Updated results from DIAMOND-01 (CLI24-001) trial: A phase I/II study of SEL24/MEN1703, a first-in-class dual PIM/FLT3 kinase inhibitor, in acute myeloid leukemia.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7023-7023
Author(s):  
Scott R. Solomon ◽  
Pau Montesinos ◽  
Aziz Nazha ◽  
Stephen Anthony Strickland ◽  
Giovanni Martinelli ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Safety Profile ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Single Agent ◽  
Median Number ◽  
Idh Mutations ◽  
De Novo Aml ◽  
Number Of Cycles ◽  
Unacceptable Toxicity

7023 Background: SEL24/MEN1703, a dual PIM/FLT3 kinase inhibitor, in the dose escalation (DE) DIAMOND-01 trial (CLI24-001, NCT03008187), showed an acceptable safety profile up to the recommended dose (RD) of 125 mg along with initial evidence of single agent activity and meaningful target engagement in heavily pre-treated patients (pts) with AML (Solomon et al, EHA 2020; Tomirotti et al, ASH 2020). Here we present updated data including pts enrolled in the Phase II, cohort expansion (CE) of the study. Methods: DIAMOND-01 trial enrolled pts unsuitable for chemotherapy having relapsed or refractory (R/R) (DE and CE) or previously untreated (DE) AML. Previous targeted therapies – except PIM inhibitors – were allowed. SEL24/MEN1703 was given orally, QD, 14 days ON / 7 days OFF until progression/unacceptable toxicity. The DE tested MEN1703 escalating doses from 25 to 150 mg, whereas in the CE the RP2D (125 mg) was administered. The key objectives of the CE were the confirmation of the safety profile determined in the DE along with further investigation of single agent activity. Adverse events (AEs) were graded according to NCI-CTCAE v.4.03; responses assessed as per ELN 2017 criteria. Results: As of January 21, 2021 (cut-off date), n = 48 pts were treated across DE (n = 25) and CE (n = 23). Median age was 69 (25-84) years. Overall, 20 (43%) and 15 (32%) pts had non de novo AML and primary refractory AML, respectively. Adverse karyotype was reported in 7 (15%) pts. Most frequently reported mutations were FLT3/ITD (23%, n = 11), DNMT3A (15% n = 7), NPM1 (15%, n = 7), IDH1 (13%, n = 6) and IDH2 (4%, n = 2), CEBPA (4%, n = 2), FLT3/TKD (2%, n = 1). Median number of cycles was 2 (1-8). At the RD (n = 30), most frequent serious treatment-emergent AEs (serious TEAEs) were pneumonia (23%), sepsis and febrile neutropenia (13%) and pulmonary mycosis (10%) whereas most frequent G≥3 TEAEs were febrile neutropenia and pneumonia (23%), leukocytosis (20%) and neutrophil count decrease, platelet count decrease, lymphocyte count decrease and sepsis (13%). Responses occurred in 2 pts in the CE, both with IDH1 mutant disease (naïve to IDH inhibitors) who achieved complete remission with incomplete hematologic recovery (CRi). Both responses occurred by Cycle 3, with a duration of 79 (ongoing at cut-off date) and 43 days, respectively. Across DE and CE, 4 CR/CRi occurred, three of which in pts with IDH mutations. A total of 3 out of 6 pts with IDH mutations treated at doses ≥75 mg achieved CR/CRi, including a CR in a patient with IDH2 mutant AML relapsed on Enasidenib. Conclusions: SEL24/MEN1703 confirmed a manageable safety profile at RD and showed preliminary single agent efficacy in R/R AML, particularly clustering in pts with IDH mutant disease either naïve or previously exposed to IDH inhibitors. These results warrant further investigation of SEL24/MEN1703 in AML, with potential focus in the IDH mutated subset. Clinical trial information: NCT03008187.

DREAMM-2: Single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma (RRMM) and high-risk (HR) cytogenetics.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8541-8541 ◽  
Author(s):  
Adam D. Cohen ◽  
Suzanne Trudel ◽  
Sagar Lonial ◽  
Edward N. Libby ◽  
Hans Chulhee Lee ◽  
...  
Keyword(s):  
Partial Response ◽  
Safety Profile ◽  
Single Agent ◽  
Median Number ◽  
Blurred Vision ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Independent Review ◽  
Clinical Responses ◽  
Number Of Cycles

8541 Background: Patients with RRMM and HR cytogenetics have a poor prognosis and need effective therapies. In DREAMM-2 (NCT03525678), single-agent belantamab mafodotin (an immunoconjugate targeting B-cell maturation antigen) demonstrated clinically meaningful activity and a manageable safety profile in patients with heavily pretreated RRMM ( Lancet Oncol.2020). We present outcomes in patients with HR-cytogenetics (9-month follow-up). Methods: Patients with RRMM received single-agent belantamab mafodotin (2.5 or 3.4 mg/kg). For this post hoc analysis, HR-cytogenetics included t(4;14), t(14;16), 17p13del, or 1q21+ (tested locally). Results: The median number of cycles was 3 (2.5: range: 1–15) and 4 (3.4: range: 1–14). Overall response rate (ORR; ≥partial response [PR] per independent review committee) was 27% in the 2.5 mg/kg group (22% with ≥very good partial response [VGPR]) and 40% in the 3.4 mg/kg group (27% with ≥VGPR). The median duration of response (DoR) was not reached in the 2.5 mg/kg group and was 6.2 months in the 3.4 mg/kg group. The most common adverse events ( > 30% in either group) were consistent with the overall population ( Lancet Oncol.2020): keratopathy (2.5: 59%;3.4: 79%), thrombocytopenia (2.5: 44%; 3.4: 65%), nausea (2.5: 27%; 3.4: 33%), anemia (2.5: 24%; 3.4: 42%), and blurred vision (2.5: 20%; 3.4: 42%). Conclusions: Patients with HR-cytogenetics maintain deep and durable clinical responses with single-agent belantamab mafodotin, comparable to that reported in the overall population. The safety profile remained consistent with previous reports. Funding: GlaxoSmithKline (205678). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT03525678 . [Table: see text]

