Intralesional Administration of the CD47 Antagonist TTI-621 (SIRPαFc) Induces Responses in Both Injected and Non-Injected Lesions in Patients with Relapsed/Refractory Mycosis Fungoides and Sézary Syndrome: Interim Results of a Multicenter Phase I Trial

Abstract Background CD47 is an immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a "do not eat" signal to suppress macrophage phagocytosis. Tumor cells, including T-cell lymphomas, frequently overexpress CD47 to escape immune surveillance. TTI-621 (SIRPαFc) is a fusion protein consisting of the CD47 binding domain of human SIRPα linked to the Fc region of human IgG1, designed to enhance phagocytosis and antitumor activity by blocking the CD47-SIRPα interaction between malignant cells and macrophages, and engaging activating Fcγ receptors. It is hypothesized that direct intralesional (IL) administration of TTI-621 may enhance both local and systemic antitumor activity. Methods A multicenter, open-label Phase 1 study is ongoing to characterize the safety, tolerability, pharmacokinetics, pharmacodynamics and antitumor activity of IL injections of TTI-621 (NCT02890368) in adult patients with relapsed/refractory (R/R) percutaneously accessible solid tumors and mycosis fungoides (MF) who have progressed on standard anticancer therapy or for whom no other approved therapy exists. The current report analyzed a cohort of R/R MF/Sézary syndrome (SS) patients enrolled by the data cut-off date. Patients received induction therapy consisting of a single IL injection (1, 3 or 10 mg), three 10 mg injections over one week, or six 10 mg injections over two weeks distributed across one to three lesions. The protocol was recently amended to enable weekly post-induction IL maintenance dosing and to explore IL TTI-621 administration in combination with subcutaneous pegylated interferon-α2a. Responses were evaluated using the Composite Assessment of Index Lesion Severity (CAILS) score a week after induction therapy and at later time points in some patients. Serial biopsies were collected to assess the impact of TTI-621 on the tumor microenvironment. Results Twenty-two patients (16 M/6F, median age 65.5 years, range 32-85) were enrolled as of June 15, 2018. Primary diagnosis included MF (n=18), MF with transformation (n=3) and SS (n=1). Clinical stages included stage IA (n=2), IB (n=3), IIA (n=1), IIB (n=13), IVA (n=2) and IVB (n=1). Patients received a median of 3 prior systemic therapy regimens. Twenty-one patients were treated with TTI-621 monotherapy and one patient with TTI-621 in combination with pegylated interferon-α2a. Single and multiple IL injections of up to 10 mg TTI-621 have been well tolerated. The most frequently reported treatment-related adverse events (AEs) were chills (n=8), injection site pain (n=7) and fatigue (n=6). All treatment-related AEs were Grade 1 or 2 in severity. No treatment-related serious AEs or dose-limiting toxicity have been observed. CAILS scores for injected lesions obtained after the last injection were available for 17 patients: 15 (88%) had measurable improvement; 7 (41%) exhibited ≥50% decrease from baseline (Figure 1). Responses were rapid and in some patients occurred after a single injection of varying doses of TTI-621. CAILS scores continued to decrease in 5/5 (100%) monotherapy patients for which post-induction therapy assessments were conducted. Seven patients with reduced CAILS of varying degree (-14% to -67%) in the injected lesions had paired assessments available in adjacent, non-injected lesions. In 6/7 patients, a reduction in CAILS was observed in the non-injected lesions (-12% to -67%), indicating that TTI-621 could induce local-regional responses that were not confined to the site of injection. Additionally, one patient with transformed MF exhibited clear evidence of abscopal effects with rapid resolution of lesions on the abdomen, left flank/back and arms less than two weeks after receiving IL TTI-621 injections in lesions on the foot and leg. The only SS patient on study achieved a reduction in circulating Sézary cells after a single 3 mg local injection of TTI-621. Conclusions Preliminary data from this ongoing study indicate that IL TTI-621 administration is well-tolerated and has single agent activity in heavily pre-treated MF/SS patients across various disease stages. The rapid responses observed occurred in both injected and non-injected lesions indicating a local-regional effect with initial evidence of distant abscopal or systemic effects. Enrollment in this study is continuing to evaluate the impact of weekly maintenance dosing and further characterize the systemic effect and durability of responses. Disclosures Querfeld: Kyowa: Membership on an entity's Board of Directors or advisory committees; Acelion: Membership on an entity's Board of Directors or advisory committees; Bioniz: Membership on an entity's Board of Directors or advisory committees; Medivir: Membership on an entity's Board of Directors or advisory committees; Trillium Therapeutics: Membership on an entity's Board of Directors or advisory committees. Thompson:Trillium Therapeutics: Research Funding. Taylor:Trillium Therapeutics: Research Funding. Johnson:Trillium Therapeutics: Employment. Catalano:Trillium Therapeutics: Employment. Petrova:Trillium Therapeutics: Employment. Thompson:Trillium Therapeutics: Employment. Uger:Trillium Therapeutics: Employment. Shou:Trillium Therapeutics: Employment. Akilov:Kyowa Kirin: Consultancy; Pfizer: Research Funding; Seattle Genetics: Consultancy; Trillium Therapeutics: Research Funding; Actelion Pharmaceuticals: Consultancy.

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Subcutaneous Versus Intravenous Bortezomib in Two Different Induction Therapies for Newly Diagnosed Multiple Myeloma – Subgroup Analysis from the GMMG-MM5 Trial

Blood ◽

10.1182/blood.v124.21.3475.3475 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3475-3475 ◽

Cited By ~ 1

Author(s):

