Final Results of a Dual-Institution Phase I Clinical Trial of Targeted Marrow Irradiation (TMI) Intensification of Reduced-Intensity Fludarabine/Busulfan (Flu/Bu) Conditioning for Allogeneic Hematopoietic Cell Transplantation for Medically Frail Patients with High-Risk Hematological Malignancies

Background Reduced-intensity conditioning (RIC) regimens provide insufficient disease control in patients with high-risk hematological malignancies who are ineligible for myeloablative hematopoietic cell transplantation (HCT) due to advanced age or comorbidities. RIC fludarabine/busulfan (Flu/Bu) is generally well tolerated, but is associated with high relapse rates. We hypothesized that intensification of RIC Flu/Bu with targeted marrow irradiation (TMI) would be feasible and improve outcomes in such patients. Methods This dose escalation phase I clinical trial incorporated 3+3 design with expansion. The primary endpoint was to estimate safety and feasibility of TMI combined with Flu/Bu. Secondary endpoints included transplant-related mortality (TRM), disease free survival (DFS) and overall survival (OS). Eligible patients were ≥ 18 years diagnosed with high-risk hematological malignancies who were not candidates for myeloablative HCT. The conditioning regimen consisted of TMI (dose levels: 3 Gy, 4.5 Gy and 6 Gy) delivered at 1.5 Gy/fraction in twice daily fractions on days -10 through -7, fludarabine (30 mg/m2) on days -6 through -2 and busulfan (AUC 4800 µM*minute) on days -5 and -4. Radiation was targeted to bone marrow and spleen using intensity modulated radiation therapy (IMRT) technique while minimizing injury to organs at risk. GVHD prophylaxis included tacrolimus and methotrexate for matched sibling and unrelated donors (UD), and tacrolimus, mycophenolate mofetil and post-cyclophosphamide for haploidentical donors. Antithymocyte globulin (ATG) was added for recipients of UD transplants. Dose limiting toxicity (DLT) was defined as engraftment failure, grade ≥ 4 mucositis and grade ≥ 3 other non-hematological adverse events (AEs) from day -10 to day +32. Results A total of 26 patients (median age 64 years [range, 25-76]; 61% females) were enrolled in two transplant centers (Table 1). Diagnoses included AML (n=15), MDS (n=5), T-PLL (n=2), CLL (n=1), DLBCL (n=1), multiple myeloma (n=1) and myeloproliferative disorder (n=1). Sixteen (61%) patients had intermediate/high HCT-comorbidity index and high/very high disease risk index (DRI). At the time of HCT, 19 (73%) patients had active or residual disease. Donors were UD (n=18), matched sibling (n=5) and haploidentical (n=3). All patients engrafted neutrophils (median, 16 days [range, 10-29]). Most frequent AEs were mucositis (65%), gastrointestinal toxicity (62%), hepatotoxicity (hyperbilirubinemia and/or increased transaminase levels) (65%) and fatigue (69%). Twenty-four grade ≥ 3 AEs occurred in 13 patients; 2 patients experienced reversible DLT (mucositis and hepatotoxicity) at 6 Gy TMI dose level. Additional escalation was halted and 6 Gy cohort was expanded. Only 1 patient experienced reversible hepatotoxicity in the expansion cohort. Grade II-IV and III-IV acute GVHD rates at day +100 were 57% (95% CI, 39%-84%) and 22% (95% CI, 9%-53%), respectively. The 1-year cumulative incidence of chronic GVHD was 42% (95% CI, 24%-74%). The 1-year cumulative incidence of TRM and relapse was 8% (95% CI, 2%-32%) and 26% (95% CI, 13%-52%), respectively (Figure 1A). The overall TRM for 3 Gy, 4.5 Gy and 6 Gy cohorts was 25%, 12.5% and 12%, respectively. With a median follow up of 12.7 months (range, 1.1-36.8), 1-year DFS was 55% (95% CI, 34%-76%) and OS was 65% (95% CI, 46%-85%) (Figure 1B). One-year DFS was equivalent for patients transplanted in CR or with active disease (54% [95% CI, 14%-93%] vs 55% [95% CI, 29%-80%]; p=0.83) (Figure 1C). While no difference in DFS was observed between the 4.5 Gy and 6 Gy cohorts, the 3 Gy cohort was associated with inferior DFS (p=0.004) (Figure 1D). One-year DFS and OS for 6 Gy cohort was 58% (95% CI, 30%-87%) and 82% (95% CI, 59%-100%), respectively. Conclusion Intensification of RIC Flu/Bu with TMI is feasible, with low incidence of TRM in medically frail patients. Reversible mucositis and hepatotoxicity prevented dose escalation beyond 6 Gy. DFS and OS at 6 Gy are promising and deserve further investigation. Disclosures Malek: Janssen: Other: Advisory board, Speakers Bureau; Medpacto: Research Funding; Sanofi: Other: Advisory board; Clegene: Other: Advisory board , Speakers Bureau; Amgen: Honoraria; Takeda: Other: Advisory board , Speakers Bureau; Bluespark: Research Funding; Cumberland: Research Funding. de Lima:Pfizer: Other: Personal fees, advisory board, Research Funding; Celgene: Research Funding; Kadmon: Other: Personal Fees, Advisory board; Incyte: Other: Personal Fees, advisory board; BMS: Other: Personal Fees, advisory board. Caimi:Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Verastem: Other: Advisory Board; Kite pharmaceuticals: Other: Advisory Board; ADC therapeutics: Other: Advisory Board, Research Funding; Celgene: Speakers Bureau.

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Plerixafor alone for the mobilization and transplantation of HLA-matched sibling donor hematopoietic stem cells

Blood Advances ◽

10.1182/bloodadvances.2018027599 ◽

2019 ◽

Vol 3 (6) ◽

pp. 875-883 ◽

Cited By ~ 7

Author(s):

Yi-Bin Chen ◽

Jennifer Le-Rademacher ◽

Ruta Brazauskas ◽

Deidre M. Kiefer ◽

Mehdi Hamadani ◽

...

Keyword(s):

Hematological Malignancies ◽

Hematopoietic Cell Transplantation ◽

Multicenter Trial ◽

Primary Objective ◽

Hematopoietic Stem ◽

Cd34 Cells ◽

Matched Sibling ◽

Multicenter Prospective Study ◽

One Year ◽

Stimulating Factor

Abstract Plerixafor, a direct antagonist of CXCR4/stromal-derived factor 1, can safely and rapidly mobilize allografts without the use of granulocyte colony-stimulating factor (G-CSF). We conducted a phase 2, multicenter, prospective study of plerixafor-mobilized HLA-identical sibling allografts for allogeneic hematopoietic cell transplantation in recipients with hematological malignancies. Donors (n = 64) were treated with subcutaneous plerixafor (240 µg/kg) and started leukapheresis (LP) 4 hours later. The primary objective was to determine the proportion of donors who were successfully mobilized: defined as collection of ≥2.0 × 106 CD34+ cells per kilogram recipient weight in ≤2 LP sessions. Recipients subsequently received reduced intensity (RIC; n = 33) or myeloablative (MAC; n = 30) conditioning. Sixty-three of 64 (98%) donors achieved the primary objective. The median CD34+ cell dose per kilogram recipient weight collected within 2 days was 4.7 (0.9-9.6). Plerixafor was well tolerated with only grade 1 or 2 drug-related adverse events noted. Bone pain was not observed. Plerixafor-mobilized grafts engrafted promptly. One-year progression-free and overall survivals were 53% (95% confidence interval [CI], 36% to 71%) and 63% (95% CI, 46% to 79%) for MAC and 64% (95% CI, 47% to 79%) and 70% (95% CI, 53% to 84%) for RIC recipients, respectively. Donor toxicity was reduced relative to G-CSF mobilized related donors. This is the first multicenter trial to demonstrate that, as an alternative to G-CSF, plerixafor rapidly and safely mobilizes sufficient numbers of CD34+ cells from matched sibling donors for HCT. Engraftment was prompt, and outcomes in recipients were encouraging. This trial was registered at clinicaltrials.gov as #NCT01696461.