Decitabine for Older AML Patients: An Effective Therapy Associated with Short Hospitalization and No Invasive Fungal Infection.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1063-1063 ◽  
Author(s):  
George Ansstas ◽  
Waseem Touma ◽  
Camille Adeimy ◽  
Gao Feng ◽  
Peter Westervelt ◽  
...  
Keyword(s):  
Median Duration ◽  
De Novo ◽  
Fungal Infections ◽  
Median Number ◽  
Invasive Fungal Infections ◽  
Response To Therapy ◽  
The Mean ◽  
De Novo Aml ◽  
Number Of Cycles ◽  
Count Recovery

Abstract Abstract 1063 Purpose: The treatment of older patients (pts) with acute myeloid leukemia (AML) continues to be controversial because of the lack of effectiveness and the toxicity of available therapies. We investigated the efficacy, toxicity, and factors predictive of response to decitabine as initial therapy in older pts with AML. Methods: This is the largest single institution, retrospective study for pts older than 60 years with either De novo AML or MDS related AML who were treated initially with IV decitabine 20 mg/m2 for 5 consecutive days of a 4-week cycle from 01/01/2005- 01/01/2010. Pts continued to receive decitabine until disease progression or an unacceptable adverse event occurred. Pts with secondary AML were excluded. Results: 45 pts were treated. Median age 71 (range, 61–83). Males-27 (60%). Females-18 (40%). Caucasians-40 (89%). African-Americans- 4 (9%). Asian-1 (2%). De novo AML-24 (53%). MDS related AML-21 (47%). Karyotypes: poor-27 (60%), intermediate -10(22%), unknown-8(18%). Median presenting WBC's 2.8 k (range, 0.6–122.2) with 26.6% of WBC's > 10k. The best response to therapy was CR/CRi-13 (29%), Stable disease/ partial remission (SD/PR) - 22 (49%), progressive disease (PD) -10 (22%). Pts who achieved CR/CRi: De novo AML-8, MDS related AML-5, poor cytogenetics-6, unknown cytogenetics-4, intermediate cytogenetics-3, presenting WBC's <10k-9, presenting WBC's >10k-4. Median number of cycles for CR/CRi was 4 (range, 1 to 5 cycles). Median number of cycles for CR/CRi was 4 in pts with presenting WBC's <10k and 4.5 in pts with presenting WBC's> 10k. 2 pts in CR/CRi group underwent consolidative BMT while on decitabine. The median duration of CR/CRi was 393 days (range, 184–748). The median time from first cycle till plt count recovery was 49 days (range, 0–294). Plt count recovery was the first hematological sign for CR preceding bone marrow biopsy confirmation in 10 out13 pts (77%). Plt count recovery on day 90 of therapy was achieved in 18 pts (40%) of whom 9 out of 18 achieved CR. The median overall survival (OS) from the time of diagnosis was 8.75 months (mo) (range, 0.5–59.8), CR/CRi-18.9 mo (range, 7.8–37.9), SD/PR-7.3 mo (range, 1.9–59.8), PD-1.9 mo (range, 0.5–12.1). Median OS for pts presented with WBC's< 10k was 11.0 mo (range, 0.5–59.8) and WBC's >10k was 7.1 mo (range, 1.9–32.7). In CR/ Cri group, the median OS for pts presented with low and high WBC's was 19.2 mo (range, 10–37.9) and 11.2 mo (range, 10.5–32.7) respectively. The 30, 60, and 100 day mortality rates after first cycle of therapy were (6/45)13.3%, (9/45) 20%, and (10/45) 22.2% respectively. The mean number of days for hospitalization while on decitabine was 19.2 days (range, 0–59), CR/CRi 14.3 days (range, 0–59), SD/PR 19.4 days (range, 0–54), PD 25.3 days (range, 5–52). 28 culture documented infection events noted in all groups: CR /CRi-5, SD/PR-22, PD-1. Staph species 14 events, Pseudomonas Aeruginosa 4 events, E-coli 3 events, C. difficile 2 events, candida species 2 events, and 1 event for each of: bacillius species, achromobacter, and enterobacter cloacae. No documented invasive fungal infections were seen. Bleeding events were observed in 3 pts (2 gastrointestinal and 1 fatal SDH due to fall). Salvage therapy was offered to 10 pts after decitabine failure (5 in CR/CRi group, 4 in SD/PR group and 1 in PD group). Different salvage regimens used including idarubicine + cytarabine (5), FLAG (1), SAHA (3), PXD 101 (1), and Gemtuzumab (1). CR was achieved in 3 out of 4 pts who received 7+3 all in CR/CRI group. Univariate analysis of factors predictive of CR and Survivals are shown in table 1. Multivariate analysis for factors predictive of survival was significant for intermediate risk cytogenetics with P value of 0.0410. Conclusion: Decitabine resulted in CR/CRi in 29% of pts after a median of 4 cycles of therapy. Median duration of CR was 393 days. The mean duration for hospital stay was 19.2 days. No documented invasive fungal infections seen and 1 fatal bleed reported. Disclosures: No relevant conflicts of interest to declare.

