Background
Medical educators need valid, reliable, and efficient tools to assess evidence-based medicine (EBM) knowledge and skills. Available EBM assessment tools either do not assess skills or are ...laborious to grade.
Objective
To validate a multiple-choice–based EBM test—the Resident EBM Skills Evaluation Tool (RESET).
Design
Cross-sectional study.
Participants
A total of 304 medicine residents from five training programs and 33 EBM experts comprised the validation cohort.
Main Measures
Internal reliability, item difficulty, and item discrimination were assessed. Construct validity was assessed by comparing mean total scores of trainees to experts. Experts were also asked to rate importance of each test item to assess content validity.
Key Results
Experts had higher total scores than trainees (35.6 vs. 29.4,
P
< 0.001) and also scored significantly higher than residents on 11/18 items. Cronbach’s alpha was 0.6 (acceptable), and no items had a low item-total correlation. Item difficulty ranged from 7 to 86%. All items were deemed “important” by > 50% of experts.
Conclusions
The proposed EBM assessment tool is a reliable and valid instrument to assess competence in EBM. It is easy to administer and grade and could be used to guide and assess interventions in EBM education.
Background The National Academies of Sciences report Improving Diagnosis in Healthcare highlighted the need for better training in medical decision-making, but most medical schools lack formal ...education in clinical reasoning. Methods We conducted a pseudo-randomized and controlled study to evaluate the impact of a clinical reasoning curriculum in an internal medicine clerkship. Students in the intervention group completed six interactive online modules focused on reasoning concepts and a skills-based workshop. We assessed the impact of the curriculum on clinical reasoning knowledge and skills and perception of education by evaluating: (1) performance on a clinical reasoning concept quiz, (2) demonstration of reasoning in hospital admission notes, and (3) awareness of attending physician utilization of clinical reasoning concepts. Results Students in the intervention group demonstrated superior performance on the clinical reasoning knowledge quiz (67% vs. 54%, p < 0.001). Students in the intervention group demonstrated superior written reasoning skills in the data synthesis (2.3 vs. 2.0, p = 0.02) and diagnostic reasoning (2.2 vs. 1.9, p = 0.02) portions of their admission notes, and reported more discussion of clinical reasoning by their attending physicians. Conclusions Exposure to a clinical reasoning curriculum was associated with superior reasoning knowledge and superior written demonstration of clinical reasoning skills by third-year medical students on an internal medicine clerkship.
Best practices for faculty development programs include longitudinal, practice-based formats incorporating experiential learning with opportunities for reflection and community building. Peer ...coaching for faculty development provides personalized, learner-centered, work-based learning. Implementation of traditional 1-on-1 peer coaching programs is challenging due to time, logistics, and methodological barriers.
We sought to improve observation and reflection skills and to expand personal teaching practices of clinician educators.
In 2016, we developed and evaluated an innovative "1-to-many" peer-coaching model utilizing large group review of video-recorded teaching encounters. Forty-three clinician-educator faculty in general internal medicine at the University of Pittsburgh attended at least 1 of 6 sessions between February and August 2016. Sessions were moderated by a master facilitator who guided direct observation of, and reflection on, observed teaching and highlighted efficacious teaching methods. The study evaluated the acceptability and efficacy of this novel faculty development program qualitatively, with semistructured, postcurriculum telephone interviews with 20 participating faculty.
All respondents stated that they would continue to attend faculty development sessions and would recommend them to others. The most frequently cited advantages included exposure to new teaching strategies, direct feedback, safe environment, community of practice, and growth mind-set, yet barriers emerged, such as discomfort reviewing video, difficulty giving feedback across hierarchy, and initial skepticism. None described the curriculum as critical or unsafe. Most reported increased self-reflection and adoption of new teaching behaviors.
This peer-coaching, video-based faculty development program was well received, feasible, and effective in changing self-reported teaching attitudes and practices.
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Background: Elderly patients (pts) with acute lymphocytic leukemia (ALL) have a poor outcome, in part due to toxicity with intensive chemotherapy. Inotuzumab ozogamicin (INO), a CD22 monoclonal ...antibody bound to a toxin, calicheamicin, has single-agent activity in relapsed/refractory ALL. The addition of INO to low-intensity chemotherapy might improve outcomes in older pts with newly diagnosed ALL.
