scholarly journals Geographical Distance from Quaternary Treatment Center Does Not Impact Choice of Upfront Therapy, Clinical Trial Participation and Outcomes in Patients with Newly Diagnosed AML

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 15-16
Author(s):  
Samantha A Hershenfeld ◽  
Steven M Chan ◽  
Vikas Gupta ◽  
Dawn Maze ◽  
Caroline J McNamara ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Research Funding ◽  
Performance Status ◽  
Treatment Center ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Quaternary Center ◽  
Upfront Therapy

Upfront therapy for newly diagnosed patients with acute myeloid leukemia (AML) includes intensive induction chemotherapy with curative intent, low dose chemotherapy, best supportive care, and clinical trials. The choice between these therapies is influenced by multiple factors including age, cytogenetic and molecular mutations, and performance status. In our single payer provincial health care system, induction chemotherapy and clinical trials are only offered at a small number of specialized quaternary care centers with geographically large catchment areas. As a result, some patients are required to travel long distances for their appointments, which may constitute a barrier to care, especially among elderly patients. We therefore asked whether distance from the quaternary center influences the choice of care for AML. We reviewed the records of patients ≥18 years of age diagnosed with AML from 2015-2017 and assessed at our quaternary care center in Toronto, Canada. We compared upfront therapy choice and survival between patients living close versus distant from the cancer center (empirically defined as <50 km versus >50km) and stratified by age. A total of 675 patients were assessed by our quaternary center for a new diagnosis of AML during the timeframe studied. Of those patients, 477 (71%) patients lived ≤50km, and 198 (29%) patients lived >50km from the quaternary center. The overall median distance from patient residence to the quaternary center was 33.2km (range: 1-1791km), and the median distance of patients in the >50km group was 93km (range: 50.2-1791km). Age, sex, baseline Eastern Cooperative Oncology Group Performance Status (ECOG), and cytogenetic risk were not significantly different between the two groups. There were no differences in the proportion of patients receiving induction chemotherapy or clinical trial as upfront therapy between patients living close versus distant from the quaternary center, even when stratified for age ≥70 years. There was no difference in overall survival between patients living ≤50km versus >50km from the quaternary center either overall, or when stratified by age. In conclusion, geographic distance from treatment center does not appear to impact choice of upfront therapy, access to clinical trials, or clinical outcomes in this study of newly diagnosed patients with AML treated in a single payer environment. Disclosures Gupta: Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Research Funding; Pfizer: Consultancy; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees. Maze:Novartis: Honoraria; Pfizer: Consultancy; Takeda: Research Funding. McNamara:Novartis: Honoraria. Schimmer:Takeda: Honoraria, Research Funding; Novartis: Honoraria; Jazz: Honoraria; Otsuka: Honoraria; Medivir AB: Research Funding; AbbVie Pharmaceuticals: Other: owns stock .

A Phase 1/2 Study of G-CSF, Cladribine, Cytarabine, and Dose-Escalated Mitoxantrone (G-CLAM) in Adults with Newly Diagnosed Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1068-1068 ◽  
Author(s):  
Anna B. Halpern ◽  
Megan Othus ◽  
Emily M Huebner ◽  
Kaysey F. Orlowski ◽  
Bart L. Scott ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Research Funding ◽  
Phase 1 ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Grade 3 ◽  
Dose Levels

Abstract Introduction:"7+3" with standard doses of cytarabine and an anthracycline has remained the mainstay of induction chemotherapy for newly diagnosed AML. Since some studies have shown improved outcomes with high-dose cytarabine, cladribine, or escalated doses of anthracyclines, we conducted a phase 1/2 study (NCT02044796) of G-CLAM using escalated doses of mitoxantrone for newly diagnosed AML or high-risk MDS (>10% blasts). Methods: Patients≥18 years were eligible if they had treatment-related mortality (TRM) scores of ≤6.9 (corresponding to a predicted risk of early death with standard induction chemotherapy of ≤6.9%) and adequate organ function (LVEF ≥45%, creatinine ≤2.0 mg/dL, bilirubin ≤2.5 times upper limit of normal). Excluded were patients with uncontrolled infection or concomitant illness with expected survival <1 year. In phase 1, cohorts of 6-12 patients were assigned to 1 of 4 total dose levels of mitoxantrone (12, 14, 16, or 18 mg/m2/day, days 1-3, compared to 10 mg/m2/day used in standard dose G-CLAM previously established in relapsed/refractory AML). Other drug doses were G-CSF 300 or 480 μg/day (for weight </≥76 kg; days 0-5), cladribine 5 mg/m2/day (days 1-5), and cytarabine 2 g/m2/day (days 1-5). In phase 2, patients were treated at the maximum tolerated dose (MTD) of mitoxantrone. A second identical course of G-CLAM was given if complete remission (CR) was not achieved with cycle 1. Up to 4 cycles of consolidation with G-CLA (mitoxantrone omitted) were allowed if CR or CR with incomplete platelet or blood count recovery (CRp/i) was achieved with 1-2 cycles of induction therapy. Dose-limiting toxicities (DLTs) were: 1) grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7-day delay of the subsequent treatment cycle; 2) grade ≥4 non-hematologic toxicity if recovery to grade ≤2 within 14 days, both excluding febrile neutropenia, infection or constitutional symptoms. Results: Among 33 patients (median age of 57.3 [range: 26-77], median TRM score 2.31 [0.16-5.90]) treated in phase 1, one DLT occurred at dose levels 3 and 4 (respiratory failure in both cases), establishing G-CLAM with mitoxantrone at 18 mg/m2/day as the MTD. Sixty-two patients, including 6 treated in phase 1, received G-CLAM at MTD. Patient characteristics were as follows: median age 58 (21-81) years, median TRM score 2.85 (0.06-6.73), with AML (n=52) or high-risk MDS (n=10). Cytogenetics were favorable in 6, intermediate in 44, and adverse in 12 (MRC criteria); 11 patients had NPM1 and 6 had FLT3 mutations. Fifty-two patients (83.9%, 95% confidence interval: 72.3-92.0%) achieved a CR (n=48 [77.4%: 65.0-87.1%]), or CRp/i (n=4 [6.5%: 1.8-15.7%]) with 1-2 cycles of therapy. Only 3 patients required 2 cycles to best response. Among the 48 CR patients, 43 (89.6%) were negative for measurable residual disease (MRDneg) by flow cytometry. Four patients had morphologic leukemia free state, 1 patient with myeloid sarcoma had a partial remission, 4 had resistant disease, and 1 died from indeterminate cause. One patient died within 28 days of treatment initiation (septic shock). Median times to an absolute neutrophil count ≥500/μL and a platelet count of ≥50,000/μL were 26 and 23 days. Besides infections and neutropenic fever, maculopapular rash, and hypoxia (fluid overload/infection-related) were the most common grade ≥3 adverse events. In addition to the phase 1/2 MTD cohort, there were 15 patients treated in an expansion cohort and 3 eligible patients treated off protocol with mitoxantrone at 18 mg/m2. For these 80 patients combined treated at MTD, the CR and CR/CRp/i rates were 76.3% and 81.2%. After multivariable adjustment, compared to 300 patients treated with 7+3 on the SWOG S0106 trial, G-CLAM with mitoxantrone 18mg/ m2 was associated with an increased probability of CR (odds ratio [OR]= 3.08, p=.02), CR/CRp/i (OR=2.96, p=.03), a trend towards improved MRDnegCR (OR= 3.70, p=.06), and a trend towards improved overall survival ([OS]; hazard ratio=0.34, p=.07). For the entire study cohort, the 6 and 12-month relapse-free survival were 73% (64-83%) and 62% (42-74%) and the 6 and 12-month OS were 89% (82- 96%) and 77% (67-88%). Conclusions: G-CLAM with mitoxantrone up to 18 mg/m2/day is well tolerated and has potent anti-leukemia activity. This regimen may warrant further randomized comparison with 7+3. We also plan to examine the addition of sorafenib to G-CLAM in newly diagnosed AML patients regardless of FLT3 status. Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Scott:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding. Erba:Ariad: Consultancy; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Sunesis: Consultancy; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Novartis: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Agios: Research Funding; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celator: Research Funding; Seattle Genetics: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Amgen: Consultancy, Research Funding.

