Interim Report of a Randomized, Open-Label, Multicenter Study to Evaluate the Safety and Efficacy of Decitabine As an Epigenetic Priming Agent When Combined with Induction Chemotherapy in Pediatric Patients (pts) with Newly Diagnosed Acute Myelogenous Leukemia (AML)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1517-1517
Author(s):  
Lia Gore ◽  
Margaret E. Macy ◽  
Francoise Mechinaud ◽  
Aru Narendran ◽  
Frank Alvaro ◽  
...  
Keyword(s):  
Organ Failure ◽  
Induction Therapy ◽  
Expression Patterns ◽  
Myelogenous Leukemia ◽  
Colon Perforation ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Open Label ◽  
Post Induction ◽  
Multisystem Organ Failure

Abstract Abstract 1517 Purpose: Decitabine, a deoxycytidine nucleoside derivative, is an inhibitor of DNA-methyltransferases indicated for treatment of myelodysplastic syndrome (MDS) including previously treated and untreated, de novo or secondary MDS of all French-American-British (FAB) subtypes, Intermediate-1, Intermediate-2, and High-Risk International Prognostic Scoring System (IPSS) groups. Laboratory evidence shows that pretreatment of AML cell lines can sensitize leukemia cells to chemotherapy as well as inhibit clonogenic potential. The purpose of this study is to evaluate the safety, pharmacokinetics, and efficacy of decitabine when used as priming before induction therapy in children with newly diagnosed AML. Exploratory analyses of genomic methylation and RNA expression patterns and minimal residual disease (MRD) are embedded correlative studies. Methods: This multicenter, randomized, two-arm, open-label study enrolls pediatric pts ages 1–16 with newly diagnosed AML to either Arm A: daunorubicin, cytarabine, etoposide (D-ADE) preceded by a 5-day course of decitabine (experimental arm) or Arm B: daunorubicin, cytarabine, etoposide (ADE; control arm). Following completion of induction on study, post-induction therapy is at the treating physician's discretion. To date, 20 pts, 10 in each arm (1–16 yrs, median 9.4 yrs in both arms) have been enrolled. Results: At the protocol-specified bone marrow sampling time 3 weeks post-induction, there were 2 CRs, 6 CRi (CR with incomplete hematopoietic recovery), 1 leukemia not in remission and 1 pt who discontinued due to an AE in Arm A. In Arm B, 6 CRs, 2CRi, 1 PR and 1 pt with marrow aplasia have been confirmed. Decitabine PK in all arm A pts (100%) were characterized by mean+SD Cmax, 297+109 ng/mL, AUC0-t, 216+73.7 ng*h/mL, CL, 136+93.9L/h, Vdss 93.1+70.7 L, t1/2 0.456+0.073 h, and median tmax0.925 h. All pts had at least one AE. Grade 3 and 4 non-hematologic AEs in Arm A that were not seen in Arm B were caecitis in 2 (20%), anorexia in 3 (30%), and hypophosphatemia in 2 (20%) of pts. All pts experienced neutropenia and thrombocytopenia as expected. One pt in Arm A had appendicitis and colon perforation on Day 6 that led to study discontinuation, later determined to have been leukemic infiltrate. Two pts have died to date (both in Arm A), one of necrotic bowel, Pseudomonas sepsis and multisystem organ failure 6 months after completing study induction therapy. One pt died 5 months following study treatment from multisystem organ failure after stem cell transplant. Epigenetic changes associated with decitabine pretreatment were analyzed and will be presented. Conclusions: Decitabine in combination with ADE chemotherapy is well tolerated in children with newly diagnosed AML. There were no AEs that had not been previously identified in adults with MDS or AML. No differences have been observed between treatment arms in hematologic toxicities based on the current sample size. To date, the decitabine-treated pts in this study may have more gastrointestinal toxicity and hypophosphatemia. Decitabine-treated pts achieved PK exposures that were similar to those observed in adults treated with decitabine. Preliminary responses by CR/CRi were similar between treatment arms; expected adverse events of neutropenia and thrombocytopenia were similar between both Arms. Molecular changes associated with decitabine pretreatment may be important in the sensitization of clonogenic AML cells. Total accrual of 40 subjects is planned. Disclosures: Off Label Use: AC220 in relapsed/refractory pediatric acute leukemia. Tarassoff:Eisai, Inc.: Employment. Jones:Eisai Inc: Employment.