Methods: Pts ≥60 years of age with newly diagnosed Philadelphia chromosome (Ph)-negative pre-B ALL were eligible. Pts were required to have a performance status of ≤3, total bilirubin ≤1.5 mg/dl, AST/ALT ≤3x ULN and creatinine ≤2 mg/dl. Pts received mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses) for up to 8 cycles, given every 4 weeks as permitted by count recovery. INO was given at a dose of 1.3-1.8mg/m2 on day 3 of cycle 1 and 0.8-1.3mg/m2 on day 3 of cycles 2-4. The first 6 pts received 1.3 mg/m2 for cycle 1 followed by 0.8 mg/m2 for subsequent cycles; pt 7 onwards received the phase II dose of 1.8 mg/m2 for cycle 1 followed by 1.3 mg/m2 for subsequent cycles. After the observation of veno-occlusive disease (VOD), the protocol was amended in 9/2015 to use lower doses of INO. After this amendment (pt 35+), INO was given at 1.3 mg/m2 for cycle 1 followed by 1 mg/m2 for subsequent cycles. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. Responding pts received POMP maintenance for up to 3 years.
Results: 52 pts have been treated, 4 of whom were in CR at enrollment. Median age was 68 years (range, 60-81 years) and median CD22 expression was 97% (range, 27-100%). 31 pts (60%) were CD20+ and received rituximab. Among 48 pts evaluable for morphologic response, 47 (98%) response (CR, n=39; CRp, n=7; CRi, n=1). Only 1 pt did not respond. MRD negativity by 6-color flow cytometry was achieved in 36/46 pts (78%) after 1 cycle and 49/51 pts (96%) overall. Median times to platelet and ANC recovery in cycle 1 were 23 and 16 days, respectively, and for subsequent cycles were 22 and 17 days, respectively. Prolonged thrombocytopenia (>6 weeks) occurred in 42 pts (81%). The 30-day and 60-day mortality rates were 0% and 4%, respectively. Infections occurred in 27 pts (52%) during induction and in 36 during (69%) during consolidation; 28 pts (54%) had grade 3-4 hyperglycemia, 16 (31%) had grade 3-4 hypokalemia; 10 (19%) had grade 3-4 transaminase elevation, 9 (17%) had grade 3-4 hyperbilirubinemia, and 7 (13%) had grade 3-4 hemorrhage. 4 pts (8%) developed VOD, 1 after subsequent allogeneic SCT. Two of the VOD cases were severe and resulted in death. Among 51 responders, 6 (12%) relapsed, 3 (6%) underwent allogeneic SCT in CR1, 29 (57%) remain on treatment or have completed maintenance, and 12 (24%) died in CR/CRp. Causes of death for pts in CR/CRp included: sepsis (n=5), VOD (n=1), gunshot wound (n=1), dementia and deconditioning (n=1), end stage renal disease (n=1) and unknown causes (n=3). With a median follow-up of 29 months (range, 1-66 months), 35 pts (67%) were alive, 30 of whom (58%) were in CR and MRD negative status. The 3-year continued remission and OS rates were 74% and 56%, respectively (Figure 1). Compared to a similar historical cohort of older pts treated with hyper-CVAD ± rituximab (n=78), mini-hyper-CVD + INO resulted in significantly higher 3-year OS (54% vs 32%; P=0.004).
Conclusions: Mini-hyper-CVD plus INO is safe and effective in elderly pts with newly diagnosed Ph-negative ALL and appears to improve outcomes compared to hyper-CVAD. A prospective study of this regimen is warranted.