Efficacy and safety of aspacytarabine (BST-236) as a single-agent, first-line therapy for patients with acute myeloid leukemia unfit for standard chemotherapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7007-7007
Author(s):  
Jessica K. Altman ◽  
Jamie Koprivnikar ◽  
James K. McCloskey ◽  
Vamsi Kota ◽  
Olga Frankfurt ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
De Novo ◽  
Single Agent ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
First Line ◽  
Standard Chemotherapy ◽  
First Line Therapy ◽  
Line Therapy ◽  
De Novo Aml

7007 Background: Aspacytarabine (BST-236) is a prodrug of cytarabine, the backbone of acute myeloid leukemia (AML) standard of care chemotherapy, associated with toxicity which precludes its administration in older patients and patients with comorbidities. Aspacytarabine is inactive in its intact prodrug form until cytarabine is gradually released at pharmacokinetics which decrease the systemic exposure to peak toxic cytarabine levels, resulting in reduced systemic toxicity and relative sparing of normal tissues, enabling therapy with high cytarabine doses to patients otherwise unfit to receive it. Methods: A phase 2b open-label, single-arm study to evaluate the efficacy and safety of aspacytarabine as a first-line single-agent therapy in newly-diagnosed AML patients unfit for standard chemotherapy (NCT03435848). Aspacytarabine is administrated at 4.5 g/m2/d (containing 3 g/m2/d cytarabine) in 1-2 induction and 1-3 consolidation courses, each consisting of 6 daily 1-hour infusions. Patients with secondary AML, prior hypomethylating agent (HMA) therapy, and therapy-related AML, are eligible. Results: To date, in the ongoing study, 46 newly-diagnosed AML patients unfit for standard chemotherapy (median age 75 years) were treated with aspacytarabine and completed 1-4 courses of 4.5 g/m2/d aspacytarabine, including 26 patients (63%) with de novo AML and 17 (37%) with secondary AML. Six patients (13%) were previously treated with HMA (median 12 courses). The baseline median bone marrow blasts was 52%, and 54% and 29% of patients had adverse or intermediate European LeukemiaNet (ELN) score, respectively. Twenty (43%) patients had ECOG 2. Aspacytarabine is safe and well-tolerated in repeated-course administration. Grade > 2 drug-related adverse events include mainly hematological events and infections. The 30-day mortality rate is 11%. Of 43 patients evaluable for efficacy analysis to date, 15 patients (35%) reached a complete remission (CR) following 1 (13 patients) or 2 (2 patients) induction courses, all with complete hematological recovery (median 27.5 days, range 22-39 days). The CR rates in de novo AML patients and patients with adverse ELN score are 46% and 33%, respectively. Of the 11 patients evaluable to date for minimal residual disease (MRD) flow cytometry test, 8 are MRD negative (73%). While aspacytarabine treatment consists of a limited number of courses, median duration of response and median overall survival for responders are not reached at 12 and 24 months, respectively (end of follow up). Updated results will be presented at the meeting. Conclusions: The cumulative clinical data suggest that aspacytarabine, a time-limited single-agent treatment, is safe and efficacious as a first-line therapy for patients who are unfit for intensive chemotherapy, which may establish it as a new tolerable AML chemotherapy backbone. Clinical trial information: NCT03435848.

A Phase I/II Study of Bortezomib and Low Dose Intravenous Melphalan (BM) for Relapsed Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2555-2555 ◽  
Author(s):  
Rakesh Popat ◽  
Heather E. Oakervee ◽  
Nicola Foot ◽  
Samir Agrawal ◽  
Patricia Smith ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Progressive Disease ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Median Number ◽  
Overall Response ◽  
Grade 3 ◽  
Number Of Cycles

Abstract Background: Bortezomib as a single agent has known efficacy in the treatment of relapsed multiple myeloma. The overall response rate (CR+PR+MR) was 35% in the SUMMIT study and 46% in the APEX study. In-vitro studies including our own have demonstrated potent synergy with other chemotherapeutic agents such as melphalan. It therefore follows that responses to bortezomib may be further improved by the combination of such drugs. Aims: The primary objectives of this Phase I/II study was to assess the safety, tolerability and response rates in patients with relapsed multiple myeloma; secondary objectives being time to progression (TTP) and overall surival (OS). Methods: This was a multi-centre, non-randomised trial for patients with relapsed myeloma. Patients received bortezomib 1.3mg/m2 on days 1,4,8 and 11 of each 28 day cycle with melphalan on day 2 at increasing dose levels. This was initially at 10mg/m2, but due to cytopenias subsequently at 2.5 and 5mg/m2 (levels 1a, 1 and 2) and we plan to escalate to 7.5mg/m2. Up to 8 cycles were given with dexamethasone added for stable or progressive disease after 4 or 2 cycles respectively. Responses were determined by EBMT criteria. Results: To date, 18 patients have been enrolled (12 male 6 female; median age 60 [range 44–73]; median number of prior therapies 3 [range 1–5] of which 17 have had at least one autologous stem cell procedure with high dose melphalan; 10 prior thalidomide and 2 prior bortezomib). 12 patients received melphalan at 10mg/m2 but due to unacceptable delays predominantly due to thrombocytopaenia, subsequent treatment levels commenced at 2.5mg/m2. The median number of cycles completed thus far is 4 (range 0–8) and of the 16 evaluable, the overall response rate (CR+PR+MR) across all treatment levels was 50% rising to 75% following the addition of dexamethasone as per protocol. At level 1a (melphalan 10mg/m2 ,N=12, median number of cycles completed =5) the best responses (with dexamethasone as indicated) were: 1CR, 1 VGPR, 5 PR, 2 MR; at level 1 (melphalan 2.5mg/m2, N=4) 1 PR, 2 MR (after 2 cycles only). The median time to any response was 1 cycle (range 1–3 ). Three patients have progressive disease, but the median TTP and OS have not yet been reached (median follow-up 3 months). Non-haematological toxicities have been modest with 7 SAEs reported of which only 1 was possibly drug related (myocardial infarction), and 4 episodes of Grade 3 neuropathy (2 resulting in study withdrawal). The commonest grade 3–4 haematological toxicity was thrombocytopaenia (N=10) complicated by bleeding in one patient, followed by neutropenia (N=6). Summary: The combination of bortezomib and intravenous melphalan can be given safely to patients with relapsed multiple myeloma and dose escalation is ongoing. Myelosupression was the commonest grade 3–4 adverse event. A response rate of 50% was seen, which was further improved to 75% with the addition of dexamethasone. This combination may therefore result in higher responses than single agent bortezomib in heavily pretreated patients.

