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

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3746-3746 ◽  
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.

Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Is Highly BCL-2 Dependent and Sensitive to Venetoclax

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4045-4045 ◽  
Author(s):  
Joan Montero ◽  
Jason Stephansky ◽  
Tianyu Cai ◽  
Gabriel K. Griffin ◽  
Katsuhiro Togami ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cell ◽  
Cytochrome C ◽  
Board Of Directors ◽  
Research Funding ◽  
Plasmacytoid Dendritic Cell ◽  
Cytochrome C Release ◽  
Advisory Committees ◽  
Cell Neoplasm ◽  
Peptide Stimulation

Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a particularly aggressive hematologic malignancy with median survival of <12 months and no standard therapy. BPDCN involves the skin in nearly all patients, and frequently infiltrates bone marrow and lymph nodes. Its normal counterpart may be the plasmacytoid dendritic cell (pDC), leading to the name BPDCN. Outcomes are poor with cytotoxic chemotherapy. An interleukin 3-diphtheria toxin fusion (SL-401) has activity in BPDCN (Frankel, Blood 2014), but additional novel agents are urgently needed. BPDCN over-expresses the anti-apoptotic protein BCL-2 compared to normal pDCs (Sapienza, Leukemia 2014). We confirmed this by RNA-sequencing 12 BPDCNs and pDCs from 4 normal donors (reads/kb mapped [RPKM] 22.7 vs 1.33, P=0.0005). BPDCN shares some genetic characteristics with myeloid malignancies, and some acute myeloid leukemias (AMLs) are dependent on BCL-2. We performed RNA-seq on 6 BPDCN and 16 AML patient-derived xenografts (PDXs) and found higher BCL-2 expression in BPDCN (RPKM 48.2 vs 11.5, P=0.0005). We analyzed BCL-2 expression by immunohistochemistry in patient skin and bone marrow biopsies and found that all BPDCNs had BCL-2 staining that was equivalent to or stronger than that of any AMLs. We next tested BPDCN cell lines, primary patient samples, and patient-derived xenografts (PDXs) for BCL-2 dependence and sensitivity to the BCL-2 inhibitor venetoclax (previously ABT-199). Using BH3 profiling, we found that BPDCN is markedly dependent on BCL-2 to prevent mitochondrial cytochrome c release in response to apoptotic stimuli. In comparison to AML, BPDCN had significantly more cytochrome c release after BAD peptide stimulation (81.1% vs 11.8%, P<0.0001), suggesting greater dependency on BCL-2 and/or BCL-XL. BPDCN was uniformly sensitive to treatment with venetoclax in vitro, in cell lines and primary cells, as measured by direct cytotoxicity and Annexin V apoptosis assays. We used dynamic BH3 profiling (Montero, Cell 2015) in primary BPDCNs and PDXs (n=7) to measure early apoptotic signals after 4-hr exposure to venetoclax, avoiding the need for prolonged culture. BPDCNs were more likely than AMLs to undergo cytochrome c release