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Papers by Michael Maris

Acta Haematologica, 2005

Case Report s 104 A Case of Chronic Myelomonocytic Leukemia with Severe Eosinophilia Having t(5;1... more Case Report s 104 A Case of Chronic Myelomonocytic Leukemia with Severe Eosinophilia Having t(5;12)(q31;p13) with t(1;7)(q10;p10)

Blood Cancer Journal, Feb 1, 2017

Journal of Clinical Oncology, Mar 20, 2005

We have used a nonmyeloablative conditioning regimen consisting of total-body irradiation (2 Gy) ... more We have used a nonmyeloablative conditioning regimen consisting of total-body irradiation (2 Gy) with or without fludarabine (30 mg/m 2 /d for 3 days) for related and unrelated hematopoietic cell transplantation (HCT) in patients with hematologic malignancies who were not candidates for conventional HCT because of age, medical comorbidities, or preceding high-dose HCT. This approach relied on graft-versus-tumor (GVT) effects for control of malignancy. We analyzed GVT effects in 322 patients given grafts from HLA-matched related (n ϭ 192) or unrelated donors (n ϭ 130). Of the 221 patients with measurable disease at HCT, 126 (57%) achieved complete (n ϭ 98) or partial (n ϭ 28) remissions. In multivariate analysis, there was a higher probability trend of achieving complete remissions in patients with chronic extensive graft-versus-host disease (GVHD; P ϭ .07). One hundred eight patients (34%) relapsed or progressed. In multivariate analysis, achievement of full donor chimerism was associated with a decreased risk of relapse or progression (P ϭ .002). Grade 2 to 4 acute GVHD had no significant impact on the risk of relapse or progression but was associated with increased risk of nonrelapse mortality and decreased probability of progression-free survival (PFS). Conversely, extensive chronic GVHD was associated with decreased risk of relapse or progression (P ϭ .006) and increased probability of PFS (P ϭ .003). New approaches aimed at reducing the incidence of grade 2 to 4 acute GVHD might improve survival after allogeneic HCT after nonmyeloablative conditioning.

British Journal of Haematology, Mar 2, 2015

This trial was conducted to determine the dose-limiting toxicities (DLTs) and maximum tolerated d... more This trial was conducted to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the first in class NEDD8-activating enzyme (NAE) inhibitor, pevonedistat, and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Pevonedistat was administered via a 60-min intravenous infusion on days 1, 3 and 5 (schedule A, n = 27), or days 1, 4, 8 and 11 (schedule B, n = 26) every 21-days. Dose escalation proceeded using a standard '3 + 3' design. Responses were assessed according to published guidelines. The MTD for schedules A and B were 59 and 83 mg/m 2 , respectively. On schedule A, hepatotoxicity was dose limiting. Multi-organ failure (MOF) was dose limiting on schedule B. The overall complete (CR) and partial (PR) response rate in patients treated at or below the MTD was 17% (4/23, 2 CRs, 2 PRs) for schedule A and 10% (2/19, 2 PRs) for schedule B. Pevonedistat plasma concentrations peaked after infusion followed by elimination in a biphasic pattern. Pharmacodynamic studies of biological correlates of NAE inhibition demonstrated target-specific activity of pevonedistat. In conclusion, administration of the first-in-class agent, pevonedistat, was feasible in patients with MDS and AML and modest clinical activity was observed.

Representative image of complete response after treatment with pelabresib.

Purpose:NF-κB, a transcription factor essential for inflammatory responses, is constitutively act... more Purpose:NF-κB, a transcription factor essential for inflammatory responses, is constitutively activated in many lymphomas. In preclinical studies, pelabresib (CPI-0610), an investigational (BET) bromodomain inhibitor, downregulated NF-κB signaling and demonstrated antitumor activity in vitro. Here we report the safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity from the first-in-human phase I study of pelabresib in patients with relapsed/refractory lymphomas (NCT01949883).Experimental Design:Sixty-four patients with relapsed/refractory lymphoma (median of 4 prior lines of therapy) were treated with either capsule (6, 12, 24, 48, 80, 120, 170, 230, 300 mg) or tablet (125, 225 mg) doses of pelabresib orally once daily on a 14 days on, 7 days off schedule.Results:The MTD was determined as the 225 mg tablet daily. The most frequent adverse events were fatigue, nausea, and decreased appetite. Thrombocytopenia, a class effect for all BET inhibitors, was dose-dep...

Cancer Research Communications

Purpose:NF-κB, a transcription factor essential for inflammatory responses, is constitutively act... more Purpose:NF-κB, a transcription factor essential for inflammatory responses, is constitutively activated in many lymphomas. In preclinical studies, pelabresib (CPI-0610), an investigational (BET) bromodomain inhibitor, downregulated NF-κB signaling and demonstrated antitumor activity in vitro. Here we report the safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity from the first-in-human phase I study of pelabresib in patients with relapsed/refractory lymphomas (NCT01949883).Experimental Design:Sixty-four patients with relapsed/refractory lymphoma (median of 4 prior lines of therapy) were treated with either capsule (6, 12, 24, 48, 80, 120, 170, 230, 300 mg) or tablet (125, 225 mg) doses of pelabresib orally once daily on a 14 days on, 7 days off schedule.Results:The MTD was determined as the 225 mg tablet daily. The most frequent adverse events were fatigue, nausea, and decreased appetite. Thrombocytopenia, a class effect for all BET inhibitors, was dose-dep...