A Phase I Study of Selinexor in Combination with Daunorubicin and Cytarabine in Patients with Newly Diagnosed Poor-Risk Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4040-4040 ◽  
Author(s):  
Kendra L. Sweet ◽  
Rami S. Komrokji ◽  
Eric Padron ◽  
Christopher L Cubitt ◽  
Leyla Khavarian ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Febrile Neutropenia ◽  
Phase I ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Poor Risk

Abstract Background: Induction chemotherapy for older adults with poor-risk AML has remained largely unchanged over the past 40 years, with complete remission (CR) rates ranging from 20-50%. Five-year overall survival (OS) ranges from 2-15%, illustrating the need for novel treatment strategies. Selinexor is an oral selective inhibitor of nuclear export (SINE) that has shown promising single agent activity in AML (NCT01607892). By inhibiting the primary export protein, XPO1, selinexor localizes tumor suppressor proteins to the nucleus leading to their activation. Furthermore, selinexor inhibits DNA damage repair, rationalizing its use in combination with DNA damaging agents. Preclinical data from our institution suggest Selinexor synergizes with daunorubicin when used in CD34+ AML cells. Here we report early results from a phase I clinical trial with selinexor plus cytarabine and daunorubicin in patients (pts) with newly diagnosed, poor-risk AML. Methods: This is a single institution phase I clinical trial with a 3+3 design and an expansion phase at the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). The primary endpoint was to determine the MTD/RP2D of selinexor. Secondary endpoints included rate of CR/CRi, overall survival (OS), relapse free survival (RFS) and toxicity assessment. Eligible pts had a diagnosis of previously untreated AML (non-M3), with poor-risk features based on karyotype, mutational profile, secondary AML (sAML) arising from an antecedent hematologic disorder (AHD) or prior chemotherapy, or age ≥60 years. Prior treatment for an AHD was allowed. Induction included daunorubicin 60 mg/m2/day on days 1-3 and cytarabine 100 mg/m2/day CIVI days 1-7 (7+3) with two dose cohorts of selinexor: 60 mg and 80 mg PO. Selinexor was given on days 1, 3, 8, 10, 15 and 17. Re-induction with 5+2 plus selinexor was allowed if indicated. Once in CR, pts received 1-2 cycles of consolidation with 5+2 plus selinexor followed by maintenance selinexor on days 1 and 8 of a 21 day cycle for up 12 months. Selinexor was given at the same dose for all phases of the study. Pts could proceed to hematopoietic stem cell transplant (HCT) at any time after achieving CR. Results: 21 pts (14 (67%) M / 7 (33%) F) were enrolled from June 2015 to June 2016. Median age was 68 years (range 37-77); 18 (86%) were age ≥60 and 9 (43%) were age ≥70. Nineteen (90%) pts were considered poor-risk (unrelated to age), and two (10%) were eligible due to age ≥60 only. Each cohort enrolled 4 pts, and 13 pts were enrolled in the expansion. One pt in each cohort was replaced before completing the 28-day DLT period; one withdrew consent and the second died on day 23 from acute renal failure related to antibiotics. At data cutoff, 18 pts were included in the safety and efficacy assessment. Three additional patients have not completed induction. The early death rate (≤60 days) was 4.8%. No DLTs occurred in the dose-escalation cohorts. The MTD of selinexor was not reached and the RP2D was 80 mg twice weekly. The most common grade 3/4 non-hematologic, treatment emergent AEs in all pts were febrile neutropenia (56%), diarrhea (22%), hyponatremia (22%) and sepsis (17%). Nine patients (50%) achieved CR/CRi. Of the 14 pts treated at the RP2D (selinexor 80 mg), 6 (43%) achieved CR/CRi. In the entire cohort, the median age of the responders was 69 (61-77) and 4 (44%) were age ≥70. Seven (78%) were considered high-risk. Four (44%) had sAML. Two (22%) required a second induction. The median time to response was 47 days (range 28-77) At a median follow up of 8.7 months in the 9 responding pts, 7 (78%) remain in remission. Overall, 4 pts (44%) underwent HCT, and 1 (11%) relapsed just prior to HCT. Conclusion: Results from this phase I trial suggest that selinexor 80mg PO twice weekly can be safely administered in combination with induction chemotherapy using cytarabine and daunorubicin to pts with poor-risk AML, including older pts. The most prominent AEs were febrile neutropenia, diarrhea and hyponatremia. Response rates are encouraging and many elderly pts proceeded to transplant, suggesting this regimen warrants further investigation in this challenging population. Disclosures Sweet: Karyopharm: Honoraria, Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau. Komrokji:Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sullivan:Karyopharm: Research Funding. Shah:Incyte: Research Funding; Rosetta Genomics: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria; Pfizer: Honoraria.

