of CHIP on survival of MM patients, specifically those receiving immunomodulator (IMiD) maintenance (Lenalidomide or Thalidomide) post autologous stem cell transplant (ASCT). Methods: We collected the cryopreserved, growth factor mobilized peripheral blood of 629 MM patients who underwent ASCT between 2003 and 2011 at the Dana-Farber Cancer Institute (DFCI). Then, we performed targeted next-generation sequencing using a 224-gene panel at a mean depth of coverage of 978X and ultra-low pass whole-genome sequencing at 0.1X to account for tumor contamination. We downloaded (dbGAP # phs000748.v6.p4) the whole-exome sequencing (WES) data of a cohort of 1144 newly diagnosed, untreated MM patients from the Multiple Myeloma Research Foundation (MMRF) Clinical Outcomes in MM to Personal Assessment of Genetic Profile (CoMMpass, NCT0145429) study (MMRC) and the WES data of a cohort of 205 newly diagnosed, untreated MM patients from the Broad Institute dataset. We analyzed their peripheral blood (average coverage of 108X) and tumor (average coverage of 107X) data separately, looking for the same CHIP genes included in our target bait panel. Results: The DFCI cohort had a median age of 58 years [range, 24-83] at time of ASCT and median follow up post ASCT of 8 years [range, 0.1-14.5] . 204 patients (32%) in the DFCI cohort had CHIP at time of ASCT. The most commonly detected mutated genes were DNMT3A, TET2, TP53, ASXL1 and PPM1D. 24 patients (3.8%) developed a second hematological malignancy at a median of 4 years [range, 1-10] post ASCT, half of whom had CHIP. Around 48% of the DFCI cohort received IMiDs as part of induction therapy. Different induction regimens had no effect on CHIP prevalence at time of ASCT. Around 56% of the DFCI cohort received IMiD maintenance, 22% of which received maintenance for at least 3 years [range, 0.06-12.8] . Among those who did not receive IMiD maintenance, patients with CHIP had worse progression free survival (PFS) (p-value 〈 0.001) and overall survival (OS) (p-value = 0.005). In patients receiving IMiD maintenance, having CHIP had no effect on PFS or OS. On the other hand, the MMRF cohort had a median age of 63 years [range, 27-93] and median follow up of 3.03 years [range, 0-5.9] from time of diagnosis. Around 52% of that cohort underwent ASCT and around 76% of those received IMiD maintenance with a median follow up of 2.7 years [range, 0-5.5] from time of ASCT. Furthermore, 200 patients of the MMRF cohort have follow-up samples of both tumor and peripheral blood that had targeted sequencing done by a 562-gene panel that included our genes of interest. Similarly, when studying the genomic results of 139 out of 1144 MMRF patients, as well as the 205 patients from the Broad Institute dataset, we detected CHIP in 25.6% of them and the top 5 most commonly mutated genes were similar to those of our cohort. Conclusion: CHIP is a common entity among MM patients, reaching a prevalence of up to 32%, that predicts a worse PFS and OS in those who do not receive IMiD maintenance therapy post ASCT. As expected, IMiD maintenance improves outcome in MM patients, with and without CHIP. In patients with CHIP, the use of IMiDs abrogated the deleterious effect imposed by CHIP to a point that outcome is identical to that of patients without CHIP. Figure Figure. Disclosures Bustoros: Dava Oncology: Honoraria. Munshi:OncoPep: Other: Board of director. Anderson:Gilead: Membership on an entity's Board of Directors or advisory committees; OncoPep: Equity Ownership, Other: Scientific founder; Celgene: Consultancy; C4 Therapeutics: Equity Ownership, Other: Scientific founder; Bristol Myers Squibb: Consultancy; Millennium Takeda: Consultancy. Richardson:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Soiffer:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Ghobrial:Celgene: Consultancy; Janssen: Consultancy; BMS: Consultancy; Takeda: Consultancy.