Maximilian Merz ◽

Hans Salwender ◽

Mathias Hänel ◽

Uta Bertsch ◽

Christina Kunz ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

Group Iv ◽

Route Of Administration ◽

Prolonged Treatment ◽

Newly Diagnosed ◽

Advisory Committees ◽

The Impact

Abstract Background: In patients with relapsed multiple myeloma (MM), Moreau and colleagues (Lancet Oncol, 2011) demonstrated that subcutaneous (SC) administration of bortezomib (BTZ) significantly reduced rates of adverse events (AE) compared to the intravenous (IV) formulation without loss of efficacy. Prospective data on SC BTZ in newly diagnosed MM are limited. We investigated the impact of SC versus IV BTZ in two different induction therapies for patients with newly diagnosed MM treated within the multicenter, prospective randomized MM5 trial of the German Myeloma Multicenter Group (GMMG). Methods: From 06/2010 until 11/2013, 604 patients were randomly assigned to receive 3 cycles of PAd (BTZ 1.3 mg/m2, days 1, 4, 8 and 11; Doxorubicin 9 mg/m2 IV, days 1-4; Dexamethasone 20 mg/d, orally, days 1-4, 9-12 and 17-20) or 3 cycles VCD (BTZ 1.3 mg/m2, days 1, 4, 8 and 11; Cyclophosphamide 900 mg/m2IV; day 1, Dexamethasone 40 mg/d, orally, days 1-2, 4-5, 8-9 and 11-12) for induction therapy. In the MM5 trial, induction therapy is followed by stem cell mobilization and harvest, high-dose therapy and Lenalidomide-based consolidation/maintenance therapy. Primary end points of the ongoing study are response to treatment after induction therapy and progression-free survival. Due to improved AE profile of SC compared to IV BTZ reported by Moreau, the administration of BTZ was changed from IV to SC in 02/2012. Therefore, we were able to perform an explorative analysis of 598 patients who received at least one dose of trial medication (PAd: n=150 IV / 140 SC; VCD: n=154 IV / 140 SC). 14 patients were excluded from the analysis because administration of BTZ was changed after start of induction therapy. We analyzed whether the route of administration influenced the applied cumulative BTZ dose, toxicity and efficacy of PAd and VCD. Results: The cumulative applied BTZ dose was significantly higher in patients treated with SC BTZ (PAd: 28.9 mg; VCD: 28.8 mg) compared to IV-treated patients (PAd: 27.6 mg; VCD: 27.9 mg; p = 0.007). Analysis of reported AEs associated to induction therapy revealed a significantly higher rate in patients treated with IV BTZ (65.1%) compared to SC-treated patients (55.7%, p = 0.02). AE > °II were reported more frequently in the IV group (IV: 52.0%; SC: 43.9%, p = 0.004). In detail, abnormal laboratory findings including leucopenia and thrombocytopenia (IV: 23.0%; SC: 16.4%, p = 0.05), metabolism and nutrition disorders (IV: 12.5%; SC: 5.4%, p = 0.004) and gastrointestinal disorders (IV: 9.9%; SC: 3.9%, p = 0.006) occurred more often in IV-treated patients. Analysis of peripheral neuropathy (PN) ≥ °II revealed no significant differences between IV and SC BTZ during the first two cycles of induction therapy (cycle 1: IV: 1.6%; SC: 2.5%; cycle 2: IV: 2.3%; SC: 3.6%) but PN occurred more often in IV-treated patients during the third cycle of induction therapy compared to the SC group (IV: 7.6%; SC: 1.8%, p = 0.001). Overall response rates (partial response or better) were not influenced by the route of administration in patients treated with PAd (IV: 72.7%; SC: 70.7%; p = 0.79) or VCD (IV: 77.9%; SC: 82.1%; p = 0.39). Analysis of the VCD arm showed that rates of VGPR or better were significantly higher in patients treated with IV BTZ compared to SC-treated patients (IV: 41.6%; SC: 28.6%, p = 0.02). Rates of VGPR or better were also higher for IV-treated patients in the PAd arm but did not reach statistical significance (IV: 36.7%; SC: 31.4%, p=0.39). Patient characteristics including baseline creatinine levels > 2 mg/dl, obesity or age at inclusion > 65 years did not influence efficacy of IV or SC BTZ in both arms. Conclusion: Last year we reported on the favorable toxicity profile and equal efficacy of VCD compared to PAd. With the current analysis we demonstrate that toxicity is further reduced with SC BTZ compared to IV. We therefore recommend VCD as induction therapy. However, we show for the first time a possible loss of efficacy in SC-treated patients. Therefore it remains unclear whether the reduced toxicity justifies the general application of SC BTZ in newly diagnosed, transplant-eligible patients or whether a prolonged treatment (4 x VCD SC) may reduce toxicity while achieving similar efficacy. Further studies are warranted since our results are partially in contrast with the previously presented data in relapsed MM and the ongoing MM5 trial was initially not designed to prospectively investigate the effect of SC or IV BTZ. Disclosures Salwender: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Binding site: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Scheid:Celgene: Honoraria; Janssen: Honoraria. Mai:Janssen: Travel support Other. Hose:Novartis: Research Funding. Schmidt-Wolf:Janssen: Consultancy, Honoraria. Weisel:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; BMS: Consultancy; Noxxon: Consultancy. Duerig:Janssen: Consultancy, Honoraria; Celgene: Honoraria. Goldschmidt:Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Polyphor: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Onyx: Consultancy, Speakers Bureau; Millenium: Consultancy, Speakers Bureau.

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Outcomes of Myeloma Patients with t(11;14) Receiving Lenalidomide, Bortezomib, and Dexamethasone (RVD) Induction Therapy

Blood ◽

10.1182/blood-2018-99-119051 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3282-3282 ◽

Cited By ~ 1

Author(s):

Jonathan L Kaufman ◽

Nisha Joseph ◽

Vikas A. Gupta ◽

Charise Gleason ◽

Craig C Hofmeister ◽

...

Keyword(s):

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

Data Monitoring Committee ◽

The Other ◽

Control Group ◽

Advisory Committees ◽

Post Induction ◽

Standard Risk

Abstract Background: In the cytogenetic risk-stratification of myeloma, identification of t(11;14) on plasma cells has long been regarded as a standard risk prognostic factor. More recently, there have been reports of inferior PFS and OS relative to the standard risk myeloma patients. These results carry significance in the current day, as an ongoing phase I trial of Bcl-2 inhibitor (venetoclax) reported an ORR of 40% among myeloma patients with t(11;14) leading way for individualized therapeutic approach for myeloma. In this context, we evaluated the clinical outcomes of t(11;14) myeloma patients receiving uniform modern day induction therapies to evaluate the prognostic implication of this translocation. Methods: Of the 1000 consecutive newly diagnosed myeloma patients treated with RVD induction therapy per Richardson et al (Blood 2010) from July 2005 until August 2016, we have FISH probes for t(11;14) tested in 867 patients. Among these patients, we identified 122 patients with t(11;14). Excluding 247 patients that had del 17p, t(4;14), t (14;16) and complex karyotype on metaphase cytogenetics, we have identified 527 patients that formed the control group of standard risk myeloma. Demographic and outcomes data for the patients were collected from our IRB approved myeloma database and responses were evaluated per IMWG Uniform Response Criteria. Results: Median age of the patients is 61 years (range 16-83). 32% of the patients are above the age of 66. Other patient characteristics include: M/F 56%/44%; W/AA 62%/36%; ISS I/II/III 48%/30%/22%; Isotype IgG/IgA/FLC 60%/18%/19%. Response rates are summarized in table 1. Post induction responses ≥VGPR are lower for t(11;14) compared with non-t(11;14): 49.5% vs 76.3% p<0.001 and similarly best VGPR for t(11;14) vs non-t(11;14): 76.3% vs 91.4% p=0.001. The median progression-free survival for the t(11;14) and non-t(11;14) groups were 51 months (95% confidence interval (CI), 30.628-71.372) and 75 months (95% CI, 57.882-92.118) months, respectively (P<0.001), at a median follow up of 39 months. This difference is more pronounced among patients not receiving maintenance therapy (29 vs 62 months, p=0.001). The median overall survival (OS) for t(11;14), and non-(11;14) groups were not reached at a median follow up of 38 months. Conclusions: Even with the use of modern day induction regimens, patients with t(11;14) have inferior outcomes compared to the other patients standard risk myeloma. The lower rates of ≥VGPR post-induction and the shorter median PFS suggests more novel regimens such as venetoclax should be studied earlier in the course to improve the outcomes of t(11;14) patients on par with the other standard risk myeloma patients. Disclosures Kaufman: Janssen: Consultancy; Abbvie: Consultancy; Karyopharm: Other: data monitoring committee; Roche: Consultancy; BMS: Consultancy. Hofmeister:Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Heffner:ADC Therapeutics: Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Research Funding; Genentech: Research Funding. Lonial:Amgen: Research Funding. Boise:AstraZeneca: Honoraria; Abbvie: Consultancy. Nooka:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Increased Charlson Comorbidity Index (CCI) Is Not Associated with Inferior Clinical Outcomes in Patients with Mantle Cell Lymphoma (MCL)