scholarly journals Physical and Psychological Impairments As Practical Frailty Markers in Elderly AML Fit for Intensive Chemotherapy; Interim Data of a Prospective Cohort Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3831-3831
Author(s):  
GI June MIN ◽  
Byung Sik Cho ◽  
Sung-Soo Park ◽  
Silvia Park ◽  
Young-Woo Jeon ◽  
...  
Keyword(s):  
Cohort Study ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Prospective Cohort ◽  
Research Funding ◽  
Handgrip Strength ◽  
Intensive Chemotherapy ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Elderly Aml

Background The comprehensive geriatric assessment (CGA) typically refers to a multidimensional assessment designed to evaluate an older person's functional ability, physical health, cognition, psychological health, nutritional status, and social support. There is a significant heterogeneity in terms of their underlying health and resilience to the burden of disease and treatments in elderly AML (eAML). To date, a few have evaluated the predictive value of CGA among newly diagnosed eAML. The purpose of this study is to investigate the potential clinical value of CGA as a screening test for frailty in eAML. We designed a comprehensive CGA battery with measures which previously validated, standardized, and widely used. This study is a single-center prospective observational cohort study focused on discriminating between those older patients who are fit for intensive therapies and those who are vulnerable and may experience excess toxicity. Patients and method This prospective cohort study is to investigate the predictive values of each domain of CGA to discriminate vulnerable patients in eAML fit for intensive chemotherapy. Between November 2016 and July 2019, we enrolled newly diagnosed eAML patients aged ≥60 years considered fit for intensive chemotherapy, who had adequate performances and organ functions. All the enrolled patients were administered various questionnaires for an initial CGA and functional evaluation divided into 3 categories; (1) Social and Nutritional support (OARS and MNA), (2) Psychological (MMSE-KC, SGDS-K, PHQ-9, NCCN distress thermometer, MADRS, and KNU-DESC), and (3) Physical function (ECOG, KIADL, SPPB, Handgrip strength, and PTA by professional ENT evaluation). Results Seventy-seven patients were enrolled, in whom the median age of 64 years (range, 60-74), 58.4% were males, and 93.5% and 77.9% of patients had on ECOG score of 0~1 and HCT-CI score of 0~2, respectively. All enrolled patients were treated with intensive chemotherapy, and 62.3% achieved the first complete remission. Three patients experienced early death within 60 days (3.9%). During induction chemotherapy, the median recovery period for neutrophil and platelet counts was 26 (range, 24-29) and 30 (range, 27-33) days, respectively. The median hospitalization days for induction chemotherapy were 32 days (range, 21-104), and infection and GI complications (NCI-CTC-AE based any grade 79.2% and 67.5% respectively) were the most common complications primarily affecting tolerance to the initial chemotherapy. The grade III to IV infection, GI complications, hepatopathy, and acute kidney injury developed in 67.5%, 42.9%, 37.7%, and 16.9% of patients, respectively. Physical impairments were significantly associated with a higher incidence of infection (intact vs. any impairments; 46.4% vs. 79.6%, p=0.003), of which handgrip strength was most accurate tool to predict infection risk (p =0.032), and a trend of more GI complications (intact vs. any impairments; 28.6% vs. 51.0%, p=0.056), resulting in prolonged hospitalization (intact vs. any impairments; 32.2±1.7 days vs. 37.5±2.1 days, p=0.088) for the period of induction chemotherapy. Psychological impairment (intact vs. any impairments; 30.9±1.3 days vs. 38.2±2.1 days, p=0.005), particularly cognitive dysfunction measured by MMSE-KC (p=0.033), was also significantly associated with prolonged hospitalization. Conclusions This data demonstrates that a significant proportion of eAML fit for intensive chemotherapy based on performance status and comorbidity had social, nutritional, physical, psychological impairments by initial CGA assessments. These interim data focusing on early events suggest that impaired physical and/or psychological functions would be useful to identify eAML with intolerance to intensive chemotherapy. This ongoing exploratory prospective study will enroll more eAML patients (targets number=100) and further follow up currently enrolled patients, which will give us invaluable data to develop practical frailty marker and a new model for fitness for intensive chemotherapy. Disclosures Kim: Takeda: Research Funding; Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Il-Yang co.: Research Funding. Lee:Achillion: Research Funding; Alexion: Consultancy, Honoraria, Research Funding. Kim:Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding.

Outcomes of Patients with CRLF2-Overexpressing Acute Lymphoblastic Leukemia without Down Syndrome: A Report from the Children's Oncology Group

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 45-46
Author(s):  
Sarah K Tasian ◽  
Yunfeng Dai ◽  
Meenakshi Devidas ◽  
Kathryn G Roberts ◽  
Richard C Harvey ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Down Syndrome ◽  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Clinical Outcomes ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Newly Diagnosed ◽  
Oncology Group ◽  
Advisory Committees