in response to BIM peptide stimulation after 4 hours of venetoclax (increase in apoptotic potential, or "delta priming" 63.4% vs 14.5%, P<0.0001). Targeted sequencing of the BPDCNs found various combinations of mutations in TP53, FLT3, JAK2, SRSF2, TET2, ASXL1, IDH2, GNB1, NRAS and/or ZRSR2. All responded equally to venetoclax, suggesting the response was independent of genotype. Next we treated two BPDCN PDXs in vivo in NSG mice with oral venetoclax (100 mg/kg/day x 28 days). PDX genetics were, PDX1: ASXL1 G646fs*, NRAS G13D, JAK2 V617F, TET2 D1017fs*, and TET2 Q1687fs*; PDX2: IDH2 R140Q, TP53 S241F, TP53 C176Y, and ZRSR2 S188*. Venetoclax caused significant reductions in BPDCN burden in peripheral blood, spleen, and bone marrow after 21 days of therapy in both models. Overall survival was improved in venetoclax compared to vehicle treated animals in a leukemia-watch cohort (57 vs 36 days, P=0.0025). On the basis of these findings, we treated a relapsed BPDCN patient with venetoclax. He is an 80 year-old male who had received 3 prior lines of therapy. He had extensive skin disease with multiple cutaneous tumors, lymph node involvement, and >80% bone marrow blasts. His BPDCN carried the mutations ASXL1 Y581fs*, ASXL1 E553fs*, GNB1 K57E, IDH2 R140W, and NRAS G12D, and expressed high levels of BCL-2 protein in bone marrow and skin. BH3 profiling of a skin tumor biopsy revealed marked BCL-2 dependence and dynamic BH3 response to venetoclax (4 hr delta priming 55.6%). We treated him using a regimen recently FDA-approved for chronic lymphocytic leukemia (CLL) consisting of weekly dose escalation (20 -> 50 -> 100 -> 200 mg), to a target dose of 400 mg daily. At the time of this writing, he had reached 200 mg without significant toxicity, including no evidence of tumor lysis syndrome. His skin disease has responded remarkably (Figure), with the first response evident within 10 days. Our data suggests that BPDCN is highly sensitive to BCL-2 inhibition, which could provide an urgently needed new treatment for patients with this disease. We propose that BCL-2 inhibition should undergo expedited clinical evaluation in BPDCN. In addition, this case offers an example of precision cancer medicine by functional rather than genetic means. Figure Figure. Disclosures Davids: Infinity: Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Gilead: Honoraria; Janssen: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Stone:ONO: Consultancy; Novartis: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy; Roche: Consultancy; Celator: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; Sunesis Pharmaceuticals: Consultancy; Xenetic Biosciences: Consultancy. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. Letai:AbbVie: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Tetralogic: Consultancy, Research Funding. Lane:N-of-1: Consultancy; Stemline Therapeutics: Research Funding.

