AML Clinical Trial Decision Making: How Often Do Physicians Follow a Consensus-Derived Assignment Scheme?

Background At our center we consider most patients with newly-diagnosed AML or MDS-EB2 to be candidates for clinical trials. The NCI website (clinicaltrials.gov) currently lists 72 adult trials implying uncertainty as to which is best. These trials often have arbitrary exclusion criteria, and even if eligible, not every patient may enroll in a given trial. Other sources of clinical trial selection bias include physician or patient preferences and logistical issues such as transportation or insurance coverage. These selection biases may contribute to the well-known difficulties in reproducing "promising" findings from early phase trials in subsequent larger studies. At our center we use a pre-determined treatment assignment scheme to allocate clinical trials to patients prior to the initial physician-patient consultation, which may increase trial enrollment and decrease bias in trial assignment. To assess selection bias, we examined how often the assigned treatment was given to patients. Methods A randomly-ordered, physician consensus-derived clinical trial list was created and updated as protocols opened and closed. Trials initiated by our investigators appeared more often on the list than trials sponsored by industry partners. Upon a patient's arrival we provided her/his physician a pre-assigned clinical trial based on that patient's age and probability of early death (using the treatment related mortality score, TRM). After being informed of options including other trials, standard care, or supportive care alone, physicians and their patients decided on a treatment. Once a treatment choice was selected, physicians received an electronic survey. In cases where the pre-assigned clinical trial was not chosen, the survey inquired about reasons for this decision. Categories were: (a) patient ineligible, (b) protocol not accruing, (c) patient and/or physician preference and (d) logistics, e.g. patient cannot stay in Seattle for length demanded by protocol) or (e) insurance denial. Results From December 2017 through June 2019, we collected surveys on 158 out of 170 (93%) arrivals for whom treatment decisions were made. The pre-assigned therapy was given in 40/158 cases (25%, 95% confidence interval [CI] 19-33%). In all 40 cases the trial chosen were ones initiated by investigators here. Twenty-four of the 118 patients (21%) in whom the assigned therapy was not given chose to be treated at home or receive palliative care only. Reasons the remaining 94 patients did not receive their assigned therapy were: physician/patient preference (51), protocol not accruing (18), logistical issues (13), and ineligibility (12 patients). Among patients not enrolled on the assigned trial due to physician/patient preference, 27 of 51 received treatment on an alternate clinical trial, and 24 received standard therapy. The intensity of the therapy was identified by the treating physician as a factor leading to the alternate treatment choice in 35 of 51 patients (67%). In 21 patients in whom a less intense therapy was assigned, intense therapy was given instead; while the opposite occurred in 14 patients. In 16 cases the preferred intensity was the same as that assigned but a different regimen was used. The median TRM score was lower among patients given high intensity vs. intermediate/low intensity treatments (medians 3.75 for high vs, 10.05 for low; Kruskal Wallis p < 0.00001). Discussion and conclusion The pre-assigned therapy was given to 25% of patients (40/158), rising to only 31% (40/128) after removing cases where the protocol was not enrolling or the patient ineligible. Factors possibly contributing to these low rates are the number, nature and specifics of the available protocols, the characteristics of the patients referred to us (e.g. distance from Seattle to their homes), availability of acceptable alternative treatment in a local setting, and characteristics of our physicians (e.g. inherent preferences for higher or lower intensity therapy). The low rate with which pre-assigned treatments were given suggests the continued presence of considerable selection bias when treatment decisions are made. The possibility of such bias should be kept in mind when interpreting the results of clinical trials. Improvements in care of AML patients will require trials to enroll patients representative of the population in need of treatment. Disclosures Gardner: Abbvie: Speakers Bureau. Halpern:Pfizer Pharmaceuticals: Research Funding; Bayer Pharmaceuticals: Research Funding. Scott:Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Speakers Bureau. Oehler:Pfizer Inc.: Research Funding; NCCN: Consultancy; Blueprint Medicines: Consultancy. Walter:Agios: Consultancy; Astellas: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding. Becker:AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; Accordant Health Services/Caremark: Consultancy; The France Foundation: Honoraria.

Download Full-text

Sickle-Cell Disease in Greece: Patient Reported Outcomes Related to Clinical Complications, Treatment Choices and Attitudes, Beliefs and Trends Affecting Potential Participation in Clinical Trials - a Greek National Multicentric Study

Blood ◽

10.1182/blood-2019-127966 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4838-4838

Author(s):

Sophia Delicou ◽

Michael D. Diamantidis ◽

Konstantinos Manganas ◽

Eftychios Eftychiadis ◽

Despoina Pantelidou ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Educational Status ◽