A Phase I Dose Escalation Study of KW-2449, An Oral Multi-Kinase Inhibitor against FLT3, Abl, FGFR1 and Aurora in Patients with Relapsed/Refractory AML, ALL and MDS or Resistant/Intolerant CML

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2967-2967 ◽  
Author(s):  
Jorge Cortes ◽  
Gail J. Roboz ◽  
Hagop M. Kantarjian ◽  
Eric J. Feldman ◽  
Judith E. Karp ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Bone Marrow ◽  
Febrile Neutropenia ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Recovery Period ◽  
Post Dose ◽  
Grade 3 ◽  
Dose Levels ◽  
Bone Marrow Blasts

Abstract Background: Activating mutations of FMS-like tyrosine kinase 3 (FLT3) occur in 30% of patients with de novo AML and confer a poor prognosis. KW-2449 is an oral multi-kinase inhibitor which is highly potent against mutant FLT3 (IC50=0 1–7 nmol/L) and other tyrosine kinases including FGFR1, TrkA, Abl (including T315I) and Aurora A serine threonine kinase. Based on the activity of KW-2449 and its metabolite (M1) in both in vitro and in vivo preclinical leukemia models, KW-2449 was evaluated in patients with leukemia and MDS in this first-in-man study. M1 is formed via monoamine oxidase-B and aldehyde oxidase mediated oxidation of KW-2449. Methods: The objectives were to assess the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic effects of KW-2449 in patients with refractory/relapsed AML, ALL and MDS, or resistant/intolerant CML. A range of daily doses of KW-2449 (12.5–250 mg twice daily, i.e. 25–500 mg/day) on 2 treatment schedules (14 or 28 days) with a recovery period of 7–28 days between cycles were evaluated. Dose limiting toxicity (DLT) and maximum tolerated dose (MTD) were assessed for the 1st cycle. The 28-day schedule was later eliminated. The plasma concentration of KW-2449 and M1 were analyzed by LC-MS/MS method. A plasma inhibitory activity (PIA) assay [Blood 108(10) 3477–83] for P-FLT3 and P-STAT5 was used to measure FLT3 inhibition. Results: 37 patients aged 26–88 years (16 male) were treated at 7 dose levels: 25, 50, 100, 200, 300, 400, and 500 mg daily. Thirty-one patients had AML, 5 CML and 1 ALL. The mean duration of therapy was 2 cycles in AML patients and 4 cycles in CML patients. KW-2449 was rapidly absorbed and metabolized to M1. The half-lives for KW-2449 and M1 were not dose-related and ranged from 2.4 to 4.9 hours and 2.6 to 6.6 hours, respectively. Administration of KW-2449 in a BID regimen led to minor accumulation and was consistent with the short half-life. The PIA assay demonstrated the near complete down-regulation of P-FLT3 and P-STAT5 2 hours post-dose at a dosing level of 400 mg daily. The extent of inhibition was lower at 8 hours and generally absent at 12 hours post-dose. The most frequently reported adverse events (AEs; any grade, regardless of causality) were nausea (70.3%), vomiting (48.6%), fatigue (45.9%), diarrhea (32.4%), dyspnea (29.7%), febrile neutropenia (29.7%), pain in extremity (29.7%), and arthralgia (27.0%). Febrile neutropenia (24.3%), pneumonia (10.8%), and thrombocytopenia (10.8%) were the most frequently reported Grade 3/4 AEs. DLTs occurred in 2 patients: Grade 3 atrial fibrillation (100 mg daily) and Grade 3 nausea and vomiting (500 mg daily). A total of 70 SAEs were reported in 27 patients including 11 on-study deaths; only atrial fibrillation and pleural effusion were considered possibly related to KW-2449. Eight of 31 patients with AML (26%) (FLT3 mutation: 5 positive and 3 negative) and 1 of 5 patients with CML (20%) exhibited a ³ 50% reduction in peripheral blasts and/or bone marrow blasts from baseline to the end of Cycle 1. One patient (500 mg daily) with AML exhibited a &gt; 50% decrease in peripheral blasts, increased platelets, and ANC, and decreased WBC count. A patient with CML (Bcr-Abl T315I +) lost the mutant clone while on KW-2449 treatment. Conclusions: KW-2449 was safe and well tolerated at the dose levels evaluated. There were no complete or partial responses, but transient decreases in peripheral blood and bone marrow blasts were observed, justifying continued investigation of this agent. Sustained inhibition of P-STAT5 and P-FLT3 was not achieved at trough at the highest BID dose evaluated. TID and QID dosing schedules should be evaluated to accommodate the short t1/2 and to achieve sufficient target inhibition.

