Hematologic Response Rate Research Articles

Prospective Comparison of Azacitidine Treatment between 7-Days and 5-Days Schedules for Patients with Higher-Risk Myelodysplastic Syndromes; Results of Japan Adult Leukemia Study Group MDS212 Trial

Prospective Comparison of Azacitidine Treatment between 7-Days and 5-Days Schedules for Patients with Higher-Risk Myelodysplastic Syndromes; Results of Japan Adult Leukemia Study Group MDS212 Trial

Optimal Therapy for Relapsed AL Amyloidosis Post Autologous Stem Cell Transplant

Introduction: There is a paucity of randomized trials to guide therapy for relapsed AL amyloidosis with treatment regimens generally extrapolated from experience in multiple myeloma. Methods: We conducted a retrospective review of patients who relapsed after receiving autologous stem cell transplant at Mayo Clinic. Patients treated for first relapse between January 2004 and December 2018 were included. Results: Three hundred and twenty-one patients were seen for relapsed AL amyloidosis post ASCT during the study period. Baseline characteristics were typical for a cohort with AL amyloidosis and are listed in Table1. 39% received therapy prior to transplant, conditioning in the majority (75%) was melphalan 200mg/m2. The median progression free survival from transplant (PFS1) was 30.7 months. Of the 321 patients 294 received treatment for relapsed disease. We categorized treatment regimens according to commonly used combinations and drug classes to further analyze outcomes. 34 patients were excluded from this analysis as they either proceeded directly to second ASCT (n=10) or received an atypical regimen not commonly considered for AL amyloidosis (n=24). Five categories of therapy regimens were identified, thalidomide based (n=110), melphalan plus steroids (n=31), 2nd generation immunomodulatory (IMiD) drug +/- alkylator (n=76), proteasome inhibitor (PI) +/- alkylator (n=116), PI plus IMiD (n=16), or daratumumab based (n=9). Disease and treatment characteristics for patients treated with these regimens are listed in Table 2. Patients treated with thalidomide had the shortest PFS1 (17.7 months) but PFS1 was similar for those treated with melphalan plus steroids, PI+IMiD and 2nd generation IMiDs (25.5, 24.3 and 25.6 months respectively). Patients treated with a PI +/- alkylator and daratumumab based regimen had the longest PFS1 (36.7 and 41.9 months respectively). The median duration of therapy was longer in patients treated with a 2nd generation IMiD or daratumumab based regimen (10.2, 12, 6.1, 5.5, 6.2 and 5.9 months for Dara based, 2nd generation IMiD, PI+/- alkylator, PI+IMiD, melphalan plus steroids and thalidomide based respectively). Hematologic response rate was lowest in those treated with melphalan plus steroids or thalidomide based regimens (44% and 55% respectively) and highest for patients treated with a PI+/- alkylator, (Figure 1). Progression free survival from relapsed therapy (PFS2) was longest amongst patients treated with daratumumab based regimens, PI +/- alkylator and 2nd generation IMiDs (not reached, 29.9 and 26.7 months respectively), Figure 2A. Overall survival from time of relapsed therapy favored patients treated with daratumumab based regimens, 2nd generation IMiDs and PI +/- alkylator, Figure 2b). Conclusion: A second generation IMiD based regimen or PI +/- alkylator produce high response rates and prolonged progression free and overall survival for relapsed AL amyloidosis. Patients treated with daratumumab based regimens and those treated with a PI plus IMiD also appear to do well, although numbers were low in our study. Patients treated with melphalan plus steroids or thalidomide based combinations have inferior outcomes and these regimens should be avoided. Disclosures Dispenzieri: Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy; Alnylam: Research Funding. Lacy:Celgene: Research Funding. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; Millenium: Consultancy; Janssen: Consultancy; alexion: Consultancy. Leung:Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Aduro: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding. Kapoor:Glaxo Smith Kline: Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Cellectar: Consultancy; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Janssen: Research Funding. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Gertz:Medscape: Consultancy, Speakers Bureau; Prothena Biosciences Inc: Consultancy; Ionis/Akcea: Consultancy; Alnylam: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Appellis: Consultancy; Amgen: Consultancy; Physicians Education Resource: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Research to Practice: Consultancy; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Other: Development of educational programs and materials; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding; Annexon: Consultancy. OffLabel Disclosure: Daratumumab off label use for AL amyloidosis.

Telomere Elongation and Clinical Improvement in Telomeropathy Patients: A Prospective Clinical Trial of Nandrolone in Telomeropathies

Telomeres are a complex of hexameric repetitive DNA sequences at the end of linear chromosomes. Telomeres erode during mitosis, and this process is accelerated in patients carrying germline pathogenic mutations in telomere-biology genes (Calado and Young, NEJM 2009). In vitro, the exposition to androgens stimulates TERT transcription and telomerase activity of lymphocytes and bone marrow CD34+ cells (Calado et al. Blood 2009). In a phase 1-2 prospective trial, the use of danazol led to telomere elongation in patients with telomeropathies (Townsley et al. NEJM 2016). The hematological response was observed in 79% of evaluable patients. Here, we describe a phase 1-2 single-center prospective study assessing the safety and the effect of the male hormone nandrolone decanoate on telomere erosion in patients with telomere diseases (ClinicalTrials.gov Identifier: NCT02055456). Entry criteria comprised patients older than two-year-old with age-adjusted mean telomere length below the 1st percentile ± identified mutations in telomerase complex genes, associated with at least one cytopenia and/or diagnosis of idiopathic pulmonary fibrosis (IPF). Patients were treated with nandrolone decanoate intramuscular at a dose of 5 mg/kg every 14 days for 24 months. The primary efficacy end point was a 20% decrease in the annual rate of telomere erosion, and the incidence of toxic effects was the primary safety end point. Secondary endpoints were hematologic response and pulmonary response. Flow-FISH was used to determine the telomere length of peripheral blood leukocytes. From May 2014 to October 2017, 20 consecutive patients were eligible for participation, and 17 were enrolled. The median age was 36 years (range, 4 - 59 years), and five patients were female. In all but one patient germline pathogenic mutations were identified (TERT, 7; RTEL1, 4; TERC, 2; WRAP53, 1; TINF2, 1; and SAMD9, 1). Eleven patients were diagnosed with bone marrow failure (9 with moderate and one with severe AA, and one with myelodysplasia). Four patients were diagnosed with IPF, and 2 patients had both moderate AA and IPF. One patient diagnosed with IPF had received an allogeneic bone marrow transplant before enrollment. Four patients had additional hepatic involvement, and 5 displayed cutaneous features of dyskeratosis congenita. The most common adverse events associated with drug were elevations in liver enzyme levels in 88%, acne in 59%, and virilization in 59%. Severe adverse events possibly related to drug occurred in six instances. Dose reductions were necessary in 5 patients due to severe or moderate adverse events. Seven patients withdrew from the study before 2 years: two patients discontinued therapy due to grade 3 adverse events (depression and acne); one patient sought alternative therapies; and four patients died during the study period, two due progressive IPF and two due intracranial hemorrhage. Out the 17 patients enrolled, a total of 15 reached 12 months of treatment and 13 were evaluable (one patient was transplanted and telomere length not evaluated; and for one patient the telomere sample was missing). Ten patients met the primary efficacy end point, showing telomere elongation. As of July 2019, nine patients reached 24 months of treatment and telomere length measured for seven patients at this time-point; all of them met end point criteria and showed telomere elongation at two years. The average increase in telomere length at 12 months was 1,119 bp (95% CI, 180-2,059 bp; P<0.04), and 1,257 bp (95% CI, 675-1,839 bp; P<0.02) at 24 months. The hematologic response rate was 60% at 3 months and 80% at 6 months. Only one patient relapsed during nandrolone use. Five of 8 transfusion-dependent patients became transfusion-independent, and one patient showed a reduction in transfusion requirements >50%. The pulmonary response rate was observed in 2 of 6 patients who had a pulmonary disease at baseline, and one patient eventually became oxygen-independent. In our study, nandrolone decanoate treatment was safe and led to telomere elongation in patients with telomeropathies. Nandrolone also improved hematologic function in patients with marrow failure. Pulmonary function remained stable or ameliorated in two-thirds of patients with pulmonary involvement. Known nandrolone side effects were common, especially liver toxicity and virilization. OffLabel Disclosure: We want to determine if treatment with male hormone nandrolone decante is safe and improves hematologic response as first-line treatment in patients with telomere disease.