Current Treatment ◽

Advisory Committees ◽

Chi Square ◽

Clinical Complications

Background: Sickle cell disease (SCD) is an autosomal recessive disorder caused by a point mutation in the β-globin chain of hemoglobin that forms hemoglobin S. It is clinically characterized by complicated episodes of veno-occlusive crises (VOC), emergency room (ER) visits and uncomplicated inpatient admissions. Aim: We investigated the clinical complications and treatment choices of a large cohort of Greek SCD patients, representative of the whole country. Most importantly, this study aimed to assess patients' attitudes and beliefs regarding their enrollment in clinical trials testing new drugs. We examined the factors influencing such a participation. Patients and Methods: A total of 254 patients from 10 Thalassemia and Sickle Cell Departments across Greece (110 men/144 women), aged 18 - over 65, 210 (82.7%) with β-thalassemia/sickle cell trait and 44 (17.3%) with homozygous SCD participated in the study. The participants had variable educational and socioeconomic background. They all answered an anonymous self-report questionnaire during their medical evaluations between November 2018 and May 2019, including their demographic and clinical characteristics, their current treatment and their opinion regarding a possible participation in a clinical trial for SCD. Descriptive statistical analysis using calculated scale variables and Chi-square test were performed. Results: All participants completed the survey. During the previous year, 64 patients (25.3%) had no admissions for VOC, 128 (50.6%) had 1-5, whereas 21 (8.3%) had 5-10 and 40 (15.8%) more than 10. Except for acute pain crises, the most frequent complications were chronic pain (59%), liver/spleen dysfunction (32.4%), infectious episodes (29.5%), iron overload (23.8%) and pulmonary hypertension (20.1%). In addition to hematological care, patients seeked medical attention from expert physicians for disease complications; 77.6% of the patients reported that they yearly visited a cardiologist, 42.4% an ophthalmologist, 31.9% an orthopedic, 28.4% a pneumonologist, 28.9% a hepatologist, 12.6% an urologist, 14% a nephrologist, 11.9% an infectious disease doctor, 10.1% a pain management specialist and 8.1% a neurologist. The therapeutic approaches included daily folic acid supplementation (86.1%), vaccines (68.3%), hydroxyurea (66.3%), antibiotics (57.1%), simple pain moderators (52.4%), opioids (48.8%) and iron chelators (30.2%). Previous experience in clinical trials was reported by only 17 patients (6.9%). Regarding the patients' attitudes towards a probable clinical trial, 41.3% were positive to try new therapies, 28.3% negative and 30.4% neutral. 67.2% were satisfied with their current treatment, without excluding a potential participation in clinical trials; such treatment satisfaction correlated significantly with older age, lower income and secondary hemochromatosis under chelation treatment (p<0.05). 40% reported that they had been waiting for years for a new treatment, but 43.2% strongly denied becoming an experimental mouse model, whereas 47.3% mentioned that they would trust their doctors' advice correlating positively with male gender and higher income (p<0.05). Lower educational status, prior intake of hydroxyurea and residence/origin in the capital in contrast to the countryside (chi-square, p<0.05) significantly correlated with a potential clinical trial participation. Internet and television information motivated patients to seek more details from their doctor. Concerning the factors rated as the most important for a potential participation in a clinical trial, 7 out of 10 patients of our cohort considered of utmost equal importance the effectiveness of a probable treatment and the relative toxicity. Conclusions: Most SCD patients have chronic complications and visit specialized physicians. Since the participation of larger number of patients in clinical trials is essential for the application of novel drugs, the most important factors of our cohort are the effectiveness of a probable treatment and the relative toxicity, along with the trust to the doctor. These factors are crucial, influencing patients' decision. Even though a proportion of our patients remain skeptical towards clinical trials, an increasing number is willing to participate, which correlates positively with residence in the capital, lower educational status and prior intake of hydroxyurea. Disclosures Kattamis: Apopharma: Honoraria; Vertex: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ionis: Membership on an entity's Board of Directors or advisory committees; ViFOR: Membership on an entity's Board of Directors or advisory committees; Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Symeonidis:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

Development and Testing of a Lymphoma Clinical Trials Specific Frailty Index: A Secondary Analysis of the LY.12 Clinical Trial

Blood ◽

10.1182/blood-2021-153037 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4076-4076

Author(s):

Abi Vijenthira ◽

Xinzhi Li ◽

Michael Crump ◽

Annette E. Hay ◽

Lois E. Shepherd ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Frailty Index ◽

Secondary Analysis ◽

Advisory Committees ◽

Frail Patients ◽

The Impact

Abstract Background: Frailty is common in older patients with lymphoma. However, it remains unknown whether frailty is prevalent in patients included in clinical trials of lymphoma, as those with frailty may meet inclusion criteria of a trial which do not include functional information beyond performance status (PS). Understanding the prevalence and impact of frailty in clinical trials is important to direct future stratification criteria, as well as to have robust data to counsel frail patients on their potential outcomes. Methods: We conducted a secondary analysis using data from the phase III LY.12 clinical trial in which patients with relapsed aggressive non-Hodgkin lymphoma were randomized to gemcitabine-dexamethasone-cisplatin or dexamethasone-high dose cytarabine-cisplatin chemotherapy prior to autologous stem cell transplant. The primary objective of our study was to construct a lymphoma clinical trials specific frailty index (FI) using previously described methods (Searle. BMC Geriatr. 2008;8:24). Secondary objectives were to describe the association of frailty (binary variable) with overall survival (OS), event-free survival (EFS), hospitalization, adverse events (AE), serious adverse events (SAE), and proceeding to transplant, and to describe the association of frailty with these outcomes, controlling for important covariates (age, sex, immunophenotype, revised international prognostic index score (rIPI), Eastern Cooperative Oncology Group (ECOG) PS, stage, and response to previous chemotherapy). Results: 619 patients in the LY12 trial were used to construct the frailty index (Table 1). Using a binary cut-off for frailty (<0.2), 15% (N=93) of patients were classified as frail. There were no differences in age or sex between frail and non-frail patients; however they differed in terms of other lymphoma-related characteristics (Table 2). Frailty was strongly associated with OS (HR 2.012, 95% CI 1.57-2.58), EFS (HR 1.94, 95% CI 1.53-2.46), frequency of the worst overall Grade >3 AE (OR 2.65 (15% vs. 6%), p=0.003), and likelihood of proceeding to ASCT (OR 0.26, 95% CI 0.15-0.43), but not hospitalization (OR 1.52, 95% CI 0.97-2.40) or SAE (6% vs. 4%, p=0.3). In multivariable analysis, frailty was not significantly associated with OS, EFS, likelihood of proceeding to ASCT, nor hospitalization (Table 3), though there was a trend to significance for ASCT. However, rIPI remained significantly associated with OS and EFS, ECOG remained significantly associated with OS (Table 3) Conclusion: A potentially broadly applicable lymphoma clinical trials specific FI was constructed through secondary analysis of LY12 data. 15% of patients were classified as frail. Frailty was significantly associated with OS, EFS, frequency of grade >3 AE and likelihood of proceeding to transplant. However, this relationship no longer was significant when controlling for lymphoma-related prognostic variables, suggesting that the impact of poor prognostic features of lymphoma supersede the impact of frailty alone in this younger clinical trial population. Interestingly, rIPI and ECOG demonstrated their value as simple predictors that are highly associated with OS and/or EFS even when controlling for other important covariates including frailty. These findings require further testing in an external data set, and would be particularly valuable to test in an older population. Calibration of the FI against clinical frailty assessment (e.g. Clinical Frailty Scale, Comprehensive Geriatric Assessment) would also be meaningful to confirm its ability to classify frail versus non-frail patients. Figure 1 Figure 1. Disclosures Crump: Epizyme: Research Funding; Roche: Research Funding; Kyte/Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Hay: Merck: Research Funding; Roche: Research Funding; Abbvie: Research Funding; Amgen: Research Funding; Karyopharm: Research Funding; Seattle Genetics: Research Funding. Prica: Astra-Zeneca: Honoraria; Kite Gilead: Honoraria.