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A Phase 1b Study of Panobinostat in Combination with Idarubicin and Ara-C in Patients with High-Risk Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v126.23.2553.2553 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2553-2553

Author(s):

Daniel J. DeAngelo ◽

Alison R. Walker ◽

Richard F. Schlenk ◽

Jorge Sierra ◽

Bruno C. Medeiros ◽

...

Keyword(s):

High Risk ◽

Myeloid Leukemia ◽

Research Funding ◽

Advisory Board ◽

Advisory Committees ◽

Expansion Phase ◽

Phase 1B ◽

Grade 3 ◽

Advisory Role

Abstract Background: For patients (pts) with acute myeloid leukemia (AML) with poor prognostic indicators, such as unfavorable cytogenetics or secondary AML, overall and event-free survival (EFS) rates are much worse, highlighting the critical need for more effective therapeutic modalities. Increasing evidence implicates epigenetic processes in the development of AML. Panobinostat (PAN), a potent pan-deacetylase inhibitor, has been shown to augment the effects of standard chemotherapies (anthracyclines and Ara-C) in preclinical studies with AML cells. These preclinical results led to a phase 1b study of PAN in combination with idarubicin and Ara-C in pts with high-risk AML. Methods: The trial included younger pts (≥ 18 y and ≤ 65 y) with newly diagnosed high-risk AML, defined as: treatment-related AML, AML following previously diagnosed myelodysplasia or medical history of relevant hematologic disorders, and presence of unfavorable cytogenetics. The primary objective was determination of the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of PAN when given in combination with idarubicin and Ara-C. Secondary objectives included safety, efficacy, and pharmacokinetics (PK). Exploratory endpoints included assessment of the relationship between efficacy and PK parameters and 1-year EFS. The study examined escalating doses (15-25 mg) of PAN given 3 times per wk for 2 wk starting on day 8 of a 28-day cycle (ie, D8, D10, D12, D15, D17, D19) in combination with standard induction doses of idarubicin (12 mg/m2/d; D1-D3) and Ara-C (100 mg/m2/d; C1, D1-D7). After 2 cycles, pts achieving a complete remission (CR) or complete remission with incomplete blood count recovery (CRi) moved to a consolidation phase with a combination of high-dose Ara-C and PAN at the dose received during induction. After determination of the RP2D, additional pts were enrolled in the expansion phase and treated at the RP2D dose. Results: A total of 46 pts with a median age of 55.5 y (range, 19-65 y) were enrolled in the study (34 in the dose-escalation phase [15 mg, n = 11; 20 mg, n = 15; 25 mg, n = 8] and 12 in the dose-expansion phase). Seven dose-limiting toxicities were observed in the escalation phase: 4 of 12 pts in the 20-mg group (left ventricular systolic dysfunction [n = 2], hepatosplenic candidiasis [n = 1], increased QTCF [n = 1]) and 3 of 7 pts in the 25-mg group (febrile neutropenia [n = 2], grade 3 diarrhea [n = 1]). Based upon the Bayesian linear regression model, the upper limit (≤ 25% probability of excessive toxicity in > 33% of pts) was not reached for determination of MTD. The RP2D of PAN was 20 mg. Among the 27 pts treated at the RP2D, common grade 3/4 adverse events (AEs) regardless of causality were mainly hematologic, including febrile neutropenia (59.3%), thrombocytopenia (48.1%), and anemia (40.7%). Although most pts experienced gastrointestinal AEs, they were largely grade ≤ 2 (all grades, 74.1%; grade 3/4, 11.1%). AEs led to discontinuation in 15% of pts treated at the RP2D. Four pts (3 of 46 during induction and 1 of 19 during consolidation) treated with RP2D died during treatment. Of the on-treatment deaths, 1 (grade 4 sepsis) was potentially related to study drug, whereas the remaining 3 (progressive AML, ischemic stroke, and cerebral hemorrhage) were determined to be unrelated. The geometric mean AUC0-24 of PAN after oral dosing increased with increasing PAN dose (42.5 hr•ng/mL [15 mg], 62.6 hr•ng/mL [20 mg], and 74.6 hr•ng/mL [25 mg]). However, AUC0-24 was higher in the expansion phase (92.7 hr•ng/mL) than at 25 mg in the escalation phase, with high variability (coefficient of variation, 32.3% [expansion]; 45.5% [25-mg escalation]). Among pts treated at the RP2D, 44.4% and 11.1% achieved CR and CRi, respectively (CR/CRi, 56%). In the subset of pts in the RP2D, no relationship was found between AUC0-24 and response rates. In the overall population, the 1-year EFS rate was 78.3%. Conclusions: The data from this study showed high variability in PAN PK and largely overlapping exposure between dose levels. Overall, these data demonstrate a safety profile consistent with those of single-agent PAN and the combination of Ara-C and idarubicin. Disclosures DeAngelo: Incyte: Other: Consulting or Advisory Role; Pfizer: Other: Consulting or Advisory Role; Novartis: Other: Consulting or Advisory Role; BMS: Other: Consulting or Advisory Role; ARIAD Pharmaceuticals Inc.: Other: Consulting & Advisory Role; Amgen: Other: Consulting or Advisory Role. Schlenk:Janssen: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria; Pfizer: Honoraria, Research Funding; Arog: Honoraria, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Teva: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Sierra:Novartis: Research Funding; Celgene: Research Funding; Amgen: Research Funding. Ocio:Novartis: Consultancy, Honoraria, Research Funding. Strickland:Sunesis Pharmaceuticals: Other: Steering Committee and Advisory Board Participation; Alexion Pharmaceuticals: Other: Advisory Board Particpation; Amgen: Other: Advisory Board Particpation; Daiichi-Sankyo: Other: Advisory Board Particpation; Boehringer-Ingelheim: Other: Advisory Board Particpation. Valera:Novartis: Employment. Wegener:Novartis: Employment. De:Novartis: Employment. Mu:Novartis: Employment. Binlich:Novartis: Employment. Stuart:Novartis: Research Funding.

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A Phase 1a/b Dose Escalation Study of the MYC Repressor Apto-253 in Patients with Relapsed or Refractory AML or High-Risk MDS

Blood ◽

10.1182/blood-2021-150049 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3411-3411

Author(s):

Maro Ohanian ◽

Martha L. Arellano ◽

Moshe Y. Levy ◽

Kristen O'Dwyer ◽

Hani Babiker ◽

...