A Retrospective Comparison of Matched Elderly Patients Treated with Laromustine (Cloretazine®) or Best Supportive Care or Low Dose Ara-C in the LRF AML14 Trial

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2960-2960 ◽  
Author(s):  
Robert Hills ◽  
Susan O’Brien ◽  
Verena Karsten ◽  
Alan K. Burnett ◽  
Francis Giles
Keyword(s):  
High Risk ◽  
Supportive Care ◽  
Low Dose ◽  
De Novo ◽  
Performance Status ◽  
Single Agent ◽  
Best Supportive Care ◽  
Cell Counts ◽  
Retrospective Comparison ◽  
De Novo Aml

Abstract Background : A substantial proportion of older patients with AML are considered unlikely to benefit from an intensive treatment approach. They often receive either best supportive care (BSC), low dose treatment such as Low Dose Ara-C (LDAC), or clinical trials of novel agents. In one of the few randomised studies where patients were prospectively considered likely to be unfit for intensive therapy, LDAC was superior to BSC with 18% v 1% patients achieving CR. No patients with high risk cytogenetics (Grimwade 1998), achieved CR (Burnett 2007). Laromustine (Cloretazine®) is a novel sulfonylhydrazine alkylating agent which preferentially targets the O6 position of guanine resulting in DNA cross-links. Laromustine has previously shown clinical activity in patients with de novo AML and high risk MDS (Giles et al. JCO 2007). A confirmatory phase II study of single agent laromustine was conducted in previously untreated patients ≥ 60 years old with de novo AML, prospectively considered likely to be unfit for intensive chemotherapy. Patients had at least one poor risk factor, defined by age ≥70, performance status 2, unfavorable cytogenetics, or cardiac, pulmonary or hepatic dysfunction. Eighty-five patients received induction therapy with 600 mg/m2 laromustine. Second induction cycles were administered in 14 patients after partial response or hematologic improvement. Eighteen patients received at least one consolidation cycle of cytarabine 400 mg/m2/day CIV for 5 days. Methods: A retrospective non-randomised comparison was performed between the 85 patients treated with laromustine, and 121 patients satisfying the same entry criteria, treated in the AML 14 trial with either BSC or LDAC. Outcomes were compared using Mantel-Haenszel and logrank methods for unadjusted comparisons, and regression methods for adjusted analyses. Results : Patients in AML14 were slightly older than those treated with laromustine (median age 75 v 73), and tended to have higher white blood cell counts; by contrast, there were significantly fewer cardiac or respiratory comorbidities reported in the AML14 population. Other important risk factors such as performance status and cytogenetics were similar between the groups. Responses overall (CR/CRp) were seen in 33% (28/85) of patients treated with laromustine, compared with 2% (1/60) and 23% (14/61) in patients treated with BSC and LDAC (p&lt;0.0001, p=0.2, respectively). In particular, 1 patient with −5/del(5q), and 3 patients with −7/del(7q) cytogenetics experienced a CR with laromustine; patients in AML 14 with adverse cytogenetics saw no remissions. Survival was significantly improved in the laromustine group compared to BSC (1 year survival 20% v 8%, unadjusted HR 0.58 [0.40–0.84] p=0.004), and roughly comparable to that of LDAC (1 year survival 20% v 25%, HR 1.04 [0.73–1.49] p=0.8). Analyses adjusted for differences in baseline demographics, and using propensity scores gave consistent figures. Conclusions: Retrospective comparison of unrandomised data has significant limitations even though care has been taken to match for factors known to be predictive for survival. Laromustine was able to achieve a higher CR rate than LDAC or BSC, and produced remissions in groups where no remissions have previously been seen with LDAC or BSC. Laromustine gave significantly better survival than BSC, and demonstrated similar survival to LDAC.

Phase III Trial of Pixantrone Dimaleate Compared with Other Agents as Third-Line, Single-Agent Treatment of Relapsed Aggressive Non-Hodgkin's Lymphoma (EXTEND): Results From the Treatment and Follow-up Periods.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1677-1677 ◽  
Author(s):  
Ruth Pettengell ◽  
Bertrand Coiffier ◽  
Geetha Narayanan ◽  
Fernando Hurtado de Mendoza ◽  
Raghunadharao Digumarti ◽  
...  
Keyword(s):  
Treatment Group ◽  
Primary Endpoint ◽  
Safety Profile ◽  
Single Agent ◽  
Median Number ◽  
Phase 3 ◽  
Comparator Group ◽  
Duration Of Response ◽  
Heavily Pretreated