Sequential Therapy with Cyclophosphamide, Bortezomib and Dexamethasone Followed By Autologous Stem Cell Transplant Is Safe and Highly Effective in AL Amyloidosis

Introduction: Autologous stem cell transplant (ASCT) is a very effective treatment in AL amyloidosis. However, its role is challenged by novel, powerful, non-transplant therapy, also due to the potentially high treatment-related mortality (TRM) that requires an extremely careful patient selection. Bortezomib-based induction and consolidation preceding and following ASCT have been proposed to improve patient outcomes. Here we report the outcome of 139 patients treated with bortezomib-based induction followed by ASCT in case of unsatisfactory response. Methods: Starting in 2009 we offered upfront therapy with cyclophosphamide (300 mg/m2), bortezomib (1.3 mg/m2) and dexamethasone (40 mg) weekly (CyBorD) to all patients with AL amyloidosis who met the eligibility criteria for transplantation at our institution. Eligibility criteria for ASCT were: age < 65 years, NT-proBNP <5000 ng/L, eGFR >50 mL/min per 1.73 m2, NYHA class >3, PS-ECOG, ≤2, left ventricular EF >45%, DLCO >50% (Palladini and Merlini, Blood 2016). Patients who did not achieve a satisfactory response after CyBorD proceeded to ASCT (with melphalan 200 mg/m2), if still eligible. A satisfactory response was defined as complete response (CR), very good partial response (VGPR) with organ response (OR), or partial response (PR) with OR. Patients with overt multiple myeloma were excluded. We assessed response rates (by intent-to-treat), overall survival (OS) and time to next line of treatment or death (TNTD). Results: Between 2009 and 2018, 139 consecutive newly diagnosed patients were eligible for ASCT and received CyBorD as first line treatment. They represented 15% of all patients diagnosed at our center during the study period. Patients' characteristics are reported in Table 1. Treatment with CyBorD continued for 2 cycles in 44 patients (32%), 4 cycles in 64 (46%), 6 cycles in 20 (14%) and 8 cycles in 11 (8%) patients. Only one patient (stage IIIa) died within 100 days from CyBorD initiation due to sudden death. After CyBorD treatment, 26 (20%) patients achieved CR, 45 (32%) VGPR, and 24 (17%) PR (overall hematologic response rate 69%). Sixty-three patients (45%) achieved a satisfactory response after CyBorD and did not proceed to ASCT. Twenty-one patients (15%) who did not reach a satisfactory response after CyBorD did not proceed to ASCT because of organ progression that made them no longer eligible (16 subjects, 12%) or patient refusal (5 cases, 4%). The remaining 55 subjects (40%) received ASCT. No patients died within 100 days from ASCT. Hematologic response after ASCT was obtained in 80% of patients, with CR in 21 subjects (38%), VGPR in 15 (27%) and PR in 8 (15%). In the overall cohort, the hematologic response rate after CyBorD or CyBorD followed by ASCT was 77%, with 47 subjects (34%) attaining CR, 40 (29%) VGPR, and 19 (14%) PR. After a median follow-up of living patients of 48 months, 27 subjects died. In the whole study cohort, overall median survival (OS) was not reached and projected OS was 78% at 4 years and 69% at 10 years. In patients who proceeded to ASCT, median OS was not reached, and projected survival was 90% at 4 years and 77% at 10 years. In patients who achieved a satisfactory response after CyBorD and did not proceed to ASCT, median OS was not reached as well, and projected survival was 84% at 4 years and 72% at 10 years (P=0.438 compared to ASCT). In patients who did not proceed to ASCT despite having failed to achieve a satisfactory response after CyBorD, median survival was 47 months (P<0.001 compared to the 2 other groups). We then compared OS in patients who achieved VGPR or CR after CyBorD alone or after CyBorD followed by ASCT and found no significant difference (Figure 1). Finally, we evaluated TNTD in patients who attained CR and found no significant difference between subjects treated with CyBorD alone and those who received ASCT after CyBorD (relapsed or dead at 4 years 36% vs. 20%, P=0.737). This is in agreement with the median time to relapse from CR of 4.3 years reported by the Boston University group (Browning, et al. Blood 2017). Conclusion: This sequential treatment approach granted a high rate of profound hematologic responses and prolonged survival with minimal TRM (<1%) that occurred during the induction phase. In patients who attained profound hematologic response (CR or VGPR), OS and durability of response were similar in subjects who responded to initial CyBorD and in those who proceeded to ASCT. Figure 1 Disclosures Milani: Janssen: Honoraria; Pfizef: Honoraria. Palladini:Sebia: Honoraria; Celgene: Other: Travel grant; Janssen-Cilag: Other: Travel grant; Janssen-Cilag: Honoraria. OffLabel Disclosure: Bortezomib in AL amyloidosis

Final Results of Prospective Treatment with Pegylated Interferon Alfa-2a for Patients with Polycythemia Vera and Essential Thrombocythemia in First and Second-Line Settings

Final Results of Prospective Treatment with Pegylated Interferon Alfa-2a for Patients with Polycythemia Vera and Essential Thrombocythemia in First and Second-Line Settings

OP201: A Phase 1/2 Study of Melflufen and Dexamethasone in Patients with Immunoglobulin Light Chain (AL) Amyloidosis