Blood ◽

10.1182/blood-2018-99-118748 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5327-5327

Author(s):

Derrick Ridley ◽

Subir Goyal ◽

Oscar Calzada ◽

Michael C Churnetski ◽

Jean L. Koff ◽

...

Keyword(s):

Board Of Directors ◽

Induction Therapy ◽

Charlson Comorbidity Index ◽

Research Funding ◽

Cell Lymphoma ◽

Advisory Committees ◽

Mantle Cell ◽

Comorbidity Index ◽

Unplanned Hospitalizations ◽

The Impact

Abstract Introduction Mantle cell lymphoma (MCL) frequently impacts elderly patients (median age of diagnosis is 68), and management of these patients can be difficult due to the presence of comorbidities in this group. Presence of comorbidities is associated with inferior outcomes in many hematologic malignancies but there has not been a systematic assessment of comorbidities in MCL. We utilized the Charlson Comorbidity Index (CCI) to describe the presence of comorbidities in MCL patients and to explore their impact on patient outcomes. Methods We included patients with MCL evaluated at Emory between January 1, 2000 and December 31, 2016. Patients with limited or inadequate follow-up or for whom data to determine the CCI were inadequate were excluded. We determined the CCI at the time of initiation of treatment for all patients with MCL and excluded "lymphoma" from this calculation. Patients were categorized into severity classes based on their summed scores. The median score of 1 was used to delineate the "low" and "high" CCI groups. For each group (low and high CCI), we evaluated baseline demographic, clinical and treatment characteristics and identified specific toxicity-related outcomes including: failure to complete induction chemotherapy, unplanned hospitalizations, or treatment related toxicities. Progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and we assessed for the impact of CCI score on PFS and OS using Cox proportional hazards models. Results Of 178 patients with MCL, 129 were male (73.3%) and median age was 61 (32-86). One hundred forty patients (86.4%) had stage IV disease. Among the 99 reported values, 31 patients (31.3%) had an elevated LDH, and ECOG PS was 0 in 47 patients, 1 in 66 patients, and 2-4 in 8 patients. Induction therapy was R-HyperCVAD (n=79; 45.4%), R-CHOP (n=49; 28.2%), BR (n=13; 7.5%) RCHOP/RDHAP (n=3; 1.7%) and Other (N=29; 16.7%). The CCI scores for the whole cohort were 0 in 78 pts (43.8%), 1 in 57 pts (32%), 2 in 24 pts (13.5%) and 3+ in 19 pts (10.7%; See Figure 1). One hundred thirty-five patients (75.8%) patients had a low CCI score (0-1) and 43 patients (24.2%) had a high CCI score (>1). Compared to patients with a low CCI, those with high CCI were older (median 67 years vs 59 years, p<0.001), were more likely to have B-symptoms at diagnosis (48% vs 30%, p=0.04) and had a decreased baseline platelet count (median 137 vs 178, p=0.02). Among the 83 patients who completed an intensive induction regimen, that contained high dose cytarabine, 71 (85.5%) had a low CCI and 12 (14.5%) had a high CCI. Twenty-eight patients experienced an unplanned hospitalization during induction, including 23 in the low CCI group (22%) and 5 in the high CCI group (16%; p=0.49). Seventeen patients de-escalated or discontinued induction therapy prematurely including 13 (12.4%) in the low CCI group and 4 (13.3%) in the high CCI group (p=1.00). There was no significant difference in OS between the low- and high-CCI groups (5-year OS 70.3% vs 68.7%, p=0.9; See Figure 2). Within the cohort of patients treated with intensive induction therapy, there was no significant impact of CCI on incidence of unplanned hospitalizations, de-escalation or discontinuation of therapy, or OS (p> 0.3). Conclusion CCI score was not shown to be a reliable predictor of unplanned hospitalizations, premature cessation of chemotherapy, or OS in our cohort, although many of our patients had very limited comorbidities. These results suggest that patients with limited comorbid conditions can likely be successfully managed with appropriate supportive care and should be considered for the most effective regimens. Future studies with a larger patient population with increased number of comorbidities may improve our ability to detect the impact of CCI on these outcomes and explore the relative contribution of specific comorbidities in MCL. Disclosures Calzada: Seattle Genetics: Research Funding. Flowers:BeiGene: Research Funding; Burroughs Wellcome Fund: Research Funding; Abbvie: Consultancy, Research Funding; Abbvie: Research Funding; Pharmacyclics/ Janssen: Consultancy; Millennium/Takeda: Research Funding; Gilead: Consultancy; Genentech/Roche: Consultancy; Janssen Pharmaceutical: Research Funding; Genentech/Roche: Research Funding; OptumRx: Consultancy; Acerta: Research Funding; Gilead: Research Funding; Denovo Biopharma: Consultancy; Celgene: Research Funding; Bayer: Consultancy; Spectrum: Consultancy; Karyopharm: Consultancy; National Cancer Institute: Research Funding; TG Therapeutics: Research Funding; Eastern Cooperative Oncology Group: Research Funding; Pharmacyclics: Research Funding; V Foundation: Research Funding. Cohen:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Takeda: Research Funding; BioInvent: Consultancy; BioInvent: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Bortezomib Maintenance (BM) or Consolidation (BC) Following Aggressive Immunochemotherapy and Autologous Stem Cell Transplant (ASCT) for Untreated Mantle Cell Lymphoma (MCL): 8 Year Follow up of CALGB 50403 (Alliance)

Blood ◽

10.1182/blood-2018-99-112655 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 146-146 ◽

Cited By ~ 4

Author(s):

