scholarly journals Conversion from MRD Positive to Negative Status in AML Patients in CR1 after Treatment with an Allogeneic Leukemia-Derived Dendritic Cell Vaccine

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-14
Author(s):  
Arjan van de Loosdrecht ◽  
Janine van Elssen ◽  
Bjørn Tore Gjertsen ◽  
Eva Maria Wagner ◽  
Tobias Holderried ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Immune Response ◽  
Dendritic Cell ◽  
Complete Remission ◽  
Immune Responses ◽  
Board Of Directors ◽  
Research Funding ◽  
Dendritic Cell Vaccine ◽  
Cell Vaccine ◽  
Advisory Committees

Background. Persistence of measurable residual disease (MRD) in patients with acute myeloid leukemia (AML) remains a poor prognostic factor and unmet medical need. The allogeneic leukemia-derived dendritic cell vaccine, DCP-001, has shown in a phase I study to generate both humoral and cellular immune responses and is safe for clinical practice (van de Loosdrecht et al., Cancer Immunol. Immunother. 2018). In the current phase II study (Clintrials.gov: NCT03697707) we show the capability of DCP-001 to convert MRD positive patients to negative, leading to deeper remissions. Additionally, it is shown that DCP-001 induces immune responses, also specifically against tumor associated antigens known to be present in DCP-001 and relevant for AML. Methods. The current trial aims to enroll up to 20 AML -patients, ineligible for HSCT, who are in in first complete remission (CR1) but who are still MRD positive. MRD is assessed in the bone marrow through flow cytometry and/or qPCR (eg NPM1). Patients receive a primary vaccination regimen of 4 times 25.106or 50.106cells per vaccination, biweekly, followed by two booster vaccinations (10.106cells/vaccination) at week 14 and 18 after start of treatment. Primary endpoints of this trial are the safety and tolerability of the two vaccination schedules and the effect of vaccination on the MRD status. Additionally, cellular and humoral immune response induced by DCP-001 are evaluated in peripheral blood using several assay methods, including flow cytometry and IFN-ϒ ELISpot against known TAA's such as WT-1, RHAMM and PRAME. Results. Up to 15 July 2020, ten patients (age 41-76; 5 male, 5 female) have been enrolled and dosed within the study, completing the first dose cohort of 25.106cells/vaccination. All vaccinations were well tolerated and adverse events to the vaccine were limited to local injection site reactions such as redness, swelling and warmth (maximum grade 2). Three of the ten patient relapsed before the vaccination schedule was completed. Four patients could be evaluated for MRD; Two patients became MRD negative at the first timepoint after the initial vaccinations (week 14), and remained negative until end of active FU (week 32), two other patients remained in CR, but with MRD positivity. For the remaining three patients, to date, no MRD outcome is available yet but patients remain in CR (see swimmers plot for overview, Figure 1). Evaluation of the immune response before, during and after DCP-001 vaccination has only be performed in a small subset of three patients thus far. Of these patients one showed a clinical response becoming MRD negative after vaccination. In this patient we observed an increase in tumor specific functional T-cells assessed by IFNγ ELISPOT, either as a recall or primary response, as shown by the response observed to WT-1 (see for example Figure 2). These tumor associated antigens are known to be expressed by DCP-001 and included WT1, PRAME and RHAMM. Induction of specific memory CD8 and CD4 cells could be observed upon vaccination which might be related to the clinical response. Conclusion/discussion.Preliminary data from this ongoing study confirms that vaccination with DCP-001 is able to generate a tumor-specific immune response and may lead to potential tumor control. Two patients were actually converted from being MRD positive at start of vaccination to MRD negative during the study. These patients continue to be in complete remission for at least a year after vaccination. This study continues to enroll patients at a higher vaccine dose of 50.106cells per vaccination and additional data on induced immune responses and MRD status will be shown. Disclosures van de Loosdrecht: novartis: Honoraria; celgene: Honoraria. Wagner:Novartis: Membership on an entity's Board of Directors or advisory committees; Shire: Other: Travel grand; MSD: Membership on an entity's Board of Directors or advisory committees; Medac: Other: Travel grand; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees. Platzbecker:Amgen: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria. Rovers:DCprime: Current Employment.