OP201: A Phase 1/2 Study of Melflufen and Dexamethasone in Patients with Immunoglobulin Light Chain (AL) Amyloidosis

Molecular Mechanisms Mediating Relapse Following Ivosidenib Monotherapy in Patients with IDH1-Mutant Relapsed or Refractory Acute Myeloid Leukemia

Molecular Mechanisms Mediating Relapse Following Ivosidenib Monotherapy in Patients with IDH1-Mutant Relapsed or Refractory Acute Myeloid Leukemia

Study Design of an Open-Label, Single-Arm, Multicenter, Phase 2 Study to Evaluate the Safety and Efficacy of Defibrotide in Adult Patients with Transplant-Associated Thrombotic Microangiopathy

Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is an uncommon, but well-recognized, hematopoietic cell transplant (HCT) complication associated with high morbidity and mortality. TA-TMA may result from microvascular endothelial cell (EC) damage induced by HCT conditioning regimens, immunosuppressive drugs, and infections, and it may be mediated by complement activation in some cases. Although there is no consensus on optimal TA-TMA treatment, common interventions include withdrawal, replacement, or dose modification of calcineurin inhibitors (CI) and/or mammalian target of rapamycin (mTOR) inhibitors (ie, CI/mTORi changes). When increased complement activity is present, terminal complement cascade inhibition has been used. Defibrotide (DF) is approved for adult and pediatric patients (pts) with hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) with renal or pulmonary dysfunction post-HCT in the US and Canada and for pts aged >1 month with severe hepatic VOD/SOS post-HCT in the EU. DF reduces EC activation, promotes fibrinolysis, and may be a novel therapy for TA-TMA. This prospective, open-label, single-arm, multicenter, phase 2 study (EUDRACT: 2018-001101-90) is designed to assess the efficacy and safety of DF for treating pts with high-risk TA-TMA (defined as definite TMA per Postalcioglu M, et al. Biol Blood Marrow Transplant. 2018;24(11):2344-2353) who have failed to respond to CR/mTORi changes. Study Design and Methods: Diagnostic criteria for "definite" TA-TMA include lactate dehydrogenase (LDH) >2 × the upper limit of normal, thrombocytopenia (platelet count <50 × 109/L or ≥50% decrease from peak platelets post-HCT), schistocytes ≥2 per high-power field in peripheral blood, serum creatinine increase >50% from baseline, and a negative Coombs test. Allogeneic HCT pts (aged ≥18 years) who have definite TA-TMA with persistent or progressive disease after 7 or 3 days, respectively, following CI/mTORi changes are eligible (Figure). Pts will be excluded if they relapse after HCT, have grade 4 acute graft-versus-host disease or VOD/SOS, or clinically significant bleeding within 24 hours of enrollment. Planned enrollment is 30 to 40 pts. Pts will receive a 2-hour intravenous infusion of DF 25 mg/kg/day (6.25 mg/kg every 6 hours) for a recommended duration of 21 days (up to 60 days). Pts will be followed for 180 days from DF start (Day 1). The study has 2 co-primary efficacy endpoints: hematologic response by Day 45 (relative to DF start) and renal response by Day 45. Hematologic response is defined as normalization of LDH and platelet count ≥50 × 109/L without platelet transfusion for 7 days (if baseline count was <50 × 109/L) or ≥50% increase in platelet count (if baseline count was ≥50 × 109/L). Renal response is defined as <25% increase or decrease in serum creatinine versus baseline at DF start (renal function stabilization) or ≥25% decrease in serum creatinine versus baseline at DF start or independence from dialysis (if pt was dialysis dependent at baseline or started dialysis after baseline) (renal function improvement). Secondary efficacy endpoints are overall survival, duration of hematologic or renal response, proportion of pts achieving hematologic or renal (measured by serum creatinine or estimated glomerular filtration rate) response by Days 60, 90, and 180, independence from dialysis at Days 60, 90, and 180 for pts with dialysis dependence, and neurologic improvement (defined as any increase in Mini-Mental Status Examination score versus baseline or resolution of TA-TMA seizure activity) at Days 7, 14, 21, and 45. Safety endpoints include incidence of treatment-emergent adverse events (AEs), treatment-emergent serious AEs, and AEs of interest (eg, hemorrhage and hypotension) occurring up to 30 days after the last DF dose. Analysis of the co-primary efficacy endpoints will be evaluated in pts who receive ≥1 DF dose. For each co-primary endpoint, a reference background rate, based upon data from literature and/or registries or research databases, will be established to represent the Day 45 hematologic and renal response rates in a similar pt population in the setting of currently available therapy without DF treatment. A clinically meaningful benefit from DF will be inferred if the lower bounds of the 95% confidence interval of the co-primary endpoints are greater than their respective reference background rates. Disclosures Ho: Jazz Pharmaceuticals: Consultancy. Keshelava:Jazz Pharmaceuticals: Employment, Equity Ownership. Swann:Jazz Pharmaceuticals: Employment, Equity Ownership. Tappe:Jazz Pharmaceuticals: Employment, Equity Ownership. OffLabel Disclosure: The abstract contains a description of off-label product use. Defibrotide is approved for treatment of hepatic VOD/SOS post-HCT (as described in the background) and this study is evaluating its use in patients with TA-TMA.

Efficacy and Safety Profile of Bortezomib Based Regimens for Treatment of Newly Diagnosed Amyloidosis: A Systematic Review of Literature

