OPB-111077 is a novel, highly specific oral signal transducer and activator of transcription 3 inhibitor that has exhibited good efficacy against solid and blood cancers, including acute myeloid ...leukemia (AML), in preclinical models. In the present study, a phase 1b, two-stage, 3+3 dose-escalation clinical trial dose level (DL)1 of 200 mg/day and DL2 of 250 mg/day on a once daily dose schedule in 28-day cycles was conducted to assess the maximum tolerated dose (MTD), safety profile and the preliminary antitumor activity of OPB-111077 in patients with high-risk AML. A preliminary preclinical analysis evaluated the anti-proliferative activity of OPB-111077 in 19 patients with AML with a Vivia Biotech ex vivo PharmaFlow precision medicine test. A total of 12 patients were ultimately enrolled in the trial: 5 patients (42%) were treated with DL1, and 7 (58%) were escalated to DL2 of OPB-111077. Dose-limiting toxicities were not observed and the MTD was not reached. In addition, the most frequently reported treatment-emergent adverse events were nausea, vomiting and fatigue. Finally, clinical activity (overall response) was observed in 3 patients (25%). On the whole, the present study demonstrates that OPB-111077 exhibits a good safety and tolerability profile and an acceptable clinical response in patients with high-risk AML. A biomarker-driven design is useful for selecting the study population upfront.OPB-111077 is a novel, highly specific oral signal transducer and activator of transcription 3 inhibitor that has exhibited good efficacy against solid and blood cancers, including acute myeloid leukemia (AML), in preclinical models. In the present study, a phase 1b, two-stage, 3+3 dose-escalation clinical trial dose level (DL)1 of 200 mg/day and DL2 of 250 mg/day on a once daily dose schedule in 28-day cycles was conducted to assess the maximum tolerated dose (MTD), safety profile and the preliminary antitumor activity of OPB-111077 in patients with high-risk AML. A preliminary preclinical analysis evaluated the anti-proliferative activity of OPB-111077 in 19 patients with AML with a Vivia Biotech ex vivo PharmaFlow precision medicine test. A total of 12 patients were ultimately enrolled in the trial: 5 patients (42%) were treated with DL1, and 7 (58%) were escalated to DL2 of OPB-111077. Dose-limiting toxicities were not observed and the MTD was not reached. In addition, the most frequently reported treatment-emergent adverse events were nausea, vomiting and fatigue. Finally, clinical activity (overall response) was observed in 3 patients (25%). On the whole, the present study demonstrates that OPB-111077 exhibits a good safety and tolerability profile and an acceptable clinical response in patients with high-risk AML. A biomarker-driven design is useful for selecting the study population upfront.
Purpose
The ENEST1st sub-analysis presents data based on Philadelphia chromosome (Ph) status, i.e., Ph+ and Ph−/
BCR-ABL1
+ chronic myeloid leukemia.
Methods
Patients received nilotinib 300 mg twice ...daily, up to 24 months.
Results
At screening, 983 patients were identified as Ph+ and 30 patients as Ph−/
BCR-ABL
+ based on cytogenetic and RT-PCR assessment; 76 patients had unknown karyotype (excluded from this sub-analysis). In the Ph−/
BCR-ABL1
+ subgroup, no additional chromosomal aberrations were reported. In the Ph+ subgroup, 952 patients had safety and molecular assessments. In the Ph−/
BCR-ABL1
+ subgroup, 30 patients had safety assessments and 28 were followed up for molecular assessments. At 18 months, the molecular response (MR) 4 rate MR
4
; BCR-ABL1 ≤0.01% on International Scale (IS) was similar in the Ph−/
BCR-ABL1
+ (39.3%) and Ph+ subgroups (38.1%). By 24 months, the cumulative rates of major molecular response (BCR-ABL1
IS
≤0.1%;), MR
4
, and MR
4.5
(BCR-ABL1
IS
≤0.0032%) were 85.7, 60.7, and 50.0%, respectively, in the Ph−/
BCR-ABL1
+ subgroup, and 80.3, 54.7, and 38.3%, respectively, in the Ph+ subgroup. In both Ph−/
BCR-ABL1
+ and Ph+ subgroups, rash (20 and 22%), pruritus (16.7 and 16.7%), nasopharyngitis (13.3 and 10.4%), fatigue (10 and 14.2%), headache (10 and 15.8%), and nausea (6.7 vs 11.4%) were frequent non-hematologic adverse events, whereas hypophosphatemia (23.3 and 6.8%), anemia (10 and 6.5%), and thrombocytopenia (3.3 and 10.2%) were the common hematologic/biochemical laboratory events.