Abstract: Childhood AML survival outcomes and treatment related adverse events remain less than optimal despite recent treatment advances. Intensive chemotherapy and hematopoietic stem cell transplant (HSCT), when suitable, are the mainstay of current therapy for newly diagnosed patients. Newer agents, such as gemtuzumab ozogamicin (GMTZ), a calicheamicin coupled anti-CD 33 monoclonal antibody, have been evaluated in adults and in phase 1 studies in children. We report data from a COG open-label pilot of intensive chemotherapy containing GMTZ in selected therapy cycles for pediatric AML patients. The primary objective was to determine the safety of adding single dose GMTZ to an intensive two course induction adapted from the Medical Research Council (MRC) regimen. The complete remission rate of the induction regimen and the safety of adding a single dose of GMTZ to one course of post-remission intensification therapy were also evaluated. Eligible patients were newly diagnosed children (≥1 month old to ≤21 years old) with de novo AML excluding those with Down syndrome and those with acute promyelocytic leukemia. Accrual occurred from December 2003 to November 2005 at COG institutions. Enrollment included 350 patients with 340 patients that were determined to be eligible by protocol guidelines. Treatment consisted of a remission induction phase (induction I and induction II) followed by intensification I, II, and III or intensification I and matched related donor HSCT. Cycle regimens were cytarabine, daunorubicin, etoposide (ADE) 10+3+5 plus GMTZ on day 6 (induction I), ADE 8+3+5 (induction II),high dose cytarabine and etoposide (AE) (intensification I), mitroxantrone, cytarabine (MA) plus GMTZ on day 7 (intensification II), and Capizzi II (intensification III). A busulfan - cyclophosphamide conditioning regimen was used for those children receiving HSCT as part of their consolidation treatment. The median length of each cycle was 36, 35, 35, 48, 48, and 111 (HSCT) days respectively. Median time (in days) for recovery of ANC and platelet counts by cycle was Induction 1: ANC 35, platelets 35, Induction II: ANC: 33, platelets: 33, Int 1: ANC 34, platelets 34, Int II: ANC 51.5, platelets 46, Int III: ANC 49, platelets 48 and HSCT: ANC 110.5, platelets 110. Median follow-up for all eligible patients alive at last contact is 775 days. Overall results show that the induction I complete response (CR) was 83%, refractory disease (RD) with 5 – 20% BM blasts was 8.6%, RD failure with & gt;20% BM blasts was 5.2%, CNS relapse/persistent disease or developed 2nd malignancy combined represented 1.5%, and death rate was 1.5%. The cumulative induction (induction I and II) CR was 87%, RD 1.6%, RD failure 8.5%, and death 2.6%. 3 year EFS from study entry was 49% ± 7% while OS was 63% ± 6%. Patients in remission after induction I had DFS 56% ± 7% and OS 65% ± 8%. For patients in remission after induction II, the DFS (58 ± 7%) and OS (67% ± 8%) were similar to those patients achieving remission after the 1st cycle. Treatment related mortality (TRM) for induction I and induction II was 9% and 7% respectively. Children with a matched related donor for transplant had an improved 3 year risk of relapse (RR) when compared to those with no donor: 22% ± 12% compared to 39% ± 9% (p=0.053). The most common non-transplant related adverse events (grade 3 or higher) reported include anorexia, febrile neutropenia, and hypokalemia. Veno-occlusive disease (VOD) was reported in 18 patients (5%): 2 patients during intensification II, 8 patients during HSCT and 8 patients during the follow-up phase. Overall, AAML03P1 therapy shows a continued historical trend for improvement in OS and EFS when compared to the previous COG AML trial (CCG-2961). TRM in this pilot study is similar to that observed in CCG-2961. VOD, a key targeted toxicity, occurs in only a small percentage of patients and is within the published rates observed with other therapies for AML. This study shows that GMTZ can be safely added to this MRC based regimen. The determination of whether GMTZ improves patient outcome is being studied in the ongoing COG Phase III randomized trial, AAML0531.