scholarly journals Favorable Long-Term Outcomes after Daratumumab Discontinuation in AL Amyloidosis Patients Achieving Deep Responses

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1884-1884 ◽  
Author(s):  
Alfred Chung ◽  
Gregory P. Kaufman ◽  
Surbhi Sidana ◽  
David Iberri ◽  
Erik Eckhert ◽  
...  
Keyword(s):  
Disease Progression ◽  
Board Of Directors ◽  
Median Duration ◽  
Research Funding ◽  
Control Group ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Free Interval ◽  
Significant Difference

Daratumumab (DARA) is a CD38-targeted antibody FDA-approved for the treatment of multiple myeloma (MM) and its efficacy has recently been demonstrated in the treatment of AL amyloidosis. DARA is conventionally given indefinitely until evidence of disease progression or intolerance for the treatment of MM. In AL amyloidosis, the optimal duration of therapy is not known, and patients may be treated indefinitely on maintenance, extrapolating from MM data. However, the plasma cell burden observed in AL amyloidosis is often lower than in MM, and thus certain patients achieving deep responses may have durable responses with time-limited treatment. Outcomes for patients who are observed after DARA discontinuation are not known. We report the outcomes of patients at our institution who received time-limited DARA. A retrospective analysis of AL amyloidosis patients treated at Stanford University from 2016 to 2019 with DARA monotherapy and dexamethasone for at least 2 months was performed, and patients who subsequently had DARA discontinued for reasons other than disease progression or lack of response were selected for the study. Hematologic responses were assessed by consensus guidelines. Duration on and off therapy were explored, along with time-to-next treatment or death (TTNT), defined as the time from DARA initiation to restarting/switching therapy or death. An exploratory analysis comparing TTNT between the study population and a control cohort who achieved hematologic CR and were maintained on DARA was conducted with the Kaplan-Meier method and log-rank testing. 67 patients received at least 2 months of DARA monotherapy and dexamethasone; among these, 15 patients discontinued therapy for reasons other than disease progression and were included. Median age was 66 years old and median lines of prior therapies was 4 (range: 1 - 6). Baseline difference between involved and uninvolved free light chains (dFLC) prior to DARA initiation was 2.6 mg/dL (range: 0 - 16.8 mg/dL). 10 of 15 patients had cardiac involvement with median NT-proBNP of 1982 pg/mL and 9 of 15 patients had renal involvement with median 24-hour proteinuria of 6.2 g and eGFR of 32 mL/min/1.73m2 at DARA initiation. Median duration from starting to stopping DARA was 7.8 months (range: 2 - 21 months). Median duration from achieving best hematologic response to stopping DARA was 3 months (range: 0 - 17 months). Reasons for discontinuation included: patient preference (5), fatigue/body aches (4), infection (2), other active medical comorbidities (3), and lack of perceived further benefit (1). At DARA discontinuation, median dFLC was 0.1 mg/dL (range: 0 - 2.2 mg/dL) and there were 12 hematologic CR, 1 VGPR, 1 PR, and 1 not assessable for response. Outcomes for all 15 patients are shown in Figure 1. The median treatment-free interval was 17.5 months (range: 5 - 34 months); estimated 2-year TTNT-free survival was 83% (95% CI: 61 - 100%). All 14 evaluable patients eventually achieved CR. 3 patients restarted DARA for rising dFLC, and all 3 patients demonstrated response to retreatment (2 achieving CR and 1 near PR with ongoing follow-up). There were 2 deaths. One patient with severe baseline cardiac amyloidosis developed sudden rise in dFLC after treatment-free interval of 21 months; although he rapidly achieved hematologic CR on retreatment, he died of heart failure within 2 months of restarting DARA. The other patient developed therapy-related AML while off therapy and underwent allogenic stem cell transplant but died of leukemia (censored for AL amyloidosis outcomes at transplant). There was no significant difference in the TTNT between the study group and a control group of 16 patients who achieved CR and were on continuous maintenance (Figure 2; p=0.807). AL amyloidosis patients achieving deep responses with DARA can have favorable outcomes after treatment discontinuation, including a long treatment-free interval. Although our sample size is small, the outcomes of these patients appeared comparable to those achieving CR on continuous DARA maintenance, and patients were able to regain responses when retreatment was necessary. These results suggest that DARA may be safely discontinued in patents achieving deep hematologic responses, which has significant implications for quality of life and financial burden of treatment. Future studies evaluating time-limited versus continuous DARA maintenance after achievement of deep responses are warranted. Disclosures Kaufman: Janssen: Other: travel/lodging, Research Funding. Liedtke:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Daratumumab for treatment of AL amyloidosis