Lawrence D Kaplan ◽

Matthew J. Maurer ◽

Wendy Stock ◽

Nancy L. Bartlett ◽

Noreen Fulton ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

Dropout Rate ◽

Advisory Committees ◽

Post Transplant ◽

Post Induction

Abstract Introduction: Aggressive chemo-immunotherapy followed by peripheral blood stem cell autografting (ASCT) in CALGB (Alliance) 59909 achieved a median progression-free survival (PFS) in MCL of 5 years (Damon et al JCO, 2009), but late recurrences occurred. Using the CALGB 59909 treatment backbone, we evaluated tolerability and efficacy of adding post-transplant bortezomib consolidation (BC) or maintenance (BM)in a randomized phase II trial. Interim results of CALGB (Alliance) 50403 were previously presented (ASH 2015) demonstrating 5 yr PFS 70% and 69% for the BM and BC arms respectively. We now report final 8 year follow up results from this trial and compare outcomes to CALGB 59909, which differed from CALGB 50403 only by the absence of post-transplant bortezomib. Methods: The primary endpoint was PFS measured from randomization for each treatment arm. Induction therapy was with 2-3 cycles of augmented R-CHOP (2000 mg/m2 cyclophosphamide) and methotrexate (300 mg/m2) followed by high-dose cytarabine/etoposide/rituximab(R)/filgrastim (EAR) stem cell mobilization and cyclophosphamide/carmustine/etoposide (CBV) ASCT. After 2 doses of post-transplant R, patients were randomized to BC (1.3 mg/ m2 IV days 1, 4, 8, 11 of a 3-week cycle for 4 cycles) or BM (1.6 mg/m2 IV weekly x4 every 8 weeks for 18 months) beginning at approximately day 90. Minimal residual disease (MRD) was analyzed using patient-specific PCR probes for the bcl-1 / IgH junction or the IgH CDR3 region. Results: 151 patients were enrolled from 10/2006 - 6/2010 at 14 sites; 147 who received treatment are included in this analysis. Median age was 59 years (29-69); stage II (2.7%), III (11.6%), IV (85.0%); MIPI low (52.4%), intermediate (30.6%), high (17.0%); blastoid histology (12.9%); bone marrow involvement (81.0%); Ki67 was evaluated in 86 and was >30% in 17.4% of patients. 118 (80%) underwent ASCT and 102 (68%) were randomized. Most withdrawals (45) were for progression (10) or adverse events (AEs) (19) including 4 treatment-related deaths. Fifty-two patients were randomized to BM and 50 to BC. Following randomization, 34 (65%) completed BM and 33 (66%) completed BC. Withdrawal for AEs occurred in 14 (28%) of BC and 7 (13%) of BM patients (p = 0.09), most for cytopenias or peripheral neuropathy. With a median follow-up 7.8 years from randomization (8.3 from registration), the median PFS from randomization for the BM arm was not reached and was 8.9 years (95% CI 7.2 to not reached) for the BC arm. Both arms had median PFS significantly greater than the null hypothesis setting median PFS to 4 years (p < 0.001; 1-sided test of exponential parameter)The 8-year PFS estimates in the BM and BC arms were 77% (95% CI 66-90%) and 58% (95% CI 44-76%), respectively. Among all 147 patients treated on CALGB 50403, 8-year PFS from time of registration was 43.6% (35.6-53.3%). PFS from registration was not significantly extended in CALGB 50403 compared with CALGB 59909 (log rank p=0.24), but using a landmark analysis from time of transplant, PFS was significantly extended in CALGB 50403 (log rank p=0.005)(fig 1). Baseline patient characteristics in the two studies were not significantly different. In CALGB 50403, 8-year PFS from registration by MIPI was 52.0% (95% CI 41.1-66.0%) in MIPI low risk, 37.5% (95% CI 25.3-55.4%) in intermediate risk, and 28.2% (95% CI 13.7-57.9%) in high-risk. Bone marrow MRD results were collected for 42 patients post-induction therapy; 8-year PFS estimates were 80.2% (95% CI 62.2-100%) (n=17) and 43.2% (95% CI 27.3-68.2%) (n=25) for MRD-negative and MRD-positive patients, respectively (p=0.009). Conclusions: Induction chemotherapy followed by ASCT and either BC or BM was efficacious and tolerable, although BC was associated with more withdrawals for toxicity. PFS was not significantly different between BC and BM. The comparison between studies 50403 and 59909 with long-term follow up continues to suggest a PFS benefit from the addition of BC or BM among patients undergoing transplant. This did not translate into a PFS benefit from time of study enrollment possibly due to the higher pre-transplant dropout rate in 50403. MRD-negativity following induction chemo-immunotherapy is highly associated with improved PFS and the role of ASCT in post-induction MRD-negative patients is currently under investigation in a randomized clinical trial. Support: U10CA180821, U10CA180882, U24CA196171; ClinicalTrials.gov Identifier: NCT00310037 Disclosures Kaplan: Bayer Pharmaceuticals: Consultancy. Maurer:Celgene: Research Funding; Morphosys: Research Funding; Nanostring: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Bartlett:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Blum:Acerta: Consultancy; Astra-Zeneca: Consultancy. LaCasce:Seattle Genetics: Consultancy, Honoraria; Humanigen: Consultancy, Honoraria; Research to Practice: Speakers Bureau; Bristol-Myers Squibb: Other: Data safety and monitoring board. Leonard:AstraZeneca: Consultancy; Juno: Consultancy; BMS: Consultancy; ADC Therapeutics: Consultancy; Gilead: Consultancy; Biotest: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; MEI Pharma: Consultancy; Celgene: Consultancy; United Therapeutics: Consultancy; Sutro: Consultancy; Genentech/Roche: Consultancy; Pfizer: Consultancy; Bayer: Consultancy. Cheson:AbbVie, Roche/Genentech, Pharmacyclics, Acerta, TG Therapeutics: Consultancy.

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NT-Probnp As Personalized Medicine Tool and New Biomarker Predicting Response to Chemotherapy and Survival in AML

Blood ◽

10.1182/blood-2021-149526 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3435-3435

Author(s):

Irene Graf ◽

Georg Greiner ◽

Rodrig Marculescu ◽

Karoline V. Gleixner ◽

Susanne Herndlhofer ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factor ◽