Abstract: Reconstitution of T-cell immunity after bone marrow transplantation (BMT) is often delayed, resulting in a prolonged period of immunodeficiency. Donor lymphocyte infusion (DLI) has been used to enhance graft-versus-leukemia activity after BMT, but the effects of DLI on immune reconstitution have not been established. We studied 9 patients with multiple myeloma who received myeloablative therapy and T-cell–depleted allogeneic BMT followed 6 months later by infusion of lymphocytes from the same donor. DLI consisted of 3 × 107 CD4+ donor T cells per kilogram obtained after in vitro depletion of CD8+ cells. Cell surface phenotype of peripheral lymphocytes, T-cell receptor (TCR) Vβ repertoire, TCR rearrangement excision circles (TRECs), and hematopoietic chimerism were studied in the first 6 months after BMT and for 1 year after DLI. These studies were also performed in 7 patients who received similar myeloablative therapy and BMT but without DLI. Phenotypic reconstitution of T and natural killer cells was similar in both groups, but patients who received CD4+ DLI developed increased numbers of CD20+ B cells. TCR Vβ repertoire complexity was decreased at 3 and 6 months after BMT but improved more rapidly in patients who received DLI (P = .01). CD4+ DLI was also associated with increased numbers of TRECs in CD3+ T cells (P  & lt; .001) and with conversion to complete donor hematopoiesis (P = .05). These results provide evidence that prophylactic infusion of CD4+ donor lymphocytes 6 months after BMT enhances reconstitution of donor T cells and conversion to donor hematopoiesis as well as promoting antitumor immunity.

Abstract: We report the results of high-dose chemoradiotherapy and anti–B-cell monoclonal antibody-purged autologous bone marrow transplantation (ABMT) in patients with relapsed indolent follicular lymphoma. Between March 1985 and May 1995, 153 patients underwent ABMT using a uniform ablative regimen with cyclophosphamide and total body irradiation and bone marrow (BM) purging. All patients received multiple chemotherapy regimens before ABMT. At BM harvest, only 30% of patients were in complete remission, and overt BM infiltration was present in 47%. The disease-free survival (DFS) and overall survival (OS) are estimated to be 42% and 66% at 8 years, respectively. Patients whose BM was negative by polymerase chain reaction (PCR) for bcl2/IgH rearrangement after purging experienced longer freedom from recurrence than those whose BM remained PCR positive (P & lt; .0001). Continued PCR negativity in follow-up BM samples was also strongly predictive of continued complete remission (CR). The 12-year survival from diagnosis for these 153 patients is 69%. Considering that the median survival from diagnosis and first recurrence of patients with advanced follicular lymphoma are 8 and 5 years, respectively, our results provide evidence that myeloablative therapy and ABMT may prolong overall survival.

Abstract: Abstract 4134 Introduction: Lenalidomide, bortezomib, and dexamethasone (RVD) is an active and well tolerated induction regimen in newly diagnosed multiple myeloma (MM). Clinical trials show this regimen to have an overall response rate (ORR) of 95–100%. Appropriately selected patients who receive RVD induction may proceed to consolidation with high-dose therapy and autologous stem cell transplantation (ASCT). In this retrospective study we characterize the experience of patients at our center who received RVD induction followed by ASCT. Methods: Demographic and outcome data were collected retrospectively among patients with MM who underwent ASCT between January 1, 2005 and December 31, 2010 (n=482) and received at least 2 cycles of RVD induction (n=82). Data collected include demographics, disease sub-type and International Staging System (ISS) stage, cytogenetics, treatment summary, treatment-related peripheral neuropathy and venous thromboembolism (VTE), CD34+ stem cell yield, time to hematopoietic recovery post-ASCT, disease response to induction and ASCT, and time to progression after ASCT. Response was based on M-protein or serum free light chain (FLC) response and bone marrow findings. Results: The cohort was 63% male with median age at induction of 57.5 years (range 24 to 71). By ISS stage, 51, 32, 12, and 5% had stage I, II, III, and unknown disease, respectively. Based on cytogenetic findings, 56, 33, and 12% had standard, high, and unknown-risk disease, respectively. IgG was the most common subtype (48% IgG, 24% IgA, and 26% light chain disease). Patients received a median of 5 cycles (range 2 to 16) of RVD induction. 