scholarly journals 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 ◽  
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.

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

Blood ◽  
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 (&lt;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 &gt;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 &gt;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.

Impact of Wait Times for Autologous Stem Cell Transplantation in Patients with Aggressive Non-Hodgkin Lymphoma, a Subset Analysis of the Canadian Cancer Trials Group (CCTG) LY.12 Clinical Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 690-690
Author(s):  
Tanya Skamene ◽  
Wenyu Jiang ◽  
Ralph M. Meyer ◽  
Michael Crump ◽  
John Kuruvilla ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
Wait Time ◽  
Salvage Chemotherapy ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Stem Cell Collection

Abstract Background: High dose chemotherapy followed by autologous stem cell transplant (ASCT) is the standard curative option for patients with relapsed or refractory, chemosensitive, aggressive non-Hodgkin lymphoma (NHL). The optimal timing for ASCT following salvage chemotherapy is not known. Cancer Care Ontario (CCO)-the cancer agency for Ontario, Canada's largest province-treatment guidelines recommend that no more than 91 days should elapse from the first day of salvage chemotherapy to stem cell transplant. We evaluated the impact of time to stem cell transplant in the context of the international CCTG LY.12 phase 3 clinical trial. Methods: Patients with relapsed or refractory (R/R) aggressive NHL were randomly assigned to gemcitabine, cisplatin and dexamethasone (GDP) or dexamethasone, cytarabine, cisplatin (DHAP), with or without rituximab, followed by ASCT [Crump JCO 2014]. Time interval definitions were based on CCO guidelines: Total Wait Time (TWT) as the number of days from the first day of salvage chemotherapy to day of ASCT; Apheresis Wait Time (AWT) as the number of days from the first day of salvage to the first day of stem cell collection; Stem cell transplant Wait Time (SWT) as the number of days from the last day of stem cell collection to the day of ASCT. Patients were considered to have experienced a delay in TWT, AWT or SWT if the time intervals exceeded 91, 70 and 21 days respectively. Overall survival (OS) and event-free survival (EFS) from transplant date were compared between patients who met and exceeded TWT targets using a Cox proportional hazards model. A linear regression model was applied to analyze TWT as a continuous variable. Univariate and multivariate analyses were performed to estimate the adjusted hazard ratio (HR) for TWT for the following co-variables: age ≤60, performance status 0/1, disease stage (I/II), presence of ≤1 extranodal sites, and response after cycle 2 (complete response, CR; complete response, unconfirmed, CRu; partial response, PR). Results: Of 619 patients enrolled on LY.12, 307 (47%) had sufficient response to salvage chemotherapy and adequate stem cell collection to complete ASCT on protocol. Among these, median age was 54.6 years, 64% were male and 94% had a performance status of 0 or 1. International Prognostic Index (IPI) score at relapse was 0-1 in 45%, 2 in 31% and ≥3 in 24%. The majority of patients had poor risk disease at study entry; 58% had a best response of stable disease (SD) or progressive disease (PD) to primary therapy, or initial duration of response < 1 year. Following up to 2 cycles of salvage chemotherapy, 75/307 (24%) achieved CR/CRu, 142/307 (46%) achieved PR, 89/307 (29%) had SD. One patient had missing data. The median TWT for the total transplanted population was 91 days (range 50-217). Median AWT and SWT were 63 (range 0-151) and 26 (range 6-146) days, respectively. Fifty percent of patients exceeded TWT target of 91 days; 32% and 57% of patients exceeded AWT and SWT targets. There was no difference in median OS (HR 0.96, 95% CI 0.66-1.39, p=0.81) or EFS (HR 1.13, 95% CI 0.82-1.55, p=0.46) between patients who exceeded and met TWT targets. The 4-year OS for patients who met and exceeded TWT was 62% and 64%, respectively. The 4-year EFS for patients who met and exceeded TWT was 43% and 50%, respectively. When analyzed as a continuous variable, TWT did not affect OS (HR 0.99) or EFS (HR 0.99). Comparison of the quartiles with shortest and longest TWT demonstrated HR 0.72 (95% CI 0.42-1.26, p=0.25) for overall survival and 0.69 (95% CI 0.44-1.09, p=0.11) for EFS. Comparison of the 10th and 90th percentiles for TWT demonstrated HR 0.67 (95% CI 0.28-1.59, p=0.36) for overall survival and 0.71 (95% CI 0.35-1.44, p=0.34) for EFS. Only the presence of ≤1 extranodal sites of disease was found to be predictive of OS in the transplanted population on univariate and multivariate analysis (adjusted HR 0.51, p=0.005). The median TWT was longer for the 31 patients transplanted at Italian centers, compared to 266 transplanted at Canadian centers (median TWT 90 vs. 118 days, t < 0.0001). Conclusion: In this exploratory analysis, limited to patients who completed transplant on the LY.12 clinical trial, we did not find evidence that those meeting current CCO ASCT wait time targets had superior outcomes compared with those who did not. Table. Table. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Kuruvilla: BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Merck: Honoraria; Roche Canada: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria. Luminari:Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Takeda: Other: Travel, Accomodations, Expenses; Teva Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Hay:Amgen: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Kite Pharmaceuticals: Research Funding.

scholarly journals Outcome of Patients with Myelofibrosis Relapsing after Allogeneic Stem Cell Transplant: A Retrospective Study By the Chronic Malignancies Working Party of EBMT

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1958-1958
Author(s):  
Donal McLornan ◽  
Richard Szydlo ◽  
Anja van Biezen ◽  
Linda Koster ◽  
Evgeny Klyuchnikov ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Median Survival ◽  
Research Funding ◽  
Working Party ◽  
Active Management ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Number Of Patients ◽  
Significant Difference