Abstract Abstract 1677 Poster Board I-703 Introduction Nearly half of patients with aggressive non-Hodgkin's lymphoma (NHL) relapse or are refractory to initial therapy. With each subsequent therapy, the probability of response decreases and the responses are less durable. An agent currently in development, pixantrone dimaleate (pixantrone), is a novel aza-anthracenedione structurally similar to mitoxantrone and anthracyclines. The clinical activity and safety profile of pixantrone are promising in patients heavily pretreated for relapsed aggressive NHL and who received prior treatment with up to 450 mg/m2 of doxorubicin. Patients and Methods This phase 3, randomized, multicenter, controlled, open-label study enrolled patients who had ≥1 prior anthracycline-containing regimen and failed 2 prior treatment regimens for relapsed aggressive (de novo or transformed) NHL. Seventy patients were randomized to a treatment group administered pixantrone 85 mg/m2 on days 1, 8, and 15 of a 28-day cycle, for up to 6 cycles. Seventy patients were randomized to the investigator's choice of a single-agent comparator (vinorelbine, oxaliplatin, ifosfamide, etoposide, or mitoxantrone; in the US only, gemcitabine and rituximab were permitted). Patients in both groups were followed up to 18 months after last treatment. The primary endpoint, CR/CRu rate, was assessed by an independent assessment panel (IAP). Other efficacy endpoints were overall response rate (ORR), responses lasting ≥4 months, progression-free survival (PFS), overall survival (OS), duration of response, and time to response. This report includes the results from the treatment period and updated results from the follow-up period, which is still ongoing. Results A total of 140 patients were randomized with 70 patients in each treatment group. Of the 140 patients, 96% received treatment (n=68 for pixantrone, n=67 for comparator). The median number of treatment cycles that patients in the pixantrone group received was 4 compared with 3 for the comparator group. The percentage of patients who received all 6 treatment cycles in the pixantrone group was 32.4% compared with 28.4% for the comparator. The primary endpoint, CR/CRu rate (assessed by IAP), in the ITT population was 20.0% for the pixantrone group compared with 5.7% for the comparator (P = 0.021). The ORR for the pixantrone group was 37.1% compared with 14.3% for the comparator (P = 0.003), and the percentage of patients with objective responses lasting at least 4 months for the pixantrone group was 25.7% compared with 8.6% for the comparator (P =0.012). The median number of months of PFS in the pixantrone group was 4.7 compared with 2.6 for the comparator (HR= 0.60, log rank P = 0.007). The median number of months of OS, while not fully mature, was 8.1 for the pixantrone group compared with 6.9 for the comparator (HR=0.88, log rank P = 0.554). Subgroup assessments of the CR/CRu rate and ORR, by risk factor, were consistently higher in the pixantrone group than in the comparator group. These subgroup assessments included prior exposure to anthracyclines ('300 mg/m2 or ≥300 mg/ m2) and rituximab (treated or not treated), IPI score ('1 or ≥2), and NHL diagnosis (refractory or relapsed), and age ('65 or ≥65). In the pixantrone group, neutropenia and leukopenia were the most common (≥10%) grade 3/4 adverse events and the incidence of febrile neutropenia was 7.4%. The percentage of patients with cardiac disorder SAEs was 8.8% in the pixantrone group compared with 4.5% for the comparator. Conclusions In this phase 3, randomized, multicenter study, patients with relapsed aggressive NHL administered single-agent pixantrone achieved superior efficacy, compared with other single-agent chemotherapeutic agents, as measured by CR/CRu rate, ORR, responses lasting ≥4 months, and PFS. Positive trends were observed in OS and duration of response. Patients in the pixantrone group tended to reach CR sooner than patients in the comparator group. Pixantrone has a tolerable safety profile in heavily pretreated patients with relapsed aggressive NHL. Disclosures Cernohous: Cell Therapeutics, Inc: Employment. Wang:Cell Therapeutics, Inc: Employment. Singer:Cell Therapeutics, Inc: Employment.

Analysis of ASXL1, IDH1, IDH2, c-CBL, and WT1 Mutations in De Novo Acute Myeloid Leukaemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1450-1450
Author(s):  
Mariam Ibañez ◽  
Esperanza Such ◽  
Jose Cervera ◽  
Irene Luna ◽  
Sandra Dolz ◽  
...  
Keyword(s):  
De Novo ◽  
Prognostic Impact ◽  
Significant Implication ◽  
Wild Type ◽  
Idh Mutations ◽  
Flt3 Mutations ◽  
Exon 4 ◽  
De Novo Aml ◽  
Cebpa Mutations ◽  
Acute Myeloid