Introduction: For more than a decade, bortezomib (V) has become an integral part of initial treatment of AL amyloidosis It is cytotoxic to plasma cells. We report published literature on efficacy and safety of bortezomib based regimens in patients (pts) with newly diagnosed amyloidosis (ND-AL). Methods: Following PRISMA guidelines, we performed a comprehensive literature search for articles published after 2007 using Pubmed, Embase, Clinical Trials.gov, Cochrane Library and Web of Science. Initially, 649 articles were identified and after a thorough screening, we finalized 9 studies involving 213 ND-AL patients. Prospective (n=91) and retrospective (n=122) studies were included. MeSH terms and keywords were bortezomib and newly diagnosed AL amyloidosis. Results: Chemotherapy followed by HDCT versus frontline HDCT / ASCT: In a retrospective study involving 31 pts by Scott et al., with induction chemotherapy with V-based regimens (n=12), with non-V-based regimens (n=6) and frontline (n=13) high dose melphalan (HDM) therapy followed by autologous stem cell transplant (ASCT). Overall hematological response (OHR) and organ response (OR) rates in the entire cohort after ASCT were 77% and 58% respectively. OHR and OR were 92% & 75% in V-pretreated group and 69% & 54% in pts who received no treatment. The trend was similar for other responses (Table 1). In a clinical trial by Huang, X., et al., induction therapy with Vd (V in combination with dexamethasone) prior to HDM/SCT was compared with frontline HDM/SCT in 58 patients. The OHR, and complete response (CR) between Vd+HDM/SCT (20 evaluable pts) and frontline HDM/SCT (23 evaluable pts) groups were 85.7% versus 53.5% and 67.9% versus 35.7% respectively. All organs showed better response in Vd+HDM/SCT group (Table 1). Vd/CyBorD (Cyclophosphamide, bortezomib, dexamethasone) prior to ASCT: In a prospective clinical trial by Sanchorawala et al., 35 pts were given induction with Vd before HDM and ASCT. Among 27 evaluable pts, OHR was 100% with CR in 76.9% and very good partial response (VGPR) in 23% pts. In a study by Hong et al., 20 patients received induction with Vd or CyBorD prior to ASCT. OHR was 89% with CR in 55%, partial response (PR) in 10% and VGPR in 33%. 5-year overall survival (OS) was 80% and 5-year progression free survival (PFS) was 69%. Vd/CyBorD without ASCT: In a retrospective study by Zhao et al., 23 pts received Vd. OHR was 100% with CR in 44% and PR in 38.9% pts. Median overall survival (mOS) was 38 months and 3-year OS was 41-72%. OR was 25% with kidney being the organ showing response in maximum pts (84%). Kikukawa et al., reported 8 pts who received CyBorD, OHR was 100% with CR in 50%, PR in 25% and VGPR in 25% pts. 63% pts showed OR in heart and/or kidney. In a study by Huang, B., et al., Vd was given to 12 renal ND-AL pts and among 10 evaluable pts, OHR was 80% with CR in 50% and PR in 10%. mOS was 8.2 months and OR was 50%. Other Regimens: In a study by Lee et al., involving 19 pts, VMP (bortezomib, melphalan, prednisone) was given as induction therapy. OHR was 84% with CR in 37%, PR in 26% and VGPR in 21% pts. OS was 39% at 2 years and PFS was 8 months. OR was 53% with heart (50%) and kidney (40%). In a retrospective review by Chari et al., 9 pts were treated with a triplet regimen (V, cyclophosphamide or lenalidomide/thalidomide and d). OHR was 88% with CR in 22% and PR in 66% pts. OR was 77% with heart and kidney both at 44%. Conclusion: In ND-AL pts, V-based combination regimens are very effective and well tolerated as induction therapy, or when used as therapy prior to HDM/ASCT and this approach resulted in better outcomes when compared to frontline HDM/ASCT. Three drug combination therapy with V is effective. Kidney and heart were the major organs to show improvement with therapy. Novel combinations need to be studied in randomized prospective clinical trials. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Preliminary Results from a Phase II Study of the Combination of Pevonedistat and Azacitidine in the Treatment of MDS and MDS/MPN after Failure of DNA Methyltransferase Inhibition

Preliminary Results from a Phase II Study of the Combination of Pevonedistat and Azacitidine in the Treatment of MDS and MDS/MPN after Failure of DNA Methyltransferase Inhibition

Safety and Efficacy of Propylene Glycol-Free Melphalan (Evomela) in Patients with AL Amyloidosis Undergoing Autologous Stem Cell Transplantation: Preliminary Results of a Phase II Study

INTRODUCTION: High dose melphalan and autologous stem cell transplantation (HDM/SCT) is effective for treatment of selected patients with light-chain (AL) amyloidosis with adequate functional status and preserved organ function. Despite rigorous patient selection, approximately 21% of AL amyloidosis patients receiving treatment with HDM/SCT develop acute renal injury and up to 22% develop cardiac arrhythmias in the peri-transplant period. Patients with AL amyloidosis are at greater risk of organ dysfunction in the peri-transplant period due to pre-existing amyloid deposition. This toxicity is potentially exacerbated by the co-solvent propylene glycol found in melphalan hydrochloride. Propylene glycol is reported to lead to metabolic acidosis, sepsis-like syndrome, renal dysfunction, and cardiac arrhythmias. Therefore a clinical trial investigating the use of propylene glycol-free melphalan during HDM/SCT was developed to evaluate the effect on organ toxicity in AL amyloidosis patients (NCT02994784). PROTOCOL: This Phase II clinical trial began enrollment in April 2018. Eligibility criteria included the following: histologic diagnosis of systemic AL amyloidosis, involvement of ≥1 vital organ, eGFR of ≥30 mL/min, DLCO ≥50%, LVEF ≥40%, ECOG <3, NYHA status <3, and no prior HDM/SCT. Subjects underwent autologous stem cell transplantation per institutional guidelines, receiving the conditioning regimen of 140 or 200 mg/m2 propylene glycol-free melphalan via IV infusion on Days -3 and -2. Stem cell infusion occurred on Day 0. Primary objectives included evaluation for renal dysfunction (defined as a ≥1 mg/dL increase in creatinine or a doubling of creatinine to ≥1.5 mg/dL for ≥2 days), cardiac dysfunction (defined as development of new arrhythmia), and autonomic dysfunction (defined as a drop in SBP ≥20 mmHg on orthostatic measurements). Secondary objectives included evaluation of time to engraftment, treatment related mortality, overall hematologic response at 6 months after SCT, organ response at 12 months after SCT, and number of hospitalizations. RESULTS : At the time of data cut-off (July 1, 2019) 17 patients had been enrolled. Median age was 59 years (range, 44-76) with 11 (65%) males. Median number of prior therapies was 0 (range, 0-2). Median number of organ systems involved was 1 (range, 0-3). 13 (76%) and 7 (41%) patients had renal and cardiac involvement, respectively. Median NT-proBNP level was 396 pg/mL (range, 63-6220), urine protein excretion was 3.14 g/24 h (range, 0-22.9), serum creatinine was 0.93 mg/L (range, 0.72-2.07), and median dFLC was 51 mg/L (range, 2-700). In the 7 patients with relapsed/refractory disease, median time from last therapy was 2 months. Subjects received either 140 mg/m2 (n = 2) or 200 mg/m2 (n = 15) of propylene glycol-free melphalan. There have been 0 deaths during the peri-transplant period or follow-up. Per the protocol defined criteria, 2 patients (11%) developed acute renal dysfunction, 3 subjects (18%) developed orthostatic hypotension, and 3 patients (18%) experienced a new cardiac arrhythmia (atrial fibrillation or ventricular tachycardia) while on study. Median time to neutrophil engraftment was 10 days. Median time to platelet engraftment was 17.5 days. Peri-transplant hospitalization occurred in 14 subjects (82%) and median hospitalization was 5 days. The most common non-hematologic adverse events included nausea/vomiting (82%), fatigue (82%), and diarrhea (88%). Of the 8 subjects who have completed their 6 month follow-up the hematologic response rates are as follows: 4 CRs (50%), 2 VGPRs (25%), 1 PR (13%) and 1 stable disease (13%). CONCLUSION: In this ongoing trial investigating the safety of propylene glycol-free melphalan in patients with AL amyloidosis the cardiac toxicities appear comparable to historical data with 18% of patients developing a cardiac arrhythmia and with potentially improved renal toxicity (11%), although additional data are required to confirm this finding. Time to engraftment is similar to published data for HDM/SCT and no peri-transplant mortality has been seen. Hematologic responses are also comparable to historical controls (50% CR and 25% VGPR). Additional data will be obtained with ongoing patient enrollment to determine if there are significant differences in the safety of propylene glycol-free melphalan in this population of patients with high risk of organ dysfunction during HDM/SCT. Disclosures Sarosiek: Acrotech: Research Funding. Sloan:Merck: Other: endpoint review commitee; Stemline: Consultancy; Abbvie: Other: Endpoint Review Committee. Sanchorawala:Proclara: Consultancy, Honoraria; Caelum: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Prothena: Research Funding; Celgene: Research Funding; Takeda: Research Funding. OffLabel Disclosure: propylene glycol-free melphalan is FDA approved for multiple myeloma, but not for AL amyloidosis (which has not FDA approved therapies)