Conclusion
Based on similar molecular response and safety results in both subgroups, we conclude that Ph−/
BCR-ABL1
+ patients benefit from nilotinib in the same way as Ph+ patients.
Autologous hematopoietic stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). However, many individuals are unable to collect optimal CD34
hematopoietic stem and progenitor ...cell (HSPC) numbers with granulocyte colony-stimulating factor (G-CSF) mobilization. Motixafortide is a novel cyclic-peptide CXCR4 inhibitor with extended in vivo activity. The GENESIS trial was a prospective, phase 3, double-blind, placebo-controlled, multicenter study with the objective of assessing the superiority of motixafortide + G-CSF over placebo + G-CSF to mobilize HSPCs for ASCT in MM. The primary endpoint was the proportion of patients collecting ≥6 × 10
CD34
cells kg
within two apheresis procedures; the secondary endpoint was to achieve this goal in one apheresis. A total of 122 adult patients with MM undergoing ASCT were enrolled at 18 sites across five countries and randomized (2:1) to motixafortide + G-CSF or placebo + G-CSF for HSPC mobilization. Motixafortide + G-CSF enabled 92.5% to successfully meet the primary endpoint versus 26.2% with placebo + G-CSF (odds ratio (OR) 53.3, 95% confidence interval (CI) 14.12-201.33, P < 0.0001). Motixafortide + G-CSF also enabled 88.8% to meet the secondary endpoint versus 9.5% with placebo + G-CSF (OR 118.0, 95% CI 25.36-549.35, P < 0.0001). Motixafortide + G-CSF was safe and well tolerated, with the most common treatment-emergent adverse events observed being transient, grade 1/2 injection site reactions (pain, 50%; erythema, 27.5%; pruritis, 21.3%). In conclusion, motixafortide + G-CSF mobilized significantly greater CD34
HSPC numbers within two apheresis procedures versus placebo + G-CSF while preferentially mobilizing increased numbers of immunophenotypically and transcriptionally primitive HSPCs. Trial Registration: ClinicalTrials.gov , NCT03246529.
Multiple myeloma (MM) is a heterogeneous disease. Evaluation of prognostic factors and risk stratification at diagnosis is necessary to compare outcome. Attempts have been made to apply a comorbidity ...score in the clinical sitting, but a standardized general approach is still lacking.
We hypothesized that a comprehensive examination of every associated disease in a large cohort of patients could better highlight the prognostic impact of comorbidity in MM.
All consecutive patients diagnosed in our institution, from 1993 to 2013, with symptomatic MM according to IMWG criteria were included in our population-based MM registry. Patients with plasma cell leukemia or with palliative management were excluded. Clinical variables analyzed were: age, sex, Durie-Salmon, International Scoring System (ISS), percentage of plasma cell in bone marrow by morphology (PC), serum creatinine (Cr) and estimated glomerular filtration rate according with Modification of Diet in Renal Disease (eGFR-MDRD). The following comorbodities were analysed: hypertension (HTA), diabetes (DM), obesity (OB) (body mass index > 30 Kg/m2), hyperlipaemia (HL), prior malignancy (PM), hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), peptic ulcer (PU), thromboembolism (TE), renal transplant (RT), splenectomy (S), cutaneous disease (CD), amyloidosis (AM), heart disease (HD) (arrhythmia, congestive heart failure, coronary artery disease, other), lung disease (LD) (chronic obstructive pulmonary disease, asthma, other), liver disease (HE) (cirrhosis, non-alcoholic fatty liver disease, other), neurological disorder (ND), psychiatric disorder (PD) and rheumatologic disorder (RD). Kaplan-Meier method was used to estimate OS curves. Cox regression was used to determine the prognostic impact of each comorbidity in a univariate and multivariate model.