Complete Remission ◽

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

Independent Prognostic Factor ◽

White Blood Count ◽

Advisory Committees ◽

The Impact

Abstract Acute myeloid leukemia (AML) is a hematologic neoplasm resulting from abnormal proliferation and accumulation of clonal myeloid precursor cells. The course and prognosis of AML vary depending on the type of AML, karyotype, and molecular abnormalities. In addition, patient-related factors and comorbidities are of prognostic relevance. Cardiac comorbidities are of particular importance as they influence treatment tolerability, early death (ED) and survival in patients receiving chemotherapy. Brain natriuretic peptide (NT-proBNP) is a well-established marker of cardiac function and often used to predict treatment tolerability and outcome. However, so far, little is known about the impact of NT-proBNP levels on the clinical course in patients with AML. We analyzed 312 AML patients (median age: 61 years; range 17-89 years; <60 years: n=141, ≥60 years: n=171; f:m-ratio: 1:1.15; observation period: February 1998 - September 2020) treated with a daunorubicin (day 1-3) and ARA-C (day 1-7)-based induction therapy and consolidation with up to 4 cycles of intermediate-dose (2x1g/m² for 3 day) or high-dose (2x3g/m² for 3 days) ARA-C. In 199 patients (63.8%), elevated NT-proBNP levels were detected, and in 113 (36.2%), NT-proBNP levels were within normal range (0-125 pg/mL). In 20 patients (6.4%) NT-proBNP exceeded 2000 pg/mL. NT-proBNP levels differed significantly between patients aged <60 years (median: 146.7 pg/mL; range: 0.5-15930 pg/mL) and patients ≥60 years (median: 226 pg/mL; range 1-19883 mg/dL; p=0.003). A weak correlation was observed between NT-proBNP levels and other clinical or laboratory parameters like age (R=0.183; p=0.001), lactate dehydrogenase (LDH; R=0.242; p<0.001) and serum creatinine levels (R=0.256; p<0.001). Applying the Charlson comorbidity index (CCI), patients without comorbidities (n=60) had the lowest median NT-proBNP levels followed by those with moderate (n=79), intermediate (n=95), and high-risk comorbidities (n=56) (139.3 pg/mL, 156.0 pg/mL, 199.5 pg/mL, and 307.7 pg/mL, respectively; p=0.028). The Eastern Cooperative Oncology Group (ECOG) performance status was available in 176 patients. Those with ECOG 1 had a significantly higher median NT-proBNP (225.1 pg/mL, range: 0.5-5369 pg/mL) compared to patients with ECOG 0 (133.6 pg/mL, range: 1-15930 pg/mL) (p=0.008). Following induction therapy, 219 patients (70.2%) achieved complete remission (CR), 63 (20.2%) had no remission (NR), and 30 (9.6%) died within 60 days after chemotherapy (ED). Median NT-proBNP levels differed significantly among CR, NR and ED patients, with 153.3, 225.9, and 735.5 pg/mL, respectively (p<0.0001) (Figure 1). The difference in NT-proBNP levels among CR, NR and ED patients was significant in patients aged <60 years and in those aged ≥60 years (p=0.004 and p=0.001, respectively). In multivariate analysis including NT-proBNP together with age, sex, the ELN-2009 classification, white blood count (WBC) and CCI, NT-proBNP remained an independent prognostic factor for treatment response (CR, NR, or ED; p<0.001). In this analysis, age and the ELN-2009 classification were also independent prognostic markers (p=0.014 and p<0.001 respectively). The median overall survival (OS) was 1.38 years (IQR 0.96-1.84) in the total cohort of patients. Significant differences in OS were observed when comparing patients with normal (>125 pg/mL), moderately elevated (125-2000 pg/mL), and highly elevated NT-proBNP levels (p=0.0002). The median OS in these groups was 3.08 (IQR 0.8-16.5), 1.14 (IQR 0.5-4.8), and 0.34 (IQR 0.04-3.7) years, respectively (Figure 2). In multivariate analysis including NT-proBNP, age, ELN-2009 classification, WBC, sex, and CCI, NT-proBNP remained an independent predictive variable for OS (p=0.006). Significant differences were also observed when analyzing OS in patients <60 years (p=0.012) but were not seen in those aged ≥60 years (p=0.203). Similar results were obtained for continuous complete remission (CCR) (median CCR of all patients: 1.6 years), where NT-proBNP was of prognostic significance in the cohort aged <60 years (p=0.011) but not in patients aged ≥60 years. Together, NT-proBNP is a new emerging biomarker and independent prognostic factor indicating the risk of induction failure, ED and reduced survival in patients with AML. The predictive power of NT-proBNP is particularly strong in AML patients aged <60 years. Figure 1 Figure 1. Disclosures Gleixner: Novartis: Honoraria; BMS: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Abbvie: Honoraria. Knoebl: Ablynx/Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire/Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Jaeger: Norvartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hoermann: Novartis: Honoraria. Valent: Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; OAP Orphan Pharmaceuticals: Honoraria. Sperr: AbbVie, BMS-Celgene, Daiichi Sankyo, Deciphera, Incyte, Jazz, Novartis, Pfizer, StemLine, Thermo Fisher: Honoraria, Research Funding.

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Biologic Basis of the Impact of Autologous Hematopoietic Cell Transplantation in Multiple Myeloma Treated with Quadruplet Therapy

Blood ◽

10.1182/blood-2021-145533 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 483-483

Author(s):

Susan Bal ◽

Saurabh Chhabra ◽

Natalie S. Callander ◽

Eva Medvedova ◽

Bhagirathbhai Dholaria ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Advisory Committees ◽

Post Induction ◽

The Impact ◽

Autologous Hematopoietic Cell Transplantation

Abstract Background Unprecedented depth of response is observed with quadruplet combinations in newly diagnosed multiple myeloma (NDMM). The incremental benefit of autologous hematopoietic cell transplantation (AHCT) in this setting has not be described and can be appraised with the serial assessment of minimal residual disease (MRD). Here we describe the impact of AHCT on MM burden assessed by next generation sequencing (NGS) for patients enrolled in the MASTER trial. Methods MASTER is a prospective, multi-center clinical trial utilizing daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd) induction, AHCT (Melphalan conditioning), followed by MRD response-adapted Dara-KRd consolidation with planned enrichment for patients with high-risk chromosome abnormalities (HRCA). MRD assessment is performed by NGS (ClonoSEQ® platform) upon completion of induction therapy with 4 cycles of Dara-KRd, 60-80 days after AHCT and after each 4 cycle-block of consolidation, where applicable. Patients with confirmed MRD negativity (MRD<10 -5 in two consecutive time points) enter treatment free observation and active surveillance of MRD resurgence ("MRD-SURE"). The primary endpoint of the study is negativity utilizing IMWG criteria (MRD<10 −5). Achievement of MRD <10 −6 is an exploratory endpoint. Patients are categorized as having 0, 1, 2+ HRCA [gain 1q, t(4;14), t(14;16), t(14;20), del(17p)]. We describe changes in MRD burden with AHCT and explore patient and disease features influencing magnitude of MRD reduction with AHCT. Results Between 3/2018 and 9/2020, 123 participants were accrued. Of those, 118 were MRD evaluable and 109 have NGS-MRD post-induction and post AHCT and are included in this analysis. The median age is 61 y (35-79) and 18% are 70 or older. Twenty-four percent of patients are non-white, 20% have ECOG 2, 19% high LDH, and 19% R-ISS3. Forty seven (43%) have 0 HRCA, 41 (38%) have 1 HRCA, and 21 (19%) with 2+ HRCA (ultra-HR MM). Forty percent achieved MRD negativity after four cycles of Dara-KRd induction, increasing to 69% after AHCT. Twenty-six percent patients were MRD<10 -6 post induction, increasing to 51% post-AHCT (Table). Of the 65 patients (60%) who remained MRD positive post-induction, 54 (83%) had a reduction in MRD burden with AHCT (figure). The median reduction in MRD with auto-HCT was 1.10 log 10 (range -1.26 to 3.41). Patients with HRCAs had a greater reduction in MRD burden (P=0.02). For patients with 0, 1 and 2+ HRCA, median reduction was 0.91 log 10 (range -0.75 to 2.14), 1.26 log 10 (range -0.21to 3.26) and 1.34 log 10 (range -1.28 to 3.41),respectively. More than 1 log 10 reduction in MRD was seen in 56.0% of patients, 43%, 74% and 71% of patients with 0, 1 and 2+ HRCA respectively. Greater than 2 log reductions in MRD was seen in 20% of patients, 11%, 17% and 43% of patients with 0, 1 and 2 HRCA, respectively. In multivariable analysis that included age, stage, performance status and treatment response post induction, the presence of HRCA was the only factor associated with greater than 1 log 10 reduction in MRD burden with AHCT (OR 3.6, 95% CI 1.27-10.2, P=0.016). Conclusions An ultrasensitive quantitative MRD assay using NGS demonstrates the incremental benefit of AHCT in the context of highly efficacious quadruplet induction. The greatest impact is afforded to the highest risk disease subset elucidating the biologic underpinnings of the impact of AHCT in MM. At this time, AHCT should remain an integral part of therapy for fit, NDMM patients, particularly those with the high-risk disease and those who remain MRD positive after induction. Future studies exploring AHCT deferral in NDMM should be focused on patients who are MRD negative post optimal induction. Figure 1 Figure 1. Disclosures Chhabra: GSK: Honoraria. Dholaria: Angiocrine: Research Funding; MEI: Research Funding; Pfizer: Research Funding; Jazz: Speakers Bureau; Takeda: Research Funding; Poseida: Research Funding; Janssen: Research Funding; Celgene: Speakers Bureau. Silbermann: Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding. Giri: PackHealth: Research Funding; CareVive: Honoraria, Research Funding. Hari: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Consultancy; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau. Costa: Karyopharm: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria.