Abstract Background: Over the last decade, there has been a significant increase in the number of patients with Myelofibrosis (MF) undergoing allogeneic stem cell transplantation (SCT). However, scarce information exists on the outcome and management of those patients who relapse following SCT. Moreover, the management of relapse occurring post-SCT is often heterogeneous and ranges from palliation to intensive salvage approaches. We therefore conducted a retrospective EBMT registry analysis of adult MF patients who relapsed following first SCT episode. Results: A total of 1216 adult patients (997 (82%) with Primary MF (PMF) and 219 (18%) with secondary MF (sMF)) underwent 1st allogeneic SCT between 2000 and 2010. A total of 251 patients from this cohort (206 with PMF and 45 with sMF) had conformed relapse ≥ day 30 after HSCT and were included in the analysis. Within this relapse cohort, there were 163 males and 88 females; median age was 55 years old (range 21.5-70 years). A total of 84 patients (33%) had received Myeloablative Conditioning (MAC) and 167 patients (67%) Reduced Intensity Conditioning (RIC). Regarding donor type, there were 123 matched siblings (49%) and 128 unrelated donors (51%). Acute GVHD (aGVHD) status was available for 243/251 (97%) patients; no aGVHD was evident in 143 patients, Grade I-II aGVHD 76 patients, Grade III-IV aGVHD 22 patients and 2 patients with aGVHD ungraded. The median time to relapse after SCT was 7.1 months (range 1-111 months). The median Overall Survival (OS) from the time of relapse was 17.7 months (95% Confidence Intervals 11-24). Collectively, there was a significant difference in survival outcome for those relapsing > 7.1 months post-SCT (median survival 30.3 months post relapse) compared to those relapsing within 7.1 months following the initial SCT episode (median survival 7.9 months post relapse; p<0.001). Absence of aGVHD or grade I aGVHD only was associated with a trend towards improved survival following relapse compared to those with Grade II-IV aGVHD (p=0.12). For PMF, disease duration prior to SCT did not significantly affect outcome post relapse. Heterogeneous practice existed as regards management of the relapse episode, with considerable variation in median survival (MS) estimates. 47 patients received Donor Lymphocyte Infusions (DLI) alone (MS 76 months); 21 had chemotherapy alone (MS 23 months) whereas 14 patients had DLI combined with chemotherapy (MS 13.6 months). As regards 2nd allografts: 53 patients underwent 2nd allograft alone (MS 23.6 months) and 26 underwent DLI and 2nd SCT (MS 53.9). In 90 patients active management -if any- was not documented (most likely many were palliative) but represented a very poor risk group with a MS of only 4.8 months. Overall, there was a significant improvement in OS post relapse for those undergoing 2nd SCT (n=79) versus those who did not have a 2nd SCT (n=172; p=0.019). Conclusions : This analysis represents the first study to define the outcome of MF patients who undergo relapse following allogeneic SCT. Treatment of relapse presents huge challenges and the heterogeneous management strategies highlighted above reflects current practice where approaches range from palliation through to intensive chemotherapy and 2nd SCT. It is clear from this analysis that early relapse has a much worse prognosis than those who relapse later than 7.1 months post-SCT. There is a definite survival advantage for those who undergo DLI and/or a 2nd SCT procedure, although we acknowledge that those patients undergoing a 2nd SCT represent a highly selected group who are fit enough to undergo such intervention. Moreover, how relapse management practice will change in the era of novel therapies such as JAK inhibitors to bridge towards 2nd SCT is currently unclear and requires evaluation in prospective studies. Disclosures McLornan: Novartis: Research Funding, Speakers Bureau. Finke:Riemser: Research Funding, Speakers Bureau; Neovii, Novartis: Consultancy, Research Funding, Speakers Bureau; Medac: Research Funding. Craddock:Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Speakers Bureau; Sunesis: Honoraria; Johnson and Johnson: Consultancy. Apperley:BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Niederwieser:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Organ Damage at Initial Presentation across the Spectrum of Advanced Systemic Mastocytosis Variants

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2567-2567
Author(s):  
Emily C. Liang ◽  
Cecelia Perkins ◽  
Rong Lu ◽  
Justin Abuel ◽  
Cheryl Langford ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Mast Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Systemic Mastocytosis ◽  
Organ Damage ◽  
Initial Presentation ◽  
Pleural Effusions ◽  
Advisory Committees ◽  
Significant Difference