Pegylated Interferon-Alfa Suppresses Clonal Hematopoiesis in Polycythemia Vera and Essential Thrombocythemia and Is Associated with Immune Responses to Tumor Antigens

Hydroxyurea is usually the first line treatment for high-risk polycythemia vera (PV) and essential thrombocythemia (ET), but interferon is an equally effective treatment. However, unlike hydroxyurea, several studies have shown higher rate of molecular response with pegylated interferon-alpha (PegINFa) and tolerable toxicity. We had reported earlier that in some female patients, polyclonal hematopoiesis is restored (Liu E et al, Blood, 2003) after interferon therapy. However, the mechanism of action of interferon on rescue of normal dormant hematopoiesis in PV and ET is not fully understood. Presence of immune response against PV & ET clone is long speculated and we had previously screened human testis cDNA library in plasma from a PV subject who converted to polyclonal hematopoiesis after interferon therapy, where presence of immune response were noted. We analyzed 48 patients diagnosed with PV and ET per WHO 2012 criteria who were treated with PegINFa at our institution. The majority of patients receiving PegINFa - 28 (58%) were second-line treatments after receiving hydroxyurea. The overall hematological response rate for PegINFa treated patients was 46 (95.8%), but 14 (29%) had to discontinue due to various toxicities. Of the 48 patients, 31 had evaluable JAK2V617F allelic burden at least at 2 time points, and the overall molecular response rate was 45% (14 of 31) with a median time of 24 months. In 4 (12.9%) patients, JAK2V617F allelic burden decreased to <1% after PegINFa treatment, with a median time of 29.5 months; however, no patients achieved complete molecular remission when examined by sensitive quantitative assay (Nussenzveig RH et al, Exp Hematol 2007) and also by digital PCR. In this pilot study, using plasma samples from 7 PV patients collected before and after treatment with PegINFa, we screened for antibody responses to a panel of 16 commercially available and 11 custom generated recombinant tumor-associated antigens (TAA) by enzyme-linked immunosorbent assay (ELISA) as previously described (Luetkens T et al., Leukemia Research 2010). In brief, we coated 96-well MaxiSorp (Nunc) plates over night at 4°C with 5mg/ml recombinant protein, blocked plates in 4% non-fat milk PBS (M-PBS) and incubated antigens with patient sera diluted 1:100 in M-PBS for 2h at room temperature. Bound antibodies were detected using a secondary anti-human immunoglobulin G antibody linked to alkaline phosphatase (Southern Biotech) followed by development with p-nitrophenyl phosphate. In patients #1, #2 and #3, who showed a decrease in JAK2V617F allelic burden after PegINFa treatment, we observed antibody responses against antigens MAGEB1, MAGEH1, MAGEA1, and DKK1 before and after PegINFa treatment. In patients #4, #5 and #7, JAK2V617F allelic burden increased after PegINFa treatment, and we did not detect substantial immune responses against any antigens in our panel. In patient #6, no immune response was seen against any antigen on the panel even though there was a decrease in JAK2V617F allele burden. These preliminary data suggest that PegINFa can induce deep molecular responses in a subset of PV and ET patients, and is associated with presence of immune responses against tumor antigens. We speculate that PegINFa may augment the efficacy of pre-existing TAA-specific immune responses against PV and ET clone. We are in the process of validating these findings in a larger cohort of PV and ET patients treated with PegINFa. Disclosures No relevant conflicts of interest to declare.

Daratumumab Monotherapy in Previously Untreated High-Risk Patients with Stage 3B Light Chain (AL) Amyloidosis: A Phase II Multicenter Study By European Myeloma Network (EMN)

Background: Advances in the anti-plasma cell therapy with the introduction of bortezomib-based therapies have improved the outcomes of patients with systemic light chain (AL) amyloidosis. However, patients with more severe cardiac involvement, (i.e., those with stage 3B disease defined as increased troponin levels with NT-proBNP level > 8500 pg/ml) still have a dismal prognosis with a median survival of 4-9 months. A delay in hematologic response and potential treatment related toxicities, may not allow for improvement in the outcome of these high-risk patients. Unfortunately, patients with stage 3B disease are excluded from clinical trials; their management remains a challenge and new treatment options are urgently needed. Daratumumab is a human IgG1ĸ monoclonal antibody that binds with high affinity to a unique epitope on CD38. It acts on plasma cells that express CD38 via different mechanisms, including direct apoptotic activity and immune system mediated responses. In patients with relapsed or refractory AL amyloidosis, daratumumab monotherapy has shown rapid, deep and high response rates, which are durable. Moreover, daratumumab has shown an excellent toxicity profile and no signal of cardiotoxicity. An ongoing prospective randomized trial evaluates the addition of daratumumab to standard bortezomib-based therapy in previously untreated patients with AL amyloidosis but patients with stage 3B are excluded. In order to offer high risk AL patients a new treatment option we designed this phase 2 trial aiming to enroll exclusively patients with stage 3B disease. Study Design and Methods: This is an open-label, multicenter, Phase 2 study in subjects with newly diagnosed stage 3B AL amyloidosis. Approximately 40 subjects will receive primary therapy with daratumumab. Subject participation will include a Screening Phase, a Treatment Phase, a Post-Treatment Observation Phase, and a Long-term Follow-up Phase. A safety run-in will include 6 subjects treated with daratumumab for at least 1 cycle to establish safety of the study drug in stage 3B AL amyloidosis patients. Dosing of these 6 patients will be staggered so that no subject will receive their first dose sooner than 48 hours after the previously enrolled subject. Safety evaluation will be performed by a Data Safety Monitoring Board after at least 1 cycle is completed for all 6 patients. If no safety signal is observed, the enrollment of the rest of the patients will begin. Subjects will initially receive daratumumab IV at a dose of 16 mg/kg, and by the end of 2019 will switch to daratumumab SC at a fixed dose of 1800 mg. Daratumumab will be administered weekly for Cycles 1-2, every 2 weeks for Cycles 3-6, and every 4 weeks thereafter. Each Cycle will last 28 days. The treatment will continue until disease progression according to Major Organ Deterioration Progression-Free Survival (MOD-PFS) criteria, start of subsequent therapy, or a maximum of 2 years. Patients who after 3 cycles of daratumumab monotherapy, have not achieved at least a hematologic VGPR or a hematologic PR with improved major organ function (i.e., cardiac or renal response per updated response criteria) may receive at the Investigator's discretion, bortezomib (1.3 mg/m2 weekly, for a maximum of 6 cycles) with low dose dexamethasone, in addition to daratumumab (Figure 1). The primary objective is to evaluate the overall survival (OS) rate at 6 months. The secondary objectives include evaluation of overall, VGPR and CR hematologic response rates at 3 and 6 months, MOD-PFS, PFS, organ response rate, treatment effects on patient-reported outcomes, time to and duration of response, safety and tolerability of daratumumab in patients with stage 3B AL amyloidosis. Minimal residual disease (MRD) may be monitored in subjects who achieve hematologic CR using high sensitivity methodologies (such as the Clonoseq NGS assay, or NGF based on the EuroFlow protocol). Safety will be measured by adverse events, laboratory tests, electrocardiograms, echocardiograms, vital sign measurements, physical examination and ECOG performance status. Health-related quality of life will be assessed via patient-reported outcome questionnaires. The study will run in 3 countries (Italy, Greece, and Netherlands), and will open for enrollment in August 2019. The recruitment is expected to last for 18 months, and the maximum time of treatment under the study protocol is 24 months. Disclosures Kastritis: Genesis: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria. Minnema:Servier: Honoraria; Jansen Cilag: Honoraria; Amgen: Honoraria; Gilead: Honoraria; Celgene Corporation: Honoraria, Research Funding. Dimopoulos:Sanofi Oncology: Research Funding. Sonneveld:SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding. Palladini:Janssen-Cilag: Other: Travel grant; Sebia: Honoraria; Janssen-Cilag: Honoraria; Celgene: Other: Travel grant. OffLabel Disclosure: Daratumumab in AL amyloidosis