50% of patients reported any-grade peripheral neuropathy. Two patients developed VTE. In 8 (10%) patients, bortezomib or lenalidomide was discontinued due to drug toxicity. In 5 (6%) patients, omission of lenalidomide in the final cycle prior to stem cell collection was planned. Partial response (PR) or better M-protein (or FLC) response was observed in 96% (95% CI: [88%, 99%]) with 44% complete response (CR), 26% very good partial response (VGPR), 26% PR, 4% stable disease (SD) pre-ASCT. 50% of patients who achieved a CR by M-protein response had no evidence of clonal plasma cells in their bone marrow. Sixty-three (77%) patients proceeded directly to ASCT after RVD induction with median time to ASCT 187 days (range 119 to 510). Nineteen (23%) patients received further therapy prior to ASCT: 8 patients to either deepen treatment response prior to ASCT (n=6) or for progressive disease (PD) after a transient response to RVD (n=2), while 11 were either observed (n=7) or received maintenance therapy (n=4) after induction with further therapy for PD or for cytoreduction prior to ASCT. Among patients who received additional therapy, 16% improved their response with median time to ASCT 394 days (range 155 to 975). Median CD34+ stem cell collection was 10.0 × 10^6 (range 2.0 × 10^6 to 75.4 × 10^6). More than 4 × 10^6 stem cells were collected in 95% of patients. Median time to neutrophil and platelet engraftment was 11 (range 6 to 19) and 19 (range 10 to 92) days, respectively. At 100 days post-ASCT, 33% showed improvement in disease response, 59% showed the same response, no one had PD, and 7% had unknown response due to no assessment ≤ 150 days post-ASCT. Lenalidomide maintenance was given to 71% of patients after day 100 post-ASCT. At median follow-up of 12.1 months, 12 subjects progressed and one patient died of angioimmunoblastic lymphoma on day 289 post-ASCT without myeloma progression (3 subjects had no follow-up data). No other second new primary malignancies were reported. The Kaplan-Meier estimate of progression-free survival (PFS) at 12 months post-ASCT is 85% (95% CI:[72;92]). Similar results were observed among the 63 patients who proceeded directly to ASCT. Conclusion: RVD is a well tolerated, highly active induction regimen for patients with newly diagnosed MM. The ORR of 96% and CR rate of 44% to RVD induction prior to ASCT in our study are consistent with previous results. Stem cell collection following RVD induction was successful in all patients and post-ASCT engraftment was rapid. ASCT improved disease response and these responses appear durable at median 12 month follow-up. Data from on-going phase III trials will provide insight in a prospective manner on outcomes after RVD induction followed by ASCT (either early or late) for MM patients. Disclosures: Richardson: Celgene: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Koreth:Millennium Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ghobrial:Bristol-Myers Squibb: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Noxxon: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Munshi:Novartis: 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; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees. Anderson:Onyx: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Novartis: Consultancy; Merck: Consultancy; Acetylon: Founder.

Abstract: The appropriate timing of bone marrow transplantation (BMT) for adults with acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) is controversial. Although allogeneic transplantation results in a lower risk of disease recurrence than intensive chemotherapy alone, overall outcome following BMT may not be improved due to the higher incidence of therapy-related fatal complications, frequently as a result of the development of graft-versus-host disease (GVHD). Selective T-cell depletion of donor marrow can reduce the incidence of GVHD and thereby limit transplant-related toxicity. Herein we report the risk of GVHD, incidence of transplant related mortality (TRM), likelihood of disease relapse, and overall survival in adult patients undergoing BMT with CD6 depleted allogeneic marrow for acute leukemia in first remission. Forty-one consecutive allogeneic transplants were performed on patients with acute leukemia and high-risk features (28 AML, 13 ALL) using T12 monoclonal antibody and complement to remove CD6+ T cells from donor marrow. No pre- or posttransplant immune suppressive medications for GVHD prophylaxis were administered. The actuarial estimated risk of grade 2 to 4 acute GVHD was 15% in patients receiving HLA identical grafts. Chronic GVHD developed in five patients. The estimated risk of TRM for patients in first complete remission was 5% at Day +100 and 16% at 2 years. Fatalities attributable to infection with cytomegalovirus or Epstein-Barr virus occurred in only three patients. Estimated probabilities of relapse, overall survival, and event-free survival at 4 years were 25%, 71%, and 63%, respectively. No significant differences in GVHD, TRM, relapse rate, or survival was observed for patients with AML compared with those with ALL. Allogeneic transplantation with CD6 depleted bone marrow is effective in consolidating remissions of high-risk patients with acute leukemia in first remission without excessive toxicity.