Abstract BACKGROUND: Systemic mastocytosis (SM) is characterized by the accumulation of neoplastic mast cells in various organs, including the bone marrow, liver, spleen, and gastrointestinal tract. Advanced SM (AdvSM) comprises 3 subtypes: aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Individuals with AdvSM often exhibit hematologic and/or non-hematologic organ damage (C-findings), which contributes to the poor prognosis of these patients (pts). To date, the presenting patterns of organ damage across the spectrum of AdvSM subtypes have not been well characterized. In addition, the definition of hematologic and non-hematologic organ damage has evolved from the initial characterization of C-findings used by the World Health Organization (WHO) to define ASM, to more clinically relevant and quantifiable organ damage criteria that are used to assess eligibility for clinical trials in AdvSM. These include the International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (IWG) criteria and a modified version of these criteria (mIWG), which differ slightly regarding splenomegaly (IWG: symptomatic splenomegaly &gt;5 cm; mIWG: spleen &gt;5 cm). In this retrospective analysis, we describe the distribution and frequency of organ damage at the time of initial presentation among the 3 subtypes of AdvSM as defined by WHO, IWG, and mIWG criteria. METHODS: Among 251 pts with mast cell disorders in our Stanford IRB-approved MPN registry, we identified 87 AdvSM pts between October 1999 and September 2020. Thirteen pts (15%) had ASM, 63 (72%) had SM-AHN, and 11 (13%) had MCL. Comparisons between continuous and categorial variables were performed using the Kruskal-Wallis test and the Fisher's exact test, respectively. We defined IWG/mIWG liver-associated organ damage as a composite of ascites/pleural effusions requiring diuretics or drainage, liver function abnormalities, and/or hypoalbuminemia. RESULTS: Median age at diagnosis was 64 years (range 24-88) and 55 pts (63%) were male. The median number of prior treatments was 1 (range, 0-4). Forty-six pts (53%) were enrolled on clinical trials, and they had a median of 2 organ damage findings by WHO or IWG/mIWG criteria. ASM, MCL, and SM-AHN pts had significantly different WBC, ANC, and monocyte counts; pts with SM-AHN had the highest median white blood cell count (11.4 x 10 9/L), absolute neutrophil count (5.69 x 10 9/L), and monocytosis (1.58 x 10 9/L). Pts with SM-AHN exhibited a trend towards a higher absolute eosinophil count compared to ASM pts (p = 0.06). There was a significant difference in IWG/mIWG-defined RBC and platelet transfusion dependence in the 12 weeks prior to initial presentation. Pts with MCL had the highest transfusion requirement, with 55% and 27% of pts requiring red blood cell and platelet transfusions, respectively. There were no differences in median hemoglobin, platelet count, liver function tests, serum albumin, pleural effusions/ascites, and liver or spleen size by palpation or volumetric imaging. Across the 3 AdvSM subtypes, a significant difference was observed between the # of pts fulfilling IWG/mIWG criteria for liver-related organ damage (p = 0.044). Pts with SM-AHN (p = 0.071) and MCL (p = 0.013) fulfilled more IWG/mIWG liver criteria compared to ASM pts. While the absolute number of IWG/mIWG non-hematologic organ damage findings was not different across the 3 subtypes, a pairwise comparison revealed a statistically higher number of IWG non-hematologic organ damage findings in MCL vs. ASM. Irrespective of the criteria, there were no significant differences in organ damage between pts receiving 0, 1, or ≥2 prior therapies. CONCLUSION: We provide a preliminary snapshot of the patterns of WHO and IWG/mIWG-defined organ damage at initial presentation across a spectrum of AdvSM pts. Pts with MCL had the highest transfusion requirements, and liver-associated organ damage appears to be more frequent in SM-AHN and MCL pts compared to ASM. We next plan to study the profile of organ damage using WHO, IWG, and mIWG criteria in AdvSM patients who enrolled on the phase I (NCT02561988) and phase II (NCT03580655) studies of avapritinib. These analyses will include clinicopathologic and genetic correlates of organ damage, including # prior therapies, KIT D816V variant allele frequency, and myeloid mutation profile. Disclosures Shomali: Incyte: Consultancy, Research Funding; Blueprint Medicines: Consultancy. Gotlib: Kartos: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cogent Biosciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair for the Eligibility and Central Response Review Committee, Research Funding; Allakos: Consultancy; BMS: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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.

Remissions after Third Induction Chemotherapy for Primary Non-Responders with Acute Myeloid Leukemia (AML) Are Uncommon and Short-Lived

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2800-2800
Author(s):  
Sara Farshchi Zarabi ◽  
Steven M. Chan ◽  
Vikas Gupta ◽  
Dina Khalaf ◽  
Andrzej Lutynski ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Palliative Care ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Research Funding ◽  
De Novo ◽  
Phase 1 ◽  
Cell Transplant ◽  
Advisory Committees ◽  
De Novo Aml