Which One, Generic Vs Original Glivec Is More Effective in Patients with Chronic Myeloid Leukemia?

Introduction:Generic imatinib formulations are increasingly being used as more affordable alternatives worldwide and a few studies have evaluated the safety and efficacy of these formulations prospectively. We have retrospectively analyzed our CML cohort in terms of first line treatment of Glivec versus generic imatinib. This study aims to evaluate the safety and efficacy of generic imatinib products in chronic phase chronic myeloid leukemia as first line treatment. Methods:We have retrospectively analyzed our CML cohort from January 2000 to December 2018 treated with either Glivec or one of generic imatinib formulations. All of our patients (with 1 exception) were initiated imatinib in chronic phase in less than 56 days from diagnosis. All of our patients were followed in accordance with European Leukemia Net (ELN) 2013 recommendations and national hematology association CML guidelines and response definitions were applied according to ELN 2013 criteria. Event free survival (EFS) was defined as the time between treatment initiation and either loss of hematological response, progression to accelerated phase (AP) or blastic phase (BP), or death from any cause. Progression free survival was defined as the time between treatment initiation and transformation to AP, BP or death while on imatinib. For statistical analyses SPSS version 21.0 was used. All p values < 0.05 were considered statistically significant. Results:A total of 192 patients were analyzed comparing 102 (53.1 %) patients on Glivec with 90 patients on (476.9 %) generic formulations. 99 (51.6 %) were female patients. The median age of our population was median 46 years (14-88 years) for Glivec and median 51 years (19-79 years) for generic group (p=0.01). Risk stratifications according to Sokal, Hasford and ELTS scores were run for both Glivec and generic formulation groups. Most of the patients had low risk according to Sokal (137, 71.4%) and Hasford (116, 60.4 %) but intermediate risk according to ELTS (113, 58.9 %) scoring systems. There was no statistically significant difference in the gender distribution, Sokal, Hasford, ELTS scores and ECOG between the two groups. The median time to initiate imatinib treatment was 23.5 (1- 156) days for Glivec group and 13 (1- 51) days generic group (p< 0.05). But the late onset of the treatment was not associated with treatment failure or death. The median follow up was 119.8 (3.7- 250.5) months for Glivec group and 43.6 (2- 150) months for generic groups, respectively (p< 0.05). This difference might be explained by the fact that Glivec has been on the market for about two decades. Similar rates of grade> 2 hematological and non- hematological toxicity were seen in Glivec (4.9 %) and generic groups (3.3 %), respectively (p> 0.05). The rates of treatment failure at 3 months were significantly higher in generic formulation (6.7 %) group than Glivec (2.9 %) group (p< 0.05). Also, the rates of treatment failure at 6 months were significantly higher in generic formulation (3.3 %) group than Glivec (0.9 %) group (p< 0.05). Optimal molecular response rate at 3 months was 76.5 % (n=78) for Glivec and 32.2 % (n=29) for generic groups (p< 0.001). Also, optimal molecular response rate at 6 months was 69.6 % (n=71) for Glivec and 45.6 % (n=41) for generic groups (p= 0.01). Median EFS was found significantly higher for Glivec group compared to generic group (168 mos (95% CI: 159-177 mos) vs 74.6 mos (95% CI: 56-93); p<0.001) (Figure). Conclusion: We found that complete hematological response rates at 3 and 6 months were similar in both groups, but in early phase of treatment the optimal response rates of Glivec group was statistical significantly higher than generic group. Generic group presented with a lower rate of optimal response at 3 months but 13.4 % improvement in optimal response rates was observed at six months. No significant difference in safety concerns was observed between the groups. We recommend that these results from single center should be clarified in a prospective, randomized study including larger population. Figure Disclosures Özcan: AbbVie: Other: Travel support, Research Funding; MSD: Research Funding; Novartis: Research Funding; Amgen: Honoraria, Other: Travel support; BMS: Other: Travel support; Jazz: Other: Travel support; Sanofi: Other: Travel support; Abdi Ibrahim: Other: Travel support; Janssen: Other: Travel support, Research Funding; Bayer: Research Funding; Celgene Corporation: Research Funding, Travel support; Takeda: Honoraria, Other: Travel support, Research Funding; Archigen: Research Funding; Roche: Other: Travel support, Research Funding. Beksac:Celgene: Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Analysis of clinical characteristics, treatment response rate and survival of 77 myelodysplastic syndrome patients with del (5q) syndrome