Abstract Abstract 1450 The clinical relevance and prognostic implications of some recently identified mutations in acute myeloid leukemia (AML) is not yet well established. Among them, we have selected to be analyzed those affecting the following genes: Additional Sex Combs-Like 1 (ASXL1), Isocitrate Dehydrogenase (IDH1 and IDH2), Casitas B-lineage Lymphoma (c-CBL), and Wilms Tumor 1 (WT1). They have been previously reported with a variable incidence: ASXL1 mutations in 10.8% patients with normal karyotype (NK), IDH1 and IDH2 mutations in 8 – 33% of de novo AML, c-CBL mutations in 2% of de novo AML, and WT1 mutations in 5–12% of de novo AML patients. In order to know the incidence and prognostic impact of these mutations and their possible cooperative role in leukemogenesis, we have screened for ASXL1, IDH1, IDH2, c-CBL, WT1, FLT3, NPM1 and CEBPa, mutations in a cohort of de novo AML patients from a single centre. We studied 174 de novo AML patients [98M/76F; median age: 62 yr. (range: 16 – 88); favourable (n= 13), intermediate (n= 86) and high (n= 51) cytogenetic risk classification by the MRC group]. DNA was isolated from bone marrow samples obtained at diagnosis. In order to determine cooperating mutations, we developed a new combination of high-resolution melting (HRM) assays on a LightCycler® 480 and lastly direct sequencing, to detect somatic mutations for ASXL1 (exon 12), IDH1 (exon 4), IDH2 (exon 4), WT1 (exons 7, 8 and 9) and c-CBL (exons 8 and 9). All mutations reported in this study were confirmed al least twice. FLT3 (ITD and D835Y), NPM1 (exon 12) and CEBPa were performed as described previously by standard methods. Sequence analysis was checked by its corresponding GeneBank Accession Number. The number of patients found to carry mutations in our series was: 16 patients with ASXL1 mutations (9.2%), 16 patients with IDH mutations (2.9% had a IDH1R132, 12.6% the SNP rs11554137 and 6.3% IDH2R140), 5 patients with WT1 mutations (2.9%), 37 patients with FLT3 mutations (21.3%), 44 patients with NPM1 mutations (25,3%) and 8 patients with CEBPa mutations (4.6%). No mutations where found in c-CBL. We could not found a pattern of cooperating mutations in the studied group of genes. WT1, FLT3 and NPM1 were associated with leukocyte count >30 × 109/L at diagnosis (80% vs. 31% for WT1, P =0,022; 68% vs. 22% for FLT3, P= 0.001; and 50% vs. 24% for NPM1, P= 0.002; in mutated vs. wild-type patients, respectively). WT1 was also associated with a platelet count > 50 × 109/L at diagnosis (100% vs. 57% in mutated vs. wild-type patients, respectively; P =0,048). Besides, FLT3 and NPM1 mutations were more frequent in the intermediate cytogenetic risk group (82% and 74%; P =0.004 and P =0.047; respectively). ASXL1 and IDH mutations were not correlated with any of the clinical and biological features studied. In univariate analysis, only age and cytogenetics had an impact on overall survival (OS, median of 12mo vs. 3mo, for patients < and ≥65 yr., P <0.001 and 24mo, 11mo and 3mo for favourable, intermediate and high risk, P =0.005). Mutational status of ASXL1, IDH1, IDH2, WT1, FLT3, NPM1 and CEBPa did not impact on outcome in the whole series. However, when the analysis was restricted to patients with intermediate cytogenetic risk, patients with FLT3 mutations had a shorter OS (19mo vs. 8mo, wild-type vs. mutated patients; P =0.047) and those with WT1 mutations showed a trend towards an inferior OS (11mo vs. 1mo, wild-type vs. mutated patients; P = 0.066). In multivariate analysis in patients with intermediate cytogenetic risk, the age [HR (95% CI) = 3.3 (1.9 − 5.9) P <0.001], and FLT3 status [HR (95% CI) = 2.2 (1.2–3.9) P =0.008] retained an independent adverse significance for OS. In terms of relapse free survival any of the variables showed a significant implication. To sum up, the incidence found for the studied genes was lower than the previously reported: ASXL1, 9.2%; IDH1R132, 2.9%; IDH2R140, 6.3%; WT1, 2.9%; and c-CBL, 0%. We were unable to find a pattern of cooperating mutations in the studied group of genes or any impact of these mutations on the outcome. Disclosures: No relevant conflicts of interest to declare.

Serum 2-Hydroxyglutarate Levels Predict Isocitrate Dehydrogenase Mutations and Clinical Outcome in Acute Myeloid Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2481-2481
Author(s):  
Courtney D. DiNardo ◽  
Ross L. Levine ◽  
Kathleen J Propert ◽  
Alison W. Loren ◽  
Elisabeth Paietta ◽  
...  
Keyword(s):  
Research Funding ◽  
De Novo ◽  
Mutational Analysis ◽  
Eastern Cooperative Oncology Group ◽  
Elevated Serum ◽  
Wild Type ◽  
Serum Samples ◽  
Prognostic Information ◽  
Idh Mutations ◽  
De Novo Aml

Abstract Abstract 2481 Purpose: Cancer-associated IDH mutations produce the metabolite 2-hydroxyglutarate (2HG), but the clinical utility of serum 2HG measurements has not been previously established. We studied whether 2HG measurements in AML patients correlate with the presence of IDH mutations and whether diagnostic or remission 2HG measurements predict survival. Patients and Methods: Serum samples from 223 previously untreated adults (≤ 60 years of age) with de novo AML from the Eastern Cooperative Oncology Group E1900 clinical trial (62 IDH mutated, 161 IDH wild-type) were analyzed for 2HG concentration by reverse-phase liquid chromatography coupled to mass spectrometry (GC-MS). Results: Pretreatment 2HG levels ranged from 10 to 30000 ng/ml and were significantly elevated in IDH-mutant samples (median 3004.1 ng/ml), as compared to the wild-type cohort (median 61.2 ng/ml) (p &lt; 0.0005). 2HG levels did not differ among the specific IDH1 or IDH2 allelic variants. In ROC analysis, a discriminatory level of 700 ng/ml segregated patients with and without IDH mutations with 86.9% sensitivity and 90.7% specificity. On repeat mutational analysis of 13 IDH wild-type samples with 2HG levels &gt;700 ng/ml, IDH mutations were identified in nine samples, most often at low allele burden. IDH mutant patients with 2HG levels ≤ 200 ng/ml at complete remission experienced improved overall survival compared to those with higher 2HG levels (HR 3.5, p = 0.02) (Figure 1). Conclusion: We establish a firm association between IDH mutations and elevated serum 2HG concentration in AML. These data confirm that peripheral blood measurement of an oncometabolite provides useful diagnostic and prognostic information for cancer therapy, and furthermore can inform patient selection of IDH mutant targeted therapies. Disclosures: Levine: Agios Pharmaceuticals: Research Funding. Straley:Agios Pharmaceuticals: Employment. Yen:Agios Pharmaceuticals: Employment. Agresta:Agios Pharmaceuticals: Employment. Carroll:Agios Pharmaceuticals: Research Funding.