Background: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) occurs in 5-30% of children and adolescents/young adults (AYAs) with B-ALL, is driven by genetic alterations that induce constitutive cytokine receptor and kinase signaling, and is associated with poor clinical outcomes across the older pediatric-to-adult age spectrum (Tasian Blood 2017c, Reshmi Blood 2017, Roberts Blood 2018). Rearrangement and/or overexpression of cytokine receptor-like factor 2 (CRLF2+) occurs in 50% of Ph-like ALL cases with frequently co-occurring JAK2 or JAK1 point mutations or IL7R indel mutations. This study reports the clinical outcomes of children and AYAs with newly-diagnosed National Cancer Institute (NCI) standard-risk (SR) or high-risk (HR) CRLF2+ ALL without Down syndrome treated on four successive Children's Oncology Group (COG) phase 3 clinical trials from 2003 to 2018. Methods: We retrospectively assessed demographic characteristics, laboratory data, and clinical outcomes of 3757 patients with B-ALL treated on COG trials AALL0331 and AALL0932 (SR) and AALL0232 and AALL1131 (HR) whose diagnostic leukemia specimens were analysed by low-density microarray (LDA), fluorescence in situ hybridization, polymerase chain reaction (PCR), and/or anchored multiplex PCR testing (Harvey and Tasian Blood Advances 2020). Minimal residual disease (MRD) was assessed by flow cytometry at the end of induction (EOI) and at the end of consolidation for a subset of EOI MRD+ patients. Results: We identified 77/1541 (5.0%) SR and 244/2216 (11.0%) HR patients with CRLF2+ B-ALL in this cohort. Amongst those with diagnostic leukemia specimens analysed by LDA, 57/72 (79.2%) of SR CRLF2+ and 175/213 (82.2%) of HR CRLF2+ patients were positive for the Ph-like gene expression profile with an 8-gene score ≥0.5. P2RY8-CRLF2 fusions and IGH-CRLF2 translocations were detected in 64/77 (83.1%) and 10/77 (13.0%) of SR CRLF2+ patients and in 98/244 (40.2%) and 103/244 (42.2%) of HR CRLF2+ patients, respectively. CRLF2 rearrangements or F232C mutations were not found in the remaining 3 SR and 43 HR CRLF2+ patients, although other Ph-like alterations were discovered in some (n=3 IGH-EPOR fusions, 1 IL7R indel). Importantly, CRLF2+ vs non-CRLF2-overexpressing (CRLF2-) status was associated with older age (10.8 ±6.5 vs 7.8 ±5.8 years [mean ±SD], p&lt;0.0001), leukocytosis (diagnostic white blood cell count 77.5 ±98.5 vs 49.8 ±119.4 x 10e9/L [mean ±SD], p&lt;0.0001), and higher rates of EOI MRD positivity at a ≥0.01% threshold (47.9% vs 30.1%, p&lt;0.0001), which appeared largely driven by the Ph-like HR cohort as expected (57.9% MRD+ vs 42.1% MRD- in HR CRLF2+ and 44.6% MRD+ vs 55.4% MRD- in SR CRLF2+ patients, p&lt;0.003). Overall, CRLF2+ patients had inferior 5-year event-free survival (EFS; 63.3% ±3.1 vs 82.1% ±0.7, p&lt;0.0001) and overall survival (OS; 79.6% ±2.6 vs 90.5% ±0.6, p&lt;0.0001) compared to CRLF2- patients (Figure 1A-B) and a greater 5-year cumulative incidence of relapse (CIR; 30.4% ±2.7 vs 13.2% ±0.6, p&lt;0.001). While 5-year EFS and OS were particularly poor in Ph-like CRLF2+ HR patients (56.3% ±4.6 and 75.4% ± 3.9, respectively) and non-Ph-like CRLF2+ HR patients (EFS 63.7% ±10.2 and OS 74.4% ±8.9), outcomes for Ph-like CRLF2+ SR (EFS 87.2% ±4.5 and OS 94.5% ±3.1) and non-Ph-like CRLF2+ SR patients (EFS 86.2% ±9.3 and OS 100%) were quite good (p&lt;0.0001 for both EFS and OS; Figure 1C-D). Discussion: Patients with newly-diagnosed CRLF2+ B-ALL treated on frontline COG trials have higher rates of EOI MRD positivity, inferior survival, and increased CIR compared to their CRLF2- counterparts. EFS is especially poor in children and AYAs with NCI HR CRLF2+ ALL, particularly those with the Ph-like expression profile. Conversely, outcomes for children with NCI SR CRLF2+ ALL are reasonably favourable, irrespective of Ph-like status. Development of successful treatment strategies to decrease relapse and to improve survival remains a major therapeutic gap for NCI HR CRLF2+ ALL patients. Current clinical trials are studying the potential efficacy of kinase inhibitor addition to chemotherapy for children, adolescents, and adults with HR Ph-like ALL harboring CRLF2 rearrangements/other JAK pathway alterations or ABL class kinase fusions (NCT0240717, NCT02723994, NCT02883049, NCT03571321). Figure 1 Disclosures Tasian: Gilead Sciences: Research Funding; Incyte Corporation: Research Funding; Aleta Biotherapeutics: Membership on an entity's Board of Directors or advisory committees. Borowitz:Amgen: Honoraria. Mullighan:AbbVie, Inc.: Research Funding; Illumina: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau. Hunger:Novartis: Consultancy; Amgen: Current equity holder in publicly-traded company, Honoraria. Raetz:Pfizer: Research Funding; Celgene/BMS: Other. Loh:Pfizer: Other: Institutional Research Funding; Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Determinants of Clinical Trial Participation and Impact on Survival Outcomes Among Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5833-5833
Author(s):  
Gabriella C Malave ◽  
Prashant Kapoor ◽  
Angela Dispenzieri ◽  
Morie A. Gertz ◽  
Martha Q. Lacy ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Clinical Trials ◽  
Board Of Directors ◽  
Research Funding ◽  
Trial Participation ◽  
Newly Diagnosed ◽  
Clinical Trial Participation ◽  
Advisory Committees ◽  
Baseline Characteristics

Background: The overall participation of cancer patients in interventional clinical trials in the United States remains very low, with ~5% of patients being enrolled in clinical trials nationwide. The outcomes of patients with MM have improved significantly over the past decade, but available data suggest that the participation rates for patients with MM is comparable to other cancers. The drivers of participation and the potential impact of clinical trial participation have not been systematically studied in MM. Patients and Methods: We identified 228 patients who were enrolled into clinical trials for initial therapy of newly diagnosed MM between 2004 and 2018, and 4 controls for each of these patients. Controls were patients with NDMM, who were diagnosed closest in time to the index patients and did not participate in an interventional treatment trial. Various baseline characteristics as well as overall survival were compared between the two groups. Results: The baseline characteristics of the two groups are as shown in the Table. Patients who entered clinical trials were more likely to be female, resided closer to the clinic, and were more likely to have a prior history of MGUS. They were more likely to have higher ISS Stage, and a higher serum LDH, but there was no difference in the FISH risk status. Other indices of disease burden such as lower hemoglobin and platelets, higher serum creatinine were all seen more often in the control group, but may have been influenced by the trial entry criteria. Looking at the outcomes, the overall survival was longer among those enrolled into clinical trials compared to those who did not [median 103 (95% CI; 86, 136) vs. 63 (95% CI; 53, 69) months, p<0.001 (Figure). Conclusions: The current study provides important clues regarding demographic determinants of trial participation and disease biology related features that reflect likelihood of trial participation. Overall survival was significantly longer among the trial participants, which likely represent a mix of reasons including baseline status of patients, intensity of monitoring and efficacy of novel treatment approaches. Table Disclosures Kapoor: Janssen: Research Funding; Celgene: Honoraria; Cellectar: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Glaxo Smith Kline: Research Funding; Takeda: Honoraria, Research Funding. Dispenzieri:Alnylam: Research Funding; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Akcea: Consultancy; Intellia: Consultancy. Gertz:Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Spectrum: Honoraria, Research Funding. Lacy:Celgene: Research Funding. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy. Leung:Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees. Russell:Imanis: Equity Ownership. Kumar:Takeda: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