Keyword(s):

Clinical Trial ◽

High Risk ◽

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Publicly Traded ◽

Advisory Committees ◽

Grade 3 ◽

Refractory Aml

Abstract INTRODUCTION: APTO-253 represses expression of the MYC oncogene by targeting a conserved G-quadruplex structure in its promoter, down-regulates MYC mRNA and protein levels and induces apoptosis in AML cell lines and marrow samples from patients with AML, MDS, and MPN in vitro. After injection, a large fraction of APTO-253 binds iron and transforms to the Fe(253) 3 complex which retains full activity. APTO-253 has been granted orphan drug designation for AML by the US FDA and is being studied in a Phase 1a/b clinical trial in patients with relapsed or refractory AML (R/R AML) or high-risk myelodysplasias (high-risk MDS) (NCT02267863). AIMS: Primary objectives are to determine the safety and tolerability of APTO-253, MTD, dose limiting toxicities (DLT), and the RP2D. Key secondary objectives are to assess the pharmacokinetic (PK) profile, pharmacodynamic (PD) activity, and preliminary evidence of antitumor activity. METHODS: Eligible patients have R/R AML or high-risk MDS for which either standard treatment has failed, is no longer effective, or can no longer be administered safely. Treatment- emergent adverse events (TEAEs) and tumor responses are evaluated using International Working Group criteria. APTO-253 is administered by IV infusion once weekly on days 1, 8, 15, and 22 of each 28-day cycle; ascending dose cohorts were enrolled at a starting dose of 20 mg/m 2 with planned escalation to 403 mg/m 2. RESULTS: As of June 7, 2021, a total of 18 patients (median age 64.0 years, 16 AML and 2 high-risk MDS) with a median of 2.5 prior treatments (range of 1 - 9) have been treated with APTO-253 at doses of 20 (n=1), 40 (n=1), 66 (n=4), 100 (n=4) and 150 mg/m 2 (n=8). Most patients were RBC (87.5% of AML and 100% of MDS) and/or platelet (75% of AML and 50% MDS) transfusion-dependent. No DLTs or drug-related serious adverse events have been reported. Only 1 patient had a drug-related TEAE of grade 3 or greater (fatigue, Grade 3, probably related). Preliminary PK analysis (Figure 1) showed that serum levels of APTO-253 were dose proportional. C max and AUC 0-72h for C1D1 dosing were 0.06, 0.02, 0.36 ± 0.37, 0.44 ± 0.41 and 0.72 ± 0.70 µM and 0.11, 0.15, 3.98 ± 1.77, 4.79 ± 0.87 and 2.51 ± 1.73 µM*h for dose levels of 20, 40, 66, 100 and 150 mg/m 2, respectively. Plasma levels for Fe(253) 3 were significantly higher than those for the APTO-253 monomer. For example, C max and AUC 0-72h of Fe(253) 3 for C1D1 dosing of patients in Cohort 150 mg/m 2 were 2- and 20- fold higher than the ATPO-253 monomer at 15.09 ± 0.42 µM and 51.52 ± 28.26 µM*h, respectively. Following dosing at 150 mg/m 2, serum concentrations of Fe(253) 3 were above 0.5 µM for > 48 h, which approaches the therapeutic range based on in vitro studies. CONCLUSIONS: APTO-253 has been well-tolerated at doses of 20, 40, 66, 100 and 150 mg/m 2 over multiple cycles and escalated to 210 mg/m 2 (Cohort 6). PK analysis revealed that APTO-253 is rapidly transformed to and co-exists with the Fe(253) 3 in serum from R/R AML and high-risk MDS patients. Enrollment of patients at the 210 mg/m 2 dose level is ongoing and updated clinical data will be presented at the meeting. Figure 1 Figure 1. Disclosures Arellano: KITE Pharma, Inc: Consultancy; Syndax Pharmaceuticals, Inc: Consultancy. Levy: AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Epizyme: Consultancy, Other: Promotional speaker; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Dova: Consultancy, Other: Promotional speaker; Novartis: Consultancy, Other: Promotional speaker; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau. Mahadevan: caris: Speakers Bureau; Guardanthealt: Speakers Bureau; PFIZER: Other: Clinical trial Adverse events committee; TG Therapeuticals: Other: Clinical trial Adverse events committee. Zhang: Aptose Biosciences, Inc.: Current Employment. Rastgoo: Aptose Biosciences, Inc.: Current Employment. Jin: Aptose Biosciences, Inc.: Current Employment. Marango: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Howell: Aptose Biosciences, Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rice: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties; Oncolytics Biotech Inc.: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Bejar: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company; Takeda: Research Funding; BMS: Consultancy, Research Funding; Gilead: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Astex: Consultancy; Silence Therapeutics: Consultancy.

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Safety and Efficacy of Ruxolitinib in an 1869-Patient Cohort of JUMP: An Open-Label, Multicenter, Single-Arm, Expanded-Access Study in Patients with Myelofibrosis

Blood ◽

10.1182/blood.v126.23.2799.2799 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2799-2799 ◽

Cited By ~ 4

Author(s):

Renato Tavares ◽

Giuseppe A. Palumbo ◽

Philipp Le Coutre ◽

Francesca Palandri ◽

Haifa Kathrin Al-Ali ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Costal Margin ◽