Journal of Clinical Oncology

TPS8071 Background: CD47 is an innate immune checkpoint that binds signal regulatory protein alph... more TPS8071 Background: CD47 is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a "don’t eat me" signal to suppress macrophage phagocytosis. TTI-622 is a fusion protein consisting of the CD47-binding domain of human SIRPα linked to the Fc region of human IgG4. It is designed to enhance phagocytosis and antitumor activity by preventing CD47 from delivering its inhibitory signal as well as generating a moderate pro-phagocytic signal via IgG4 Fc. CD47 is significantly increased in multiple myeloma (MM) bone marrow mononuclear cells and expression inversely correlates with survival in patients. Relapsed/Refractory (R/R) MM shows particularly high expression of CD47. Preclinical studies demonstrate that the addition of proteasome inhibitors to CD47 blockade significantly increases phagocytosis of MM cells in vitro and anti-myeloma activity in vivo. The ongoing phase 1a part of this study has been previously described. The phase 1b part of...

Transplantation and Cellular Therapy, 2021

Journal of Clinical Oncology, 2018

TPS2603Background: Survival outcomes in patients with relapsed/refractory multiple myeloma (MM), ... more TPS2603Background: Survival outcomes in patients with relapsed/refractory multiple myeloma (MM), acute myeloid leukemia (AML), or diffuse large B-cell lymphoma (DLBCL) remains poor, and there is a ...

Annals of Oncology, 2018

Background: NF-kB has been found to be constitutively activated in many lymphomas, such as diffus... more Background: NF-kB has been found to be constitutively activated in many lymphomas, such as diffuse large B-cell lymphomas (DLBCL), particularly the ABC subgroup. In preclinical studies, CPI-0610, a BET specific small molecule inhibitor, results in downregulation of NF-jB signaling activity, accompanied by loss of viability of ABC-DLBCL cell lines. Here we report the results from the first-in human Phase 1 study of CPI-0610 in patients with relapsed or refractory lymphomas (NCT01949883). Methods: Eligible patients were those whose lymphoma had progressed and for whom no effective therapies are available. Doses (mg) of 6 12, 24, 48, 80, 120, 170, 230, 300 (capsules) and 125 and 225 (tablets) administered orally QD on a 14 day on, 7 days off schedule were evaluated. The primary objective was to determine the maximum tolerated dose (MTD) and key secondary objectives were to determine the pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of CPI-0610. Results: 64 patients were enrolled (56% DLBCL) with a median of 4 prior lines of therapy. MTD for this trial was 225 mg QD tablets. Ten patients were treated at MTD with only 1 DLT (thrombocytopenia). The most frequent treatment related adverse events were thrombocytopenia (45%), fatigue (34%), nausea (27%) decreased appetite (27%) and anemia (25%). Thrombocytopenia, a class effect for all BET inhibitors, was dose limiting however, is was reversible (<1 week) and not cumulative. Five patients had an objective response; 2 CRs (1 T-cell/histocyte-rich DLBCL, 1 ABC-DLBCL), 3 PRs (1 follicular lymphoma, 2 ABC-DLBCL) and 5 patients had prolonged (> 6 months) SD. Three of the responses and 1 of the prolonged SD were in patients with ABC-DLBCL. PK was dose-proportional with C max reached after 3 hours and a half-life of 16 hours. PD analysis of BET target genes demonstrated dose dependent decreases in IL8 and CCR1 mRNA between 2-8 hours post dose. Conclusions: CPI-0610 is a well-tolerated, oral BET inhibitor that has demonstrated anti-tumor activity in advanced lymphoma patients. Clinical trial identification: NCT01949883

Bone Marrow Transplantation, 2011

We describe 20 patients with myeloma and 1 with primary amyloidosis from 15 centres, all with adv... more We describe 20 patients with myeloma and 1 with primary amyloidosis from 15 centres, all with advanced renal failure, most of whom had PBSC mobilised using plerixafor following previous failed mobilisation by conventional means (plerixafor used up-front for 4 patients). For 15 patients, the plerixafor dose was reduced to 0.16 mg/kg/day, with a subsequent dose increase in one case to 0.24 mg/kg/day. The remaining six patients received a standard plerixafor dosage at 0.24 mg/kg/ day. Scheduling of plerixafor and apheresis around dialysis was generally straightforward. Following plerixafor administration, all patients underwent apheresis. A median CD34 þ cell dose of 4.6 Â 10 6 per kg was achieved after 1 (n ¼ 7), 2 (n ¼ 10), 3 (n ¼ 3) or 4 (n ¼ 1) aphereses. Only one patient failed to achieve a sufficient cell dose for transplant: she subsequently underwent delayed re-mobilisation using G-CSF with plerixafor 0.24 mg/kg/day, resulting in a CD34 þ cell dose of 2.12 Â 10 6 /kg. Sixteen patients experienced no plerixafor toxicities; five had mild-to-moderate gastrointestinal symptoms that did not prevent apheresis. Fifteen patients have progressed to autologous transplant, of whom 12 remain alive without disease progression. Two patients recovered endogenous renal function post autograft, and a third underwent successful renal transplantation. Plerixafor is highly effective in mobilising PBSC in this difficult patient group.