scholarly journals Treatment with an Allogeneic Leukemia-Derived Dendritic Cell Vaccine in AML Patients Shows MRD Conversion and Improved Survival

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1274-1274
Author(s):  
Arjan A. Van de Loosdrecht ◽  
Jacqueline Cloos ◽  
Eva Maria Wagner ◽  
Uwe Platzbecker ◽  
Tobias A. W. Holderried ◽  
...  
Keyword(s):  
Overall Survival ◽  
Complete Remission ◽  
Board Of Directors ◽  
Research Funding ◽  
Residual Disease ◽  
Dendritic Cell Vaccine ◽  
Cell Vaccine ◽  
Advisory Committees ◽  
Dose Cohort ◽  
Intradermal Administration

Abstract Background. Persistence of measurable residual disease (MRD) is a poor prognostic factor and predicts relapse in acute myeloid leukemia (AML). In a phase I study, the allogeneic leukemia-derived dendritic cell vaccine, DCP-001, has shown safety and humoral and cellular immune responses (A.A. van de Loosdrecht, et al. Cancer Immunol. Immunother. 2018;67:1505). In the current phase II study, (Clintrials.gov: NCT03697707) we report on progress and evaluation of MRD conversion, as primary endpoint, relapse free and overall survival. Methods. AML-patients, ineligible at screening for HSCT, who are in first complete remission (CR1) but with MRD receive 4 biweekly doses of 25e6 or 50e6 cells per vaccination (cells/vc) followed by 2 doses of 10e6 cells/vc as boosts at week 14 and 18. MRD is assessed at 4 timepoints (baseline, week 14, 20 and 32) by flow cytometry and/or molecular analyses. Primary endpoints are the effect of vaccination on MRD status and safety and tolerability of the two vaccination schedules. Secondary endpoints include relapse free, overall survival and immunological response evaluation. Results. As of 28 th July 2021, 19 patients have been enrolled, of which 10 patients have been given at least 4 vaccinations with 25e6 cells/vc and 9 with 50e6 cells/vc. No serious adverse events (AE) or severe AE (grade 3 or higher) related to DCP-001 have been reported. AE's related to DCP-001 are mainly injection site reactions, occurring within 48 hours after intradermal administration. In the 25e6 cells/vc cohort all patients have completed the treatment phase up to week 32, allowing full assessment of MRD response. Three patients have converted to MRD negative, 4 patients relapsed (followed by HSCT for 1 patient), 3 patients remained MRD positive, of which 2 patients underwent HSCT immediately after completion of the full dosing schedule. In this cohort 2 patients eventually died during follow up. Treatment is still ongoing in the 50e6 dose cohort, with thus far one additional MRD conversion reported and two relapses, 3 patients with stable MRD levels, and 3 have no MRD data available yet. Median follow-up of patients in the 25e6 cells/vc cohort was 288 days (range 148 - 546). Median RFS and OS have not yet been reached, but estimated RFS and OS at 12 months is calculated at 57% and 79%, respectively (Figure 1). MRD converted patients after DCP-001 vaccination, showed improved survival, compared to patients without MRD conversion (Figure 2). All 4 patients who converted to MRD negative are still in CR and alive (FU median 423.5 days (range 140 - 546). Immunological monitoring of patients is currently being performed. As previously reported (abstract #168, ASH2020), 3 of 4 evaluable patients show at least 1 or more responses against tumor-associated antigens known to be present in DCP-001 in IFNy ELISPOT assay. Conclusion/discussion. Four patients have shown MRD conversion (3 in the 25e6 dose cohort, and 1 in the 50e6 dose cohort). Six patients remained in complete remission with stable or declining levels of MRD, 6 patients relapsed and for 3 patients no MRD data is available yet. Median RFS and OS have not yet been reached. MRD conversion showed improved relapse free and overall survival. Treatment with DCP-001 is very well tolerated, with limited side effects mainly related to intradermal administration. Immunological analyses for specific tumor-associated antigen responses and general immune profiling are currently being performed. Preliminary data from this study shows that the relapse vaccine DCP-001 is a promising treatment for patients with AML in complete remission but with residual disease aiming to deepen responses and prolong survival. Its excellent safety profile allows for future combination therapy. Figure 1 Figure 1. Disclosures Van de Loosdrecht: Novartis: Consultancy; Alexion: Consultancy; Roche: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Research Funding. Cloos: Takeda: Research Funding; Novartis: Consultancy, Other, Research Funding; Navigate: Patents & Royalties; Merus: Other, Research Funding; Janssen: Research Funding; Helsinn: Other; Genentech: Research Funding; DC-One: Other, Research Funding; Astellas: Speakers Bureau. Platzbecker: AbbVie: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Celgene/BMS: Honoraria; Geron: Honoraria; Takeda: Honoraria. Holderried: Gilead Sciences: 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; Amgen: Speakers Bureau; MSD: Speakers Bureau; GSK: 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; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Therakos: Other: Travel support; Abbvie: Other: Travel support; Medac: Other: Travel support; Eurocept Pharmaceuticals: Other: Travel support; Janssen: Other: Travel support; Daiichi Sankyo: Other: travel support. Giagounidis: Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. van Zeeburg: Immunicum AB: Current Employment; Kiadis: Ended employment in the past 24 months. Rovers: Immunicum AB: Current Employment. Gjertsen: KinN Therapeutics: Current holder of stock options in a privately-held company; Alden Cancer Therapy: Current holder of stock options in a privately-held company; Pfizer Inc.: Consultancy; BerGenBio: Consultancy; Novartis: Consultancy.