An Economic Evaluation of Bortezomib-Based Induction Therapy in Double Transplant Protocols for Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2386-2386
Author(s):  
Si-Tien Wang ◽  
Mei Sheng Duh ◽  
Hui Huang ◽  
Leigh Ann White ◽  
Eva Chang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Medical Care ◽  
Induction Therapy ◽  
Treatment Costs ◽  
Patient Treatment ◽  
Newly Diagnosed ◽  
Phase 3 ◽  
Post Transplant ◽  
Post Induction

Abstract Background: Induction therapy for multiple myeloma (MM) patients who are eligible for autologous stem cell transplant (ASCT) has evolved with the introduction of novel agents, such as bortezomib (VELCADE®, Vel) and thalidomide (THALOMID®, Thal). Phase 3 trial data show the clinical effectiveness of front-line bortezomib-based therapies, but little is known about the comparative economic benefit of bortezomib-based regimens in newly diagnosed MM in the transplant setting. Here we report a pharmacoeconomic analysis of the IFM 2005-01, GIMEMA MMY-3006, and the Myeloma-Autogreffe Group (MAG) phase 3 trials, comparing the relative costs of Vel–dexamethasone (Vel/Dex), vincristine–doxorubicin–dexamethasone (VAD), Vel–Thal–Dex (VTD), and Thal–Dex (TD). Methods: Expanding on a previous budget impact model of bortezomib treatment for relapsed MM (Fullerton et al. Blood2007: Abstract 3324), an Excel-based model was developed to calculate the cost of therapy for MM patients eligible for ASCT, including costs incurred during induction therapy and single or double transplant. Per IFM 2005-01 protocol design, we assumed that patients who achieved at least very good partial response (≥VGPR) after their first transplant did not need a second transplant; the GIMEMA and MAG trials were based on a similar tandem transplant protocol. Costs were evaluated from a health system perspective and included: induction therapy costs (drugs, medical care, adverse events [AEs], and prophylaxis treatment), cost of the first ASCT, and cost of the second ASCT if required. Drug costs were calculated based on 2008 Average Wholesale Price and applied to trial regimens. Medical care costs were based on the Medicare physician fee schedule and assumptions drawn from National Comprehensive Cancer Network (NCCN) MM treatment guidelines. AE costs (grade ≥3 AEs reported in at least two studies) were estimated using available incidence data and reported as per-event costs or annual costs depending on the data source. The unit cost of a transplant ($139,220) was calculated based on data from 1,917 MM patients treated at >120 centers in the OptumHealth database. Results: In IFM 2005-01, estimated mean per-patient treatment costs from start of induction to completion of second transplant (if required) were lower for patients receiving Vel/Dex induction ($201,793) versus VAD ($217,526), due to better post-induction response with Vel/Dex. More patients achieved post-transplant ≥VGPR with Vel/Dex than with VAD (72% vs 52%), and therefore did not require a second transplant. Similarly, in GIMEMA MMY-3006, post-induction and posttransplant ≥VGPR achieved with VTD induction was greater than that achieved with TD (post-induction: 60% vs 27% and post-transplant: 77% vs 54%), thereby reducing the need for a second transplant among patients receiving VTD induction therapy. Consequently, estimated mean treatment costs were lower for patients receiving VTD induction ($200,093) versus TD ($218,886). Estimated mean treatment costs for patients receiving VD induction in IFM 2005-01 ($201,793) and VTD induction in GIMEMA MMY-3006 ($200,093) were both lower than those for patients receiving TD induction in the MAG phase 3 trial ($239,851). Conclusions: In summary, the model showed that total costs were lower for patients receiving bortezomib-based induction compared with TD induction in both the GIMEMA MMY-3006 and MAG trials. These health economic analyses also suggest that bortezomib-based induction results in lower mean per-patient treatment costs when compared with VAD or TD induction, primarily due to better response post-first ASCT. Table: Cost Summaries of ASCT Trials Induction costs VD (IFM) VTD (GIMEMA) TD (MAG) Drugs $15,940 $24,273 $16,596 Medical care $4,147 $3,578 $1,019 Adverse events $2,948 $1000 $5,610 Total induction costs (per patient) $23,035 $28,852 $23,225 Transplant costs 1st ASCT $139,220 $139,220 $139,220 2nd ASCT $39,538 $32,021 $77,406 Total transplant costs (per patient) $178,758 $171,241 $216,626 TOTAL costs $201,793 $200,093 $239,851