Download Full-text

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

Blood ◽

10.1182/blood-2019-131776 ◽

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.

Download Full-text

Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): A Large Single-Center Experience: Analysis of Clinical and Molecular Characteristics and Patient Outcomes

Blood ◽

10.1182/blood.v126.23.3746.3746 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3746-3746 ◽

Cited By ~ 5

Author(s):

Naveen Pemmaraju ◽

Hagop M. Kantarjian ◽

Jorge E. Cortes ◽

Madeleine Duvic ◽

Joseph D Khoury ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Dendritic Cell ◽

Board Of Directors ◽

Research Funding ◽

Plasmacytoid Dendritic Cell ◽

Cell Transplant ◽

Advisory Committees ◽

Significant Difference ◽

Cell Neoplasm

Abstract Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematologic malignancy with heterogeneous clinical presentation and no available standard therapy. Little is known about the clinical characteristics, molecular characterization, and outcomes of patients (pts) with BPDCN. Methods: We conducted a retrospective review of pts age ≥18 years with a confirmed pathological diagnosis of BPDCN. Results: 37 pts evaluated at our institution between October 1998-June 2015 were identified. Table 1 shows baseline pt characteristics. Bone marrow (BM) was involved in 23 (62%), skin in 26(70%), lymph nodes in 11(30%), central spinal fluid (CSF) in 3 (8%) and 1 (3%) pt each had disease involving brain, uterus/ovary, elbow/soft tissue, and pleural fluid. Tumor immunophenotype demonstrated: CD4+ (31/32), CD56+ (29/32), TCL-1+ (19/21), CD 123+ (22/23). Additionally, CD22 was expressed in 3/9 pts. Frontline therapies received: 19 (51%) HCVAD; 5 (14%) CHOP, 5 (14%) clinical trials, 2 (5%) bortezomib-based, 1 AML induction with daunorubicin+ARAC, 1 oral MTX, 1 IFN-based therapy, 3 other regimens. 5 (14%) pts received radiation (XRT) as part of their therapy. Median follow-up time was 7 months [1-27 mo]. Median number of chemotherapy regimens was 1 [1-6]. Complete remission (CR1) (by standard AML criteria) was achieved in 19 pts (51%) with a median CR1 duration of 19 mo [1-39 mo]. Median overall survival (OS) was 23 mo [6-45 mo]. 23 (69%) pts died, the most common cause of death being multi-organ failure. Among 14 (38%) pts without BM involvement at diagnosis, all 14 had skin involvement. Comparison of pts with BM involvement versus skin-only showed no difference in outcomes. For pts with BM disease, median OS and median CR1 were 23 mo [1-45 mo] and 21 mo [1-39 mo], respectively. For pts with skin-only disease,median OS and median CR1 were 18 mo [1-31 mo] and 19 mo [1-23 mo], respectively, p =0.43 (OS), p=0.78 (CR1). 10 pts (27%) received stem cell transplant (SCT) [7 allogeneic (including 3 cord blood) and 3 autologous). The median OS for pts receiving SCT (n=10) was 18 mo [8-40 mo] versus 23 mo [1-45] for non-SCT group (n=27), p = 0.98. 19 pts (51%) received HCVAD as part of first-line therapy: median OS was 18 mo [1-45 mo] and median CR1: 21 mo [1-39 mo]. Out of 16 pts evaluable for response, 15 achieved CR1; 1 pt died at day 15 (pneumonia). A clinically validated 28-gene molecular panel (next-generation sequencing for commonly mutated genes in myeloid malignancies) is now being performed prospectively on all new pts with BPDCN seen at our institution (thus far, n=9); notably, all 9 have expressed some form of TET2 mutation [ordered mutations=3(c.1648C>T p.R550; c.3781C>T p.R1261C; c.4365del p.M1456fs*2)], ordered+variant=2,variants=4], confirming our earlier finding of occurrence of TET2 mutations in pts with BPDCN (Alayed K, et al Am J Hematol 2013). Thus far, there has been no statistically significant difference in terms of response rates in pts with known TET2 mutations/variants (n=9) vs all others/not done (n=26). Conclusions: Among patients with BPDCN, we observed an older, male predominance, a high incidence of TET2 mutations and, despite intensive chemotherapy and achievement of CR1 in many pts, most still experience relapse and short survival. Therefore, there is an urgent need for novel therapies. Therapies targeting cell surface CD123 and CD56, are available in 2 separate clinical trials at our institution: SL-401 (DT-IL3), which demonstrated 7/9 (78%) major responses including 5 CR, after a single cycle of therapy, (Frankel et al, Blood 2014) is currently being tested in an ongoing multicenter phase I/II trial (Stemline Therapeutics Inc, ClinicalTrials.gov Identifier: NCT02113982, refer to separate abstract ASH 2015) and Lorvotuzumab Mertansine (ImmunoGen, Inc), an antibody-drug conjugate targeting CD56 (ClinicalTrials.gov Identifier: NCT02420873), is in an ongoing ph II trial in CD56-expressing hematologic malignancies, including BPDCN. Table 1. Baseline characteristics (N = 37) Characteristic N (%) / [range] Median age, years 62[20 - 86] Male 33 (89) Median WBC x 109/L 5.9 [1.7-76.5] Median Hemoglobin g/dL 12.9 [6.8-17.1] Median Platelet x 109/L 130 [22-294] Median BM blast 13[0-95] Cytogenetics (n=27)DiploidComplexDeletion 12p13 17 8 1 Miscellaneous 1 28-gene profile (n=9); includes mutations& variantsTET2ASXL1MPLTP53IDH1IDH2 9 3 2 1 1 1 Disclosures Pemmaraju: Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Off Label Use: No standard of care available. clinical trial drug therapies/investigation/trial only various cytotoxic chemotherapies used in ALL, AML, other blood cancers. Cortes:BMS: Consultancy, Research Funding; BerGenBio AS: Research Funding; Teva: Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Duvic:Innate Pharma: Research Funding; Tetralogics SHAPE: Research Funding; Cell Medica Ltd: Consultancy; Array Biopharma: Consultancy; Oncoceutics: Research Funding; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spatz Foundation: Research Funding; Therakos: Research Funding, Speakers Bureau; Huya Bioscience Int'l: Consultancy; MiRagen Therapeutics: Consultancy; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Rhizen Pharma: Research Funding; Allos (spectrum): Research Funding; Soligenics: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin, Co: Membership on an entity's Board of Directors or advisory committees, Research Funding. Daver:ImmunoGen: Other: clinical trial, Research Funding. O'Brien:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Frankel:Stemline: Consultancy, Patents & Royalties, Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.