Phase 3 ◽

Advisory Committees ◽

Safety And Efficacy ◽

Expanded Access ◽

Grade 3

Abstract BACKGROUND: Ruxolitinib (RUX) is a potent JAK1/JAK2 inhibitor that demonstrated improvements in splenomegaly and disease-related symptoms, as well as improved survival, in patients (pts) with intermediate (Int)-2- or high-risk myelofibrosis (MF), and has proved superior to placebo and best available therapy in the phase 3 COMFORT studies. JUMP is an expanded-access phase 3b trial designed to assess the safety and efficacy of RUX in pts with MF and includes patients with no access to RUX outside a clinical trial. As of Dec 2014, final enrollment was 2233 pts in 26 countries. METHODS: Eligible pts had Int-2- or high-risk MF with or without splenomegaly, or Int-1-risk MF with a palpable spleen (≥ 5 cm from the costal margin). Pts received starting doses of RUX based on platelet counts at baseline (5 mg twice daily [bid; ≥ 50 to < 100 × 109/L], 15 mg bid [100 to 200 × 109/L], or 20 mg bid [> 200 × 109/L]). The primary endpoint was assessment of safety and tolerability of RUX. Additional analyses included changes in palpable spleen length and symptom scores as measured by the FACT-Lymphoma total score (FACT-Lym TS). The final analysis will be performed after all pts have completed 24 months of treatment or discontinued the study. RESULTS: This analysis includes 1869 pts (primary MF, 59.1%; n = 1105) who started treatment ≥ 1 year before the data cutoff date (01 Jan 2015). At baseline, median age was 67 y (range, 18-89 y); 54.1% were male; median palpable spleen length was 12 cm below the costal margin; 87 pts did not have splenomegaly. Median hemoglobin (Hb) was 106 g/L, and 38.9% of pts had Hb levels ˂ 100 g/L; median platelet count was 257 × 109/L; mean FACT-Lym TS and FACIT-Fatigue score were 113.7 and 33.2, respectively. At data cutoff, 37.0% of pts remained on treatment; 26.1% had completed treatment per protocol. Primary reasons for discontinuation included adverse events (AEs; 17.4%), disease progression (8.2%), and death (3.4%). Median exposure was 13.6 months; the median average daily dose was 36.7 mg for pts starting at 20 mg bid (n = 1168; 62.5%) and 23.2 mg for pts starting at 15 mg bid (n = 559; 29.9%). The majority of pts (66.0%) had dose modifications, and 26.2% had a dose interruption. Grade 3/4 hematologic AEs included anemia (34.0%), thrombocytopenia (14.9%), and neutropenia (3.9%), which led to discontinuation in 2.2%, 3.3%, and 0.2% of pts, respectively. The most common nonhematologic AEs (≥ 10%) were pyrexia (14.5%), asthenia (13.8%), diarrhea (12.4%), and fatigue (10.3%), and were primarily grade 1/2; grade 3/4 AEs were low overall (≤ 2%), except pneumonia (3.9%), which led to discontinuation in 9 pts (0.5%). Rates of infections were low; all-grade infections ≥ 5% included pneumonia (6.2%), urinary tract infection (5.7%), and nasopharyngitis (5.3%). Tuberculosis was reported in 5 pts (0.3%; grade 3/4, 0.1%); hepatitis B was reported in 1 pt (0.1%; grade 3/4, 0.1%). At wk 24 and 48, 57.2% (742/1297) and 62.0% (588/949) of pts with baseline splenomegaly achieved a ≥ 50% reduction from baseline in palpable spleen length; 22.9% (297/1297) and 19.0% (180/949) had 25% to 50% reductions, respectively. Most pts (70.5%; 1208/1713) experienced a ≥ 50% reduction at any time; 23.3% (399/1713) had complete resolution of splenomegaly (Figure). At wk 24 and 48, 96.6% (57/59) and 91.5% (43/47) of evaluable pts without splenomegaly at baseline continued to have a nonpalpable spleen; 1.7% (1/59) and 4.3% (2/47) had a spleen that was 0-5 cm, and 1.7% (1/59) and 4.3% (2/47) had a spleen ≥ 5 cm. A large proportion of pts achieved a response (ie, a clinically significant improvement) on the FACT-Lym TS and FACIT-Fatigue at wk 24 (43.0% [525/1220]; 47.1% [593/1258]) and wk 48 (43.2% [368/852]; 45.7% [396/867]). Similar responses were seen in pts without a palpable spleen (FACT-Lym TS: wk 24, 44.0% [22/50]; wk 48, 36.1% [13/36]; FACIT-Fatigue: wk 24, 49.1% [27/55]; wk 48, 35.1% [13/37]). CONCLUSIONS: To date, JUMP includes the largest cohort of pts with MF treated with RUX. Consistent with previous findings, anemia and thrombocytopenia were the most common AEs but rarely led to discontinuation. As observed previously, most pts experienced reductions in splenomegaly and symptoms with RUX treatment. Clinically meaningful improvements in symptoms were also seen in pts with no palpable spleen, a pt group not included in the COMFORT studies. Overall, the safety and efficacy profile of RUX in JUMP is consistent with that in the phase 3 COMFORT studies. Disclosures Palumbo: Novartis: Honoraria, Other: Advisory Board. Le Coutre:Novartis: Honoraria. Al-Ali:Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Ullrich:Novartis: Honoraria. Brittain:Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Foltz:Promedior: Research Funding; Gilead: Research Funding; Novartis: Honoraria, Research Funding. Raanani:Bristol-Myers Squibb: Other: Advisory Board; Novartis: Other: Advisory Board, Research Funding; Ariad: Other: Advisory Board; Pfizer: Other: Advisory Board. Gupta:Incyte: Honoraria, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ghosh:Novartis Pharmaceuticals Corporation: Employment. Tannir:Novartis Pharma AG: Employment. Perez Ronco:Novartis Pharma AG: Employment. Vannucchi:Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Clinical Impact of Cytokine Release Syndrome on Outcomes of Peripheral Blood Stem Cell Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide

Blood ◽

10.1182/blood-2020-143166 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 10-11

Author(s):

Salman Otoukesh ◽

Hany Elmariah ◽

Dongyun Yang ◽

Sally Mokhtari ◽

Madiha Siraj ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Multivariable Analysis ◽

Advisory Board ◽

Board Meeting ◽

Advisory Committees ◽

Gvhd Prophylaxis ◽

Haploidentical Hematopoietic Cell Transplantation ◽

Grade 3

Peripheral blood stem cell (PBSC) as a graft source compared to bone marrow has been reported to result in lower risk of relapse after haploidentical hematopoietic cell transplantation (haplo-HCT) with use of post-transplant cyclophosphamide (PTCy) as a graft-versus-host-disease (GvHD) prophylaxis. However, cytokine release syndrome (CRS) is a common complication of this platform that can affect the outcomes of patients after PBSC haplo-HCT. CRS occurs due to rapid activation and proliferation of alloreactive donor T cells resulting in the elevated secretion of inflammatory cytokines. In this study, we sought to examine the risk factors for CRS and the effect of CRS severity on outcomes of PBSC haplo-HCT. We identified total of 271 consecutive patients with hematological malignancies who received their first PBSC haplo-HCT with PTCy-based GVHD prophylaxis at City of Hope (n=157) or Moffitt (n=114) Cancer Centers between 2014 and 2019. The median patient age at HCT was 54 years (INQ range, 37-64) for the entire cohort and 48% of the patients had HCT-CI ³3. Close to 70% of the study cohort had acute leukemia and 33% of all patients had high/very high-risk disease risk index. Myeloablative conditioning was used in 52% of the cases and 81% of all HCT recipients were CMV seropositive. The median donor age at HCT was 33 years (INQ range, 26-43). The HLA -A, -B, -C, -DRB1, -DQB1, or -DPB1 mismatch between the recipient and the donor in the GVH direction was 5/10 in 51%, 4/10 in 29% and £3/10 in 20% of cases. Offspring donors were used in 54% of the patients, sibling donors in 35%, and parent/other relative donors in 11%. Female donors to male recipients were used in only 22% of patients. The median infused CD34 dose was 5.25 x106 cells/kg (range, 2.3-22.4x106) and the CD3 dose was 2.48x108 cells/kg (range, 0.002-8.88 x108). CRS of any grade by ASTCT criteria was observed in 92% of study patients within first 7 days of HCT: 54% had grade 1, 39% grade 2, and 5.2% grade 3-4. Infused cell doses of CD34 >5x106 cells/kg and of CD3 >2.5x108 cells/kg had no significant effect on grade 3-4 CRS. On multivariable analysis, the use of reduced-intensity conditioning (RIC) was associated with increased grade 2-4 CRS (HR = 1.6, 95% CI: 1.11.-2.33, p=0.01) and grade 3-4 CRS (HR = 14.7, 95% CI: 1.97-109.5, p=0.009) compared with the myeloablative conditioning. Donor 5/10 HLA-mismatch was also associated with increased grade 2-4 CRS (HR = 1.5, 95% CI: 1.05-2.18; p=0.03) and grade 3-4 CRS (HR = 3.50, 95% CI: 1.00-12.32; p=0.05) compared with £4/10 HLA-mismatch. Non-relapse mortality (NRM) at day 100, and 1-year overall survival (OS) by CRS severity is shown in Figure. Comparing with the grade 0-1 CRS in multivariable analysis (Table), increase in CRS severity was associated with lower probability of neutrophil engraftment (HR = 0.9 for grade 2 and HR = 0.4 for grade 3-4; p=0.03). Increased CRS severity as compared to the grade 0-1 was also predictive of higher risks of NRM (HR = 1.6, 95% CI: 0.95-2.79 for grade 2 and HR = 6.6, 95% CI: 3.12-13.78 for grade 3-4; p<0.001), lower disease-free survival (DFS; HR = 1.3 for grade 2 and HR = 4.5 for grade 3-4; p<0.001) and lower OS (HR = 1.2 for grade 2 and HR = 4.1 for grade 3-4; p<0.001) after HCT. We observed no association between CRS severity and risk of relapse or the incidence and severity of acute GvHD after transplant. We conclude that CRS is a common complication after PB haplo-HCT/PTCy. CRS severity is associated with post-HCT outcomes with grade 3-4 CRS associated with the highest risk of NRM and overall mortality after HCT. Infused CD34 or CD3 cell doses effect on CRS is unclear. RIC and higher degree of HLA-mismatch are predictive of higher-grade CRS. Identification of modifiable risk factors can help to mitigate the risk for serious CRS and subsequent mortality after PB haplo-HCT/PTCy. Figure 1 Disclosures Nishihori: Karyopharm: Other: Research support to institution; Novartis: Other: Research support to institution. Pidala:CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Johnson and Johnson: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; BMS: Research Funding; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees. Nakamura:Merck: Other: advisory board meeting; Alexion: Other: Support on a meeting presentation; Kyowa-Kirin: Other: Support on a meeting presentation; Celgene: Other: Support on seminar; Magenta Therapeutics: Other: Advisory board meeting; Viracor: Consultancy; Kadmon Corporation: Other: Advisory board meeting; NapaJen Pharma: Consultancy. Al Malki:Rigel Pharma: Consultancy; Jazz Pharmacuticals, Inc: Consultancy; Neximmune: Consultancy. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees.