Treatment of Newly Diagnosed Acute Promyelocytic Leukemia (APL) in the Elderly: A Joint Analysis of the French -Belgian-Swiss and PETHEMA Groups.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 845-845
Author(s):  
Lionel Ades ◽  
Pau Montesinos ◽  
Sylvie Chevret ◽  
Edo Vellenga ◽  
Emmanuel Raffoux ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Induction Therapy ◽  
Research Funding ◽  
Age Groups ◽  
Early Death ◽  
The Elderly ◽  
Joint Analysis ◽  
Induction Treatment ◽  
Newly Diagnosed ◽  
Post Induction

Abstract Abstract 845 Background: ATRA combined to anthracycline-based chemotherapy (CT) for induction and consolidation followed by prolonged maintenance is a standard treatment of newly diagnosed APL, but the outcome and prognostic factors in the elderly are less well established than in younger patients (pts). Methods: We performed a joint analysis of elderly pts included in two subsequent trials of the PETHEMA group (LPA96 and LPA99) and and on the French -Belgian-Swiss APL group (APL93 and APL2000). In the PETHEMA trials, pts received induction therapy with ATRA and idarubicin (Ida 12 mg/m2/d, d2,4,6,8), consolidation with 3 anthracycline monochemotherapy courses (2 with Ida and 1 with mitoxantrone, with ATRA and higher idarubicin dose for Sanz's int and high risk pts in LPA99 trial), and 2-year maintenance with intermittent ATRA and continuous low-dose CT (6MP + MTX). In APL 93 and 2000 trials: pts received induction therapy with ATRA and DNR (60mg/m2/d ×3d)+AraC, (200 mg/m2/d×7) followed by consolidation with a similar course and a final DNR (45 mg/m2/d × 3) + AraC (1-2 g/m2/12h × 8) course (omitted in pts >65y) and the same maintenance as in PETHEMA trials. Median follow up was 75 and 42 months in PETHEMA and APL trials, respectively. Results: 1575 consecutive newly diagnosed APL pts were enrolled in the 4 trials, including 1288 (81%), 105 (6.6%), 91 (5.7%) and 91 (5.7%) aged <60, 60-65, 65-70, and >70, respectively (ie 287 pts (18%) older than 60). CR rates in these age groups were 94.6%, 84.8%, 81.8% and 78.4% (p=0.0002). All failures were due to early death, except one due to resistant leukemia, in a younger adult. The 5-year cumulative incidence of relapse was 16.5%, 19.1% ,11.9% and 13.5% in pts <60, 60-65, 65-70 and >70, respectively (p= 0.63). The 5-year OS in these age groups was 85.8%, 68.7%, 63.8% and 56.4% (p<0.0001). The 5-year rate of death in CR , mainly resulting from myelosuppression during post induction treatment, increased with age, from 3.1%, 11.8%, 14.6% up to 17.9% in patients <60, 60-65, 65-70 and >70 years, respectively (p<0.0001). By multivariate analysis stratified on the trial (APL and LPA), better OS was associated with age <60 (HR 2.645, p<0.0001), female gender (HR 0.77, p=0.05), lower WBC (HR 1.007, p<0.0001) and higher platelets (HR 0.996, p=0.03). In pts >60 yrs, by multivariate analysis, early death was associated with increased WBC (p=0.046), and increased creatinine level (p=0.002). Higher CIR was associated with increased WBC (p=0.002) . In patients older than 60 years, age had no significant impact on CR rate and survival. Finally, no significant differences in outcome were seen between French Belgian Swiss and PETHEMA trials. Conclusion: In pts older than 60, classical APL treatment with ATRA combined to anthracycline based CT followed by prolonged maintenance gives no initial leukemic resistance and similar relapse rate as in younger pts, but significantly lower OS due to a higher incidence of early deaths and of deaths in CR compared with younger pts. Higher WBC counts are associated with an increased incidence of both early deaths and deaths in CR. Improvement in prognosis, therefore, requires better supportive care during induction treatment, while reduction of the amount of myelosuppressive drugs during post induction treatment may be required to reduce deaths in CR. Disclosures: Fenaux: CELGENE: Research Funding; AMGEN: Research Funding.