Download Full-text

How Median Follow-up Time Informs Survival Outcomes: Lessons from a Trial of Acute Myeloid Patients Treated with Venetoclax and Azacitidine

Blood ◽

10.1182/blood-2019-126344 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5897-5897

Author(s):

Diana Abbott ◽

Andrew Hammes ◽

Jonathan A Gutman ◽

Daniel A Pollyea ◽

Clayton Smith

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Board Of Directors ◽

Research Funding ◽

Trial Data ◽

Time To Event ◽

Advisory Committees ◽

Kaplan Meier ◽

The Stability

Background: Follow-up time in clinical trials must leverage conflicting aims. To ensure patient safety, investigators often assess toxicity and efficacy endpoints at various times throughout a trial. Yet accurate analysis requires stable estimates of time-to-event outcomes, which can require longer follow-up than is observed in interim analyses. While median follow-up is routinely reported in clinical trials, the stability of time-to-event estimates and their relationship to follow-up times are rarely discussed. However, the potential follow-up of study participants who are censored in a clinical trial can impact time-to-event estimates (Betensky 2015). Methods: A clinical trial of venetoclax + azacitidine in 33 newly diagnosed older patients with AML was conducted at our institution and is described in detail elsewhere (Pollyea 2018). Trial data consisting of follow-up from January 2015 through February 2018 established promising results (overall response rate = 91%; median response duration, progression-free survival, and overall survival (OS) were not yet reached). Due to ongoing interest in median time-to-event patient outcomes that were not reached and thus could not be reported at the time of publication, the data have been re-analyzed on repeated occasions as follow-up has continued, with OS of particular interest. Median follow-up was calculated using the reverse Kaplan-Meier method. Median OS was calculated using Kaplan-Meier product limit estimates. Analysis of trial data has occurred at 6 different censoring time points: December 4, 2017; February 28, 2018; October 3, 2018; December 31, 2018; March 8, 2019; and May 20, 2019. Upper and lower limits of the Kaplan-Meier OS estimate were calculated to explore the stability of OS estimates over time (Betensky 2015). Analyses were performed using SAS version 9.4 (SAS Institute). Results: Median OS was not reached until analysis was conducted as of October 3, 2018. At this analysis the median OS (1130 days) exceeded the median follow-up time (867 days). This phenomenon also occurred for data censored on December 31, 2018, with the median OS (1130 days) also exceeding the median follow-up time (956 days). In the most recent two analyses of the data (March 8, 2019 and May 20, 2019), the median OS settled at a consistent value (880 days) that did not exceed the median follow-up times (1023 days and 1096 days, respectively). Exploration of the stability of OS estimates revealed that a single patient enrolled early in the study and died after 1130 days of follow-up skewed the median OS estimate upward. Conclusions: Interest in our clinical trial results motivated numerous follow-up analyses of our data. As such, we encountered a peculiar result in which median OS exceeded median follow-up. In investigating the stability of the OS K-M estimates, a single patient's study data was found to skew results in these instances. Removal of this patient's data in these instances (when the relationship between median follow-up and median OS suggest estimate instability) results in a median OS consistent with subsequent analyses at later censoring dates (880 days for the modified analysis). We therefore conclude that time-to-event estimate stability is informative and should be incorporated into survival analysis of clinical trial data. Disclosures Pollyea: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty-Seven: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Diachii Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Racial Disparities and Their Impact on Knowledge, Behavioral Patterns, and Preferences Towards Participation in Clinical Trials Among Cancer Patients