Abstract: Background: BB-10901 is a humanized monoclonal antibody that binds with high affinity to CD56 and is covalently linked to a novel cytotoxic maytansinoid DM1. Once bound to CD56, the conjugate is internalized and releases DM1. CD56 is expressed on a variety of tumor types such as small cell lung carcinoma, neuroendocrine tumors and hematological malignancies including multiple myeloma (MM) and acute leukemia. About 70% of MM patients have evidence of CD56 expression. Based on our preliminary results that BB-10901 has significant in vitro and in vivo anti-myeloma activity in a murine model, we have now initiated a phase I clinical study. Objectives: To determine the maximum tolerated dose (MTD), the dose limiting toxicities (DLTs), and pharmacokinetics (PK) of BB-10901 given on a weekly schedule. Methods: Relapsed or relapsed/refractory MM patients who have failed at least one prior therapy and have CD56 expressing myeloma received a single IV infusion of BB-10901 on 2 consecutive weeks every 3 weeks. Subjects are enrolled in cohorts of 3 at each dose level. The starting dose was 40 mg/m2/week based on experience from a prior phase I trial in solid tumors. Results: Five patients have received BB-10901, 3 at 40 mg/m2/week and 2 at 60 mg/m2/week. No patients have experienced DLTs and no serious adverse events related to study drug were observed. In addition, no patients have experienced serious hypersensitivity reactions or evidence of HAHA or HADA formation. Our preliminary PK findings demonstrate that there is no evidence of accumulation of BB-10901. Detailed PK analysis and updated toxicity and efficacy data will be presented. Immunohistochemistry performed on marrow aspirates about 24 hours after huN901-DM1 infusion at 40 mg/m2 confirmed the presence of huN901-DM1 on myeloma cells in the marrow. Two patients treated at 60 mg/m2/week and who had failed multiple prior therapies including bortezomib, thalidomide and/or lenalidomide demonstrated anti-tumor response with a decrease in M proteins of 90% and 33%, respectively. Both patients received a fifth cycle of therapy and one continues on study. Conclusions: This phase I study provides preliminary evidence of safety and clinical activity of BB-10901 in patients with CD56-positive MM who have failed established MM treatments. Targeting of BB-10901 to myeloma cells in the marrow was confirmed. The MTD is not yet defined and enrollment is ongoing.

Abstract: Donor lymphocyte infusions (DLI) can induce remissions in patients who have relapsed after allogeneic bone marrow transplantation (BMT). However, DLI frequently also result in significant acute and/or chronic graft-versus-host disease (GVHD). Several clinical and experimental lines of evidence have suggested that CD8+ T cells play a critical role in the pathogenesis of GVHD. To develop methods to reduce the incidence of GVHD associated with DLI, we administered defined numbers of CD4+ donor T cells after ex vivo depletion of CD8+ lymphocytes to 40 patients with relapsed hematologic malignancies after allogeneic BMT. Cohorts of patients received 0.3, 1.0, or 1.5 × 108CD4+ cells/kg. Overall, 12 of 38 patients (32%) evaluable for toxicity developed acute or chronic GVHD. However, 6 of 27 patients (22%) receiving 0.3 × 108 CD4 cells/kg developed GVHD compared with 6 of 11 patients (55%) who received ≥1.0 × 108 CD4 cells/kg (P = .07). Treatment-related mortality was low (3%), with 1 death related to infection in the setting of immunosuppression for GVHD. Disease responses after CD4+ DLI were documented in 15 of 19 patients (79%) with early-phase chronic myelogenous leukemia (CML) relapse, 5 of 6 patients (83%) with relapsed multiple myeloma, and 1 patient with myelodysplasia. For patients with early-phase CML relapse, the Kaplan-Meier probability of achieving complete cytogenetic remission was 87% and the probability of complete molecular response was 78% at 1 year after DLI. The median time to complete cytogenetic response and molecular response in patients with CML was 13 weeks (range, 9 to 30 weeks) and 34 weeks (range, 10 to 56 weeks), respectively. The median time to response in patients with multiple myeloma was 26 weeks (range, 15 to 62 weeks). All patients in this trial who developed GVHD demonstrated tumor regression, but the presence of GVHD was not required for patients to achieve a response, because 48% of responding patients never developed evidence of GVHD. Two patients with CML who did not respond at dose level 1 subsequently achieved complete cytogenetic remission after a second infusion of CD8-depleted cells at dose level 2. In patients with evidence of mixed hematopoietic chimerism who achieved a complete remission after DLI, cytogenetic analysis of marrow cells also demonstrated conversion to complete donor hematopoiesis in all evaluable patients. These studies suggest that relatively low numbers of CD8-depleted donor lymphocytes are effective in inducing complete remissions in patients with stable-phase CML and multiple myeloma who have relapsed after allogeneic BMT. Because of the relatively low risk of toxicity associated with the infusion of defined numbers of CD4+donor cells, further studies can be undertaken in the setting of persistent minimal residual disease to prevent relapse after allogeneic BMT.