Clofarabine, Idarubicin, and Cytarabine (CIA) As Frontline Therapy for Patients Younger Than 61 Years with Newly Diagnosed Acute Myeloid Leukemia (AML)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1550-1550
Author(s):  
Aziz Nazha ◽  
Farhad Ravandi ◽  
Hagop M. Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Research Funding ◽  
Response Rate ◽  
De Novo ◽  
Phase Iii ◽  
Molecular Profile ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Elevated Bilirubin

Abstract Abstract 1550 Background: Clofarabine is a second generation nucleoside analogue with activity in adults with AML. A recent randomized phase III study in AML relapse showed higher response rates and better event-free survival with the combination of clofarabine and cytarabine (CA) compared to cytarabine alone. We have also reported the feasibility and safety of the addition of idarubicin to CA (CIA) in a previous phase I and II study. To explore this combination further, we conducted a phase II study of CIA in pts</= 60 years with previously untreated AML. Patients and Methods: Patients (Pts) were eligible if they were </=60 yrs of age with newly diagnosed AML. Pts were excluded for ECOG PS > 2, cardiac ejection fraction < 45%, or active and uncontrolled infection. For the first 30 pts, induction therapy consisted of Clofarabine 22.5 mg/m2 iv daily (days 1–5), Idarubicin 6 mg/m2 daily (days 1–3), and Cytarabine 0.75 g/m2 daily (days 1–5). From pt 31 onward, induction doses were amended to Clofarabine 20 mg/m2 × 5, Idarubicin 10 mg/m2 × 3, and Cytarabine 1 g/m2 × 5. Pts who have not achieved a complete remission following the induction could receive one re-induction course. Pts in CR or CRp continued with up to 6 consolidation cycles with Clofarabine 22.5 mg/m2 × 3, Idarubicin 6 mg/m2 (days 1–2), and Cytarabine 0.75 g/m2 × 3, subsequently amended to Clofarabine 15 mg/m2 × 3, Idarubicin 8 mg/m2 × 2, and Cytarabine 0.75 g/m2 × 3. Supportive care was standard. Pts ≥ 50 yrs were admitted to a laminar air flow room for the duration of the induction. Results: From April 2010 until August 2011, 51 pts have been accrued with a median age of 49 yrs (range 19–59): 33 pts (65%) with de novo AML and 18 pts (35%) with secondary AML (18 related to MDS, 7 related to therapy). Three pts (5%) had a PS of 2. Median WBC at diagnosis was 3.4 × 109/L (0.6-92.3). Thirty-three (65%) pts had abnormal cytogenetics (21/33[64%] poor risk and 5/33 [15%] intermediate risk). Molecular profile: 6 pts (11%) had FLT3/ITD, 3 pts (6%) CEBPA, and 8 pts (16%) NPM1 mutations. Thirty-five pts (69%) achieved CR and 1 (2%) CRp for an overall response rate (ORR) of 71%. 61% pts (31/51) achieved CR following one induction cycle. 18% (9/51) pts required a re-induction and 44% (4/9) of them responded after the re-induction. Responding pts received a median of 2 courses (1–8) courses. With a median follow-up of 23 weeks (3–36+) median remission duration has not been reached with a 1-yr remission probability of 85%. Ten pts (19%) died on study including 2 (4%) who died < 28 days from treatment start (one from septic shock and multi-organ failure, and one from Steven Johnson syndrome). Median overall survival (OS) for responding pts has not been reached (2–36 weeks). One-yr survival probability is 65%. Sixteen pts (31%) proceeded with an allogenic stem cell transplant in CR1. Most toxicities were </= grade 2 and included rash (41 %), nausea (29%), diarrhea (23%), elevated transaminases (21%), and elevated bilirubin (17%). Toxicities > grade 2 included elevated bilirubin (4%), hypokalemia (4%), cellulitis (4%) and seizure (1%). Myelosuppression was ubiquitous but prolonged myelosuppression > 42 days was infrequent. 76 % (39/51) pts had neutropenic fever. Conclusion: Clofarabine, Idarubicin and Cytarabine achieve a response rate of 71% in patients </=60 yrs with previously untreated AML. Induction mortality was low and the toxicity profile was expected and manageable. Longer follow up and comparisons with standard induction therapy will be needed to further assess the role of this combination in AML therapy. Disclosures: Off Label Use: Clofarabine, use of Clofarabine in AML. Ravandi:Genzyme: Research Funding. Kantarjian:Genzyme: Research Funding. Faderl:Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Response and Overall Survival Is Impaired in Obese Patients with Acute Myelogenous Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1522-1522
Author(s):  
Martina Crysandt ◽  
Edgar Jost ◽  
Susanne Isfort ◽  
Tim H Brümmendorf ◽  
Stefan Wilop
Keyword(s):  
Risk Factors ◽  
Overall Survival ◽  
Induction Therapy ◽  
Risk Group ◽  
Myelogenous Leukemia ◽  
Prognostic Impact ◽  
Obese Patients ◽  
Newly Diagnosed ◽  
Laboratory Parameters