Blood ◽

10.1182/blood-2020-140390 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Meghna Ailawadhi ◽

Mays F Abdulazeez ◽

Leyla Bojanini Molina ◽

Victoria R. Alegria ◽

Taimur Sher ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Board Of Directors ◽

Cancer Patients ◽

Research Funding ◽

Treatment Plan ◽

Term Treatment ◽

Trial Participation ◽

Advisory Committees ◽

Long Term Treatment

Background: Clinical trials are critical to drug development and the formulation of evidence-based guidelines which are essential to providing crucial and often life-saving treatment to cancer patients. Clinical trial participation is very poor in the United States overall, with a dismal representation of racial minorities. While this has been a focus of several efforts focused on education, targeted enrollment etc., there is a lack of understanding of the patient's knowledge and preferences, and how that may be shaping their decision to consider participation in clinical trials. We undertook a patient-reported survey to explore these factors and understand any underlying disparities. Methods: A 15-question paper-based anonymous questionnaire addressing the cancer patient's knowledge about their disease and clinical trials, as well as factors that may shape their understanding of, or may be barriers to their participation in clinical trials was used. This was administered to adult patients with lymphoid malignancies at the Mayo Clinic in Florida. Categorical and continuous variables between white and minority respondents were compared using the Chi-square test and U Mann Whitney with a significance level of 0.05. Results: The survey was completed by 203 cancer patients. Of these, 3 patients did not report race and ethnicity and so responses from 200 patients were included in the final analysis. Of the respondents, 73% (n=146) were white and 27% (n=54) were minorities. Whites were older than minorities, although not statistically significant (median 67 vs. 61.5 yrs, p=0.06). Minority patients had lower education level with 41% having ≤high school education as compared to 16% whites (p<0.001). Majority of white patients (53%) reported their physicians as the highest ranked source of information for cancer vs. 33% minority patients (p=0.01). Other sources of information explored were internet, nurses, family/friends, books/flyers or other patients. A higher number of white patients reported treatment and its side effects to be the topic of most importance to them at the time of cancer diagnosis as compared to minorities (33% vs. 15%, p=0.01). Similarly, prognosis was more important for a higher number of whites than minorities (21% vs. 15%, p=0.03). Understanding of the diagnosis and financial impact were also explored but not found to have any significant difference. Understanding their treatment and long-term treatment plan was the most frequent knowledge gap reported by whites (81%) vs. minorities (54%, p=0.004). Minorities had several knowledge gap areas (understanding the diagnosis, treatment, side effects, long-term treatment plan, financial impact, survival) more evenly distributed. Regarding clinical trials, minorities were more likely to agree that clinical trials were of benefit for patients (42% vs. 28%, p=0.05) and that in a clinical trial the experimental drug always works better than the one it is being compared to (65% vs. 38%, p<0.001). Minority patients were less likely to agree to participating in clinical trials just based on their doctor's recommendation and judgement (83% vs. 93%, p=0.03). A higher number of minority patients felt that pharmaceutical companies have a big influence on the result of a clinical trial (83% vs. 65%, p=0.01). Fear of not benefiting from clinical trials was the reason for not participating among a higher number of whites (36% vs. 19%, p=0.02) while minorities more frequently reported fear of being a guinea pig (22% vs. 14%) and fear of financial burden (17% vs. 8%) although these were not statistically significant. Conclusions: Racial disparities exist at various aspects of cancer-related knowledge resources, gaps and needs. Minorities have more widespread knowledge gaps and depend on more resources for cancer-related knowledge, which may affect their clinical trial participation and preferences. There appears to be mistrust and misinformation guiding minority patient's understanding, leading to more widespread fears of clinical trials. Knowledge gaps and misinformation needs to be addressed in order to achieve higher participation in clinical trials in general, and among minority patients in particular. Disclosures Manochakian: AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Guardant health: Membership on an entity's Board of Directors or advisory committees; Novocure: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Ailawadhi:Phosplatin: Research Funding; Medimmune: Research Funding; BMS: Research Funding; Cellectar: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Takeda: Honoraria; Amgen: Research Funding; Celgene: Honoraria.

Download Full-text

Disparities in Participation in Interventional Clinical Trials for Myelodysplastic Syndromes

Blood ◽

10.1182/blood-2018-99-117538 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4374-4374

Author(s):

David P. Steensma ◽

Rami S. Komrokji ◽

Amy E. DeZern ◽

Gail J. Roboz ◽

Andrew M. Brunner ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Board Of Directors ◽