Blood, Mar 29, 2018

RP2D of PEV 20 mg/m 2 in PEV/AZA combo did not alter toxicity profile of AZA; dose-limiting toxic... more RP2D of PEV 20 mg/m 2 in PEV/AZA combo did not alter toxicity profile of AZA; dose-limiting toxicities were transiently elevated AST/ALT. l In treatment-naive older AML patients, the intent-to-treat ORR was 50%. Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study of pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ‡60 years with treatment-naive AML (unfit for standard induction therapy) received PEV 20 or 30 mg/m 2 IV on days 1, 3, and 5 combined with fixed-dose AZA (75 mg/m 2 IV/ subcutaneously) on days 1 to 5, 8, and 9, every 28 days. The most common treatmentemergent adverse events were constipation (48%), nausea (42%), fatigue (42%), and anemia (39%). In total, 11 deaths were observed and considered unrelated to study therapy by the investigators. Transient elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were dose limiting. The recommended phase 2 dose (RP2D) of PEV in this combination is 20 mg/m 2 . PEV PK was not altered by the addition of AZA. Overall response rate (ORR) based on an intent-to-treat analysis was 50% (20 complete remissions [CRs], 5 complete remission with incomplete peripheral count recovery, 7 partial remissions [PRs]), with an 8.3-month median duration of remission. In patients receiving ‡6 cycles of therapy (n 5 23, 44%), ORR was 83%. In patients with TP53 mutations, the composite CR/PR rate was 80% (4/5). Two of these patients stayed on study for >10 cycles. Baseline bone marrow blast percentage or cytogenetic/molecular risk did not influence ORR. This study was registered at www.clinicaltrials.gov as

Blood, Oct 15, 2003

Idiopathic pneumonia syndrome (IPS) is a significant noninfectious complication of hematopoietic ... more Idiopathic pneumonia syndrome (IPS) is a significant noninfectious complication of hematopoietic stem cell transplantation (HSCT). We compared the incidences and outcomes of IPS among patients who underwent allogeneic HSCT after nonmyeloablative (n ‫؍‬ 183) compared with conventional (n ‫؍‬ 917) conditioning between December 1997 and December 2001. Patients given nonmyeloablative conditioning were older than those given conventional conditioning (median ages, 53 vs 41 years; P ‫؍‬ .001). The cumulative incidence of IPS was significantly lower at 120 days after nonmyeloablative conditioning than conventional conditioning (2.2% vs 8.4%; P ‫؍‬ .003). In addition, greater patient age (older than 40 years), diagnosis of acute leukemia or myelodysplastic syndrome, and severe acute graftversus-host disease were associated with significantly increased risks for IPS. Among older patients (older than 40 years) given conventional conditioning, highdose total body irradiation (TBI) was associated with an increased risk for IPS than were non-TBI-based regimens (16% vs 5.8%; P ‫؍‬ .001). IPS occurred early after transplantation, progressed rapidly, and was associated with a high mortality rate (75%) despite aggressive support. Initiation of mechanical ventilation and the presence of renal insufficiency at IPS onset were associated with increased risks for death after IPS. These findings support the concept that lung damage from the conditioning regimen plays a crucial role in the development of IPS after HSCT.

Leukemia, Nov 3, 2005

Transplant outcome was analyzed in 150 patients with myelodysplastic syndrome (MDS) or acute myel... more Transplant outcome was analyzed in 150 patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia transformed from MDS (tAML) conditioned with nonmyeloablative or myeloablative regimens. A total of 38 patients received nonmyeloablative regimens of 2 Gy total body irradiation alone (n ¼ 2) or with fludarabine (n ¼ 36), 90 mg/m 2. A total of 112 patients received a myeloablative regimen of busulfan, 16 mg/ kg (targeted to 800-900 ng/ml), and cyclophosphamide 120 mg/ kg. Nonmyeloablative patients were older (median age 62 vs 52 years, Po0.001), more frequently had progressed to tAML (53 vs 31%, P ¼ 0.06), had higher risk disease by the International Prognostic Scoring System (53 vs 30%, P ¼ 0.004), had higher transplant specific comorbidity indices (68 vs 42%, P ¼ 0.01) and more frequently had durable complete responses to induction chemotherapy (58 vs 14%). Three-year overall survival (27%/48% (P ¼ 0.56)), progression-free survival (28%/ 44%, (P ¼ 0.60)), and nonrelapse mortality (41%/34%, (P ¼ 0.94)) did not differ significantly between nonmyeloblative/myeloablative conditioning. Overall (HR ¼ 0.9, P ¼ 0.84) and progression-free survivals (HR ¼ 1, P ¼ 0.93) were similar for patients with chemotherapy-induced remissions irrespective of conditioning intensity. Graft vs leukemia effects may be more important than conditioning intensity in preventing progression in patients in chemotherapy-induced remissions at the time of transplantation. Randomized prospective studies are needed to further address the optimal choice of transplant conditioning intensity in myeloid neoplasms.