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Results for Phase II Clinical Trial of LCL161, a SMAC Mimetic, in Patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (post-PV MF) or Post-Essential Thrombocytosis Myelofibrosis (post-ET MF)

Blood ◽

10.1182/blood.v128.22.3105.3105 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3105-3105 ◽

Cited By ~ 8

Author(s):

Naveen Pemmaraju ◽

Bing Z Carter ◽

Hagop M. Kantarjian ◽

Jorge E. Cortes ◽

Tapan M. Kadia ◽

...

Keyword(s):

Clinical Trial ◽

High Risk ◽

Phase Ii ◽

Research Funding ◽

Myeloproliferative Neoplasm ◽

Advisory Board ◽

Janus Kinase ◽

Common Reason ◽

Jak Inhibitor ◽

Jak Inhibitors

Abstract Background: There is no standard therapy for patients (pts) with intermediate (Int)-2 or high risk myelofibrosis (MF) who have failed or are intolerant to Janus kinase (JAK) inhibitors such as ruxolitinib. Second mitochondria-derived activator of caspases (SMAC) mimetics, or inhibitors of apoptosis (IAP) antagonists, lead to increased apoptotic cancer cell death, especially in high TNFα-expressing tumor models. An emerging concept in myeloproliferative neoplasm (MPN) tumor pathobiology is the finding of significantly increased levels of TNFαin pts with MF(Fleischman AG et al, Blood 2011). Objectives: Primary objective: to determine efficacy (IWG-MRT, 2013) of LCL161 as monotherapy for pts with MF. Secondary objectives: to determine safety, durability of response, and changes in symptom burden [Myeloproliferative Neoplasm (MPN)-Total Symptom Score]. Exploratory objectives: to assess JAK2V617F and CALR allele burden; 28-gene panel for molecular mutations via next generation sequencing; and markers of IAP pathway degradation. Methods: We conducted an investigator-initiated, single-center, phase II study of LCL161 for pts with MF in a Simon's Optimal two-stage design. Pts age ≥18, PS=0-2, Int to high risk MF, who were intolerant to, ineligible for, or relapsed/refractory to JAK inhibitors were eligible. There was no threshold requirement for spleen size or platelet (plt) count, and pts with prior allogeneic stem cell transplant (SCT) were eligible. LCL161, an oral (po) drug, was given at starting dose 1500mg po once weekly. Each cycle=28 days. After 3 cycles, bone marrow exam and objective response assessments were performed. Results: From January 2015 to July 2016, 21 pts have been enrolled. Baseline characteristics: Median Age: 72 years [56-81], 86% with primary MF. Baseline laboratory values: Hb 9 g/dL (6.3-12); WBC 5.3 K/uL [1.1-38]; platelets 45 K/uL [6-1365]. JAK2V617F mutations were present in 14(67%), CALR mutations in 3(14%), and MPLW515L mutation in 1(5%) pt. Additionally, the most common other molecular mutations were: TET2(n=4); DNMT3A(n=3); RAS(n=1); EZH2(n=1). 17 (81%) had ≥2 prior therapies. Most common prior therapy was a JAK inhibitor (67%). 2 pts had prior SCT. By IPSS, 14 (67%) were high risk MF; 6(28%) were Int-2. Median number of cycles received=3[1-19], median treatment duration=2.8 months (mos)[0.2-16.7]. 19 pts are alive, with median follow-up of 7 mos[0.2-17.7]. Among 21 pts, 5 have been recently enrolled and have not yet reached 12-week evaluation period; among 16 evaluable pts, 6 pts had 9 objective responses (3 pts achieved 2 separate IWG-MRT 2013 response categories): Clinical improvement (CI) (anemia) in 2 pts; CI (Symptom) in 5 pts; CI (Spleen) in 1 pt; Cytogenetic remission in 1 pt. Grade 3/4 non-hematologic adverse events: syncope, n=2. No pts had cytokine release syndrome. Most common grade 1/2 non-hematologic toxicities: fatigue (n=10), nausea (n=10), dizziness/vertigo (n=9). Dose reductions: 7 pts: 6 pts to dose -1 level (1200 mg po once weekly) and 1 pt to dose -2 (900mg po once weekly); importantly, the most common reason was due to grade 2 fatigue (n=6). 10 pts are now off study [n=5 no response; n=3 toxicity; n=1 transformation to AML; n=1 patient on study proceeded to SCT]. Preliminary, ongoing correlative studies demonstrate on-target inhibition (by Western blot) of CIAP1 in eight pts: strong (n=4) or moderate (n=4); among the 6 clinically responding pts, 4 of 4 of these pts with viable/available samples for analysis demonstrated strong on-target CIAP1 inhibition. Conclusions: In this study, in a cohort of older pts with MF, 67% IPSS high risk, with median plt count of 45 at study entry, in whom 81% had received ≥2 prior therapies, we have observed objective responses in 38% (6/16 evaluable for response). LCL161 has a convenient (po, weekly) dosing schedule, represents a novel target for pts with MPNs, and is able to be administered to pts who have failed or intolerant/ineligible for JAK inhibitor therapy. Notably, grade 2 fatigue was commonly observed, and represents the most common reason for dose reduction and study discontinuation. Based on early responses observed, this study has met criteria for the pre-planned analysis for efficacy (Simon Stage 1) and therefore is able to proceed to Simon Stage 2. This clinical trial is registered at www.clinicaltrials.gov/ct2/show/NCT02098161. Disclosures Carter: PRISM Pharma/Eisai: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. DiNardo:Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Bose:Novartis: Research Funding. Verstovsek:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Celgene: Research Funding; AstraZeneca: Research Funding; Geron: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Bristol-Myers Squibb: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Galena BioPharma: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Gilead: Research Funding; Lilly Oncology: Research Funding.