目的探讨符合WHO（2016）诊断分型标准的骨髓增生异常综合征（MDS）5q−综合征患者的临床特征、来那度胺（LEN）疗效和生存情况。方法回顾性分析2008年1月至2018年4月于中国医学科学院血液病医院就诊的77例符合WHO（2016）诊断分型标准的MDS 5q−综合征患者临床资料，比较单纯5q−与5q−伴1个非−7/7q−的其他染色体异常（ACA）患者临床特征、疗效及生存情况，并比较LEN与非LEN药物治疗的疗效与生存情况。结果77例患者中，单纯5q−者64例，5q−伴ACA者13例，确诊时5q−伴ACA患者的中位年龄显著低于单纯5q−患者[58（29~64）岁对63（31~82）岁，z=2.164，P=0.030]。5q−伴ACA患者CD41免疫组化染色小巨核细胞（直径≤40 µm）检出率（91.7%，11/12）显著高于单纯5q−患者（60.0%，33/55）（P=0.046）。可评估LEN疗效的29例患者中，单纯5q−患者（19例）与5q−伴ACA患者（10例）血液学总反应率（78.9%对80.0%）、血液学完全缓解（CR）率（57.9%对60.0%）、细胞遗传学反应（CyR）率[69.2%（9/13）对66.7%（4/6）]、完全细胞遗传学反应（CCyR）率[61.5%（8/13）对33.3%（2/6）]相当。单纯5q−与5q−伴ACA患者中位总生存（OS）时间差异无统计学意义（62个月对78个月，P=0.313）。29例LEN组患者的血液学总反应率（79.3%对36.0%）、CR率（58.6%对8.0%）、CyR率[68.4%（13/19）对11.1%（1/9）]、CCyR率[52.6%（10/19）对0（0/9）]均高于非LEN组患者（25例），但两组患者中位OS时间差异无统计学意义（78个月对62个月，P=0.297）。结论单纯5q−与5q−伴ACA患者临床特征大体相似，两组患者LEN疗效、中位OS时间无明显差异。LEN治疗5q−综合征患者的疗效肯定，优于非LEN药物。

513P - Phase II study of vitamin B12 and folate supplementation for patients undergoing chemotherapy with pemetrexed

BackgroundTo assess the safety and efficacy of vitamin B12 and folic acid starting 24 to 48 hours before the chemotherapy including pemetrexed (PEM). MethodsPatients with advanced non-squamous non-small cell lung cancer or malignant pleural mesothelioma diagnosed and scheduled for chemotherapy including PEM were enrolled. Vitamin B12 and folic acid were administered 24-48 hours before the initiation of chemotherapy and we assessed the safety and efficacy of chemotherapy prospectively. As hematologic toxicity by this method has been confirmed in previous study, the primary endpoint was the incidence of non-hematologic toxicity grade 3 or worse during treatment and the secondary endpoint was hematologic toxicity, response rate, progression-free survival, and homocysteine concentration. Results103 patients were enrolled. The median age was 67 years (range 31-84 years), the gender was 59 male and 44 female and PS 0/1/2 were 33/69/1. Histological types were 96 cases of advanced non-squamous non-small cell lung cancer and 7 cases of malignant pleural mesothelioma. The regimens were CDDP+PEM 80 cases, PEM single agent 11 cases, CBDCA+PEM 7 cases, CDDP+PEM+BEV 3 cases, CBDCA+PEM+BEV 2 cases. The incidence of nonhematologic toxicity at grade 3 or worse was 11 cases (10.7%), achieving the primary endpoint. The incidence of hematologic toxicity at grade 3 or worse was 25 cases (24.3%). The response rate for CDDP+PEM in advanced non-squamous non-small cell lung cancer was 51.4% and a median progression-free survival was 4.8 months. ConclusionsThe method of administering vitamin B12 and folic acid 24 to 48 hours before initiation of chemotherapy including PEM was safe and there was no problem in efficacy. Clinical trial identificationUMIN000010570. Legal entity responsible for the studyYukio Hosomi. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Descriptive analysis of dosing and outcomes for patients with ibrutinib-treated relapsed or refractory chronic lymphocytic leukemia in a Canadian centre.

Ibrutinib is an approved treatment for relapsed or refractory chronic lymphocytic leukemia (cll) and small lymphocytic lymphoma (sll). The effect of ibrutinib dose reduction compared with discontinuation in a population-based setting is unclear. To examine the patterns of ibrutinib use in a Canadian population-based setting, we analyzed a retrospective cohort of patients with relapsed or refractory cll or sll treated with ibrutinib. The 64 patients diagnosed with cll or sll had a median age of 76.5 years. Most had unmutated ighv (immunoglobulin variable heavy chain). A hematologic response occurred in 39 patients regardless of the ibrutinib dose. The most common toxicities were infection, bruising or bleeding, and musculoskeletal problems, with a median time to first toxicity of 14 days. More than half the cohort experienced a dose reduction, with musculoskeletal problems, cytopenias, and infection being the leading causes; surgery was the most frequent indication for holding treatment. Only 26 of the 64 patients (40.6%) stayed on the recommended maximal dose of ibrutinib. No differences in reported toxicities or hematologic response rates were evident between the patients receiving maximal and submaximal therapy. At the end of the study period, 53 patients from the initial cohort remained on ibrutinib. More than half the study patients received ibrutinib therapy at a submaximal dose without evidence of increased frequency of toxicities or disease progression. The rate of ibrutinib discontinuation was lower in our cohort than has been reported in other settings. Submaximal ibrutinib dosing will have to be further systematically evaluated.

The efficacy and safety of bortezomib-based chemotherapy for immunoglobulin light chain amyloidosis: A systematic review and meta-analysis

BackgroundThe role of bortezomib in the treatment of immunoglobulin light chain (AL) amyloidosis is not well defined. We performed this meta-analysis to evaluate the efficacy and safety of bortezomib-based regimens in patients with AL amyloidosis who are not eligible for or refuse autologous stem cell transplantation. MethodsA systematic search of Medline, Embase, and the Cochrane Library was conducted to identify related studies. ResultsTwenty-four studies with 1238 patients were included. The pooled overall response rate (ORR) and complete hematological response rate (CHR) were 0.72 (95% CI, 0.67–0.77) and 0.35 (95% CI, 0.30–0.40), respectively. Bortezomib significantly improved the outcome of ORR compared to other regimens (RR 1.28, 95% CI, 1.04–1.57, P = .02). Similar results were observed in CHR (RR 1.90, 95% CI, 1.45–2.50, P < .001) and cardiac response (RR 2.03, 95% CI, 1.31–3.13, P = .002), but not in overall survival (HR 0.82, 95% CI, 0.62–1.09, P = .17). In addition, once-weekly bortezomib was associated with improved overall survival compared with twice-weekly bortezomib (HR 0.52, 95% CI, 0.27–0.99, P = .05). Peripheral neuropathy was the most widely reported adverse event. Incorporation of bortezomib into the standard melphalan + dexamethasone setting showed a trend of increased serious adverse events, though this was not statistically significant (RR 1.29, 95% CI, 0.95–1.75, P = .10). ConclusionsCurrent evidence indicates that bortezomib-based regimens might be effective and safe therapies for patients with AL amyloidosis. There is a great need to conduct more well-designed randomized controlled trials to provide high-quality evidence.