Abstract: Donor lymphocyte infusions (DLI) can induce remissions in patients who have relapsed after allogeneic bone marrow transplantation (BMT). However, DLI frequently also result in significant acute and/or chronic graft-versus-host disease (GVHD). Several clinical and experimental lines of evidence have suggested that CD8+ T cells play a critical role in the pathogenesis of GVHD. To develop methods to reduce the incidence of GVHD associated with DLI, we administered defined numbers of CD4+ donor T cells after ex vivo depletion of CD8+ lymphocytes to 40 patients with relapsed hematologic malignancies after allogeneic BMT. Cohorts of patients received 0.3, 1.0, or 1.5 × 108CD4+ cells/kg. Overall, 12 of 38 patients (32%) evaluable for toxicity developed acute or chronic GVHD. However, 6 of 27 patients (22%) receiving 0.3 × 108 CD4 cells/kg developed GVHD compared with 6 of 11 patients (55%) who received ≥1.0 × 108 CD4 cells/kg (P = .07). Treatment-related mortality was low (3%), with 1 death related to infection in the setting of immunosuppression for GVHD. Disease responses after CD4+ DLI were documented in 15 of 19 patients (79%) with early-phase chronic myelogenous leukemia (CML) relapse, 5 of 6 patients (83%) with relapsed multiple myeloma, and 1 patient with myelodysplasia. For patients with early-phase CML relapse, the Kaplan-Meier probability of achieving complete cytogenetic remission was 87% and the probability of complete molecular response was 78% at 1 year after DLI. The median time to complete cytogenetic response and molecular response in patients with CML was 13 weeks (range, 9 to 30 weeks) and 34 weeks (range, 10 to 56 weeks), respectively. The median time to response in patients with multiple myeloma was 26 weeks (range, 15 to 62 weeks). All patients in this trial who developed GVHD demonstrated tumor regression, but the presence of GVHD was not required for patients to achieve a response, because 48% of responding patients never developed evidence of GVHD. Two patients with CML who did not respond at dose level 1 subsequently achieved complete cytogenetic remission after a second infusion of CD8-depleted cells at dose level 2. In patients with evidence of mixed hematopoietic chimerism who achieved a complete remission after DLI, cytogenetic analysis of marrow cells also demonstrated conversion to complete donor hematopoiesis in all evaluable patients. These studies suggest that relatively low numbers of CD8-depleted donor lymphocytes are effective in inducing complete remissions in patients with stable-phase CML and multiple myeloma who have relapsed after allogeneic BMT. Because of the relatively low risk of toxicity associated with the infusion of defined numbers of CD4+donor cells, further studies can be undertaken in the setting of persistent minimal residual disease to prevent relapse after allogeneic BMT.