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Kantarjian:Bristol-Meyers Squibb: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Pfizer: Research Funding. Jain:Abbvie: Research Funding; Incyte: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Research Funding; Celgene: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Daver:Incyte Corporation: Honoraria, Research Funding; Jazz: Consultancy; Kiromic: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Otsuka America Pharmaceutical, Inc.: Consultancy; Pfizer Inc.: Consultancy, Research Funding; Immunogen: Research Funding; Karyopharm: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; Bristol-Myers Squibb Company: Consultancy, Research Funding; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding. Thomas:Amgen: Honoraria; Pfizer: Honoraria. Pemmaraju:cellectis: Research Funding; roche diagnostics: Consultancy, Honoraria; affymetrix: Research Funding; Incyte Corporation: Consultancy, Honoraria; novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria; abbvie: Research Funding; stemline: Consultancy, Honoraria, Research Funding. Khoury:Stemline Therapeutics: Research Funding; Pfizer: Research Funding; Angle: Research Funding; Kiromics: Research Funding. Cortes:Sun Pharma: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Burger:Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Wierda:Emergent: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; GSK/Novartis: Consultancy, Honoraria, Research Funding; Karyopharm: Research Funding; Celgene: Consultancy, Honoraria; The University of Texas MD Anderson Cancer Center: Employment; AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Acerta: Research Funding; Juno: Research Funding; Kite: Research Funding; Janssen: Research Funding; Genentech/Roche: Consultancy, Honoraria, Research Funding. DiNardo:AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. O'Brien:GSK: Consultancy; TG Therapeutics: Consultancy, Other: Research Support: Honorarium, Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy; Astellas: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Other: Research Support: Honorarium, Research Funding; ProNAI: Other: Research Support: Honorarium, Research Funding; Acerta: Other: Research Support: Honorarium, Research Funding; Aptose Biosciences, Inc.: Consultancy; Janssen: Consultancy; Regeneron: Other: Research Support: Honorarium, Research Funding; Vaniam Group LLC: Consultancy; Celgene: Consultancy; AbbVie: Consultancy; Sunesis: Consultancy; Alexion: Consultancy; Gilead Sciences, Inc.: Consultancy, Other: Research Support: Honorarium, Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy.
Background: The hyper-CVAD regimen is an effective frontline regimen for de novo adult ALL. Expression of CD20 was identified as an adverse prognostic factor, associated with a higher incidence of ...relapse, lower 3-year complete remission duration (CRD) and lower 3-year overall survival (OS) rate. The addition of rituximab to the hyper-CVAD regimen in patients with CD20-positive ALL (≥20% expression by multicolor flow cytometry) improved outcome with 3-year CRD and OS rates of 68% and 65%, respectively (Deborah Thomas et al. J Clin Oncol 2010;28:3880-9). Ofatumumab (HuMax-CD20) targets a membrane proximal small-loop epitope on the CD20 molecule and was found to be more potent than rituximab in promoting complement-dependent cytotoxicity in vitro. Ofatumumab’s safety and efficacy has been proven in chronic lymphocytic leukemia. Therefore a combination of the hyper-CVAD regimen and ofatumumab may be associated with better response rates, higher 3-year CRD and overall survival rates. The aims of this study are to evaluate response rate, CRD, OS, and to assess the safety of this regimen.
Methods: Patients with newly diagnosed ALL (CD20 expression >1%) and patients who received one prior course of chemotherapy received 4 courses of hyper-CVAD (fractionated cyclophosphamide, vincristine VCR, doxorubicin, dexamethasone; the odd courses 1, 3, 5, 7); ofatumumab was given on courses 1 and 3, and 4 courses of MTX-Ara-C (methotrexate-cytarabine; the even courses 2, 4, 6, 8); ofatumumab was given on courses 2 and 4. This treatment would be followed by POMP (6-mercaptopurine, MTX, VCR, prednisone) maintenance therapy for approximately 30 months, interrupted by intensifications months 6, 7 and 18, 19 with MTX/Pegylated asparaginase and hyper-CVAD-ofatumumab. Central nervous system prophylaxis with MTX and Ara-C was administered. When indicated local radiotherapy was administered in patients with bulky mediastinal disease.