Iron Overload Diminishes the Effectiveness of the Innate Immune Response in Thalassemia Major: a Possible Mechanism for Increased Infection Risk.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4071-4071
Author(s):  
Patrick B Walter ◽  
Paul R Harmatz ◽  
Annie Higa ◽  
David Killilea ◽  
Nancy Sweeters ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Immune Response ◽  
Iron Overload ◽  
Board Of Directors ◽  
Innate Immune Response ◽  
Research Funding ◽  
Innate Immune ◽  
Healthy Controls ◽  
Advisory Committees ◽  
Fluorescent Intensity

Abstract Abstract 4071 Poster Board III-1006 Introduction Infection is the second most common cause of death in thalassemia. The innate immune system provides a first line of defense against infection and specificity depends on pattern recognition receptors (PRRs) specific to microbial pathogens. One class of PRR called the toll-like receptors (TLRs) are important for transducing the signal for bacterial Lipopolysaccharide (LPS), resulting not only in cytokine production, but also in the control of extracellular iron levels through production of neutrophil gelatinase associated Lipocalin (NGAL). However, the exact role that NGAL plays and the expression level of PRRs are unknown in thalassemia. Thus, the goal in these studies is to investigate the relationship of iron overload to the innate immune cell expression of PRRs and NGAL in thalassemia. Patients and Methods Fifteen transfusion dependent thalassemia patients (11 – 29 yrs old) participating in the combination trial of deferasirox (an oral iron chelator) and deferoxamine were enrolled (Novartis sponsored CICL670AUS24T). Fasting blood samples were obtained i) at baseline after a 72 hr washout of chelator, and ii) at 6 and 12 months on study. Five healthy controls (13 - 18 yrs old) were also enrolled. Fresh monocytes were isolated using antibody-linked magnetic microbeads (Miltenyi Biotec Inc). Highly enriched populations of CD14+ monocytes were verified by flow cytometry. The expression of TLR4, also examined by flow cytometry is reported as the mean fluorescent intensity (MFI). In patients with thalassemia, liver iron concentration (LIC) was analyzed by biomagnetic susceptibility (“SQUID”, Ferritometer®). The plasma levels of NGAL were analyzed by ELISA. Results At baseline the expression of monocyte TLR4 (mean 18.8 ± 3.5 MFI) was reduced 30% compared to the healthy controls (mean 26.9 ± 7.6 MFI, p<0.05). The expression of TLR4 over the follow-up period of 52 weeks in patients receiving intensive combination chelator therapy significantly increased 27% / year (7 MFI / year, p=0.005). Interestingly the expression of monocyte TLR4 was negatively correlated with LIC (r=-0.6, p=0.04). Finally, thalassemia patients at baseline have significantly higher levels of NGAL (80 ± 20 ng/ml) compared to controls (42 ± 15 ng/ml, p=0.01). Conclusions These preliminary studies support the hypothesis that iron burden has a negative impact on