Abstract Abstract 1522 Introduction Dose calculation of chemotherapeutic agents is mainly based on body surface area (BSA). Historically, in many institutions, doses are not adapted to a BSA above 2 sqm, although recent data suggested that this relative dose reduction in patients above 2 sqm is associated with a worse outcome. Obesity is a widespread and increasing phenomenon in the developed countries and is mainly defined by the body mass index (BMI). It is known, that the risk to develop haematological or solid malignancies is increased in obese patients – and, additionally, weight influences outcome in several tumours. Therefore, in our study, we analyzed the prognostic impact of obesity in newly diagnosed AML regarding the response to the first cycle of induction therapy and overall survival. Methods We identified 145 patients with newly diagnosed AML who were treated with induction therapy containing cytarabine and an anthracycline in our institution. Clinical data including several laboratory parameters associated with nutritional status (cholesterol, triglycerides, protein, C-reactive protein, albumin, lymphocyte count, transferrin, pseudo-cholinesterase, fT3, b-type natriuretic peptide), long-term medication with statins, chemotherapy dosing as well as response and overall survival have been assessed retrospectively from the institution's database. In our institution, all patients with a high BSA received a chemotherapy-dose calculated with a cut-off of not more than 2 sqm. Results In our cohort, median BMI was 25.2 kg/sqm (range 17.0 – 48.1). Seventeen patients had a BMI above 31 kg/sqm, 128 below. The median BSA of all patients was 1.83 sqm (range 1.49 – 2.40). In 41 patients, chemotherapy doses have been adjusted owing to a BSA of more than 2 sqm. We included cytogenetic risk group, BMI, BSA above 2.0 sqm, weight, long-term medication with statins and laboratory parameters in our univariate and multivariate analysis. Only cytogenetic risk group (p=0.001), triglycerides (p=0.008) and the BMI (p=0.032) were independent risk factors for overall survival. Univariate analysis showed similar results. Patients with a BMI >31 showed a significantly worse response (PR + CR) on first induction therapy (47.1% vs. 74.8%, p=0.018) and a shorter median survival (11.2 vs. 25.1 months, p=0.004). Both BMI-groups showed the same distribution of well-known risk factors including age, cytogenetic risk groups and secondary AML. Discussion/Conclusion In our cohort, a high BMI was associated with poorer response and impaired overall survival, whereas BSA was not. This leads to the conclusion, that the adverse effect may be mediated by obesity itself and not caused by underdosing of chemotherapy. Although an effect of BMI is known from several solid tumours, the reason remains unclear. Possible explanations include altered metabolisation and production of growth factors in adipose tissue (possibly indicated by elevated triglycerides), impaired or accelerated hepatic drug activation and/or metabolisation or impact on immune function. This study is limited by the retrospective single-center design and the relatively small patient number. Nevertheless, the data clearly confirmed other well established risk factors like the cytogenetic risk group supporting the validity of this approach. The study results suggest BMI as an independent risk factor for AML. Disclosures: No relevant conflicts of interest to declare.