Blood, Nov 16, 2004

We have used a nonmyeloablative conditioning regimen consisting of total-body irradiation (2 Gy) ... more We have used a nonmyeloablative conditioning regimen consisting of total-body irradiation (2 Gy) with or without fludarabine (30 mg/m 2 /d for 3 days) for related and unrelated hematopoietic cell transplantation (HCT) in patients with hematologic malignancies who were not candidates for conventional HCT because of age, medical comorbidities, or preceding high-dose HCT. This approach relied on graft-versus-tumor (GVT) effects for control of malignancy. Patients and Methods We analyzed GVT effects in 322 patients given grafts from HLA-matched related (n ϭ 192) or unrelated donors (n ϭ 130). Results Of the 221 patients with measurable disease at HCT, 126 (57%) achieved complete (n ϭ 98) or partial (n ϭ 28) remissions. In multivariate analysis, there was a higher probability trend of achieving complete remissions in patients with chronic extensive graft-versus-host disease (GVHD; P ϭ .07). One hundred eight patients (34%) relapsed or progressed. In multivariate analysis, achievement of full donor chimerism was associated with a decreased risk of relapse or progression (P ϭ .002). Grade 2 to 4 acute GVHD had no significant impact on the risk of relapse or progression but was associated with increased risk of nonrelapse mortality and decreased probability of progression-free survival (PFS). Conversely, extensive chronic GVHD was associated with decreased risk of relapse or progression (P ϭ .006) and increased probability of PFS (P ϭ .003). Conclusion New approaches aimed at reducing the incidence of grade 2 to 4 acute GVHD might improve survival after allogeneic HCT after nonmyeloablative conditioning.

It is unknown whether the severity, timing, and quality of graft-versus-host disease (GVHD) may b... more It is unknown whether the severity, timing, and quality of graft-versus-host disease (GVHD) may be different after nonmyeloablative as compared with myeloablative hematopoietic stem cell transplantation (HSCT). Therefore, GVHD incidence, morbidity of skin, liver, and gut, requirements for immunosuppressive therapy, and survival were retrospectively analyzed in 44 patients who underwent nonablative HSCT and 52 who underwent ablative HSCT (median ages, 56 and 54 years, respectively). The nonablative transplantation regimen consisted of low-dose total body irradiation (TBI), preceded in some patients by fludarabine administration and followed in all patients by immu-nosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP). Those who underwent myeloablative HSCT were prepared with different TBI-and non-TBIcontaining regimens and received CSP plus methotrexate or MMF for GVHD prophylaxis. The cumulative incidence of grades II-IV acute GVHD was lower after nonablative transplantation (64% vs 85%; P ‫؍‬ .001), but there were no differences in the cumulative incidence of chronic GVHD requiring treatment (73% vs 71%; P ‫؍‬ .96). Nonablative transplantation was associated with the delayed initiation of steroid treatment for GVHD (0.95 months vs 3.0 months; P < .001) and with the use of fewer systemic immunosuppressants in the first 3 months after transplantation (P < .04). This corresponded to more prevalent skin and more severe gut morbidity 6 to 12 months after nonablative transplantation. Our results show that nonablative HSCT is associated with a syndrome of acute GVHD occurring after day 100 in many patients. This "late-onset acute GVHD" should be taken into consideration in the design of prospective studies comparing GVHD resulting from the two types of transplantation procedures.

Journal of Clinical Oncology, Jan 10, 2008

Few effective treatment options exist for chemotherapy-refractory indolent or transformed non-Hod... more Few effective treatment options exist for chemotherapy-refractory indolent or transformed non-Hodgkin's lymphoma (NHL). We examined the outcome of nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) in this setting. Patients and Methods Sixty-two patients with indolent or transformed NHL were treated with allogeneic HCT from related (n ϭ 34) or unrelated (n ϭ 28) donors after conditioning with 2 Gy of total-body irradiation with or without fludarabine. Nine unrelated donors were mismatched for Ն one HLA antigen. Sixteen patients had histologic transformation before HCT. Twenty patients (32%) had progressive disease after previous high-dose therapy with autologous HCT. Median age was 54 years, and patients had received a median of six lines of treatment before HCT. Median follow-up time after HCT was 36.6 months. Results At 3 years, the estimated overall survival (OS) and progression-free survival (PFS) rates were 52% and 43%, respectively, for patients with indolent disease, and 18% and 21%, respectively, for patients with transformed disease. Patients with indolent disease and related donors (n ϭ 26) had 3-year estimated OS and PFS rates of 67% and 54%, respectively. The incidences of grade 2 to 4 acute graft-versus-host disease (GVHD), grade 3 and 4 acute GVHD, and extensive chronic GVHD were 63%, 18%, and 47%, respectively. Among survivors, the median Karnofsky performance status at last follow-up was 85%. Conclusion Nonmyeloablative allogeneic HCT can produce durable disease-free survival in patients with relapsed or refractory indolent NHL, even in this relatively elderly and heavily pretreated cohort. Outcomes were particularly good in patients with untransformed disease and related donors, whereas patients with transformed disease did poorly. Long-term survivors reported good overall functional status.