PTPN11 Mutations Are Associated with Poor Outcomes across Myeloid Malignancies

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-9
Author(s):  
David M Swoboda ◽  
Najla E. Al Ali ◽  
Eric Padron ◽  
Andrew T. Kuykendall ◽  
Jinming Song ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Research Funding ◽  
Juvenile Myelomonocytic Leukemia ◽  
Newly Diagnosed ◽  
Wild Type ◽  
Advisory Committees ◽  
Myeloid Malignancies ◽  
Poor Outcomes

Background: Gain of function mutations of the PTPN11 gene encoding SHP2 tyrosine phosphtase are commonly seen in juvenile myelomonocytic leukemia and rarely observed in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In AML, PTPN11 mutation (mt) is associated with poor outcomes (Alfayez et al. Leukemia 2020). However, PTPN11 is not well characterized in other myeloid malignancies. Patients and Methods: Between 2013 and 2019, all pts with myeloid malignancies and PTPN11 mt at Moffitt Cancer Center were identified with clinical variables obtained at time of diagnosis. Newly diagnosed and previously treated patients (pts) were included. Overall survival was calculated from time of PTPN11 detection by next generation sequencing. Results: We identified 78 PTPN11-mt pts, AML (56), MDS (14), MDS/MPN (4) and PMF (4). The majority (63%) of PTPN11-mt were detected at time of diagnosis. Median age was 68 years. Cytogenetics included normal (49%), complex (15%), chr. 7(19%) and chr. 5 (8%) abnormalities. Co-mutations observed in &gt;10% were DNMT3A, NPM1, TET2, ASXL1, RUNX1, BCOR, FLT3 ITD, U2AF1, NRAS and SRSF2. In multivariate analysis including age, karyotype category and allogeneic hematopoietic stem cell transplant (AHSCT), U2AF1 was an independent covariate for inferior survival (HR 3.9 p=0.001). In newly diagnosed PTPN11-mt pts, PTPN11 VAF &gt;20% was associated with worse outcomes (OS 8.9 vs 20.5mo p=0.043). AHSCT, which occurred 30% of pts, (n=23) was associated with improved OS (24.4 vs 5.5mo p&lt;0.001). WWe then compared PTPN11-mt to wild type (wt) pts among each disease category. In PTPN11-mt AML (n=56 vs n=380 in wt AML), there was female predominance (54% vs 39% p=0.04), platelet count was higher (65 vs 45 p=0.02) and no PTPN11-mt had favorable cytogenetics (0 vs 9% p=0.02). NPM1, NRAS and SRSF2 were more prevalent in PTPN11-mt AML (p&lt;0.05). There was no difference in ORR and CR rates between mt and wt patients when comparing induction chemotherapy or hypomethylating agent. Among PTPN11-mt AML pts 32% underwent AHSCT vs 26% in wt (p=0.34). PTPN11-mt AML pts who underwent AHSCT had an OS of 24.4 vs 42.7 mo. (p=0.025) whereas OS in pts that did not undergo AHSCT was 5.6 vs 10.1 mo. (p=0.04). In our cohort, AHSCT significantly improved outcomes for PTPN11-mt AML pts (OS 5.6 vs 24.4 p=0.001). Of the 13 pts that underwent AHSCT in PTPN11-mt AML, 92.3% (n=12) received induction chemotherapy. Finally, in multivariate analysis including age, ECOG, sAML, ELN and AHSCT, PTPN11 was an independent predictor of poor outcomes (HR 1.58 p=0.015). WNext, we evaluated pts with PTPN11-mt (n=14) vs wt (n=106) MDS. PTPN11-mt MDS pts had higher bone marrow blast % (9 vs 3 p=0.026) and more pts with MDS-EB1/2 by WHO (11/14 (79%) vs 49/105 (46%) p=.043). Interesting however, no PTPN11-mt MDS pts had complex karyotype and there was no difference in IPSS-R categories between groups. ASXL1, RUNX1 and SRSF2 were more frequently co-mutated in PTPN11-mt MDS (p&lt;0.05) however no pts had monocyte % &gt;10. In newly diagnosed cohort, there were no responses to frontline HMA (ORR 0/5 (0%) for mt vs 16/34(47%) wt p=0.066). Additionally, PTPN11-mt MDS had significantly worse outcomes (OS 8.7 vs 22.3 mo. p=0.001). In multivariate analysis include age, IPSS-R and AHSCT, the survival disadvantage was maintained (HR 2.9 p=0.018). WFinally, although rare, we evaluated pts with PTPN11-mt MDS/MPN and PMF. We first compared the 4 PTPN11-mt MDS/MPN (3 CMML, 1 MDS/MPN-U) pts to a cohort of 62 PTPN11-wt MDS/MPN (53 CMML). Clinical characteristics were similar between the two cohorts with the exception of increased blast % (10 vs 4) and lower baseline hemoglobin (7.6 vs 10.9) neither of which was significant. Median time to AML transformation was 1.7 mo. in PTPN11-mt. PTPN11-mt MDS/MPN had significantly worse outcomes compared to wild type (OS 2.2 vs 15.5 mo. p=0.001). We then compared 4 PTPN11-mt PMF pts with 49 wt. There were no clinical or mutational differences between cohorts. When evaluating newly diagnosed PMF, PTPN11-mt appeared to predict worse outcomes (OS 3.4 vs 12.3 p=.063) however this was not statistically significant due to sample size. Conclusions: The overall outcome of PTPN11-mt patients appear dismal across myeloid malignancies. In patients that are eligible, high intensity therapy followed by BMT resulted in the best outcome in PTPN11-mt AML. In conclusion, novel therapies are needed to target this high-risk subtype of myeloid malignancies. Figure Disclosures Padron: Kura: Research Funding; Incyte: Research Funding; BMS: Research Funding; Novartis: Honoraria. Kuykendall:Novartis: Research Funding; Incyte: Research Funding; BMS: Research Funding; Blueprint Medicines: Research Funding. Lancet:Astellas Pharma: Consultancy; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria. Sweet:Agios: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; BMS: Membership on an entity's Board of Directors or advisory committees; Stemline: Honoraria. Sallman:Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy; Celgene, Jazz Pharma: Research Funding. Komrokji:Novartis: Honoraria; Acceleron: Honoraria; Incyte: Honoraria; Abbvie: Honoraria; Geron: Honoraria; Jazz: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Agios: Speakers Bureau.