Overall survival (OS) and stem cell transplant (SCT) in patients with FLT3 mutations treated with CPX-351 versus 7+3: Subgroup analysis of a phase III study of older adults with newly diagnosed, high-risk acute myeloid leukemia (AML).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e18507-e18507 ◽  
Author(s):  
Bruno C. Medeiros ◽  
Donna Hogge ◽  
Laura F. Newell ◽  
Dale L. Bixby ◽  
Scott R. Solomon ◽  
...  
Keyword(s):  
High Risk ◽  
De Novo ◽  
Phase Iii ◽  
Molar Ratio ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Open Label ◽  
Serious Adverse Events ◽  
Flt3 Mutations ◽  
De Novo Aml

e18507 Background: FLT3+ AML patients (pts; 20%-30% of AML pts) often have rapid post-induction relapse, highlighting the need for therapies that improve the bridge to SCT. CPX-351 is a liposomal formulation that delivers a synergistic 5:1 molar ratio of cytarabine (C) and daunorubicin (D). CPX-351 demonstrated efficacy versus 7+3 in a randomized, open-label, controlled phase III trial in pts aged 60-75 years with newly diagnosed, high-risk AML; our analysis investigated outcomes in the subset of FLT3+ pts. Methods: Pts were randomized 1:1 to induction with 1-2 cycles of CPX-351 (100 u/m2 [C 100 mg/m2 + D 44 mg/m2] on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (C 100 mg/m2/day x 7 days [2nd induction: x 5 days] + D 60 mg/m2on Days 1, 2, and 3 [2nd induction: Days 1 and 2]). Pts with complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive up to 2 consolidation cycles. Results: Of the pts who had FLT3 mutations assessed and received study treatment, 22/138 (16%) pts in the CPX-351 arm and 20/136 (15%) pts in the 7+3 arm had baseline FLT3 mutations. AML subtypes in FLT3+ pts were: tAML (19%); AML after MDS with (38%) or without (10%) prior hypomethylating agents; AML after CMMoL (12%); and de novo AML with MDS karyotype (21%). In FLT3+ pts, median OS was longer with CPX-351 (10.25 mo) versus 7+3 (4.55 mo; HR = 0.57 [95% CI: 0.24, 1.33]; P= 0.093) and the rate of CR+CRi was higher (68% vs 25%). A greater number of FLT3+ pts treated with CPX-351 were able to undergo SCT (n = 10/22 [45%]; 4 pts were alive as of this analysis, after a median post-SCT follow up of 692 days [range: 96-769]) compared with 7+3 (n = 2/20 [10%]; neither pt still alive). The on-study safety profile of CPX-351 in FLT3+ pts was comparable to 7+3 and consistent with the overall study population. Serious adverse events were experienced by 7 (32%) FLT3+ pts in the CPX-351 arm and 10 (50%) in the 7+3 arm. Conclusions: CPX-351 demonstrated numerical improvement in median OS in older pts with newly diagnosed, FLT3+ high-risk AML and allowed more pts to undergo SCT. The analysis was limited by small number of pts. Clinical trial information: NCT01696084.