Myelodysplastic Syndromes ◽

Research Funding ◽

World Health ◽

International Prognostic Scoring System ◽

Eligibility Criteria ◽

Advisory Committees ◽

Trial Participants

Abstract Background: Only a minority of patients diagnosed with myelodysplastic syndromes (MDS) enroll in interventional clinical trials, which impedes development of novel therapies. Factors contributing to low trial accrual are incompletely understood but have been hypothesized to include the older age and frail nature of many patients with MDS, narrow trial eligibility criteria, lack of "precision medicine" agents, perception of MDS as an indolent or lower-risk disease, and difficulty or expense of traveling to trial centers (Steensma D et al Cancer 2018). Methods: We analyzed a pooled patient database from institutions of the US MDS Clinical Research Consortium (MDS CRC) to compare characteristics of participants in interventional trials with those patients who never enrolled in a trial during their disease course. Demographics, ZIP code of patient residence (a surrogate measure for income), distance from home to the referral center, presenting blood counts, World Health Organization (WHO) 2008 MDS classification, and Revised International Prognostic Scoring System (IPSS-R) score were compared between trial participants and non-participants. Results: Clinical trial enrollment data were available on 2,138 patients with MDS who had been evaluated at sites in the MDS CRC, of whom 515 (24.1%) participated in an interventional clinical trial. The median age of patients was 67.0 years and 63.4% were male. Patients who participated in trials were on average 1.2 years younger than non-participants (66.1 vs 67.3 years, p=0.037) while men were more likely to participate in a trial (70% of trial participants were male compared to 30% female, compare to non-participants of whom 61% were male and 39% female; p<0.01.) Clinical trial participants tended to live a little closer to the trial center (median distance 134.5 miles for participants vs. 154.8 miles for non-participants, p=0.15). Race was not associated with likelihood of trial enrollment, but Hispanic ethnicity was associated with trial non-participation (p=0.045) and patients in more affluent ZIP codes had a higher participation rate (p<0.01). Patients with RAEB-2, RCMD and RARS were over-represented in trials compared to disease subtype prevalence, while del(5q) was underrepresented (p=0.06). IPSS-R did not influence participation. Conclusion: Even at large referral centers, only a minority of patients with MDS enroll in interventional trials. Younger, male, affluent non-Hispanic patients were more likely to enroll in studies. Understanding barriers to trial accrual may help investigators and study sponsors design trials that will accrue more rapidly and augment treatment options for patients with MDS. Disclosures Komrokji: Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Roboz:Sandoz: Consultancy; Astex Pharmaceuticals: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Sandoz: Consultancy; Jazz Pharmaceuticals: Consultancy; Celltrion: Consultancy; Eisai: Consultancy; Orsenix: Consultancy; Cellectis: Research Funding; Jazz Pharmaceuticals: Consultancy; Otsuka: Consultancy; Eisai: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Celgene Corporation: Consultancy; Roche/Genentech: Consultancy; Argenx: Consultancy; Bayer: Consultancy; Aphivena Therapeutics: Consultancy; Pfizer: Consultancy; Janssen Pharmaceuticals: Consultancy; Pfizer: Consultancy; Argenx: Consultancy; Novartis: Consultancy; AbbVie: Consultancy; Astex Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Aphivena Therapeutics: Consultancy; Celgene Corporation: Consultancy; Cellectis: Research Funding; Janssen Pharmaceuticals: Consultancy; Roche/Genentech: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; AbbVie: Consultancy. Brunner:Celgene: Consultancy, Research Funding; Takeda: Research Funding; Novartis: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Unexpected Toxicities When Nivolumab Was Given after Allogeneic Stem Cell Transplantation

Blood ◽

10.1182/blood-2019-123887 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1956-1956

Author(s):

Amy Wang ◽

Justin Kline ◽

Wendy Stock ◽

Satyajit Kosuri ◽

Andrew S. Artz ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Stem Cell ◽

Adverse Events ◽

Maintenance Therapy ◽

Board Of Directors ◽

Research Funding ◽

Checkpoint Inhibitors ◽

Advisory Committees ◽

Relapsed Disease

Background:Treatment options are limited for patients (pts) with hematologic malignancies who relapse after allogeneic stem cell transplantation (allo-SCT). We hypothesized that checkpoint inhibitors may offer a novel approach for maintaining remission after allo-SCT. Data from pre-clinical studies have suggested a potential role for PD-1/PD-L1 inhibitors in acute myeloid leukemia (AML) (Zhang et al., Blood 2009), so it is possible that immunomodulation with checkpoint inhibitors could stimulate the donor anti-leukemia immune response and prevent disease relapse. However, the safety of checkpoint blockade early after allografting remains to be established. Methods:We conducted a pilot study to assess the tolerability and efficacy of Nivolumab, a PD-1 inhibitor, as maintenance therapy after allo-SCT (NCT02985554). Pts were eligible if they were post allo-SCT without evidence of relapse or active graft-vs-host disease (GVHD) or history of prior greater than stage I skin acute GVHD. Nivolumab was to be administered intravenously at 1mg/kg every 2 weeks for 4 doses followed by dosing every 12 weeks. Treatment started 4 weeks after routine immunosuppression was discontinued until 2 years after the transplant. The primary objective was to determine the tolerability of Nivolumab on this schedule. Secondary objectives were evaluation of adverse events, relapse, and overall survival. Results:Four pts were enrolled from December 2017 through November 2018. (Table 1)All pts experienced immune-related adverse events (irAE) from Nivolumab, and 2 (50%) pts experienced serious adverse events. (Table 2)One pt developed grade (G) 4 neutropenia soon after the first dose. (Figure 1)The absolute neutrophil count nadired at 20 cells/µL, at which point pegfilgrastim was administered. An interim bone marrow biopsy (BMBx) confirmed no evidence of relapsed disease. Full neutrophil recovery occurred approximately 3 months after the initial dose, and no subsequent toxicities occurred. Another pt developed G3 autoimmune encephalopathy concurrently with G2 transaminitis and G2 thrombocytopenia after one dose of Nivolumab. (Figure 2)Intravenous methylprednisolone (1mg/kg daily for 3 days) and immunoglobulin (2g/kg in 4 divided doses) were administered, followed by a 7-week steroid taper with full resolution of symptoms. Relapsed disease was ruled out by a BMBx. A third pt developed G2 skin rash approximately 10 days after the first dose of Nivolumab. Skin biopsy demonstrated drug hypersensitivity reaction vs GVHD, and the pt was treated with a 3-week prednisone course (starting at 1mg/kg followed by a taper). A mild flare recurred 2 weeks later, which was treated with topical steroids only. However, Nivolumab was not resumed. The fourth pt developed G2 elevated TSH approximately 2 months into therapy and after 4 doses of Nivolumab. Thyroid hormone replacement was initiated with subsequent symptom improvement and normalization of TSH over a 4-month period. As a result of these unexpected severe toxicities, the study was closed to further enrollment, and further Nivolumab administration ceased. Thus far, one pt (#1) relapsed after a total remission duration of 530 days; the remission duration after starting Nivolumab was 318 days. One pt has mild chronic skin GVHD. All 4 patients remain alive with a median overall survival of 2.3 years (range, 1.9-4.7). Conclusions:Even at low doses, the use of Nivolumab as maintenance therapy in the post allo-SCT setting was not tolerable at the current dosing and schedule due to an unexpected number of high grade irAEs. Additional studies of dose and timing after allo-SCT are needed to improve safety and tolerability, in conjunction with correlative studies to better understand the immunomodulatory processes in the post-transplant setting. Disclosures Kline: Merck: Honoraria; Merck: Research Funding. Stock:Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria; Research to Practice: Honoraria. Artz:Miltenyi: Research Funding. Larson:Agios: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials; Celgene: Consultancy. Riedell:Novartis: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Speakers Bureau; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau. Bishop:CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Liu:Arog: Other: PI of clinical trial; BMS: Research Funding; Agios: Honoraria; Novartis: Other: PI of clinical trial; Karyopharm: Research Funding. OffLabel Disclosure: Nivolumab used as maintenance therapy in the post-transplant setting