Acta Haematologica, 2005

Case Report s 104 A Case of Chronic Myelomonocytic Leukemia with Severe Eosinophilia Having t(5;1... more Case Report s 104 A Case of Chronic Myelomonocytic Leukemia with Severe Eosinophilia Having t(5;12)(q31;p13) with t(1;7)(q10;p10)

Blood Cancer Journal, Feb 1, 2017

Journal of Clinical Oncology, Mar 20, 2005

We have used a nonmyeloablative conditioning regimen consisting of total-body irradiation (2 Gy) ... more We have used a nonmyeloablative conditioning regimen consisting of total-body irradiation (2 Gy) with or without fludarabine (30 mg/m 2 /d for 3 days) for related and unrelated hematopoietic cell transplantation (HCT) in patients with hematologic malignancies who were not candidates for conventional HCT because of age, medical comorbidities, or preceding high-dose HCT. This approach relied on graft-versus-tumor (GVT) effects for control of malignancy. We analyzed GVT effects in 322 patients given grafts from HLA-matched related (n ϭ 192) or unrelated donors (n ϭ 130). Of the 221 patients with measurable disease at HCT, 126 (57%) achieved complete (n ϭ 98) or partial (n ϭ 28) remissions. In multivariate analysis, there was a higher probability trend of achieving complete remissions in patients with chronic extensive graft-versus-host disease (GVHD; P ϭ .07). One hundred eight patients (34%) relapsed or progressed. In multivariate analysis, achievement of full donor chimerism was associated with a decreased risk of relapse or progression (P ϭ .002). Grade 2 to 4 acute GVHD had no significant impact on the risk of relapse or progression but was associated with increased risk of nonrelapse mortality and decreased probability of progression-free survival (PFS). Conversely, extensive chronic GVHD was associated with decreased risk of relapse or progression (P ϭ .006) and increased probability of PFS (P ϭ .003). New approaches aimed at reducing the incidence of grade 2 to 4 acute GVHD might improve survival after allogeneic HCT after nonmyeloablative conditioning.

British Journal of Haematology, Mar 2, 2015

This trial was conducted to determine the dose-limiting toxicities (DLTs) and maximum tolerated d... more This trial was conducted to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the first in class NEDD8-activating enzyme (NAE) inhibitor, pevonedistat, and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Pevonedistat was administered via a 60-min intravenous infusion on days 1, 3 and 5 (schedule A, n = 27), or days 1, 4, 8 and 11 (schedule B, n = 26) every 21-days. Dose escalation proceeded using a standard '3 + 3' design. Responses were assessed according to published guidelines. The MTD for schedules A and B were 59 and 83 mg/m 2 , respectively. On schedule A, hepatotoxicity was dose limiting. Multi-organ failure (MOF) was dose limiting on schedule B. The overall complete (CR) and partial (PR) response rate in patients treated at or below the MTD was 17% (4/23, 2 CRs, 2 PRs) for schedule A and 10% (2/19, 2 PRs) for schedule B. Pevonedistat plasma concentrations peaked after infusion followed by elimination in a biphasic pattern. Pharmacodynamic studies of biological correlates of NAE inhibition demonstrated target-specific activity of pevonedistat. In conclusion, administration of the first-in-class agent, pevonedistat, was feasible in patients with MDS and AML and modest clinical activity was observed.

Representative image of complete response after treatment with pelabresib.

Purpose:NF-κB, a transcription factor essential for inflammatory responses, is constitutively act... more Purpose:NF-κB, a transcription factor essential for inflammatory responses, is constitutively activated in many lymphomas. In preclinical studies, pelabresib (CPI-0610), an investigational (BET) bromodomain inhibitor, downregulated NF-κB signaling and demonstrated antitumor activity in vitro. Here we report the safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity from the first-in-human phase I study of pelabresib in patients with relapsed/refractory lymphomas (NCT01949883).Experimental Design:Sixty-four patients with relapsed/refractory lymphoma (median of 4 prior lines of therapy) were treated with either capsule (6, 12, 24, 48, 80, 120, 170, 230, 300 mg) or tablet (125, 225 mg) doses of pelabresib orally once daily on a 14 days on, 7 days off schedule.Results:The MTD was determined as the 225 mg tablet daily. The most frequent adverse events were fatigue, nausea, and decreased appetite. Thrombocytopenia, a class effect for all BET inhibitors, was dose-dep...

Cancer Research Communications

Purpose:NF-κB, a transcription factor essential for inflammatory responses, is constitutively act... more Purpose:NF-κB, a transcription factor essential for inflammatory responses, is constitutively activated in many lymphomas. In preclinical studies, pelabresib (CPI-0610), an investigational (BET) bromodomain inhibitor, downregulated NF-κB signaling and demonstrated antitumor activity in vitro. Here we report the safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity from the first-in-human phase I study of pelabresib in patients with relapsed/refractory lymphomas (NCT01949883).Experimental Design:Sixty-four patients with relapsed/refractory lymphoma (median of 4 prior lines of therapy) were treated with either capsule (6, 12, 24, 48, 80, 120, 170, 230, 300 mg) or tablet (125, 225 mg) doses of pelabresib orally once daily on a 14 days on, 7 days off schedule.Results:The MTD was determined as the 225 mg tablet daily. The most frequent adverse events were fatigue, nausea, and decreased appetite. Thrombocytopenia, a class effect for all BET inhibitors, was dose-dep...