Results: To date 55 patients with de novo ALL and 4 patients in complete remission (CR) previously treated (2 with one prior cycle of hyper-CVAD, 1 post fludarabine-cytarabine based regimen, 1 with cyclophosphamide and dexamethasone) have received a median of 8 cycles (1-8) of therapy. Median age was 41 years (18-71). Median WBC at diagnosis was 4.6 x 109/L (1 -202 x 109/L). CD20 expression above 20% was found in 37 patients (63%), between 10% and 20% in 5 (8%) and between 10% and 1% in 14 (24%). Two patients (5%) had concomitant CNS disease at diagnosis. Among the 50 patients with evaluable baseline cytogenetic analysis, 29 (58%) were abnormal. All but one patient (98%) achieved a CR after cycle 1 (4 patients were in CR at the start); 1 patient died of septic shock and multiple organ failure at day 21 of cycle 1. Fifty-three (93%) patients achieved minimal residual disease (MRD) negativity as assessed by multicolor flow cytometry; of whom 34 (54%) achieved MRD negativity after induction. By binary logistic regression analysis, the lower CD20 levels was an adverse predictive factor for negative MRD at D21 (p=0.044); age at diagnosis did not affect negative MRD at D21 (p=0.604). Twenty-four (41%) patients did not receive full 8 cycles; 21 (36%) are receiving maintenance in CR; 9 (15%) in CR finished maintenance. 8 patients (14%) were referred to allogeneic stem cell transplantation (ASCT) due to complex karyotype (n=1), hyperdiploid karyotype (n=2), delay in achieving negative MRD (n=1), persistent MRD (n=2), and Philadelphia-like phenotype (n=2). Median time to neutrophil and platelet recovery for cycle 1 was 18 and 21 days after induction chemotherapy, respectively; 16 and 22 days after subsequent cycles, respectively. With a median follow up of 20 months (<1-58), 47 patients are alive; of them 43 in CR, 3 relapsed and 1 had molecular relapse only. Twelve (20%) patients died: 5 patients died post relapse and 1 post MRD relapse; 2 post ASCT; 1 post therapy related AML; 1 intracranial hemorrhage at C1D22; 1 sepsis at C3D17; and 1 sepsis on maintenance therapy C16D35. Eight (14%) patients have undergone ASCT. The 3-year CRD and OS rates were 78% and 68% respectively (Figure 1a). The 3-year OS in patients with CD20 <20% and ≥20% were 82% and 64%, respectively (p=0.96) (Figure 1b).
Conclusion: The combination of hyper-CVAD with ofatumumab is highly effective in patients with CD20-positive ALL.
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Daver:Otsuka: Consultancy, Honoraria; Karyopharm: Honoraria, Research Funding; Sunesis: Consultancy, Research Funding; Kiromic: Research Funding; Ariad: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Research Funding. Burger:Pharmacyclics: Research Funding. DiNardo:Abbvie: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Agios: Other: advisory board, Research Funding; Celgene: Research Funding. Jain:BMS: Research Funding; Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Infinity: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Novimmune: Consultancy, Honoraria; Abbvie: Research Funding; Celgene: Research Funding. Wierda:Genentech: Research Funding; Gilead: Research Funding; Novartis: Research Funding; Acerta: Research Funding; Abbvie: Research Funding. Verstovsek:Promedior: Research Funding; Lilly Oncology: Research Funding; Geron: Research Funding; Celgene: Research Funding; AstraZeneca: Research Funding; Seattle Genetics: Research Funding; Roche: Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI BioPharma Corp: Research Funding; Galena BioPharma: Research Funding; Pfizer: Research Funding; Genentech: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Konopleva:Calithera: Research Funding; Cellectis: Research Funding. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.
Background: Minimal residual disease (MRD) assessment by multiparameter flow cytometry (MFC) is prognostic for survival in newly diagnosed patients (pts) with acute lymphoblastic leukemia (ALL). The ...significance of achieving MRD negativity in the relapsed/refractory setting is less clear.
Methods: Between 6/2010 and 5/2015, we identified 130 adult pts with relapsed/refractory B-cell ALL treated at our institution with either inotuzumab ozogamicin (n=75), blinatumomab (n=20) or mini-hyper-CVD plus inotuzumab ozogamicin (HCVD+InO; n=35) in either salvage 1 (S1; n=68) or salvage 2 (S2; n=62). MRD by MFC was assessed on remission bone marrow specimens at the time of achievement of CR/CRp/CRi. The MRD assay used a 15-marker, 6-color panel with a sensitivity of ≤0.01%.