S875 SUBCUTANEOUS DARATUMUMAB + CYCLOPHOSPHAMIDE, BORTEZOMIB, AND DEXAMETHASONE (CYBORD) IN PATIENTS WITH NEWLY DIAGNOSED AMYLOID LIGHT CHAIN (AL) AMYLOIDOSIS: UPDATED SAFETY RUN‐IN RESULTS OF ANDROMEDA

Background:The achievement of deep and sustained hematologic response in AL amyloidosis is needed to improve organ function and overall survival. Daratumumab‐based combinations have resulted in deep responses and minimal additional toxicity in multiple myeloma, making such combinations potentially ideal in the treatment of AL amyloidosis.Aims:We present the 1‐year follow up on safety and efficacy data for the 28 patients enrolled in the safety run‐in cohort of ANDROMEDA (NCT03201965), a phase 3 study investigating subcutaneous DARA + CyBorD in patients with newly diagnosed AL amyloidosis.Methods:Eligible patients had ≥1 involved organs, Eastern Cooperative Oncology Group (ECOG) score ≤2, estimated glomerular filtration rate ≥20 mL/min/1.73m2, and NT‐ProBNP ≤8,500 ng/L. In the safety run‐in, patients received DARA (1,800 mg in 15 mL) co‐formulated with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.) administered subcutaneously (SC) qw Cycles 1–2, q2w Cycles 3–6, and q4w thereafter for ≤2 y. Cy 300 mg/m2 PO or IV, Bor 1.3 mg/m2 SC, and D 40 mg were administered qw ≤6 cycles. Hematologic response evaluations (per international amyloidosis consensus criteria, Comenzo Leukemia 2012) were q4w cycles 1–6 and every other month thereafter.Results:Patients (N = 28) had a median (range) age of 68 (35–83) years and a median of 2 (1–4) involved organs. Heart and kidney involvement affected 54% and 61% of patients, respectively; 21% were Mayo cardiac stage IIIA at screening. Median (range) follow‐up was 341 (17–449) days. Median treatment duration was 11 (0.2–14) months. Patients received a median of 11 (1–16) treatment cycles; 79% received DARA SC maintenance (&gt;6 cycles). The overall hematologic response rate was 96% and the rate of very good partial response (VGPR) or better was 82%; 10 (36%) patients achieved CR. An additional 5 (18%) patients achieved CR based on normalization of involved free light chain (iFLC) level and negative serum and urine immunofixation, but due to suppression of uninvolved FLC (uFLC) below the lower limit of normal did not normalize the FLC ratio and thus could not be formally classified as CR. Median time to first response was 23 days, and median time to CR and VGPR were 85 (29–226) and 22 (7–228) days, respectively. At the time of data cutoff (median follow‐up 341 days), one patient (with no response to treatment) experienced disease progression. All of the 10 patients achieving CR and the 5 patients with normalized iFLC level and negative serum and urine immunofixation without normalized FLC ratio continue to respond to treatment. Median duration of CR was not reached. Six patients received subsequent autologous stem cell transplant (ASCT). Four patients have died (2 due to disease progression and 2 due to events following ASCT). The most common treatment emergent adverse events included diarrhea (64%), fatigue and peripheral edema (50% each). Two patients (7%) experienced infusion related reactions, all of which were grade 1.Summary/Conclusion:DARA‐CyBorD provides high overall hematologic response and CR rate in patients with newly diagnosed AL amyloidosis with a well‐tolerated safety profile. Enrollment into the randomized portion of ANDROMEDA is ongoing.

S876 GILTERITINIB SIGNIFICANTLY PROLONGS OVERALL SURVIVAL IN PATIENTS WITH FLT3-MUTATED (FLT3MUT+) RELAPSED/REFRACTORY (R/R) ACUTE MYELOID LEUKEMIA (AML): RESULTS FROM THE PHASE 3 ADMIRAL TRIAL

Background: The achievement of deep and sustained hematologic response in AL amyloidosis is needed to improve organ function and overall survival. Daratumumab-based combinations have resulted in deep responses and minimal additional toxicity in multiple myeloma, making such combinations potentially ideal in the treatment of AL amyloidosis. Aims: We present the 1-year follow up on safety and efficacy data for the 28 patients enrolled in the safety run-in cohort of ANDROMEDA (NCT03201965), a phase 3 study investigating subcutaneous DARA + CyBorD in patients with newly diagnosed AL amyloidosis. Methods: Eligible patients had ≥1 involved organs, Eastern Cooperative Oncology Group (ECOG) score ≤2, estimated glomerular filtration rate ≥20 mL/min/1.73m2, and NT-ProBNP ≤8,500 ng/L. In the safety run-in, patients received DARA (1,800 mg in 15 mL) co-formulated with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.) administered subcutaneously (SC) qw Cycles 1–2, q2w Cycles 3–6, and q4w thereafter for ≤2 y. Cy 300 mg/m2 PO or IV, Bor 1.3 mg/m2 SC, and D 40 mg were administered qw ≤6 cycles. Hematologic response evaluations (per international amyloidosis consensus criteria, Comenzo Leukemia 2012) were q4w cycles 1–6 and every other month thereafter. Results: Patients (N = 28) had a median (range) age of 68 (35–83) years and a median of 2 (1–4) involved organs. Heart and kidney involvement affected 54% and 61% of patients, respectively; 21% were Mayo cardiac stage IIIA at screening. Median (range) follow-up was 341 (17–449) days. Median treatment duration was 11 (0.2–14) months. Patients received a median of 11 (1–16) treatment cycles; 79% received DARA SC maintenance (>6 cycles). The overall hematologic response rate was 96% and the rate of very good partial response (VGPR) or better was 82%; 10 (36%) patients achieved CR. An additional 5 (18%) patients achieved CR based on normalization of involved free light chain (iFLC) level and negative serum and urine immunofixation, but due to suppression of uninvolved FLC (uFLC) below the lower limit of normal did not normalize the FLC ratio and thus could not be formally classified as CR. Median time to first response was 23 days, and median time to CR and VGPR were 85 (29–226) and 22 (7–228) days, respectively. At the time of data cutoff (median follow-up 341 days), one patient (with no response to treatment) experienced disease progression. All of the 10 patients achieving CR and the 5 patients with normalized iFLC level and negative serum and urine immunofixation without normalized FLC ratio continue to respond to treatment. Median duration of CR was not reached. Six patients received subsequent autologous stem cell transplant (ASCT). Four patients have died (2 due to disease progression and 2 due to events following ASCT). The most common treatment emergent adverse events included diarrhea (64%), fatigue and peripheral edema (50% each). Two patients (7%) experienced infusion related reactions, all of which were grade 1. Summary/Conclusion: DARA-CyBorD provides high overall hematologic response and CR rate in patients with newly diagnosed AL amyloidosis with a well-tolerated safety profile. Enrollment into the randomized portion of ANDROMEDA is ongoing.