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Phase 1 Dose Escalation Study of MDM2 Inhibitor DS-3032b in Patients with Hematological Malignancies - Preliminary Results

Blood ◽

10.1182/blood.v128.22.593.593 ◽

2016 ◽

Vol 128 (22) ◽

pp. 593-593 ◽

Cited By ~ 12

Author(s):

Courtney D DiNardo ◽

Joseph Rosenthal ◽

Michael Andreeff ◽

Oleg Zernovak ◽

Prasanna Kumar ◽

...

Keyword(s):

Research Funding ◽

Hematological Malignancies ◽

Single Agent ◽

Advisory Board ◽

Wild Type ◽

Plasma Exposure ◽

Dose Escalation Study ◽

Grade 3 ◽

Dose Levels ◽

Refractory Aml

Abstract Background:MDM2, a negative regulator of the tumor suppressor p53, is overexpressed in a number of cancers including hematological malignancies. Disrupting the MDM2-p53 interaction represents an attractive approach to treat cancers expressing wild-type functional p53, and the inhibition of MDM2 and antitumor activity with the small molecule DS3032b has been demonstrated in preclinical studies and in patients with solid tumors. Here, we report the initial results of the Phase I trial aimed at characterizing the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles and preliminary efficacy of DS3032b in in patients with hematological malignancies. Methods:This study (NCT02319369) is a dose escalation study of DS-3032b as an oral single agent with a starting dose of 60 mg and escalating through 90 mg, 120 mg, 160 mg and 210 mg dose levels guided by a modified continuous reassessment method using a Bayesian logistic regression model following escalation with overdose control principle. The drug was administered orally once daily (QD) in 21 of 28 days per cycle (QD 21/28). The patient population included relapsed/refractory AML and high-risk MDS. Results:Thirty eight subjects with relapsed/refractory AML or high-risk MDS were enrolled in the study in 5 dose levels; 60 mg (7 pts), 90 mg (6 pts), 120 mg (12 pts), 160 mg (8 pts) and 210 mg (5 pts). Twenty four (63%) subjects were males. The median age was 68.5 (range 30-88) years, with approximately two-thirds over 65 years. Thirty-seven of 38 patients were p53 wild type, and one subject had known pathogenic insertion mutation with an allele frequency of about 20%. DS-3032b was tolerated up to 160 mg QD in the 21/28 days schedule that was determined to be the maximum tolerated dose. All subjects experienced at least one treatment emergent adverse event (TEAE) of any grade, and 93% subjects experienced a grade ≥3 TEAE at a data cut off on May 2, 2016. The most common (≥20%) TEAEs of any grade regardless of attribution were nausea (73%), diarrhea (57%) vomiting (33%), fatigue (37%), anemia (33%), thrombocytopenia (33%), neutropenia (20%) hypotension (30%), hypokalemia (23%) and hypomagnesemia (20%). A total of 5 subjects experienced dose limiting toxicities; two subjects in the 160 mg cohort due to grade 3 hypokalemia and grade 3 diarrhea, and three subjects in the 210 mg cohort due to grade 3 nausea and vomiting, grade 2 creatinine elevation/ renal insufficiency, and grade 3 anorexia and fatigue.. Preliminary PK results showed plasma exposure (Cmax and AUClast) increased with dose; and approximately 2-fold drug accumulation was observed on Day 15 following the daily oral dosing. Increase in the serum levels of macrophage inhibitory cytokine (MIC-1) as a p53 target gene was used as a circulating pharmacodynamic biomarker, where magnitude of MIC-1 serum level increase corresponded with DS3032 plasma exposure. Clinical activity of single agent DS-3032b was observed from the reduction in bone marrow blasts by the end of cycle 1 (4 weeks) in 15 of 38 patients. Complete remission was observed in 2 subjects with AML; 1 subject each at 120 mg and at 160 mg, with a remission duration of >4 and >10 months, respectively. One subject with MDS achieved marrow CR with platelet improvement, of 4 months duration, at the 120 mg dose level. Of note, each of these three subjects developed a TP53 mutation while on treatment, two at the time of disease progression and one subject who remains in an ongoing response. Further evaluation of DS-3032b in rational combinations such as with hypomethylating agents is being planned. Conclusions: Disruption of MDM2-p53 interaction by DS-3032b appears to be a promising approach to treat haematological malignancies. MDM2 expression/amplification in leukemic blasts is being investigated as a potential predictor of response. Rational combinations with agents targeting different mechanistic pathways may offer the most promise for further development. Disclosures DiNardo: Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Zernovak:Daiichi Sankyo: Employment. Kumar:Daiichi Sankyo: Employment. Gajee:Daiichi Sankyo: Employment. Chen:Daiichi Sankyo: Employment. Rosen:Daiichi Sankyo: Employment. Song:Daiichi Sankyo: Employment. Kochan:Daiichi Sankyo: Employment. Limsakun:Daiichi Sankyo: Employment.

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Comparison of Haploidentical Donor Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide to Matched-Sibling, Matched-Unrelated, Mismatched-Unrelated, and Umbilical Cord Blood Donor Transplantation in Adults with Acute Lymphoblastic Leukemia: A CIBMTR Study

Blood ◽

10.1182/blood-2020-137186 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 50-51

Author(s):

Matthew J. Wieduwilt ◽

Leland Metheny ◽

Mei-Jie Zhang ◽

Hai-Lin Wang ◽

Noel Estrada-Merly ◽

...

Keyword(s):