the innate immune response in thalassemia as demonstrated by the decreased expression of TLR4. After intensive chelation, the levels of TLR4 increased, indicating that decreased iron overload with chelation may improve innate immune responsiveness. Finally, the iron transport protein NGAL is significantly elevated in thalassemia possibly acting to prevent essential iron uptake by pathogenic bacteria. Disclosures: Harmatz: Novartis: Research Funding; Apotex : Membership on an entity's Board of Directors or advisory committees; Ferrokin: Membership on an entity's Board of Directors or advisory committees. Vichinsky:Novartis: Consultancy, Research Funding.

scholarly journals Influence of Immunotherapy with Autologous Dendritic Cells on Innate and Adaptive Immune Response in Cancer

2013 ◽  
Vol 7 ◽  
pp. CMO.S12268 ◽  
Author(s):  
Bruna F. Matias ◽  
Tânia M. De Oliveira ◽  
Cláudia M. Rodrigues ◽  
Douglas R. Abdalla ◽  
Letícia Montes ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Immune Response ◽  
Dendritic Cell ◽  
B Lymphocytes ◽  
Dendritic Cell Vaccine ◽  
Cell Vaccine ◽  
Enzyme Linked Immunosorbent Assay ◽  
Autologous Dendritic Cell ◽  
Tnf Α ◽  
Ifn Γ

The objective of this study was to evaluate some of the mechanisms involved in the activation of the immune system in patients with advanced-stage cancer (n = 7) who received an autologous dendritic cell vaccine. We examined the immune response mediated by macrophages (CD14+), natural killer cells (CD56+), and B lymphocytes (CD19+) by flow cytometry and assessed the expression of Th1 (IFN-γ, TNF-α, IL-2, and IL-12), Th2 (IL-4), and Treg (TGF-β) cytokines by flow cytometry and an enzyme-linked immunosorbent assay. The CD14+ TNF-α+ population was significantly increased ( P < 0.04) when patients received the vaccine; IL-2 expression in both NK cells and in B lymphocytes was increased after a transient initial increase showed a nearly significant decrease ( P < 0.07 and P < 0.06 respectively), whereas the CD19+ and CD56+ populations did not show significant changes. Dendritic cell-based immunotherapy led to increased secretion of IFN-γ and IL-12 and reduced secretion of TGF-β. In conclusion, it is likely that the autologous dendritic cell vaccine stimulated the immune cells from the peripheral blood of patients with cancer and generally increased the production of Th1 cytokines, which are related to immunomodulatory responses against cancer.

scholarly journals Durable Responses and Survival in High Risk AML and MDS Patients Treated with an Allogeneic Leukemia-Derived Dendritic Cell Vaccine

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1381-1381 ◽  
Author(s):  
Luca L.G. Janssen ◽  
Theresia M. Westers ◽  
Jeroen Rovers ◽  
Peter Valk ◽  
Jacqueline Cloos ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Dendritic Cell ◽  
High Risk ◽  
Complete Remission ◽  
Research Funding ◽  
Medical Center ◽  
Phase 1 ◽  
Dendritic Cell Vaccine ◽  
Cell Vaccine