Download Full-text

Northstar-2: Updated Safety and Efficacy Analysis of Lentiglobin Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia and Non-β0/β0 Genotypes

Blood ◽

10.1182/blood-2019-126046 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3543-3543 ◽

Cited By ~ 1

Author(s):

Alexis A. Thompson ◽

Mark C. Walters ◽

Janet L. Kwiatkowski ◽

Suradej Hongeng ◽

John B. Porter ◽

...

Keyword(s):

Gene Therapy ◽

Clinical Trials ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Adult Patients ◽

Employment Equity ◽

Advisory Committees ◽

Transfusion Independence ◽

Equity Ownership

Background Transfusion-dependent β-thalassemia (TDT) is treated with regular, lifelong red blood cell (RBC) transfusions and despite iron-chelating therapy, carries a risk of serious organ damage from iron overload and other complications. Transplantation with autologous CD34+ cells encoding a βA-T87Q-globin gene (LentiGlobin for β-thalassemia) is being evaluated in patients with TDT. Interim results are presented here from the ongoing, international, single-arm, phase 3 Northstar-2 study (HGB-207; NCT02906202) of LentiGlobin gene therapy in pediatric, adolescent, and adult patients with TDT (defined by receiving ≥100 mL/kg/yr of RBCs or ≥8 RBC transfusions/yr) and non-β0/β0 genotypes. Methods Patients undergo hematopoietic stem cell (HSC) mobilization with G-CSF and plerixafor. Following apheresis, CD34+ cells are transduced with BB305 lentiviral vector and infused into patients after pharmacokinetic-adjusted, single-agent busulfan myeloablation. The primary efficacy endpoint is transfusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without RBC transfusions for ≥12 months). HSC engraftment, βA-T87Q-globin expression, Hb levels, detection of replication competent lentivirus (RCL), and adverse events (AE) are also assessed. Patients are followed for 2 years and offered participation in a long-term follow-up study. Summary statistics are presented as median (min - max). Results Twenty patients were treated in Northstar-2 as of 13 December 2018 and have been followed for a median of 8.1 (0.5 - 22.2) months. At enrollment, median age was 16 (8 - 34) years; 5 patients were <12 years of age. Median drug product cell dose was 8.0 (5.0 - 19.9) x106 cells/kg and vector copy number was 3.2 (1.9 - 5.6) copies/diploid genome. Time to neutrophil and platelet engraftment in the 18/20 and 15/20 evaluable patients was 22.5 (13 - 32) and 45 (20 - 84) days, respectively. Non-hematologic grade ≥3 AEs in ≥3 patients after LentiGlobin infusion included stomatitis (n=12), febrile neutropenia (n=6), pyrexia (n=4), epistaxis (n=3), and veno-occlusive liver disease (n=3). One serious AE of grade 3 thrombocytopenia was considered possibly related to LentiGlobin. No patient died, had graft failure, or had detection of RCL. No insertional oncogenesis has been observed. Gene therapy-derived HbAT87Q stabilized approximately 6 months after infusion. In adolescent and adult patients treated with LentiGlobin, median HbAT87Q at Months 6, 12 and 18 was 9.5 (n=11), 9.2 (n=8), and 9.5 (n=3) g/dL, respectively. The median total Hb without transfusions at Months 6, 12, and 18 were 11.9 (n=11), 12.4 (n=8), 12.3 (n=2) g/dL, respectively. At Month 6, 91% (10/11) of patients had total Hb of >11 g/dL without transfusions. Five adolescent and adult patients were evaluable for the primary endpoint of transfusion independence, 4 (80%) of whom achieved TI. The median weighted average Hb during TI was 12.4 (11.5 - 12.6) g/dL which compared favorably to pre-transfusion nadir Hb levels before enrollment (median 9.1 g/dL [7.5 - 10.0 g/dL]). At time of analysis, the median duration of TI was 13.6 (12.0 - 18.2) months. One patient who did not achieve TI stopped transfusions for 11.4 months but resumed transfusions due to recurrent anemia. This patient had a 71.4% reduction in RBC transfusion volume from Month 6 to Month 18 compared to baseline. Marrow cellularity and myeloid:erythroid (M:E) ratios were evaluated in 8 adolescent and adult patients with ≥12 months follow-up to assess the effect of LentiGlobin treatment on dyserythropoiesis. Seven of 8 patients had improved marrow M:E ratios at Month 12 (0.63 - 1.90) compared with baseline (0.14 - 0.48). In patients who stopped transfusions, soluble transferrin receptor levels were reduced by a median of 72% (58% - 78%) at Month 12 (n=6). Updated outcomes in adolescents and adults and outcomes in pediatric patients will be reported. Summary In this update of the Northstar-2 study of LentiGlobin gene therapy in patients with TDT and non-β0/β0 genotypes, transfusion independence was observed in 4/5 evaluable adolescent and adults and 10/11 treated patients had total Hb of >11 g/dL without transfusion support 6 months after LentiGlobin infusion. HbAT87Q stabilized approximately 6 months after treatment and patients who stopped RBC transfusions had improved erythropoiesis. A safety profile consistent with busulfan conditioning was observed after LentiGlobin gene therapy. Disclosures Thompson: bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Walters:TruCode: Consultancy; AllCells, Inc: Consultancy; Editas Medicine: Consultancy. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Terumo: Research Funding; Celgene: Consultancy; Agios: Consultancy; Imara: Consultancy; Apopharma: Research Funding; Novartis: Research Funding. Porter:Protagonism: Honoraria; Celgene: Consultancy, Honoraria; Bluebird bio: Consultancy, Honoraria; Agios: Consultancy, Honoraria; La Jolla: Honoraria; Vifor: Honoraria; Silence therapeutics: Honoraria. Thrasher:Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Generation Bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; 4BIOCapital: Membership on an entity's Board of Directors or advisory committees. Thuret:BlueBird bio: Other: investigators for clinical trials, participation on scientific/medical advisory board; Celgene: Other: investigators for clinical trials, participation on scientific/medical advisory board; Novartis: Other: investigators for clinical trials, participation on scientific/medical advisory board; Apopharma: Consultancy. Elliot:bluebird bio, Inc.: Employment, Equity Ownership. Tao:bluebird bio, Inc.: Employment, Equity Ownership. Colvin:bluebird bio, Inc.: Employment, Equity Ownership. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria.