Journal of Clinical Oncology

TPS8071 Background: CD47 is an innate immune checkpoint that binds signal regulatory protein alph... more TPS8071 Background: CD47 is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a "don’t eat me" signal to suppress macrophage phagocytosis. TTI-622 is a fusion protein consisting of the CD47-binding domain of human SIRPα linked to the Fc region of human IgG4. It is designed to enhance phagocytosis and antitumor activity by preventing CD47 from delivering its inhibitory signal as well as generating a moderate pro-phagocytic signal via IgG4 Fc. CD47 is significantly increased in multiple myeloma (MM) bone marrow mononuclear cells and expression inversely correlates with survival in patients. Relapsed/Refractory (R/R) MM shows particularly high expression of CD47. Preclinical studies demonstrate that the addition of proteasome inhibitors to CD47 blockade significantly increases phagocytosis of MM cells in vitro and anti-myeloma activity in vivo. The ongoing phase 1a part of this study has been previously described. The phase 1b part of...

Transplantation and Cellular Therapy, 2021

Journal of Clinical Oncology, 2018

TPS2603Background: Survival outcomes in patients with relapsed/refractory multiple myeloma (MM), ... more TPS2603Background: Survival outcomes in patients with relapsed/refractory multiple myeloma (MM), acute myeloid leukemia (AML), or diffuse large B-cell lymphoma (DLBCL) remains poor, and there is a ...

Annals of Oncology, 2018

Background: NF-kB has been found to be constitutively activated in many lymphomas, such as diffus... more Background: NF-kB has been found to be constitutively activated in many lymphomas, such as diffuse large B-cell lymphomas (DLBCL), particularly the ABC subgroup. In preclinical studies, CPI-0610, a BET specific small molecule inhibitor, results in downregulation of NF-jB signaling activity, accompanied by loss of viability of ABC-DLBCL cell lines. Here we report the results from the first-in human Phase 1 study of CPI-0610 in patients with relapsed or refractory lymphomas (NCT01949883). Methods: Eligible patients were those whose lymphoma had progressed and for whom no effective therapies are available. Doses (mg) of 6 12, 24, 48, 80, 120, 170, 230, 300 (capsules) and 125 and 225 (tablets) administered orally QD on a 14 day on, 7 days off schedule were evaluated. The primary objective was to determine the maximum tolerated dose (MTD) and key secondary objectives were to determine the pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of CPI-0610. Results: 64 patients were enrolled (56% DLBCL) with a median of 4 prior lines of therapy. MTD for this trial was 225 mg QD tablets. Ten patients were treated at MTD with only 1 DLT (thrombocytopenia). The most frequent treatment related adverse events were thrombocytopenia (45%), fatigue (34%), nausea (27%) decreased appetite (27%) and anemia (25%). Thrombocytopenia, a class effect for all BET inhibitors, was dose limiting however, is was reversible (<1 week) and not cumulative. Five patients had an objective response; 2 CRs (1 T-cell/histocyte-rich DLBCL, 1 ABC-DLBCL), 3 PRs (1 follicular lymphoma, 2 ABC-DLBCL) and 5 patients had prolonged (> 6 months) SD. Three of the responses and 1 of the prolonged SD were in patients with ABC-DLBCL. PK was dose-proportional with C max reached after 3 hours and a half-life of 16 hours. PD analysis of BET target genes demonstrated dose dependent decreases in IL8 and CCR1 mRNA between 2-8 hours post dose. Conclusions: CPI-0610 is a well-tolerated, oral BET inhibitor that has demonstrated anti-tumor activity in advanced lymphoma patients. Clinical trial identification: NCT01949883

Bone Marrow Transplantation, 2011

We describe 20 patients with myeloma and 1 with primary amyloidosis from 15 centres, all with adv... more We describe 20 patients with myeloma and 1 with primary amyloidosis from 15 centres, all with advanced renal failure, most of whom had PBSC mobilised using plerixafor following previous failed mobilisation by conventional means (plerixafor used up-front for 4 patients). For 15 patients, the plerixafor dose was reduced to 0.16 mg/kg/day, with a subsequent dose increase in one case to 0.24 mg/kg/day. The remaining six patients received a standard plerixafor dosage at 0.24 mg/kg/ day. Scheduling of plerixafor and apheresis around dialysis was generally straightforward. Following plerixafor administration, all patients underwent apheresis. A median CD34 þ cell dose of 4.6 Â 10 6 per kg was achieved after 1 (n ¼ 7), 2 (n ¼ 10), 3 (n ¼ 3) or 4 (n ¼ 1) aphereses. Only one patient failed to achieve a sufficient cell dose for transplant: she subsequently underwent delayed re-mobilisation using G-CSF with plerixafor 0.24 mg/kg/day, resulting in a CD34 þ cell dose of 2.12 Â 10 6 /kg. Sixteen patients experienced no plerixafor toxicities; five had mild-to-moderate gastrointestinal symptoms that did not prevent apheresis. Fifteen patients have progressed to autologous transplant, of whom 12 remain alive without disease progression. Two patients recovered endogenous renal function post autograft, and a third underwent successful renal transplantation. Plerixafor is highly effective in mobilising PBSC in this difficult patient group.