Background. Maintenance of induced responses remains a significant unmet medical need in patients with acute myeloid leukemia (AML) or high risk myelodysplastic syndrome (MDS) not eligible for allogeneic hematopoietic stem cell transplantation (HSCT). The allogeneic leukemia-derived dendritic cell vaccine, DCP-001, has shown to generate both humoral and cellular immune responses and is safe for clinical practice (van de Loosdrecht et al., Cancer Immunol. Immunother. 2018). In this study we show additional data on long-term follow up and patient-related risk factors from the phase 1 study. Methods. AML- or MDS-patients (n=12), ineligible for HSCT, were included in a post-hoc clinical analysis of the DCP-001 phase I trial, receiving DCP-001 vaccination at the Amsterdam University Medical Center, VU University Medical Center, Amsterdam, the Netherlands (NCT01373515). All clinical data, including baseline characteristics as cytogenetics, pre-and post-vaccination treatment and morphologic blast counts in follow up, were retrospectively collected from corresponding patient files. Targeted next generation sequencing (NGS) gene panel data and cytogenetics were utilized to determine (cyto-)genetic risks following the European Leukemia Net (ELN) 2017 criteria. We defined 'response' as decreased or stable morphologic blast counts in bone marrow at day 126 (last day of official study evaluation) compared to study entry. Results. Seven out of twelve patients responded to treatment, the other patients showed progressive disease (data are summarized in table 1). The median relapse free survival (RFS) for the responding patients was 420 days (range 90-1849) and overall survival (OS) was 1090 days (90-2160); two patients died early in complete remission (CR) due to infection (respectively at 90 and 184 days). Notably, three of these patients were intermediate risk and four were poor risk patients based on the ELN risk classification for AML or Revised International Prognostic Scoring System (IPSS-R) for MDS. The median OS for the non-responders was 144 days (range 59-209). These five patients had relapsed or refractory disease at start of vaccination with detectable circulating peripheral blasts; four of them received additional azacitidine (AZA) therapy prior to vaccination. Moreover, they were vaccinated after induction and consolidation therapy with a median time between diagnosis and first vaccination of 611 days (219-2310) compared to 240 days (105-1398) for the seven responding patients. Of the latter, all were in complete remission (CR) (n=5) or had morphologic marrow blast counts &lt;10% (n=2) at the start of vaccination. Two responders that progressed and two that relapsed after vaccination were treated with AZA, resulting in one complete remission and two partial responses (one non-evaluable due to sample failure), see figure 1. Conclusion/discussion. Clinical data of the phase 1 trial show that DCP-001 may prolong duration of remission or smoldering disease in intermediate and high risk AML or MDS patients. Response was associated with treatment by vaccination shortly after achieving CR. This should be taken into account in selection criteria of future vaccination studies. Hence, an international multi-center phase 2 study (ADVANCE II; NCT03697707) is currently being conducted to determine the effect of DCP-001 on measurable residual disease (MRD) in AML patients, aiming to convert them to a MRD negative state. Furthermore, we demonstrated that AZA can be applied as rescue therapy upon progression after vaccination. Disclosures Rovers: DCprime: Employment. Cloos:Daiicchi Sankyo: Speakers Bureau; Glycomimetics: Research Funding; Takeda: Research Funding; Novartis: Other: MRD assessments of clinical trials, Research Funding; Merus: Other: MRD assessment of a clinical trial , Research Funding; Genentech: Consultancy, Research Funding; Helsinn: Other: MRD assessment of a clinical trial; DCPrime: Other: MRD assessment of a clinical trial. de Gruijl:DCprime: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Phase I Study of Ixazomib Added to Chemotherapy in the Treatment of Acute Lymphoblastic Leukemia in Older Adults

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 41-42
Author(s):  
Philip C. Amrein ◽  
Karen K. Ballen ◽  
Kristen E. Stevenson ◽  
Traci M. Blonquist ◽  
Andrew M. Brunner ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Advisory Committees ◽  
Survival Estimate ◽  
Grade 3 ◽  
Experienced Grade