Abstract The outcome of adult patients with AML who are primary non-responders to two courses of induction chemotherapy is poor. However, the utility of a 3rd induction for a select subgroup of these patients is uncertain. Here, we evaluated the rates of response and survival after a 3rd course of induction chemotherapy for primary non-responders with AML. We identified 98 patients from the Princess Margaret Cancer Centre between May 1999 and March 2015 who were non-responders to induction and reinduction chemotherapy. No-response to re-induction chemotherapy was defined according to the Revised Recommendations of the International Working Group for AML (JCO, 2003) as patients who survived > 7 days post re-induction and had persistent AML in blood or bone marrow (>5%). Median age was 58.3 years [range: 20-76.6]. 50 (51%) were male. 2% had favorable, 18% normal, 18% intermediate, and 48% adverse cytogenetics. 50% had de novo AML, 23% had AML secondary to MDS or MPN, and 17% had therapy-related AML. Induction chemotherapy consisted of "7+3" (n =88), Nove-HiDAC (n=1), Flag-Ida (n= 2), or similar variants (n=7). Reinduction chemotherapy consisted of Nove-HiDAC (n=70), Flag-Ida (n=7), "7+3" (n=1) or other similar variants (n =20). No patients received the same regimen for both induction and reinduction. Of the 98 primary non-responders, 15 received a 3rd induction regimen, while the others received supportive/palliative care ± low-dose chemotherapy (57 pts), or a non-induction clinical trial (26 pts). Average age was 56.4 (sd: 12.9) for patients who received supportive/palliative care and 47.0 (sd: 17.5) for patients who received a 3rd induction (p=0.008). Other baseline characteristics including gender, cytogenetic risk, marrow blast count post 2nd induction, and time between 1st and 2nd induction, did not differ between patients who did and did not receive a 3rd induction. Time to 3rd induction was a median of 54 days [range:36-126] from the start of the 2nd induction. Of the 15 third inductions, 7 were clinical trials evaluating novel agents in combination with induction chemotherapy, while the other 8 were combinations of standard chemotherapeutics (Flag-Ida n=1), AMSA+HiDAC (n=2), Daunorubicin+ HiDAC (n=1), Nove-HiDAC (n=4). Of the 15 patients who received a 3rd induction, 3 (20%) achieved a CR following Nove-HiDAC and Flag-Ida or AMSA+HiDAC chemotherapy, where the Ara-C was given as continuous infusion. 1 patient underwent allogeneic stem cell transplant (SCT) approximately 3.7 months after 3rd induction and remains alive 4.6 years post CR. 2 patients relapsed 2.3 and 4.7 months post CR without having received alloSCT. None of the 12 other patients responded to the 3rd induction and none had prolonged aplasia. 2 of 15 (13%) died during 3rd induction. Among the 83 patients who did not receive a 3rdinduction, 1 achieved a CR after a phase 1 clinical trial (MDM2 inhibitor) and remains in CR 3.6 years following an alloSCT. For patients who survived the immediate post induction period and were discharged from hospital median overall survival from the start of the 2nd induction did not differ between patients who did and did not receive a 3rd induction (276 days [range: 78-1304] vs 181.5 days [range: 47-1855] respectively p= 0.14). Median duration of hospital stay (including subsequent admissions) was longer for patients receiving a 3rd induction compared to those who did not (94 days following start of the 2nd induction [range: 47-169] vs 57 days [range: 51-181], respectively;(p= 0.003)). In summary, remissions after 3rd inductions for primary non-responders are uncommon, and short-lived, suggesting that 3rd inductions should be considered with caution and only when an SCT strategy is in place. Disclosures Gupta: Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Schuh:Amgen: Membership on an entity's Board of Directors or advisory committees. Yee:Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Schimmer:Novartis: Honoraria.

scholarly journals Belumosudil for Patients with Chronic Graft-Versus-Host Disease: Combined Analysis of Failure-Free Survival (FFS) in the KD025-208 and Pivotal Rockstar Trials

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3898-3898
Author(s):  
Aleksandr Lazaryan ◽  
Corey Cutler ◽  
Zhongming Yang ◽  
Jonathan Ieyoub ◽  
David Eiznhamer ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Prognostic Factors ◽  
Treatment Failure ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Transplant ◽  
Advisory Committees ◽  
End Point ◽  
Increased Risk ◽  
Recurrent Malignancy