A Phase II Study of Modified Lenalidomide, Bortezomib, and Dexamethasone (RVD lite) for Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3454-3454 ◽  
Author(s):  
Elizabeth O'Donnell ◽  
Jacob P. Laubach ◽  
Andrew J Yee ◽  
Carol Ann Huff ◽  
Frank Basile ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Interim Analysis ◽  
Research Funding ◽  
Response Rate ◽  
Performance Status ◽  
Pharmacokinetic Analysis ◽  
Newly Diagnosed ◽  
Ecog Performance Status ◽  
Advisory Committees

Abstract Background: Multiple myeloma (MM) is primarily a disease of older adults with a median age at diagnosis of 66 years. Despite significant improvements in patient outcomes, there is a lag in survival in older transplant-ineligible patients compared to their younger counterparts. Traditionally, melphalan and prednisone-based regimens were the most widely accepted treatment options in this older, transplant-ineligible population. More recently, the FIRST trial has explored the use of lenalidomide and dexamethasone in these patients. Here, we sought to incorporate optimal novel agent-containing regimens in transplant-ineligible, older patients that balance efficacy with toxicity. Building on our prior experience with RVD in predominantly younger patients, our study evaluated a 3-drug regimen of modified RVD in the transplant-ineligible population. Methods: Modified RVD (“RVD-lite”) was administered over a 35-day cycle. Lenalidomide was given as a single daily oral dose of 15 mg days 1-21; bortezomib 1.3 mg/m2 once weekly subcutaneously on days 1, 8, 15, and 22; and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22 and 23 for patients ≤75 yrs and days 1, 8, 15, 22 for patients older than 75 yrs. Intravenous bortezomib was used only in cycle 1 for the first 10 patients for pharmacokinetic analysis. Eligibility requirements included ECOG performance status ≤ 2 and acceptable hepatic, renal and hematologic function. The primary objective was to evaluate the objective response rate (ORR) of modified RVD in transplant-ineligible patients. Secondary objectives included evaluation of the safety profile of modified RVD, progression free survival, overall survival, time to response, response duration, the response rate with respect to cytogenetics, and the pharmacokinetic profile of intravenous and subcutaneous bortezomib. Exploratory analysis will determine minimal residual disease (MRD) status by genotyping and correlate with outcomes in patients who achieve a VGPR or better. Results: Forty-one eligible patients have enrolled between 4/17/13 and 7/18/14, and of those 38 received at least one dose of therapy. Median age at study entry was 73 years (range 65-91) with 22 women and 16 men. ECOG performance status of patients enrolled was 0 in 19 (46.3%), 1 in 15 (36.6%), and 2 in 6 (14.6%) patients. The ISS stage was I in 15 (36.6%), II in 9 (22.0%), and III in 10 (24.4%) patients. Treatment-related toxicities were reported for 34 subjects. Fatigue was the most commonly reported toxicity occurring in 17/34 (50.0%), and of those 16/17 were grade 1 or 2 and manageable. Peripheral neuropathy of any grade was reported in 14/34 (41.2%) of patients including Grade 1 -7 (20.6%), 2 – 6 (17.6%), and 3 – 1 (2.9%). 12/34 (35.3%) reported edema of which 11/12 (91.7%) were grade 1. Grade 3 or greater toxicities included hypophosphatemia - 11 (32.3%), Rash - 4 (11.8%), and mood changes - 2 (5.9%). Pharmacokinetic data comparing intravenous and subcutaneous dosing of bortezomib has been completed and analysis is in process. At a planned interim analysis after 4 cycles that included 33 patients, the investigator-reported ORR of PR or better was 81.8% (CR -5, VGPR – 11, PR - 11, SD 3). Three patients withdrew from the study after less than 1 cycle. Of those, one withdrew for worsening adrenal insufficiency, one for rash attributed to lenalidomide, and one for an unrelated toxicity prompting withdrawal at the Investigator’s discretion. Five additional patients have enrolled but have not completed 4 cycles. Of those, responses thus far include 1 CR, 2 PRs, 1 SD, and 1 patient who has not completed one cycle at the time of this analysis. Exploratory data on bone marrow samples on patients achieving VGPR or better have been collected and analysis for MRD is in process. Conclusions: ModifiedRVD appears to be a well-tolerated and highly effective regimen in the transplant-ineligible population. The ORR rate after up to 4 cycles suggests that this combination at the modified doses and on a weekly schedule is very active. The side effect profile proved manageable and well-tolerated in an older population despite the variance of performance statuses at study entrance. Interim analysis of 38 patients suggests that alternative dosing and schedule of RVD may both improve tolerability and enhance clinical benefit in newly diagnosed, transplant-ineligible MM patients. Disclosures Laubach: Onyx, Novartis, Millenium, Celgene: Research Funding. Huff:Celgene, Millenium: Consultancy. Basile:Celgene: Speakers Bureau. Ghobrial:Millennium/Takeda: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Schlossman:Millennium: Consultancy. Munshi:Celgene, Onyx, Janssen, Sanofi-Aventi, Oncopep: Consultancy; Oncopep: Equity Ownership; Oncopep: Oncopep Patents & Royalties. Richardson:Celgene, Millenium, Johnson&Johnson: Membership on an entity's Board of Directors or advisory committees. Raje:Amgen, Novartis, Onyx, Celgene, Millenium: Consultancy; Eli Lilly, Acetylon: Research Funding.