Introduction: While progress has been made in the treatment of childhood leukemia, the outlook for patients &gt;60 years of age with acute lymphoblastic leukemia (ALL) is poor with complete remission rates (CR) of approximately 60% and 3-year survivals (OS) of less than 15%. Intensified treatment in a later CALGB trial showed little improvement with a CR=61% and 5-year OS=6% (Stock, Cancer 2013). Ixazomib is an oral proteasome inhibitor, which has shown single agent activity and promising combination activity in pediatric ALL patients (Messinger, Blood 2012). We sought to assess the safety and tolerability, as well as early efficacy of adding ixazomib to a current MGH-DFCI/HCC multi-agent regimen for older adults with ALL. Methods: Patients aged 51 to 75 years of age with newly diagnosed B-ALL and T-ALL were screened for eligibility. Patients with mature ALL (including Burkitt's) were excluded. Patients with Philadelphia chromosome positive ALL (BCR-ABL1+) were eligible, and dasatinib was added to the chemotherapy on Day 10 for these patients. The chemotherapy treatment schedule from induction through maintenance is outlined in Table 1. A standard 3 + 3 patient cohort dose escalation design was used to determine the maximum tolerated dose (MTD) of ixazomib during induction for these patients, the primary objective of the trial. After consolidation I, patients in complete remission (CR) with a suitable donor were offered a hematopoietic stem cell transplantation (HSCT) as per institutional guidelines. Those not going to HSCT continued therapy as noted in the table. Results: There were 19 patients with B-ALL enrolled, none with T-ALL. Among these patients, 7 harbored BCR-ABL1 rearrangements. The median age was 65 years, 74% were male, and 90% had a performance status 0 or 1. The MTD was 2.3 mg of ixazomib, as 2 patients at 3.0 mg developed DLT's: a grade 3 peripheral neuropathy and a grade 5 acute kidney injury (Table 2). Grade 3 and 4 toxicities encountered at any time consisted mainly of grade 4 neutropenia in 13 patients and grade 4 thrombocytopenia in 12 patients. One patient experienced grade 3 neutropenia and 5 patients experienced grade 3 thrombocytopenia. Two patients with grade 2 neuropathy did not meet the definition of DLT. Among the 19 patients, 15 (79%, [95% confidence interval (CI), 54-94%]) achieved CR (14) or CRi (1), and 5 patients went on to HSCT. The median follow-up time was 2 years (range, 1-5) for 8 patients remaining alive. The 1-year overall survival estimate was 53% [95% CI, 29-72%], while the 2-year overall survival estimate was 47% [95% CI, 24-67%]. Conclusions: A dose of 2.3 mg of ixazomib in combination with induction chemotherapy among older patients with ALL was well-tolerated and associated with a promising rate of complete remission. Disclosures Amrein: Takeda: Research Funding; AstraZeneca: Consultancy, Research Funding; Amgen: Research Funding. Brunner:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Hobbs:Novartis: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria; Constellation: Honoraria, Research Funding; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding. Neuberg:Celgene: Research Funding; Pharmacyclics: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company. Fathi:Takeda: Consultancy, Research Funding; Agios: Consultancy, Research Funding; PTC Therapeutics: Consultancy; Amphivena: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Newlink Genetics: Consultancy; Pfizer: Consultancy; Blueprint: Consultancy; Trillium: Consultancy; Kura Oncology: Consultancy; Forty Seven: Consultancy; Jazz: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Trovagene: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy. OffLabel Disclosure: MLN 9708, ixazomib is FDA approved for multiple myeloma. In this trial it is used to treat acute lymphoblastic leukemia.

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

Blood ◽  
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.