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Impact of Modified Thalidomide Dosing in Bortezomib/Thalidomide/Dexamethasone for Patients with Newly Diagnosed Multiple Myeloma Who Are Transplant-Eligible: A Matching-Adjusted Indirect Comparison

Blood ◽

10.1182/blood-2019-122775 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4739-4739

Author(s):

Pieter Sonneveld ◽

Maria-Victoria Mateos ◽

Adrián Alegre ◽

Thierry Facon ◽

Cyrille Hulin ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Board Of Directors ◽

Research Funding ◽

Indirect Comparison ◽

Employment Equity ◽

Advisory Committees ◽

Post Transplant ◽

Post Induction ◽

Adjusted Indirect Comparison ◽

Equity Ownership

Introduction: For patients with newly diagnosed multiple myeloma (NDMM) who are transplant-eligible, bortezomib/thalidomide/dexamethasone (VTd) is a standard of care (SoC) for induction and consolidation therapy. Clinical practice has evolved to use a modified VTd dose (VTd-mod; 100 mg thalidomide daily), which is reflected in recent treatment guidelines. As VTd-mod has become a real-world SoC, a matching-adjusted indirect comparison (MAIC) of the VTd-mod dose from recent clinical trials versus the dose included in the label (VTd-label; ramp up to 200 mg thalidomide daily) was performed to understand the effect on efficacy of modified VTd dosing for patients with NDMM who are transplant-eligible. Methods: For each outcome (overall survival [OS], progression-free survival [PFS], overall response rates [ORR] post-induction and post-transplant, and rate of peripheral neuropathy), a naïve comparison and a MAIC were performed. Data for VTd-label were obtained from the phase 3 PETHEMA/GEM study (Rosiñol L, et al. Blood. 2012;120[8]:1589-1596). Data for VTd-mod were pooled from the phase 3 CASSIOPEIA study (Moreau P, et al. Lancet. 2019;394[10192]:29-38) and the phase 2 NCT00531453 study (Ludwig H, et al. J Clin Oncol. 2013;31[2]:247-255). Patient-level data for PETHEMA/GEM and CASSIOPEIA were used to generate outcomes of interest and were validated against their respective clinical study reports; aggregate data for NCT00531453 were extracted from the primary publication. Matched baseline characteristics were age, sex, ECOG performance status, myeloma type, International Staging System (ISS) stage, baseline creatinine clearance, hemoglobin level, and platelet count. Results: Patients received VTd-mod (n = 591) or VTd-label (n = 130). After matching, baseline characteristics were similar across groups. For OS, the naïve comparison and the MAIC showed that VTd-mod was non-inferior to VTd-label (MAIC HR, 0.640 [95% CI: 0.363-1.129], P = 0.121; Figure 1A). VTd-mod significantly improved PFS versus VTd-label in the naïve comparison and MAIC (MAIC HR, 0.672 [95% CI: 0.467-0.966], P = 0.031; Figure 1B). Post-induction ORR was non-inferior for VTd-mod versus VTd-label (MAIC odds ratio, 1.781 [95% CI: 1.004-3.16], P = 0.065). Post-transplant, VTd-mod demonstrated superior ORR in both the naïve comparison and MAIC (MAIC odds ratio, 2.661 [95% CI: 1.579-4.484], P = 0.001). For rates of grade 3 or 4 peripheral neuropathy, the naïve comparison and MAIC both demonstrated that VTd-mod was non-inferior to VTd-label (MAIC rate difference, 2.4 [⁻1.7-6.49], P = 0.409). Conclusions: As naïve, indirect comparisons are prone to bias due to patient heterogeneity between studies, a MAIC can provide useful insights for clinicians and reimbursement decision-makers regarding the relative efficacy and safety of different treatments. In this MAIC, non-inferiority of VTd-mod versus VTd-label was demonstrated for OS, post-induction ORR, and peripheral neuropathy. This analysis also showed that VTd-mod significantly improved PFS and ORR post-transplant compared with VTd-label for patients with NDMM who are transplant-eligible. A limitation of this analysis is that unreported or unobserved confounding factors could not be adjusted for. Disclosures Sonneveld: Takeda: Honoraria, Research Funding; SkylineDx: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding. Mateos:Janssen, Celgene, Takeda, Amgen, Adaptive: Honoraria; AbbVie Inc, Amgen Inc, Celgene Corporation, Genentech, GlaxoSmithKline, Janssen Biotech Inc, Mundipharma EDO, PharmaMar, Roche Laboratories Inc, Takeda Oncology: Other: Advisory Committee; Janssen, Celgene, Takeda, Amgen, GSK, Abbvie, EDO, Pharmar: Membership on an entity's Board of Directors or advisory committees; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Takeda Oncology.: Speakers Bureau; Amgen Inc, Janssen Biotech Inc: Other: Data and Monitoring Committee. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. Facon:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Hashim:Ingress-Health: Employment. Vincken:Janssen: Employment, Equity Ownership. Kampfenkel:Janssen: Employment, Equity Ownership. Cote:Janssen: Employment, Equity Ownership. Moreau:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

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Impact of DNMT3a Status on Post Induction NPM1 MRD Predictive Value on Survival in Elderly AML Patients Treated Intensively

Blood ◽

10.1182/blood-2020-141890 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 7-8

Author(s):

Maël Heiblig ◽

Hélène Labussière ◽

Marie Virginie Larcher ◽

Gaelle Fossard ◽

Marie Balsat ◽

...