Efficacy of Single-Agent Decitabine in Relapsed and Primary Refractory (rel/ref) Acute Myeloid Leukemia (AML)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2518-2518
Author(s):  
Andrew Hantel ◽  
Niloufer Khan ◽  
Richard A. Larson ◽  
Lucy A. Godley ◽  
Michael J. Thirman ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Genetic Risk ◽  
Research Funding ◽  
De Novo ◽  
Median Number ◽  
Advisory Committees ◽  
Secondary Aml ◽  
Induction Regimen ◽  
De Novo Aml ◽  
Wbc Count

Abstract Introduction Improving therapy for rel/ref AML remains a challenge. Decitabine, a DNA methyl-transferase inhibitor, initially showed promise in AML as a 5-day, first-line induction regimen and more recently as a 10-day regimen in older and unfit patients (1). However, little is known about the activity of decitabine in the rel/ref patient population despite increased use. Therefore, we sought to analyze the outcomes of these pts treated at our institution. Methods To obtain data regarding decitabine efficacy in rel/ref AML, we performed a retrospective analysis of outcomes following decitabine treatment in 34 adult pts treated at The University of Chicago from January 2009 to June 2014. Permission to access patient charts was granted by the medical centerÕs Institutional Review Board. AML was defined by WHO criteria, genetic risk grouping and complete remission (CR) was according to ELN classification; PR was defined as >50% decrease in bone marrow blasts and normalization of blood counts. Rel/ref AML was defined as either having had a prior CR with recurrence of disease or having received a prior induction regimen (1-2 cycles) without CR. Results Median pt age was 62 yrs (range, 18-81) and 60% were male. Median Charlson comorbidity index (CCI) was 5 (range, 0-8); 29% had ECOG performance status 0-1 and 71% had >2. 21 pts (62%) had de novo AML (7 with myelodysplasia-related changes), 3 (9%) had therapy-related myeloid neoplasm (t-MN), and 10 (29%) had secondary AML after myelodysplastic syndrome. 6% were in the ELN favorable genetic group, 3% intermediate-I, 18% intermediate-II, and 67% adverse; 2 cases were unevaluable. The median number of prior treatment regimens was three. 9% had received prior azacitidine, 85% had received prior HiDAC, and 38% had a prior allogeneic stem cell transplant (SCT). 34 pts received a total of 71 cycles of decitabine, 20 mg/m2 daily, in 5 or 10-day cycles every 28 days. All patients received 10-day courses, 91% had an initial 10-day course, and 74% had only 10-day courses. The median number of cycles per pt was 2; 59% received >1 cycle. 7 (21%) achieved CR and 4 (12%) had a partial response (PR), for an overall response rate (OR) of 33%. Responses occurred in 24% of pts with de novo AML, 66% with t-MN, and 50% with secondary AML. Intermediate and adverse group pts had OR of 14% and 39%, respectively. All pts achieving CR did so after 1 cycle; PR required a median of 3 cycles. Pts who achieved CR or PR had a significantly lower pretreatment WBC count (median, 9.5 vs 49.5 x 103/µL in non-responders; p=0.015) and blast percentage (44 vs 59.4; p=0.035) than those who did not. Pts with secondary AML or t-MN had a higher probability of OR compared to those with de novo AML (54 vs 23%; p=0.042). Median overall survival (OS) of all pts was 256 days; prior SCT was associated with reduced OS (p=0.017). When comparing de novo to secondary AML & t-MN, 1-year OS was not significantly different (Figure 1). Responders had a significantly longer OS (median, 622 days vs 278 days for non-responders; p=0.012). Age, race, CCI, ECOG PS, genetic risk group, prior HiDAC, dysplasia, azacitidine, and number of prior treatments did not impact OR or OS. 16 (47%) pts proceeded to SCT. During treatment, 70% had a grade 3-4 non-hematologic toxicity (based on NCI CTACE v4.0); the most common was fatigue. The median number of hospitalizations for complications per patient was 2 (range, 0-7). Causes of hospitalization were febrile neutropenia (40%), infection (22%), cytopenias (18%), rash (6%), acute kidney injury (6%), and 8% were for other causes. Conclusion Decitabine treatment of 34 adults with rel/ref AML resulted in an OR of 33% (21% CR) and allowed nearly one-half of these pts to proceed to SCT. All pts achieving CR did so after 1 cycle. Responding pts had improved OS over those without response (p=0.012). Interestingly, secondary AML or t-MN were 7.8 times more likely to achieve a response compared to de novo AML (p=0.046); lower WBC count and marrow blast percentage also correlated with higher OR. Further delineation of molecular subsets associated with response to decitabine should be evaluated in a larger prospective trial in this high-risk AML population. Citation 1. Blum KA, et al. Phase I trial of low dose decitabine targeting DNA hypermethylation in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: dose-limiting myelosuppression without evidence of DNA hypomethylation. Br J of Haem. Jul 2010;150(2):189-195. Figure 1. Figure 1. Disclosures Off Label Use: Decitabine is indicated for treatment of MDS but is often used to treat newly diagnosed or relapsed/refractory AML. In this study we analyzed results of patients with AML who were treated with decitabine in the relapsed/refractory setting.. Thirman:AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Merck: Research Funding; AbbVie: Research Funding; Gilead: Research Funding; Merck: Research Funding. Odenike:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Liu:Astra Zeneca/Medimmune: Consultancy; Pfizer: Consultancy; Astra Zeneca/Medimmune: Consultancy; Pfizer: Consultancy. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees.

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