Results: Of the initial 130 pts, 78 (60%) achieved morphological response with a median time to response of 30 days (range, 13-99 days) and are the subject of this analysis. Of the 78 responding pts, 41 (53%) received inotuzumab, 11 (14%) blinatumomab, and 26 (33%) HCVD+ino. 46 pts (59%) were in S1 and 32 (41%) in S2. The median number of cycles to best response was 1 (range, 1-3). MRD negativity was achieved in 41 pts (53%). MRD negativity rates for pts in CR, CRp, and CRi were 57%, 53%, and 16%, respectively. Among pts who achieved remission, MRD negativity was achieved in 17 pts (41%) with inotuzumab, 8 (73%) with blinatumomab, and 16 (62%) with HCVD+InO (P=0.10). 26 pts (57%) in S1 and 15 (47%) in S2 became MRD-negative (P=0.40).
The median follow-up duration was 27 months (range, 6-55 months). The median event-free survival (EFS) was 12 months in pts who achieved MRD negativity vs. 6 months in those who remained MRD-positive (P=0.09). The median overall survival (OS) was 17 months versus 9 months, respectively (P=0.18). Among pts in S1, achieving MRD negativity was associated with a longer EFS (median 18 months versus 7 months; 2-year EFS rate 46% versus 17%; P=0.06; Figure 1A) and OS (median 27 months versus 9 months; 2-year OS 52% versus 36%; P=0.15; Figure 1B). EFS and OS were similar in S2 regardless of MRD response. As expected, among pts who achieved MRD negativity, those in S1 had longer EFS (median 18 months vs. 5 months; P=0.001) and OS (median 27 months vs. 7 months; P=0.01) compared to those in S2. In contrast, for pts who remained MRD-positive, EFS and OS were similar regardless of salvage status (P=0.41 and P=0.39, respectively).
In a 2-month landmark analysis of 64 pts, survival >2 years was observed in all groups of pts regardless of salvage treatment, salvage status or MRD status. 42 (66%) of the pts in this analysis underwent allogeneic stem cell transplantation (alloSCT). EFS and OS did not significantly differ between pts who did or did not undergo alloSCT, although a clear trend for improved long-term survival with alloSCT was observed. Among pts who achieved MRD negativity, the median EFS was 17 months and 12 months, and 2-year EFS rates were 46% and 28% for pts who underwent alloSCT vs. those who did not (P=0.24). The median OS was 24 months and 23 months, and 2-year OS rates were 55% and 46%, respectively (P=0.41). Pts who achieved MRD negativity after S1 treatment and then underwent alloSCT had the best outcomes. Of the 22 pts who achieved MRD negativity after S1 treatment, the median EFS for pts who underwent alloSCT (n=14) compared to those who did not (n=8) was not reached vs. 18 months, and the median OS was not reached vs. 27 months, respectively (P=0.28 for both). Among the 14 pts who achieved MRD negativity after S1 treatment and subsequently underwent alloSCT, 10 (71%) are still alive with a median follow-up of 24 months (range, 5-55 months).
Conclusions: In patients with relapsed/refractory ALL, achievement of MRD negativity is associated with improved outcomes. Patients with relapsed/refractory ALL who achieve MRD negativity in S1 can achieve excellent long-term survival, especially if alloSCT is performed.
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O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. DiNardo:Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Jain:Genentech: Research Funding; Incyte: Research Funding; BMS: Research Funding; Celgene: Research Funding; Infinity: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Novimmune: Consultancy, Honoraria; Abbvie: Research Funding; Seattle Genetics: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Konopleva:Cellectis: Research Funding; Calithera: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.
Background: The combination of tyrosine kinase inhibitors (TKIs) with chemotherapy is highly effective in Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Ponatinib is a ...more potent BCR-ABL inhibitor, and is effective against the T315I clone which commonly causes disease recurrences. The combination of hyper-CVAD with ponatinib may produce better response rates and higher likelihood of eradication of minimal residual disease (MRD) as compared to that reported with other TKIs.