A Phase II Study of Modified Lenalidomide, Bortezomib, and Dexamethasone (RVD-lite) for Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4217-4217 ◽  
Author(s):  
Elizabeth K. O'Donnell ◽  
Jacob P. Laubach ◽  
Andrew J. Yee ◽  
Carol A. Huff ◽  
Frank G. Basile ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Performance Status ◽  
Plasma Concentrations ◽  
Newly Diagnosed ◽  
Ecog Performance Status ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background: Multiple myeloma (MM) is primarily a disease of older adults with median age at diagnosis of 66 years. Although melphalan and prednisone-based regimens were traditionally the most accepted treatment options, recent use of lenalidomide and dexamethasone in this older, transplant-ineligible population as presented in the FIRST trial is the new standard of care in these patients (pts) (NEJM 2014). Here, we sought a regimen that incorporates optimal novel agents in transplant-ineligible, older pts that balances efficacy with toxicity. Building on our promising prior experience with RVD in predominantly younger pts (Blood 2010), our study evaluated a 3-drug regimen of modified RVD in the transplant-ineligible population. Methods: Modified RVD ("RVD-lite") was administered over a 35-day cycle. Lenalidomide 15 mg was given on days 1-21; bortezomib 1.3 mg/m2 once weekly subcutaneously (SC) on days 1, 8, 15, and 22; and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22 and 23 for pts ≤75 yrs and days 1, 8, 15, 22 for pts older than 75 yrs. Intravenous (IV) bortezomib was used in cycle 1 for the first 10 pts for pharmacokinetic (PK) analysis. Eligibility requirements included ECOG performance status ≤ 2 and acceptable hepatic, renal and hematologic function. The primary objective was to evaluate the objective response rate (ORR) of modified RVD in transplant-ineligible pts. Secondary objectives included evaluation of the safety profile, progression free survival (PFS), overall survival, response rate with respect to cytogenetics, and the PK profile of IV and SC bortezomib. Exploratory analysis will determine minimal residual disease (MRD) status by deep sequencing and correlate with outcomes in patients who achieve a VGPR or better. Results: Fifty-three eligible pts have enrolled between 4/17/13 and 7/25/15, and of those, 50 received at least one dose of therapy. Median age at study entry was 72 years (range 65-91) with 29 women and 24 men. ECOG performance status of pts enrolled was 0 in 25 (47%), 1 in 20 (38%), and 2 in 8 (15 %) pts. The ISS stage was I in 21 (40%), II in 16 (30%), and III in 16 (30%) pts. Treatment-related toxicities were reported for 49 pts. Fatigue was the most commonly reported toxicity occurring in 31/49 (63%), and was mostly grade 1 or 2 and manageable (25/31). Peripheral neuropathy of any grade was reported in 21/49 (43%) pts including grade 1 (11, 22%), 2 (9, 18%), and 3 (1, 2%). Grade 3 or greater toxicities included hypophosphatemia in 15 (31%) and rash in 5 (10%) pts. PK data comparing IV and SC dosing showed no significant differences in plasma concentrations of bortezomib at 5 hours. In the SC route, high body mass index (BMI) patients tended to have low concentration at both the 5 and 30 minute measures but not at 5 hours. There was no correlation with BMI using the IV route. At the planned analysis after 4 cycles that now includes 40 pts, the investigator-reported ORR of PR or better was 90% (CR - 10, VGPR - 14, PR - 12, SD - 4). Five pts withdrew from the study after less than 4 cycles. Of those, one withdrew for worsening adrenal insufficiency, one for rash attributed to lenalidomide, one at the Investigator's discretion, and two for excessive travel distance. Five additional pts have been enrolled but have not completed 4 cycles. Of 48 evaluable patients, the median survival has not been reached. Median duration of follow-up is 17.2 months and the 1-year PFS is 95% (95% CI 0.888, 1) and 2-year PFS is 68% (95% CI 0.512, 0.908). Exploratory data on bone marrow samples on pts achieving VGPR or better have been collected and analysis for MRD is in process. Gene expression profiling was performed using MMprofiler (SkylineDx). High-risk signature will be correlated with pt outcomes. Conclusions: ModifiedRVD is a well-tolerated and highly effective regimen in the transplant-ineligible population. The ORR rate after 4 cycles suggests that this combination at modified doses and on a weekly schedule is very active. The side effect profile proved manageable and was well tolerated in an older population despite the variance of performance status at study entry. There were no significant differences in plasma concentrations of bortezomib observed between IV and SC dosing. The study is fully accrued and this analysis suggests that alternative dosing and schedule of RVD may both improve tolerability and enhance clinical benefit in newly diagnosed, transplant-ineligible MM pts. Disclosures O'Donnell: Millennium: Consultancy. Laubach:Novartis: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Schlossman:Millennium: Consultancy. Anderson:Millennium: Consultancy; BMS: Consultancy; Gilead: Consultancy; Oncopep: Equity Ownership; Acetylon: Equity Ownership; Celgene: Consultancy. Richardson:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Raje:AstraZeneca: Research Funding; Onyx: Consultancy; Millenium: Consultancy; Acetylon: Research Funding; Eli Lilly: Research Funding; Novartis: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; BMS: Consultancy; Amgen: Consultancy.

scholarly journals Anthracycline Choices for Induction Chemotherapy Among 797 Consecutive Adult Patients with Acute Myeloid Leukemia: Daunorubicin-60 Vs Idarubicin-12 Vs Daunorubicin-90

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1267-1267
Author(s):  
Kebede H. Begna ◽  
Naseema Gangat ◽  
Mithun V. Shah ◽  
Hassan B. Alkhateeb ◽  
Mrinal M. Patnaik ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Advisory Board ◽  
Risk Category ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Treatment Groups