Research Funding ◽

Lymphoblastic Leukemia ◽

Advisory Board ◽

Unrelated Donor ◽

Research Support ◽

Allogeneic Hct ◽

Sibling Donor ◽

Gvhd Prophylaxis ◽

Matched Sibling ◽

Grade 3

Background The relative benefits of haploidentical HCT using PTCy compared to traditional matched-sibling donor, traditional unrelated donor and umbilical cord blood (UCB) allogeneic HCT for adult acute lymphoblastic leukemia (ALL) is still being defined. Methods We performed a retrospective analysis using the Center for International Blood and Marrow Transplant Research (CIBMTR) database comparing post-HCT outcomes of haploidentical donors with PTCy to HLA-identical sibling donors, 8/8 HLA-MUDs, 7/8 HLA-MUDs, and UCB. Outcomes were overall survival (OS) leukemia-free survival (LFS), relapse, non-relapse mortality (NRM), grade 2-4 and grade 3-4 acute graft-versus-host disease (aGVHD), and chronic GVHD (cGVHD). Eligible patients were adults with ALL in complete remission (CR1, CR2, or CR3) undergoing first allogeneic HCT from 2013 to 2017. Key exclusion included not receiving PTCy for haploidentical HCT and ex vivo T-cell depleted or CD34-selected grafts. Cox proportional hazards multivariable regression analysis was used to compare the treatment groups. Results 4201 patients were studied: 393 haploidentical donor (92 centers), 1627 HLA-identical sibling donor (206 centers), 1646 8/8 HLA-MUD (181 centers), 230 7/8 HLA-MUD (90 centers), and 305 UCB (79 centers). Groups were well matched, however, notable differences between included race, time from diagnosis to HCT (CR1 only), conditioning regimen intensity, donor age, graft source for non-cord (peripheral blood or bone marrow), GVHD prophylaxis modality, and the use of in vivo T-cell depletion. Compared to other groups, haploidentical HCT had the lowest percentage of non-Hispanic white patients (43% vs. 49-74%), was more likely to use reduced-intensity conditioning (42% vs 17-25%), and was more likely to use bone marrow (41% vs. 14-29%). In multivariate analysis comparing haploidentical to matched-sibling donor HCT, no differences were observed in OS, LFS, NRM, relapse, or aGVHD. Compared to haploidentical HCT, the risk of cGVHD was significantly higher with matched-sibling donor HCT (D/R sex match F/M, HR 2.59, P<0.001, D/R sex match, other, HR 1.37, P=0.003). Comparing haploidentical to 8/8 HLA-MUD HCT, no differences were seen in OS, LFS, relapse, or Grade 2-4 aGVHD but 8/8 HLA-MUD HCT was associated with increased incidences of NRM (HR 1.42, P=0.02), grade 3-4 aGVHD (HR 1.59, P=0.005), and cGVHD (HR D/R sex match F/M, HR 2.91, P<0.001, D/R sex match, other, HR 1.38, P=0.001). Comparing haploidentical to 7/8 HLA-MUD HCT, no differences were seen in LFS or relapse but 7/8 HLA-MUD HCT was associated with worse OS (HR 1.38, P=0.01) and increased incidences of NRM (HR 2.13, P=<0.001), grade 2-4 aGVHD (HR 1.33, P=0.04) , grade 3-4 aGVHD (HR 1.86, P=0.003), and cGVHD (HR 1.72, P=<0.001). Comparing haploidentical to UCB HCT, no differences were seen in late OS (>18 months), late LFS, relapse, or cGVHD. Compared to haploidentical HCT, UCB HCT was associated with worse early OS (≤18 months, HR 1.93, P<0.001), worse early LFS (HR 1.40, P=0.007) and increased incidences of NRM (HR 2.08, P<0.001), grade 2-4 aGVHD (HR 1.83, P<0.001), and grade 3-4 aGVHD (HR 1.97, P<0.001). Similar outcomes were observed in sensitivity analyses restricting cohorts to (1) MA conditioning with peripheral blood stem cells and (2) calcineurin inhibitor-based GVHD prophylaxis for matched-sibling, unrelated donor, and UCB HCT. Conclusions For OS and LFS, haploidentical HCT using PTCy for adult ALL was superior to traditional HCT using 7/8 HLA-MUDs and UCB but equivalent to traditional HCT using matched-sibling donors and 8/8 HLA-MUDs. Results were consistent across all subgroups. Haploidentical HCT had a lower incidence of aGVHD compared to 8/8 HLA-MUD, 7/8 HLA-MUD, and UCB HCT and a lower incidence of cGVHD compared to matched-sibling donor, 8/8 HLA-MUD, and 7/8 HLA-MUD HCT. Based on these data, haploidentical HCT with PTCy results in similar survival with less GVHD compared to traditional matched-sibling and 8/8 HLA-matched donor HCT and is the superior alternative donor option for adult patients with ALL needing allogeneic HCT in CR. Figure Disclosures Wieduwilt: Leadiant: Research Funding; Shire: Research Funding; Merck: Research Funding; Macrogeneics: Research Funding; Amgen: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. de Lima:Incyte: Other: Personal Fees, advisory board; BMS: Other: Personal Fees, advisory board; Pfizer: Other: Personal fees, advisory board, Research Funding; Celgene: Research Funding; Kadmon: Other: Personal Fees, Advisory board. Kebriaei:Novartis: Other: Served on advisory board; Pfizer: Other: Served on advisory board; Kite: Other: Served on advisory board; Ziopharm: Other: Research Support; Amgen: Other: Research Support; Jazz: Consultancy. Hourigan:Merck: Other: Research Support (CRADA); Sellas: Other: Research Support (CRADA). Weisdorf:FATE Therapeutics: Consultancy; Incyte: Research Funding.

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28-Day Metronomic Therapy for Relapsed Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2020-142210 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 13-13

Author(s):

Tarek H Mouhieddine ◽

Julia Hieulle ◽

Erin Moshier ◽

Josh R. Richter ◽

Hearn Jay Cho ◽

...

Keyword(s):

Clinical Trial ◽

Multiple Myeloma ◽

High Risk ◽

Partial Response ◽

Clinical Benefit ◽

Research Funding ◽

Complete Response ◽

Chemotherapeutic Agents ◽

Metronomic Therapy ◽

Grade 3

Background: The advent of novel therapies has led to tremendous progress in the treatment of multiple myeloma (MM). However, management of patients with high-risk disease who have failed approved agents and have rapidly progressive disease with cytopenias continues to be challenging. While palliative care is an option, many patients hope to qualify for a clinical trial option. Here we report results of a 28-day metronomic therapy (METRO-28) consisting of continuous administration of very low doses of classical chemotherapeutic agents. Sixteen-day cycles of metronomic therapy were previously shown to have a favorable response with acceptable toxicity profiles in MM patients (Papanikolaou et al. Haematologica 2013). Aim: To investigate the efficacy and toxicity in patients with high-risk relapsed refractory MM (RRMM) ineligible for clinical trial options receiving 1 cycle of METRO-28. Method: We retrospectively analyzed the clinical outcomes of 106 RRMM, treated with 1 cycle of 28-day metronomic chemotherapy at the Tisch Cancer Institute - The Mount Sinai Hospital. METRO-28 consists of 6 agents: dexamethasone 8 mg on days 1 through 4, 7 through 10, 13 through 16, 19 through 22 and 25 through 28; bortezomib 1 mg/m2 on days 1, 4, 7, 10, 13, 16, 19, 22, 25, 28; cisplatin 1 mg/m2 daily; doxorubicin 1 mg/m2 daily; thalidomide 100 mg daily; and vincristine flat dose 0.06 mg daily. METRO-28 was administered through a central line in either the inpatient or outpatient setting. Result: Our cohort of 106 RRMM patients has a median age of 65 years (range: 35-85) and at a median of 59 months from time of diagnosis; 42% were females. They had a median of 7 prior lines of therapy (range: 1 - 25); with 73% triple- and 58% penta-refractory cases. Prior autologous transplantation was utilized in 69% of patients including tandem transplants in 30%. Moreover, 78% of patients carried high-risk cytogenetic features, including 1q21 duplication/amplification (89%), 17p deletion (49%), t(4;14) (17%), t(14;16) (17%) or t(14;20) (3%). At the time of METRO-28 initiation, patients were cytopenic with grade 3 and 4 anemia (21%), neutropenia (8%) and thrombocytopenia (23%). Profound cytopenias in some patients led to early discontinuation of treatment; forty-three patients (41%) received the full 28-day course of METRO-28, while 11%, 17%, 20% and 11% were treated for <1 week, <2 weeks, <3 weeks or <4 weeks, respectively. Grade 3-4 cytopenia increased: anemia 66%, leucopenia 61%, neutropenia 55% and thrombocytopenia 76%. On an intent to treat basis (106 patients), the deepest response included 2% stringent complete response (sCR), 7% near complete response (nCR), 7% very good partial response (VGPR), 28% partial response (PR), 11% minimal response (MR) and 12% stable disease (SD). Only 43 patients (41%) completed all 4 weeks of METRO-28 and had a 72% overall response rate (ORR) and 88% clinical benefit rate (CBR). Seventy-four percent of these patients were able to move on to new therapies, including novel agents and clinical trials. Their overall survival (OS) was 11.8 months (range: 6.1-NE) as opposed to an OS of 4.2 months (range: 3.4-7.2) for patients with <4 weeks of METRO-28. Sixty-three patients had their treatment interrupted: 34 due to disease progression or absence of response, 18 due to bacterial or viral infections and 11 due to hematologic toxicity. Conclusion: Giving 1 cycle of METRO-28 is better tolerated in patients with good hematologic reserve and offers an opportunity for a clinical benefit and a bridge to a subsequent treatment option for these advanced refractory myeloma patients. Disclosures Richter: Takeda: Consultancy; Janssen: Speakers Bureau; Sanofi: Consultancy; AstraZeneca: Consultancy; X4 Pharmaceuticals: Consultancy; Adaptive Biotechnologies: Consultancy, Speakers Bureau; Oncopeptides: Consultancy; Secura Bio: Consultancy; Antengene: Consultancy; Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Speakers Bureau. Parekh:Foundation Medicine: Consultancy; Celgene: Research Funding; Karyopharm: Research Funding. Chari:Adaptive Biotechnology: Honoraria; The Binding Site: Honoraria; Array BioPharma: Honoraria; Novartis: Honoraria; Secura Bio: Consultancy; Glaxo Smith Kline: Consultancy; Antengene: Consultancy; Takeda: Consultancy, Research Funding; Oncopeptides: Consultancy; Seattle Genetics: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Karyopharm: Consultancy; Pharmacyclics: Research Funding; Bristol Myers Squibb: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Jagannath:Legend Biotech: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Madduri:Janssen: Consultancy; BMS: Consultancy; Takeda: Consultancy; Legend: Consultancy; Sanofi: Consultancy; GSK: Consultancy; Kinevant: Consultancy; Foundation Medicine: Consultancy.