311 patients were eligible. Median age was 66 years (12-91), 148 men (47.6 %) and 163 women. Percentage of comorbidities was: HTA 45; OB 32.5; DM 20.4; HD 20.4; LD 15.2; PU 10; HL 9.7; ND 8; PM 7.8; PD 6.5; HBV 3.9; HE 3.9; TE 3.6; RD 3,5; AM 2.3; HCV 1.9; CD 1.6; S 1; RT 0.6; HIV 0.3. 63 patients (20.4 %) showed no comorbidities. Univariate analysis (table 1) demonstrated that AM (P=0.022), HCV (0.038), HIV (0.022), PD (0.015) and ND (0.05) were significantly associated with shorter OS. The variables associated with mortality in the multivariate analysis were age (p=0.002), ISS (III vs I: p=0.01), PC (p=0.05) and Cr (p=0.02). Results will be validated in another MM series and presented during the meeting.
ComorbidityDefinitionN (%)Median OSHR (95% CI)P-valueHypertension-No-Yes170139 (45)31341,009(0,764-1,332)0,951Diabetes-No-Yes24663 (20,4)32421,111(0,794-1,554)0,540Obesity-No-Yes16479 (32,5)49361,226(0,861-1,745)0,258Hyperlipaemia-No-Yes27930 (9,7)32470,723(0,427-1,223)0,227Prior malignancy-No-Yes28524 (7,8)34291,172(0,712-1,928)0,533HBV-No-Yes29712 (3,9)32NR0,365(0,117-1,142)0,083HCV-No-Yes3036 (1,9)3372,575(1.053-6,294)0.038HIV-No-Yes3081 (0,3)33110,290(1,402-75,542)0,022Peptic ulcer-No-Yes27831 (10)32400,971(0,623-1,512)0,895Thromboembolism-No-Yes29811 (3,6)33331,777(0,936-3,372)0,079Renal transplant-No-Yes3072 (0,6)3352,075(0,288-14,934)0,468Splenectomy-No-Yes3063 (1)33291,5590,386-6,302)0,533Cutaneous disease-No-Yes3045 (1,6)33670,598(0,148-2,410)0,470Amyloidosis-No-Yes3037 (2,3)34132,428(1,139-5,176)0,022Heart disease-No-Yes-Arrhythmia-CHF-CAD-Other24763 (20,4)20211753332324229251,245(0,898-1,727)0,189Lung disease-No-Yes-COPD-Astma-Other26247 (15,2)2714632333152331,075(0,740-1,562)0,702Liver disease-No-Yes-Cirrhosis-NAFLD-Other29712 (3,9)264331018161,341(0,709-2,536)0,367Neurological disorder-No-Yes28625 (8)34241,610(0,989-2,621)0,056Psychiatric disorder-No-Yes28920 (6,5)33151,894(1,130-3,176)0,015Rheumatologic disorder-No-Yes30011 (3,5)33880,702(0,311-1,584)0,394
The overall prognosis of MM depends on a variety of host and disease-related characteristics. We confirm age, ISS, PC and Cr as robust and independent prognostic factors. Adjusting for these factors, no isolated comorbidity reach statistical significance; however, comorbidity seems to have a role in MM prognosis. More studies are warranted to define the prognostic impact of comorbidities in MM.
No relevant conflicts of interest to declare.
▪
Background: The cytogenetic hallmark of chronic myeloid leukemia (CML) is a translocation, t(9;22)(q34;q11), resulting in the Philadelphia (Ph) or derivative 22 chromosome. Cytogenetic studies ...indicate that 90-95% of cases have the Ph chromosome or recognized variant (Ph+ CML), with the remaining 5-10% having a normal or near normal karyotype despite the presence of the BCR-ABL fusion (Ph-negative, BCR-ABL-positive CML). Tyrosine kinase inhibitors (TKIs) have been approved for the treatment of patients with Ph+ CML. The effect of TKIs in patients with Ph- CML has not been described in detail.
Objective: ENEST1st (Evaluating Nilotinib Efficacy and Safety in clinical Trials as First-Line Treatment) sub-group analysis was planned to explore the effect of nilotinib in patients with Ph- CML.
Patients and Methods: ENEST1st (NCT01061177) is a phase 3b, multicenter, open-label study of nilotinib 300 mg twice daily (BID) in adults with newly diagnosed BCR-ABL+ CML-CP. Patients with confirmed Ph- CML-CP were included in the sub-analysis. Primary endpoint was rate of MR4 (defined as BCR-ABL ≤ 0.01% on the International Scale BCR-ABLIS or undetectable BCR-ABL in cDNA with ≥ 10,000 ABL transcripts) at 18 mo.