Multiple Myeloma In Complete Remission After Autologous Stem Cell Transplantation: Impact of Bone Marrow Plasma Cell Assessment by Conventional Morphology on Disease Progression

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2946-2946
Author(s):  
Carlos Fernández de Larrea ◽  
Natalia Tovar ◽  
María Rozman ◽  
Laura Rosiñol ◽  
Juan I. Aróstegui ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Complete Remission ◽  
Board Of Directors ◽  
Research Funding ◽  
Bone Marrow Aspirate ◽  
Advisory Committees ◽  
Bone Marrow Plasma ◽  
Serum And Urine

Abstract Abstract 2946 Background: The achievement of complete remission (CR) is the crucial step for a long-lasting response and prolonged survival after autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM). The European Group for Blood and Marrow Transplantation (EBMT) criteria for CR include the negativity of serum and urine immunofixation (IFE) and less than 5% of bone marrow plasma cells (BMPCs). Additionally, the International Myeloma Working Group (IMWG) has even proposed a stringent CR category, which requires to rule out the clonal nature of the BMPCs. However, few studies have addressed this issue in patients with MM and negative IFE. The aim of the present study was to determine the impact of plasma cell count in the bone marrow aspirate on the long-term outcome of patients with MM with negative IFE after ASCT. Methods: Thirty-five patients (16M/19F; median age at ASCT 55 years, range 26–68) with MM who underwent ASCT from March 1994 to December 2008, were studied. All patients had achieved a negative serum and urine IFE after high dose therapy with melphalan-based regimens. Bone marrow aspirate was performed when negative serum and urine IFE was achieved and at least three months from ASCT (median 3.24 months). The analysis was based on microscopic revision for May-Grünwald-Giemsa stained bone marrow smears performed according to standard procedures. BMPC percentage was calculated independently by two observers counting 500 bone marrow total nucleated cells in random areas from two different slides (1000 cells on each patient). Results: Median BMPCs percentage was 0.8 (range 0.1–5.8). Only two patients had more than 3% BPMCs. These results are in contrast with a recent report from the Mayo Clinic group, where 14% of the patients with MM and negative IFE had 5% or more BMPCs. In univariate Cox-model regression analysis, the number of BMPCs significantly correlated with progression-free survival (PFS)(p=0.021) with no impact on overall survival (OS)(p=0.92). This statistical significance on PFS was retained in the multivariate analysis, when baseline prognostic factors such as age, hemoglobin level, serum creatinine, β2-microglobulin and Durie-Salmon stage were added to the model (p=0.003). To establish the best predictive cut-off for progression and survival, a receptor-operator curve (ROC) analysis was developed. It showed the value of 1.5% BMPCs, with a sensitivity of 53%, specificity of 90% and area under the curve of 0.66 for predicting progression. Ten patients had more than 1.5% BMPC, and 25 equal or less than 1.5% BMPC. Median PFS was 8.5 years (CI 95% 2.6 to 14.3) and was not reached in patients with ≤1.5% BMPCs versus 3.1 years in patients with >1.5% BMPCs, with a hazard ratio probability to progression of 3.02 (CI 95% 1.18 to 9.71)(p=0.016) in the group with more than 1.5% of BMPCs (Figure 1). Median OS was not reached in patients with ≤1.5% compared with a median of 9.7 years in those with more than 1.5% BMPCs (p=0.195) (Figure 2). It is likely that serological CR with very low percentage of BMPCs (i.e. ≤1.5%) is equivalent to negative MRD assessed by MFC or molecular studies. In fact, all 8 patients in continued CR between 9 and 16 years beyond ASCT (“operational cures”) are in the group with ≤1.5% BMPCs, while all patients in the group with >1.5% BPMC have relapsed within the first 9 years from ASCT (Figure 1). Conclusion: The percentage of BMPCs in patients with MM in CR after ASCT is a strong predictor of progression. Bone marrow morphology examination is an easy, inexpensive, and non-time consuming test and it should be the first step in the estimation of the residual tumor mass in patients with MM in CR after ASCT. Disclosures: Rosiñol: Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cibeira:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Blade:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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