Blood, Mar 29, 2018

RP2D of PEV 20 mg/m 2 in PEV/AZA combo did not alter toxicity profile of AZA; dose-limiting toxic... more RP2D of PEV 20 mg/m 2 in PEV/AZA combo did not alter toxicity profile of AZA; dose-limiting toxicities were transiently elevated AST/ALT. l In treatment-naive older AML patients, the intent-to-treat ORR was 50%. Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study of pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ‡60 years with treatment-naive AML (unfit for standard induction therapy) received PEV 20 or 30 mg/m 2 IV on days 1, 3, and 5 combined with fixed-dose AZA (75 mg/m 2 IV/ subcutaneously) on days 1 to 5, 8, and 9, every 28 days. The most common treatmentemergent adverse events were constipation (48%), nausea (42%), fatigue (42%), and anemia (39%). In total, 11 deaths were observed and considered unrelated to study therapy by the investigators. Transient elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were dose limiting. The recommended phase 2 dose (RP2D) of PEV in this combination is 20 mg/m 2 . PEV PK was not altered by the addition of AZA. Overall response rate (ORR) based on an intent-to-treat analysis was 50% (20 complete remissions [CRs], 5 complete remission with incomplete peripheral count recovery, 7 partial remissions [PRs]), with an 8.3-month median duration of remission. In patients receiving ‡6 cycles of therapy (n 5 23, 44%), ORR was 83%. In patients with TP53 mutations, the composite CR/PR rate was 80% (4/5). Two of these patients stayed on study for >10 cycles. Baseline bone marrow blast percentage or cytogenetic/molecular risk did not influence ORR. This study was registered at www.clinicaltrials.gov as

Blood, Oct 15, 2003

Idiopathic pneumonia syndrome (IPS) is a significant noninfectious complication of hematopoietic ... more Idiopathic pneumonia syndrome (IPS) is a significant noninfectious complication of hematopoietic stem cell transplantation (HSCT). We compared the incidences and outcomes of IPS among patients who underwent allogeneic HSCT after nonmyeloablative (n ‫؍‬ 183) compared with conventional (n ‫؍‬ 917) conditioning between December 1997 and December 2001. Patients given nonmyeloablative conditioning were older than those given conventional conditioning (median ages, 53 vs 41 years; P ‫؍‬ .001). The cumulative incidence of IPS was significantly lower at 120 days after nonmyeloablative conditioning than conventional conditioning (2.2% vs 8.4%; P ‫؍‬ .003). In addition, greater patient age (older than 40 years), diagnosis of acute leukemia or myelodysplastic syndrome, and severe acute graftversus-host disease were associated with significantly increased risks for IPS. Among older patients (older than 40 years) given conventional conditioning, highdose total body irradiation (TBI) was associated with an increased risk for IPS than were non-TBI-based regimens (16% vs 5.8%; P ‫؍‬ .001). IPS occurred early after transplantation, progressed rapidly, and was associated with a high mortality rate (75%) despite aggressive support. Initiation of mechanical ventilation and the presence of renal insufficiency at IPS onset were associated with increased risks for death after IPS. These findings support the concept that lung damage from the conditioning regimen plays a crucial role in the development of IPS after HSCT.

Leukemia, Nov 3, 2005

Transplant outcome was analyzed in 150 patients with myelodysplastic syndrome (MDS) or acute myel... more Transplant outcome was analyzed in 150 patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia transformed from MDS (tAML) conditioned with nonmyeloablative or myeloablative regimens. A total of 38 patients received nonmyeloablative regimens of 2 Gy total body irradiation alone (n ¼ 2) or with fludarabine (n ¼ 36), 90 mg/m 2. A total of 112 patients received a myeloablative regimen of busulfan, 16 mg/ kg (targeted to 800-900 ng/ml), and cyclophosphamide 120 mg/ kg. Nonmyeloablative patients were older (median age 62 vs 52 years, Po0.001), more frequently had progressed to tAML (53 vs 31%, P ¼ 0.06), had higher risk disease by the International Prognostic Scoring System (53 vs 30%, P ¼ 0.004), had higher transplant specific comorbidity indices (68 vs 42%, P ¼ 0.01) and more frequently had durable complete responses to induction chemotherapy (58 vs 14%). Three-year overall survival (27%/48% (P ¼ 0.56)), progression-free survival (28%/ 44%, (P ¼ 0.60)), and nonrelapse mortality (41%/34%, (P ¼ 0.94)) did not differ significantly between nonmyeloblative/myeloablative conditioning. Overall (HR ¼ 0.9, P ¼ 0.84) and progression-free survivals (HR ¼ 1, P ¼ 0.93) were similar for patients with chemotherapy-induced remissions irrespective of conditioning intensity. Graft vs leukemia effects may be more important than conditioning intensity in preventing progression in patients in chemotherapy-induced remissions at the time of transplantation. Randomized prospective studies are needed to further address the optimal choice of transplant conditioning intensity in myeloid neoplasms.