Abstract: Introduction Erythropoietic Protoporphyria (EPP) or X-Linked Protoporphyria (XLP) are inborn errors of heme biosynthesis caused by the abnormal accumulation of erythrocyte protoporphyrin IX (ePPIX). These protoporphyrias are characterized by excruciating painful attacks on prolonged sunlight exposure. Before the onset of phototoxic pain, patients experience characteristic prodromal symptoms which serves as a warning signal to avoid further sun exposure. Of note, patients with higher ePPIX levels report shorter times to symptoms compared to patients with lower median ePPIX levels (JAMA Derm, 2017; 153). Here we report the safety and effectiveness of Dersimelagon (MT-7117), a novel, orally-administered, small molecule, selective melanocortin-1 receptor (MC1R) agonist that increases skin melanin without sun exposure and is being developed to increase light tolerance in EPP/XLP patients. Results of the primary, secondary efficacy endpoints, and post-hoc subgroup analyses evaluating effects of baseline ePPIX levels on treatment response will be presented. Methods The MT-7117-A01 (ENDEAVOR) study was a Phase 2, multi-center, randomized, placebo-controlled study with a 16-week double-blind treatment period. A total of 102 EPP/XLP patients were randomized to 3 groups: placebo once daily (QD) (n=35 [31 EPP/4 XLP]), MT-7117 100 mg QD (n=33 [31 EPP/2 XLP] ), and MT-7117 300 mg QD (n=34 [31 EPP/3 XLP]). Results of the primary endpoint, increase in the average daily time (min) to first prodromal symptom during sunlight exposure, and secondary endpoints including 1) average daily duration of sunlight exposure without prodromal symptoms, 2) total number of sunlight exposure episodes with prodromal symptoms, and 3) total number of pain events, and post-hoc subgroup analyses evaluating baseline median ePPIX levels are presented here. Safety and tolerability were also assessed. Results There was a significant improvement in average daily time ( & gt;50 min) to first prodromal symptom [the primary endpoint] associated with sunlight exposure in subjects treated with MT-7117 100 mg (p=0.008) or 300 mg (p=0.003) compared to placebo at Week 16. Multiple secondary endpoints supported primary endpoint. There was a significant increase in average daily minutes of sunlight exposure without prodromal symptoms at Week 16 in 100 mg (p=0.009) and 300 mg (p=0.004) treated subjects compared to placebo, with an increased average exposure time without prodromal symptoms of ~50 min in MT-7117 subjects at both doses compared to placebo. There was also a 40% reduction in the total number of sunlight exposure episodes with prodromal symptoms in 100 mg (p=0.019) and 300 mg (p=0.006) subjects compared to placebo. There was a significant decrease in the total number of pain events reported in 100 mg (p=0.027, 60% reduction) and 300 mg (p=0.028, 50% reduction) subjects compared to placebo. The post-hoc subgroup analysis evaluating the effects of baseline ePPIX levels in subjects grouped based on the baseline median ePPIX level of 1981 µg/dL. There was a statistically significant increase in average daily time to first prodromal symptom in the subgroup with ePPIX levels ≥1981 µg/dL receiving 100 mg (p=0.020) and 300 mg (p=0.003) compared to placebo. A trend to beneficial effect was also observed for the subgroup of subjects with ePPIX levels & lt;1981 µg/dL receiving 100 mg (p=0.180) and 300 mg (p=0.216) compared to placebo. MT-7117 had an acceptable safety and tolerability profile. The most common treatment-related treatment emergent adverse reactions were nausea (27.9%), ephelides (23.5%), and skin hyperpigmentation (20.6%). Conclusion The results of the primary efficacy endpoint and multiple secondary endpoints in this Phase 2 study indicate that the oral, MC1R agonist dersimelagon was efficacious after 16 weeks of treatment in increasing symptom-free light exposure in patients with EPP or XLP at doses of 100 and 300 mg QD and showed an acceptable safety and tolerability profile. The post-hoc analyses showed more profound and statistically significant efficacy at both doses for the subgroup with higher baseline median ePPIX levels. Disclosures Balwani: Alnylam Pharmaceuticals: Consultancy, Honoraria, Research Funding; Recordati Rare Diseases: Consultancy, Honoraria, Other: Disease information video recording. Anderson:Alnylam Pahrmaceuticals: Consultancy; Recordati Rare Diseases: Consultancy; Mitsubishi Tanabe Pharma: Consultancy.