Abstract ABSTRACT Introduction: Belumosudil (KD025) is a novel oral selective rho-associated coiled-coil-containing kinase-2 (ROCK2) inhibitor specifically designed for the treatment of cGVHD following an allogeneic hematopoietic cell transplant. It has been evaluated in the phase 2a dose-finding (KD025-208) and the pivotal phase 2 ROCKstar trials. Patients with cGVHD in the KD025-208 trial received belumosudil after failure of 1 to 3 prior systemic lines of therapy (LOTs), and those in the ROCKstar trial received belumosudil after failure of 2 to 5 prior systemic LOTs. The best overall response rate (95% CI) achieved, which was the primary end point, was 72% (64%-78%) across the 3 dosages (belumosudil 200 mg QD, 200 mg BID and 400 mg QD) that were studied across the 2 trials. This led to the recent FDA approval of the 200-mg QD dose for the treatment of adult and pediatric patients aged ≥12 years with cGVHD after failure of ≥2 prior systemic LOTs. FFS was a secondary end point in both trials. FFS is an established composite indicator for treatment success in cGVHD, as it incorporates recurrent malignancy, nonrelapse mortality (NRM) and the absence of subsequent cGVHD therapy. Historic rates of FFS in a prior large observational study of patients with cGVHD after second-line systemic therapy were 56% at 6 months, 45% at 12 months and 31% at 24 months (Inamoto, Blood 2013). Given limited data from contemporaneous clinical trials on FFS and prognostic factors of treatment failure, we studied pooled FFS and its determinants from the KD025-208 and ROCKstar trials. Methods: A total of 186 patients from the KD025-208 (n=54) and ROCKstar (n=132) trials treated with belumosudil 200 mg QD, 200 mg BID or 400 mg QD were analyzed . The median duration of belumosudil treatment was 9.9 months (range, 0.4-44.7 months). Prior therapies included tacrolimus (58%), sirolimus (46%), extracorporeal photopheresis (42%), mycophenolate mofetil (27%), ibrutinib (27%), ruxolitinib (21%) and cyclosporine (5%). Results: At enrollment, 70% of patients had severe cGVHD according to NIH global score, 52% had ≥4 organs involved and 37% received &gt;3 prior LOTs. Overall, belumosudil was well tolerated, with drug discontinuations occurring in 10% of patients due to possible drug-related adverse events. The median FFS was 14 months. The estimated overall FFS (95% CI) rates were 75% (68%-81%), 54% (47%-61%) and 38% (29%-47%) at 6, 12 and 24 months, respectively (Table 1 and Figure). Reasons for failure included recurrent malignancy (6%), NRM (7%) and the addition of a new systemic cGVHD therapy (43%). Factors associated with increased risk of treatment failure (1-FFS) in both univariate and multivariate analyses (Table 2) included progressive onset of cGVHD (multivariate hazard ratio [HR]=2.1 [1.2-3.4]), absence of glucocorticoids in upfront therapy for cGVHD (HR=2.2 [1.2-4.0]) and ≥2 prior LOTs (HR=3.7 [1.2-12.2]). Conclusion: Treatment with belumosudil resulted in high FFS rates compared with historic benchmarks in cGVHD refractory to prior LOTs. Both NRM and relapse rates were low with the use of belumosudil. We identified distinct prognostic factors for FFS that can inform risk stratification and prognostication of patients being treated with belumosudil. Figure 1 Figure 1. Disclosures Lazaryan: Humanigen: Membership on an entity's Board of Directors or advisory committees; Avrobio: Membership on an entity's Board of Directors or advisory committees; Kadmon: Consultancy. Cutler: Mesoblast: Consultancy; Syndax: Consultancy; Omeros: Consultancy; Incyte: Consultancy; CareDx: Consultancy; Mallinckrodt: Consultancy; Pfizer: Consultancy; Kadmon: Consultancy; Editas: Consultancy; Cimeio: Consultancy; Deciphera: Consultancy; Jazz: Consultancy. Yang: Kadmon: Current Employment. Ieyoub: Kadmon: Current Employment. Eiznhamer: Kadmon: Current Employment. Blazar: BlueRock Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Carisma Therapeutics, Inc: Research Funding; Rheos Medicines: Research Funding; Tmunity Therapeutics: Other: Co-founder; Equilibre Pharmaceuticals Corp: Research Funding; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Lee: Amgen: Research Funding; Incyte: Research Funding; Novartis: Other: clinical trials, Research Funding; Pfizer: Research Funding; Kadmon: Research Funding; Takeda: Research Funding; Syndax: Research Funding; AstraZeneca: Research Funding; JANSSEN: Other; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees. Pavletic: Center for Cancer Research: Research Funding; National Cancer Institute: Research Funding; National Institutes of Health: Research Funding; Celgene: Research Funding; Actelion: Research Funding; Eli Lilly: Research Funding; Pharmacyclics: Research Funding; Kadmon: Research Funding.

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