Download Full-text

Efficacy Outcomes of Treatments for Double Relapsed/Refractory Follicular Lymphoma (R/R FL): A Systematic Literature Review

Blood ◽

10.1182/blood-2020-136228 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 42-43

Author(s):

Brad S. Kahl ◽

Anik R. Patel ◽

Omer Zaidi ◽

Sonya J. Snedecor ◽

Anna G. Purdum

Keyword(s):

Clinical Trials ◽

Follicular Lymphoma ◽

Board Of Directors ◽

Clinical Data ◽

Research Funding ◽

Treatment Options ◽

Unmet Need ◽

Progression Free Survival ◽

Disease Stage ◽

Advisory Committees

ABSTRACT Introduction: Patients with indolent non-Hodgkin lymphomas (iNHL), including follicular lymphoma (FL), have high response to first-line treatment. However, retreatment is often required when relapses occur, and those with multiple relapses represent a patient population with an unmet need for effective treatment. Clinical data for several treatment options exist for the general relapsed and refractory (R/R) population; however, there are relatively fewer data specific to FL patients with ≥2 lines of prior treatment. This work systematically identified the available efficacy data in the double R/R FL population. Methods: The MEDLINE and EMBASE databases were searched through February 10, 2020. Studies were limited to interventional clinical trials of R/R FL patients (or mixed histologies with a predominance of FL) and articles published in English. Studies also must have reported one or more efficacy measures, such as overall response rate (ORR), complete response (CR), duration of response (DoR), time to next treatment (TTNT), progression-free survival (PFS), and overall survival (OS). Potential interventions of interest were lenalidomide ± rituximab (R), duvelisib, ibrutinib, venetoclax, polatuzumab vedotin + R, obinutuzumab, copanlisib, umbralisib, idelalisib, and tazemetostat. Results: Of 35 publications examining treatment outcomes in R/R FL patients, only 14 (representing 5 unique clinical trials) were specific to the ≥ 2-line population. These trials were: CHRONOS Part B (copanlisib), DAWN (ibrutinib), DELTA (idelalisib), DYNAMO (duvelisib), and Morschhauser et al. 2019 (tazemetostat) and included a total of 605 participants. All studies used similar inclusion criteria, and patients included were similar in age (median 62-65), disease stage (III/IV), and ECOG score (0-2). Patients in the CHRONOS study had a median number of prior treatments of 2, whereas those in the DELTA study had 5. ORR ranged from 21% (ibrutinib) to 59% (copanlisib) (Table). The DoR ranged from 8.3 months in tazemetostat patients with EZH2 gene mutation to 19.4 months for ibrutinib. PFS ranged from 5.7 months in tazemetostat patients with wild-type EZH2 to 11.2 months for copanlisib. Median TTNT was only reported in the DAWN study (16 months). Conclusions: Very few clinical data exist reporting efficacy outcomes specific to the double R/R FL population. The limited data indicate that current treatments do not produce durable responses for most double R/R FL patients, demonstrating an unmet need. Further research is needed to fully understand the efficacy and safety of other potential interventions for this population. Disclosures Kahl: Genentech:Consultancy;Pharmacyclics LLC:Consultancy;AstraZeneca Pharmaceuticals LP:Consultancy, Membership on an entity's Board of Directors or advisory committees;ADC Therapeutics:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Celgene Corporation:Consultancy;AbbVie:Consultancy;Roche Laboratories Inc:Consultancy;BeiGene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Janssen:Consultancy, Membership on an entity's Board of Directors or advisory committees;Acerta:Consultancy, Research Funding.Patel:Kite, a Gilead Company:Current Employment.Zaidi:BMS:Consultancy.Snedecor:Pharmerit - an OPEN Health Company:Other: Employment at consultancy paid by Kite Pharma to conduct this work.Purdum:Kite, a Gilead Company:Current Employment.

Download Full-text