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Aggressive Smoldering Curative Approach Evaluating Novel Therapies (ASCENT): A Phase 2 Trial of Induction, Consolidation and Maintenance in Subjects with High Risk Smoldering Multiple Myeloma (SMM): Initial Analysis of Safety Data

Blood ◽

10.1182/blood-2020-142584 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 35-36

Author(s):

Shaji K. Kumar ◽

Al-Ola Abdallah ◽

Ashraf Z. Badros ◽

Betsy Laplant ◽

Binod Dhakal ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

High Risk ◽

Research Funding ◽

Advisory Board ◽

Phase 2 ◽

Phase 3 ◽

Phase 2 Trial ◽

Risk Of Progression ◽

M Spike

Background: Smoldering multiple myeloma (SMM) represents an intermediate stage between monoclonal gammopathy of undetermined significance and active myeloma with a high risk of progression to active MM, especially during the initial years after diagnosis. Available clinical risk factors have enabled development of risk stratification systems that allow for identification of patients at the highest risk of progression, opening opportunities for early intervention. Two phase 3 trials using lenalidomide with dexamethasone or lenalidomide alone have both shown benefit for early intervention by decreasing the risk of progression and improving the overall survival in the former. It remains unknown if an approach using a single active drug to delay progression, or one that uses therapies like active myeloma, represent a better approach; both are being studied in phase 3 trials. We designed this phase 2 trial to examine if an intense but limited duration therapy can possibly provide a significant elimination of the tumour burden that can potentially lead to long term responses. Patients and Methods: Patients with SMM (per updated IMWG definition of SMM) with high risk disease (defined by the IMWG updated risk stratification criteria- presence of any two of the following: Serum M spike > 2 gm/dL OR an involved to uninvolved FLC ratio > 20 OR bone marrow PC% > 20%) or a score of ≥9 using the risk scoring system using FLC ratio, serum M spike, marrow plasma cell% and presence of high risk FISH were enrolled provided they had adequate marrow and organ function. Patients with significant comorbidities such as heart disease were excluded from the trial. Treatment consisted of three phases: induction, consolidation and maintenance. Patients received carfilzomib (36 mg/m2 twice weekly or as per updated protocol 56mg/m2 weekly for 2 weeks), lenalidomide (25 mg daily for three weeks), daratumumab (weekly for 8 doses, every other week for 16 weeks) and dexamethasone 40 mg weekly, in 4 week cycles for 6 cycles as part of induction, the same regimen was administered with daratumumab every 4 weeks and dexamethasone 20 mg weekly for another 6 cycles for consolidation. This was followed by 12 cycles of maintenance therapy with lenalidomide (10 mg daily for three weeks), daratumumab (day 1 every other cycle) of a 4-week cycle. Appropriate antiviral, and thrombosis prophylaxis were mandated. The primary endpoint of this trial is the rate of confirmed sCR as best response across all cycles of treatment. We plan to accrue 83 patients to this trial with one-stage binomial trial design to test the null hypothesis that the true success (sCR) proportion is at most 65% and the alternate hypothesis of 80%. Results: Forty-six patients have been accrued to the trial as of July 14, 2020. The median age of the study population is 63 years (range 47 - 76); 70% are male. Overall, 2% have completed the maintenance, 50% have completed the consolidation, 80% have completed the induction and 15% are in the induction phase; only two patients have gone off treatment. The reasons for going off treatment were patient preference. At least one patient needed a dose modification for each drug; 17%, 2%, 13% and 7% required dose reductions for carfilzomib, daratumumab, lenalidomide and dexamethasone respectively. The relative median dose intensity for the drugs were 85%, 92%, 80% and 98% for carfilzomib, daratumumab, lenalidomide and dexamethasone respectively across the delivered cycles. The adverse events seen in at least 5% of the patients are as shown in the figure. A grade 3 or higher AE was seen in 52% of patients. There were no treatment related deaths observed. Response rate and depth have been as expected for this regimen in myeloma and analysis is pending completed accrual. Figure 1 Disclosures Kumar: Adaptive Biotechnologies: Consultancy; Sanofi: Research Funding; Cellectar: Other; Genecentrix: Consultancy; Novartis: Research Funding; Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Tenebio: Other, Research Funding; Merck: Consultancy, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Kite Pharma: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Carsgen: Other, Research Funding. Badros:Amgen: Consultancy; University of Maryland: Current Employment. Dhakal:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Other: AdvIsory Board, Research Funding; Janssen: Consultancy, Other: Advisory Board, Research Funding; Takeda: Consultancy, Other: Advisory Board; GSK: Consultancy, Research Funding, Speakers Bureau; Sanofi: Research Funding. Abonour:Celgene: Consultancy; Janssen: Honoraria, Research Funding; Takeda: Consultancy; BMS: Consultancy, Research Funding. Rosenbaum:Celgene: Honoraria; Akcea: Honoraria; Amgen: Research Funding; Janssen: Research Funding; GlaxoSmithKline: Research Funding. Bensinger:GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria, Research Funding, Speakers Bureau. Bhutani:Prothena: Other: Clinical Trial Funding to Institute; Sanofi Genzyme: Consultancy; Janssen: Other: Clinical Trial Funding to Institute; BMS: Other: Clinical trial funding to institute, Speakers Bureau; Amgen: Speakers Bureau; MedImmune: Other: Clinical Trial Funding to Institute; Takeda: Other: Clinical trial funding to institute, Speakers Bureau. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

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