Results: Of the 1089 patients included in ENEST1st study, 30 patients (2.7%) were Ph- (only one of those had a cytogenetic aberration del9q34), 983 patients (90.3%) were Ph+ and 76 (7.0%) patients had an unknown karyotype at baseline. Among these patients, 28 pts (2.7%) Ph- and 952 pts (90.5%) Ph + with b2a2 and/or b3a2 BCR-ABL transcripts and treated with imatinib for ≤ 3 mo were analyzed for molecular response (MR).
Median age of patients with Ph- CML was 51.5 years (range, 21.0 to 75.0). EUTOS score was low in 86.7% and high in 6.7% of patients (6.7% missing). Sokal risk score was low, intermediate, and high in 33.3%, 30.0%, and 23.3% of patients, respectively (13.3% missing).
In Ph+ CML patients, the median age was 53.0 years (range, 18.0 to 91.0). EUTOS score was low in 82.0% and high in 9.2% of pts (8.9% missing). Sokal risk score was low, intermediate, and high in 34.8%, 37.2%, and 18.1% of pts, respectively (9.9% missing).
The MR4 rate at 18 mo in Ph- population was 39.3% (95% CI, 21.2% - 57.4%). The cumulative incidence of MR4 by18 mo was60.7% (95% CI, 42.6% - 78.8%). Rates of cumulative MMR (BCR-ABLIS ≤0.1%) and MR4.5 (BCR-ABLIS ≤0.0032%) by 18 mo were 85.7% (95% CI, 72.8% - 98.7%) and 46.4% (95% CI, 28.0% - 64.9%), respectively.
For the Ph+ CML population, the MR4 rate at 18 mo was 38.1% (95% CI, 35.0% - 41.2%).
The cumulative incidence of MR4 by 18 mo was48.1% (95% CI, 44.9% - 51.3%). Rates of cumulative MMR (BCR-ABLIS ≤0.1%) and MR4.5 (BCR-ABLIS ≤0.0032%) by 18 mo were 76.8% (95% CI, 74.1% - 79.5%) and 31.4% (95% CI, 28.5% - 34.4%), respectively.
Rates of MMR, MR4, and MR4.5 at 18 and 24 mo among Ph- population and the Ph+ CML population are summarized in the Table.
The 3-month BCR-ABL level has been shown to be predictive of MR in the Ph+ CML population.
Among Ph- population not pretreated with imatinib (n = 14), 85.7% achieved BCR-ABLIS ≤ 1%, no patients had BCR-ABLIS > 1% to ≤ 10% and > 10% at 3 mo. Two patients did not have the assessment at 3 mo.
Among patients with Ph+ CML not pretreated with imatinib (n = 802), 70.0% , 17.0%, and 2.7% of patients achieved BCR-ABLIS ≤ 1% , > 1% to ≤ 10%, and >10% respectively. Eighty-five patients did not have the assessment at 3 mo.
Most common AEs experienced by the Ph- population were hypophosphatemia (25%), rash (18%), pruritus (14%), nasopharyngitis (14%), alanine aminotransferase increase (14%), and blood bilirubin increase (14%). In the Ph+ population, the list of most common AEs includes rash (22%), pruritus (17%), headache (16%), and fatigue (14%).
Conclusions: The MR rates observed in Ph- CML subgroup are similar to the rates observed in Ph+ CML patients. These results indicate that nilotinib is active in this previously unexplored population as well and larger studies should be conducted to confirm the results. The safety results observed in Ph-CML patients are similar to the ones observed in the Ph+ CML pts.
aCML patients with typical b2a2 and/or b3a2 BCR-ABL transcripts and ≤3 mo of prior imatinib
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Hochhaus:ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Mahon:Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Coriu:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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. Ossenkoppele:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Cross:Ariad: Consultancy, Honoraria, Research Funding; Qiagen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Müller:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. Rea:Pfizer: Honoraria; Ariad: Honoraria; BMS: Honoraria; Novartis: Honoraria. Steegmann:Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria, Research Funding. Castagnetti:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria. Hellmann:Novartis: Research Funding; BMS: Research Funding. Rosti:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau. Gattermann:Novartis: Honoraria, Research Funding. Gutierrez:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; PFIZER: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tubazio:Novartis: Employment. Pellegrino:Novartis: Employment. Dezzani:Novartis: Employment. Giles:Novartis: Consultancy, Honoraria, Research Funding.
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