Keyword(s):

Elderly Patients ◽

Board Of Directors ◽

Predictive Value ◽

Scoring System ◽

Research Funding ◽

Risk Group ◽

Advisory Committees ◽

Post Induction ◽

Mutational Status ◽

Elderly Aml

Minimal residual disease is now a powerfull surrogate marker to assess response to chemotherapy in acute myeloid leukemia (AML). In younger adults, NPM1 MRD has recently demonstrated to be a favorable predictive marker for EFS and OS independently of fms-like tyrosine kinase-3 internal tandem duplications (FLT3-ITD) status. However, there is very few datas regarding predictive value of NPM1 MRD in elderly patients treated with intensive chemotherapy. Moreover, numerous studies have suggested the negative impact of DNMT3a mutation in NPM1 AML patients, especially in those with concurrent FLT3-ITD mutation. In this study, we aimed to investigate the impact of DNMT3a status on post induction NPM1 MRD1 predictive value for survival in a retrospective cohort of AML patients aged over 60 years old treated intensively. A total of 138 patients treated for NPM1 mutated AML in two French institutions (Lyon, Lille) were analyzed retrospectively. Median age of the entire cohort was 66.1 years old (range 60-78.2). An FLT3-ITD mutation was evidenced in 52 of 138 patients (37.6%) with a median FLT3-ITD AR of 0.53 (range, 0.05-3). With a median follow-up of 19.61 months (0.07-128.4), the overall CR rate was 89.9% with no influence of DNMT3a or FLT3 mutational status on the probability of CR. In this elderly cohort of NPM1mut patients, a 4log reduction of NPM1 bone marrow (BM) MRD1 was associated with better outcome (median OS: NR vs 13.4 months, HR=0.35, p<0.01)(Figure A). Overall, DNMT3 status did not influence the probability of having a ≥ 4log MRD1 reduction after induction. However, only 9/44 (20.4%) FLT3-ITD patients reached ≥ 4log MRD1 reduction whereas 38/80 FLT3wt (47.5%) were good molecular responders (p<0.001). FLT3-ITD mutated patients who achieved a 4log reduction had a superior outcome compared to those who did not (HR=0.34; 95% CI, 0.16 to 0.70; P <0.001). Similarly, NPM1mut FLT3wt patients with a 4log reduction in NPM1 BM-MRD1 had a longer OS (3-year OS, 68.1%; 95% CI, 48.8 to 82.9) than those without good molecular response (3-year OS, 46.5%; 95% CI, 30.2 to 61.7)(Figure B). DNMT3a negative patients who achieved a 4log reduction had a superior outcome to those who did not reached at least a 4log reduction (HR=0.23; 95% CI, 0.07 to 0.72; P <0.001). However, postinduction NPM1 MRD1 reduction was not predictive of OS and leukemia free survival (LFS) in DNMT3amut patients. DNMT3amut patients has a very poor LFS which was even worst in poor NPM1 MRD1 responders compared to those who reached at least 4log reduction (median LFS: 8.3 months vs 17.4 months, HR = 0.48, 95% CI, 0.25-0.91, p=0.023)(Figure C). In multivariate analysis, only DNMT3a mutational status and a 4-log reduction in NPM1 BM-MRD were significantly associated with survival. Based on these results, we identified among NPM1 positive patients 3 groups with distinct prognosis, based on FLT3-ITD, DNMT3a status and NPM1 BM-MRD post induction response (NPM1 scoring system)(Figure D). When compared to ELN 2017 intermediate risk group (AUC=0.695), NPM1 scoring system (NPM1 SS) was more accurate for OS prediction in patients within intermediate (AUC=0.833) and unfavorable (AUC=0.863) NPM1 SS risk group. However, there was no significant difference in AUC between NPM1 SS favorable and ELN 2017 favorable risk group. These results confirm that post-induction NPM1 MRD1 is a reliable tool to assess disease outcome in elderly AML patients. However, the presence of DNMT3a also identify a subgroup of patients at very high risk of relapase, despite good molecular responses. As hematopoietic stem cell transplantation (HSCT) might improve OS in elderly patients, DNMT3a positive AML elderly patients should be considered for HSCT or post induction maintenance strategies, even within the favorable ELN risk group. Figure Disclosures Sujobert: Gilead/Kyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding.

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Early Death in Patients with Disseminated Intravascular Coagulation during Induction Therapy for Acute Promyelocytic Leukemia: A Nationwide Analysis

Blood ◽

10.1182/blood-2020-134554 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 31-31

Author(s):

Kensuke Matsuda ◽

Taisuke Jo ◽

Kazuhiro Toyama ◽

Kumi Nakazaki ◽

Hideo Yasunaga ◽

...

Keyword(s):