Blood, Nov 16, 2004

We have used a nonmyeloablative conditioning regimen consisting of total-body irradiation (2 Gy) ... more We have used a nonmyeloablative conditioning regimen consisting of total-body irradiation (2 Gy) with or without fludarabine (30 mg/m 2 /d for 3 days) for related and unrelated hematopoietic cell transplantation (HCT) in patients with hematologic malignancies who were not candidates for conventional HCT because of age, medical comorbidities, or preceding high-dose HCT. This approach relied on graft-versus-tumor (GVT) effects for control of malignancy. Patients and Methods We analyzed GVT effects in 322 patients given grafts from HLA-matched related (n ϭ 192) or unrelated donors (n ϭ 130). Results Of the 221 patients with measurable disease at HCT, 126 (57%) achieved complete (n ϭ 98) or partial (n ϭ 28) remissions. In multivariate analysis, there was a higher probability trend of achieving complete remissions in patients with chronic extensive graft-versus-host disease (GVHD; P ϭ .07). One hundred eight patients (34%) relapsed or progressed. In multivariate analysis, achievement of full donor chimerism was associated with a decreased risk of relapse or progression (P ϭ .002). Grade 2 to 4 acute GVHD had no significant impact on the risk of relapse or progression but was associated with increased risk of nonrelapse mortality and decreased probability of progression-free survival (PFS). Conversely, extensive chronic GVHD was associated with decreased risk of relapse or progression (P ϭ .006) and increased probability of PFS (P ϭ .003). Conclusion New approaches aimed at reducing the incidence of grade 2 to 4 acute GVHD might improve survival after allogeneic HCT after nonmyeloablative conditioning.

It is unknown whether the severity, timing, and quality of graft-versus-host disease (GVHD) may b... more It is unknown whether the severity, timing, and quality of graft-versus-host disease (GVHD) may be different after nonmyeloablative as compared with myeloablative hematopoietic stem cell transplantation (HSCT). Therefore, GVHD incidence, morbidity of skin, liver, and gut, requirements for immunosuppressive therapy, and survival were retrospectively analyzed in 44 patients who underwent nonablative HSCT and 52 who underwent ablative HSCT (median ages, 56 and 54 years, respectively). The nonablative transplantation regimen consisted of low-dose total body irradiation (TBI), preceded in some patients by fludarabine administration and followed in all patients by immu-nosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP). Those who underwent myeloablative HSCT were prepared with different TBI-and non-TBIcontaining regimens and received CSP plus methotrexate or MMF for GVHD prophylaxis. The cumulative incidence of grades II-IV acute GVHD was lower after nonablative transplantation (64% vs 85%; P ‫؍‬ .001), but there were no differences in the cumulative incidence of chronic GVHD requiring treatment (73% vs 71%; P ‫؍‬ .96). Nonablative transplantation was associated with the delayed initiation of steroid treatment for GVHD (0.95 months vs 3.0 months; P < .001) and with the use of fewer systemic immunosuppressants in the first 3 months after transplantation (P < .04). This corresponded to more prevalent skin and more severe gut morbidity 6 to 12 months after nonablative transplantation. Our results show that nonablative HSCT is associated with a syndrome of acute GVHD occurring after day 100 in many patients. This "late-onset acute GVHD" should be taken into consideration in the design of prospective studies comparing GVHD resulting from the two types of transplantation procedures.

Journal of Clinical Oncology, Jan 10, 2008

Few effective treatment options exist for chemotherapy-refractory indolent or transformed non-Hod... more Few effective treatment options exist for chemotherapy-refractory indolent or transformed non-Hodgkin's lymphoma (NHL). We examined the outcome of nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) in this setting. Patients and Methods Sixty-two patients with indolent or transformed NHL were treated with allogeneic HCT from related (n ϭ 34) or unrelated (n ϭ 28) donors after conditioning with 2 Gy of total-body irradiation with or without fludarabine. Nine unrelated donors were mismatched for Ն one HLA antigen. Sixteen patients had histologic transformation before HCT. Twenty patients (32%) had progressive disease after previous high-dose therapy with autologous HCT. Median age was 54 years, and patients had received a median of six lines of treatment before HCT. Median follow-up time after HCT was 36.6 months. Results At 3 years, the estimated overall survival (OS) and progression-free survival (PFS) rates were 52% and 43%, respectively, for patients with indolent disease, and 18% and 21%, respectively, for patients with transformed disease. Patients with indolent disease and related donors (n ϭ 26) had 3-year estimated OS and PFS rates of 67% and 54%, respectively. The incidences of grade 2 to 4 acute graft-versus-host disease (GVHD), grade 3 and 4 acute GVHD, and extensive chronic GVHD were 63%, 18%, and 47%, respectively. Among survivors, the median Karnofsky performance status at last follow-up was 85%. Conclusion Nonmyeloablative allogeneic HCT can produce durable disease-free survival in patients with relapsed or refractory indolent NHL, even in this relatively elderly and heavily pretreated cohort. Outcomes were particularly good in patients with untransformed disease and related donors, whereas patients with transformed disease did poorly. Long-term survivors reported good overall functional status.