Methods: Patients with newly diagnosed Ph+ ALL received 8 cycles of hyper-CVAD alternating with high dose methotrexate and cytarabine every 21 days. Ponatinib was given at 45 mg po daily for the first 14 days of cycle 1 then continuously for the subsequent 7 cycles. Patients in complete response (CR) received maintenance with ponatinib 45 mg daily and vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. After an increased incidence of vascular toxicities was recognized, patients were offered the option to switch TKIs or to continue with a reduced dose of ponatinib of 30 mg with further decrease to 15 mg in patients in CMR. The evaluation of MRD status was performed by multicolor flow cytometry (FCM), and reverse transcription polymerase chain reaction (RT-PCR). The objective of this study is to evaluate response rates, CR duration, and overall survival (OS), and to assess the safety of this regimen. Rituximab and intrathecal chemotherapy were given for the first 4 courses.
Results: To date, 53 patients with untreated Ph+ ALL and 4 patients previously treated (2 patients in CR; 2 patients not in CR) have received a median of 6 cycles (2-8); 11 patients are receiving maintenance in CR; 10 patients underwent allogeneic stem cell transplantation (ASCT) after a median of 4 cycles. Baseline patient characteristics and outcomes are described in table 1. The overall complete cytogenetic response (CCyR), major molecular response (MMR), and complete molecular response (CMR) rates were 100%, 96%, and 79%, respectively. The median time to MMR and CMR were 3 weeks (range, 2-14) and 11 weeks (range, 2- 96), respectively. The median time to MRD negativity by 6-color flow cytometry (FCM) was 3 weeks (range, 3-14). Median time to platelet and neutrophil recovery for cycle 1 was 22 days (range, 17-35) and 18 days (range, 13-29), respectively, and 22 days (range, 0-35) and 16 days (range, 0-28) for subsequent cycles. Grade ≥ 3 toxicity included infections during induction (47%), increased liver function tests (34%), thrombotic events (8%), myocardial infarction (6%), hypertension (15%), skin rash (15%), and pancreatitis (19%). With a median follow up of 33 months (range, 2-51), 44 81(%) patients remain alive and in CR (41 in CR1, and 3 in CR2). Six patients died in CR: 1 patient died in CR from an unrelated cardiac event 4 months after being taken off therapy and placed on imatinib, 1 from multiple organ failure due to sepsis (C2D13), 1 from non-ST elevation myocardial infarction (C2D41; ponatinib 45 mg daily), 1 from potential myocardial infarction (C4D42; ponatinib 30 mg daily), 1 from head injury after a fall (C4D13), and 1 from sepsis post allogeneic stem cell transplantation. Of 44 patients alive at the last follow-up, 20 (46%) patients remained on ponatinib (15 mg daily in 15, and 30 mg daily in 5), 12 (27%) switched to another TKI (9 to dasatinib, 2 to nilotinib, and 1 to imatinib), 8 (18%) underwent ASCT, 3 (7%) relapsed, and 1 (2%) had positive MRD by FCM and RT-PCR. No further vascular events were observed in patients receiving lower doses of ponatinib. The 3-year CR duration and OS rates are 82% and 80%, respectively (Figures 1). Of 10 patients who underwent ASCT while in first CR, 8 patients are alive in CR, 1 died of sepsis in CR, and 1 relapsed and died of disease progression. Landmark analysis at 4 months by ASCT showed no difference in 3-year CR duration (no ASCT, 79%; ASCT, 88%; p=0.48), and 3-year OS (no ASCT, 92%; ASCT, 79%; p=0.31).
Conclusion: The combination of hyperCVAD with ponatinib is highly effective in patients with Ph+ ALL. Due to the vascular events observed, the ponatinib dose was modified to 30 mg daily during consolidation with subsequent reduction to 15 mg in patients in CMR without further episode of cardiovascular events.
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Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Pemmaraju:incyte: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria; stemline: Consultancy, Honoraria, Research Funding; cellectis: Consultancy, Research Funding; affymetrix: Research Funding. DiNardo:Celgene: Research Funding; Agios: Other: advisory board, Research Funding; Abbvie: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding. Konopleva:Cellectis: Research Funding; Calithera: Research Funding. Jain:BMS: Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Novimmune: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Abbvie: Research Funding; Infinity: Research Funding; Novartis: Consultancy, Honoraria; Genentech: Research Funding; Seattle Genetics: Research Funding. Wierda:Novartis: Research Funding; Abbvie: Research Funding; Acerta: Research Funding; Gilead: Research Funding; Genentech: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria.
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