Elderly Patients ◽

Hospital Mortality ◽

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

Promyelocytic Leukemia ◽

Hospital Death ◽

Conventional Chemotherapy ◽

Advisory Committees ◽

Soluble Thrombomodulin

Background: Real-world data studies showed poorer outcomes in patients with acute promyelocytic leukemia (APL) than randomized controlled trials, because elderly patients were excluded in such trials. Reportedly, the main cause of death was severe bleeding due to disseminated intravascular coagulation (DIC) during induction therapy for APL. The management of DIC was therefore crucially important especially in elderly patients. This study aimed to clarify factors associated with in-hospital death in all patients, and elderly patients with DIC during induction therapy for APL. Study Design and Methods: We retrospectively identified 1,463 patients with newly diagnosed APL who received induction therapy including all-trans retinoic acid (ATRA) between July 2007 and March 2018 from a nationwide inpatient database in Japan. In-hospital death was evaluated with multivariable logistic regression models in all patients, and in ≥60 year-old patients. Anticoagulants included recombinant human soluble thrombomodulin, delteparin (low molecular weight heparin), danaparoid sodium, gabexate mesilate, and nafamostat mesilate which were administered within three days from admission. Patients who died within three days from the admission were excluded from the study to avoid immortal time bias. Results: We identified a total of 1,138 (78%) patients who developed DIC. We excluded 23 patients who died within three days from the admission. The remaining 1,115 patients were analyzed. During hospitalization, 172 (15%) patients died at a median of 13 days (interquartile range: 7-30). Compared with younger patients (20 to 39 years old), elderly patients were significantly associated with higher in-hospital mortality (60 to 79 years old: odds ratio 5.58 [95% confidence interval 3.05-10.22], 80 years or older: 13.51 [6.07-30.08]). Patients who received ATRA monotherapy had significantly higher incidence of in-hospital death (2.48 [1.54-4.01]). Delayed initiation of ATRA was significantly associated with higher mortality (1.60 [1.11-2.30]). A total of 699 patients (63%) received anticoagulant therapies, but none of these were significantly associated with lower mortality. Use of multiple anticoagulants was significantly associated with higher in-hospital mortality (2.47 [1.16-5.26]). Subgroup analyses in patients ≥60 years old were then conducted. During hospitalization, 122 of 416 (29%) patients died at a median of 13 days (interquartile range: 7-29). Both late initiation of conventional chemotherapy and no conventional chemotherapy were significantly associated with higher in-hospital mortality (1.88 [1.01-3.49], 3.25 [1.74-6.06], respectively). Use of recombinant human soluble thrombomodulin and use of multiple anticoagulants were significantly associated with higher mortality (1.91 [1.09-3.35], 2.64 [1.01-6.90], respectively). Conclusions: Elderly patients who developed DIC during induction therapy for APL were significantly associated with higher in-hospital mortality. Immediate initiation of ATRA and early initiation of conventional chemotherapy may have contributed to preferable outcomes. Disclosures Matsuda: Kyowa Kirin: Speakers Bureau. Jo:Tsumura: Other: Belongs to joint program with Tsumura, Research Funding. Toyama:Bristol-Myers Squibb: Speakers Bureau; Eisai: Speakers Bureau; Kyowa Kirin: Speakers Bureau; Celgene: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Chugai Pharmaceutical,: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau; Otsuka Pharmaceutical: Speakers Bureau; Takeda Pharmaceutical: Speakers Bureau. Kurokawa:Ono: Research Funding, Speakers Bureau; Jansen Pharmaceutical: Speakers Bureau; Teijin: Research Funding; Eisai: Research Funding, Speakers Bureau; Shire Plc: Speakers Bureau; Nippon Shinyaku: Research Funding, Speakers Bureau; MSD: Consultancy, Research Funding, Speakers Bureau; Chugai: Consultancy, Research Funding, Speakers Bureau; Sanwa-Kagaku: Consultancy; Pfizer: Research Funding; Otsuka: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Bioverativ Japan: Consultancy; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sumitomo Dainippon Pharma: Research Funding, Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau.

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Increased Idarubicin Dosage during Consolidation Therapy for Adult Acute Myeloid Leukemia Improves Leukemia-Free Survival

Blood ◽

10.1182/blood.v128.22.338.338 ◽

2016 ◽

Vol 128 (22) ◽

pp. 338-338

Author(s):

Bradstock Kenneth ◽

Emma Link ◽

Juliana Di Iulio ◽

Jeff Szer ◽

Paula Marlton ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Board Of Directors ◽

Induction Therapy ◽

Myeloid Leukemia ◽

Research Funding ◽

Consolidation Therapy ◽

Advisory Committees ◽

Free Survival ◽

Acute Myeloid

Abstract Background: Anthracylines are one of the major classes of drugs active against acute myeloid leukemia (AML). Increased doses of daunorubicin during induction therapy for AML have been shown to improve remission rates and survival. The ALLG used idarubicin in induction therapy at a dose of 9 mg/m2 x 3 days (total dose 27 mg/m2) in combination with high-dose cytarabine and etoposide (Blood 2005, 105:481), but showed that a total idarubicin dose of 36 mg/m2 was too toxic in this context (Leukemia 2001, 15:1331). In order to further improve outcomes in adult AML by anthracycline dose escalation, we conducted a phase 3 trial comparing standard to an increased idarubicin dose during consolidation therapy. Methods: Patients achieving complete remission after 1 or 2 cycles of intensive induction therapy (idarubicin 9 mg/m2 daily x3, cytarabine 3 g/m2 twice daily on days 1,3,5 and 7, and etoposide 75 mg/m2 daily x7; ICE protocol) were randomized to receive 2 cycles of consolidation therapy with cytarabine 100 mg/m2 per day for 5 days, etoposide 75 mg/m2 for 5 days, and idarubicin 9mg/m2 daily for either 2 or 3 days (standard and intensive arms respectively). No further protocol therapy was given. The primary endpoint was leukemia-free survival from randomization to consolidation therapy (LFS) with overall survival (OS) as secondary endpoint. Results: A total of 422 patients with AML (excluding cases with CBF rearrangements or APL) aged 16 to 60 years were enrolled between 2003-10, with 345 (82%) achieving complete remission, and 293 being randomized to standard (n=146) or intensive (n=147) consolidation arms. The median age was 45 years in both arms (range 16- 60), and both groups were balanced for intermediate versus unfavorable karyotypes and for frequency of mutations involving FLT3-ITD and NPM1 genes. Of the randomized patients, 120 in the standard arm (82%) and 95 in the intensive arm (65%) received the second consolidation cycle (p<0.001). The median total dose of idarubicin received in the 2 consolidation courses was 36 mg/m2 (range 17-45), or 99% (47-125%) of the protocol dose in the standard arm, versus 53 mg/m2 (18-73), or 98% (33-136%) of the protocol dose in the intensive arm. The durations of grades 3-4 neutropenia and thrombocytopenia were significantly longer in the intensive arm, but there were no differences in grade 3 or 4 non-hematological toxicities. There were no non-relapse deaths during consolidation on the standard arm and 2 in the intensive (0% vs 1%; p =0.50). Subsequently, 41 patients in the standard arm and 37 in the intensive arm underwent elective allogeneic BMT during first remission. On intention to-treat analysis uncensored for transplant and with a median follow-up time of 5.3 years (range 0.6 - 9.9), there was improvement in LFS in the intensive arm compared with the standard arm (3 year LFS 47% (95% CI 40-56%) versus 35% (28-44%); HR 0.74 (95% CI 0.55-0.99); p=0.045) (Figure 1). The 3 year OS for the intensive arm was 61% (95% CI 54-70%) and 50% (95% CI 43-59%) for the standard arm; HR 0.75 (95% CI 0.54-1.05); p=0.092). Although adverse cytogenetics, presence of FLT3-ITD mutation, and absence of NPM1 mutation were all associated with poorer outcomes, there was no evidence of a benefit of intensive consolidation being confined to specific cytogenetic or gene mutation sub-groups. Conclusion: We conclude that in adult patients in complete remission after intensive induction chemotherapy an increased dose of idarubicin delivered during consolidation therapy results in improved LFS, without increased non-hematologic toxicity. Figure 1. Figure 1. Disclosures Szer: Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees. Marlton:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wei:Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; CTI: Consultancy, Honoraria; Abbvie: Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Cartwright:ROCHE: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roberts:Servier: Research Funding; Janssen: Research Funding; Genentech: Research Funding; AbbVie: Research Funding. Mills:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Meeting attendance sponsorship. Gill:Janssen: Membership on an entity's Board of Directors or advisory committees. Seymour:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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