Abstract Objective : We describe the Mayo Clinic experience in 797 newly-diagnosed patients with acute myeloid leukemia (AML) serially treated with 7+3 induction chemotherapy that included 3 days of daunorubicin at a daily dose of 60 mg/m2 (dauno-60; n=239) or 90 mg/m2 (dauno-90; n=52), or idarubicin 12 mg/m2 (IDA-12; n=506). Our objective was to compare overall (OS) and relapse-free (RFS) survival outcome. Methods : Newly-diagnosed AML patients seen at our institution and received intensive induction chemotherapy were identified from the Mayo Clinic AML database. Treatment period spanned from January 2004 through May 2021. Follow-up information was updated as of June 2021. Conventional criteria were used to diagnose AML, assign cytogenetic risk category, and classify treatment response. Results : The study group included 797 patients (median age 60 years, range 18-88; 58% males): 506 (63%) patients received IDA-12, 239 (30%) dauno-60, and 52 (7%) dauno-90. The respective median (range) ages were 60 (18-88), 61 (19-82), and 53 (22-72) years (p=0.01) (Table). Primary, secondary, and therapy-related AML accounted for 65%, 25% and 10% of patients treated with IDA-12, 69%, 22%, and 9% of those treated with dauno-60, and 75%, 23% and 2% of patients treated with dauno-90, respectively (p=0.1). The corresponding frequencies of adverse karyotype were 34%, 25% and 25% (p=0.05). CR/CRi was documented in 78% (620/793) of all evaluable patients: IDA-12 80% (400/503), dauno-60 75% (175/238), and dauno-90 87% (45/52) (p=0.1). 210 (34%) patients underwent allogenic hematopoietic stem cell transplant (AHSCT), including 125 (25%), 59 (25%) and 26 (50%) patients, in the three treatment groups, respectively (p=0.0004). After a median (range) follow up 19 (0.2-203) months, 348 (54%) relapses and 518 (65%) deaths were documented. Median (range) survivals for IDA-12, dauno-60 and dauno-90 groups were 21 (0.3-243), 14.5 (0.45-198), and 27.7 (0.2-180) months (p=0.07; figure 1). The respective 1-, 3-, and 5-year OS rates were 67%, 42%, and 34% (IDA-12); 66%, 37%, and 30% (dauno-60); and 78%, 51%, and 49% (dauno-90), respectively; the trend favoring dauno-90 was no longer apparent during age-adjusted analysis (p=0.33). Multivariable analysis that accounted for age, cytogenetic risk category, FLT3-ITD/NPM1 status and AML subtype confirmed the lack of additional contribution from IDA-12 vs dauno-60 vs dauno-90 (p=0.2) while affirming the independent prognostic value of the other four variables; AHSCT carried an additional predictive value for superior survival without altering these results. A total of 348 (54%) relapses were documented: 228 (57%) in the IDA-12; 99 (57%) in the dauno-60; and 21 (47%) in the dauno-90 cohorts (p=0.7); RFS was similar in the three treatment groups (p=0.1; figure 2). Conclusion :In the current large single-institution study of consecutive adult patients with AML, neither the choice of anthracycline (idarubicin vs daunorubicin) or the dose of daunorubicin (60 vs 90 mg/m2) appeared to effect outcome in terms of remission rates or overall or relapse-free survival. The study otherwise confirms the independent favorable effect of younger age, non-adverse karyotype, FLT3-ITD-/NPM1+ status, and AHSCT. Figure 1 Figure 1. Disclosures Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Litzow: Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Jazz: Other: Advisory Board; Biosight: Other: Data monitoring committee; Omeros: Other: Advisory Board; AbbVie: Research Funding; Astellas: Research Funding.

Pretreatment Next-Generation Sequencing Is Associated with Response to Induction Chemotherapy in Patients Newly Diagnosed with Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-34
Author(s):  
Anastasia Tsagianni ◽  
Konstantinos Lontos ◽  
Mounzer Agha ◽  
Anastasios Raptis ◽  
Jing-Zhou Hou ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Secondary Aml ◽  
Tp53 Mutations ◽  
Generation Sequencing ◽  
Acute Myeloid

Introduction: Next-generation sequencing (NGS) has redefined the genetic landscape of acute myeloid leukemia (AML) and has prognostic and, potentially, therapeutic implications in AML.Advances in the biological understanding of AML pathogenesis have led to the approval of new targeted agents that increase the therapeutic options for the treatment of AML. Despite these approvals, induction chemotherapy is still widely used for the treatment of patients newly diagnosed with AML. Unfavorable risk cytogeneticand secondary AML have been associated with low responses to induction chemotherapy. In the current study, we investigated the predictive role of molecular abnormalities detected with NGS related to responses to induction chemotherapy in newly diagnosed AML patients. Methods:We used the Medical Archival Retrieval System to identify newly diagnosed AML patients who had NGS analysis performed at our institution.. Patients treated with induction chemotherapy at AML diagnosis were included in the analysis. Response to therapy was evaluated two weeks after therapy was initiated and at count recovery. The difference in distribution of each mutation between the patients who responded to chemotherapy after one or two courses of induction chemotherapy and non-responders was analyzed using Fisher's exact test and the Cochran-Armitage Trend test. Findings with an expected false discovery rate ≤ 10% were reported as positive. The study was approved by the University of Pittsburgh IRB committee. Results: One hundred twenty-seven newly diagnosed AML patients (median age 61 years, interquartile range 51-68 years) were treated with induction chemotherapy. Sixteen patients (13%) had favorable risk cytogenetics, 73 patients (58%) had intermediate risk cytogenetics, and 36 patients (29%) had unfavorable risk cytogenetics. The most common molecular event was an NPM1 (28%) mutation followed by DNMT3A (25%), FLT3-ITD (22%), NRAS (13%), ASXL1 (12%), TET2 (12%), and TP53 (11%) as shown in Figure 1. Eighty-five of 127 patients (67%) achieved CR after one course of chemotherapy with idarubicin and cytarabine (7+3) and 17 patients (13%) responded after a second course with mitoxantrone and etoposide. Twenty-five patients (20%) did not respond to one or two courses of induction chemotherapy. From the 102 patients that responded, measurable residual disease (MRD) data were available in 59 (58%) patients. 29% patients were MRD positive and 71% patients were MRD negative. Secondary AML and poor cytogenetics were associated with poor response. Among the 17 genes with at least 5% prevalence, only TP53 mutations were associated with worse response. TP53 mutations increased monotonically with worse outcomes; TP53 mutations were present in only 2% of those responding to one course of chemotherapy, in 18% responding to two courses, and in 38% with no response to either course (p &lt; 0.0001). Ninety-three percent of patients (13 of 14 patients) with TP53 mutations had poor cytogenetics. After induction chemotherapy, 21% of patients with TP53 mutations achieved CR and 14% achieved morphologic leukemia-free state (MLFS); 2 patients achieved CR after one course and, after the second course, 1 patient achieved CR and 2 patients MLFS. From the 5 patients that responded, 4 had available MRD data; 2 patients were MRD positive and 2 patients were MRD negative. NPM1 mutations were associated with higher response rates to induction chemotherapy (p =0.002). Ninety-four percent of patients (32 of 34 patients) with NPM1 mutations had intermediate cytogenetics. After induction chemotherapy, 92% of patients with NPM1 mutations achieved CR and 3% achieved MLFS; 32 patients (89%) achieved CR after one course. Two patients received a second course; one patient achieved CR and one MLFS. From the 34 patients that responded, 20 patients had available MRD data; 9 patients were MRD positive and 11 patients were MRD negative. Conclusion: Among 17 gene mutations detected using NSG at AML diagnosis, only TP53 and NPMI mutations were associated with responses to induction chemotherapy. Patients with TP53 mutations at AML diagnosis were associated with lower response rates to induction chemotherapy, whereas NPM1 mutations were associated with improved response. Disclosures Raptis: INTEGRA: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; UPMC: Current Employment. Hou:Genentech: Consultancy, Other: PI; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Other: PI. Dorritie:Kite-Gilead: Research Funding; Juno Therapeutics: Research Funding. Sehgal:TP Therapeutics: Research Funding; Prothena: Research Funding; Gilead Sciences: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Juno Therapeutics: Research Funding.

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