Outcome in patients with refractory high-risk neuroblastoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10537-10537
Author(s):  
Amir Bari Siddiqui ◽  
Akosua Oppong ◽  
Cindy Yuan ◽  
Guimin Gao ◽  
Rochelle Bagatell ◽  
...  
Keyword(s):  
High Risk ◽  
Metastatic Disease ◽  
Induction Therapy ◽  
Tumor Biology ◽  
Induced Response ◽  
Cell Transplant ◽  
Refractory Disease ◽  
Disease Response ◽  
Post Induction ◽  
The Impact

10537 Background: Outcome for high-risk neuroblastoma (HRNBL) patients (pts) with refractory disease at end of induction (EOI) is poor. The impact of therapies such as I-131-MIBG or irinotecan/temozolomide/dinutuximab (I/T/DIN) prior to autologous stem cell transplant (ASCT) on outcome is unknown. Methods: A multi-center, retrospective study of HRNBL pts diagnosed between 2008-2018 with refractory disease at EOI was conducted. Demographics, tumor biology, treatment response, and outcomes were abstracted. 3-year (yr) EFS and OS from time of diagnosis were estimated by the Kaplan-Meier method. Results: 3-yr EFS and OS were 54% and 79% for the 136 pts analyzed. 91 pts received no additional therapy prior to ASCT (Cohort 1); 32 pts received post-induction therapy prior to ASCT (Cohort 2); and 13 pts did not undergo ASCT (Cohort 3). The prevalence of metastatic disease in Cohort 1, 2, and 3 was 65%, 97%, and 85%. 3-yr EFS and OS were not statistically different between Cohort 1 (3-yr EFS and OS; 62% and 81%) and Cohort 2 [3-yr EFS and OS; 49% (p = 0.48) and 82% (p = 0.19)]. Outcome for Cohort 3 pts was significantly worse than Cohort 1 [3-yr EFS: 15% vs. 62% (p < .001); and 3-yr OS: 48% vs. 81% (p = 0.003)] and Cohort 2 [3-yr EFS: 15% vs. 49% (p < .001); and 3-yr OS 48% vs. 82% (p = 0.035)]. For Cohort 2 pts with metastatic disease, post-induction therapy included I/T/DIN (n = 12), MIBG (n = 16), MIBG plus I/T/DIN (n = 1), and other (n = 2). Metastatic disease response was observed in 10/12 (83%) pts who received I/T/DIN and 9/16 (56%) who received MIBG. MIBG plus I/T/DIN (n = 1) or MIBG with chemotherapy (n = 1) also induced response. Among the 21 pts with metastatic disease response, 3-yr EFS and OS were 69% and 94%; significantly better than Cohort 2 patients who did not respond to post-induction therapy [3-yr EFS and OS: 11% (p = 0.016) and 66% (p = 0.2)]. 6 Cohort 2 pts achieved a complete response (CR) in metastatic sites following I/T/DIN (n = 5) or MIBG (n = 1), and all are alive without relapse with median follow-up of 3.4 years (range 2.7-8.1). The single Cohort 3 patient who achieved a metastatic CR with I/T/DIN and did not undergo ASCT remains disease-free 2.4 years from diagnosis. Conclusions: Patient characteristics differed in the 3 Cohorts, reflecting the influence of refractory disease on treatment decisions. For Cohort 2 pts, outcome was better for those with metastatic disease at EOI who responded to post-induction therapy compared to those who did not. Pts who achieved a metastatic CR of refractory disease had excellent survival. Prospective studies testing the efficacy of I/T/DIN in pts with refractory metastatic disease at EOI are warranted.

scholarly journals A Multi-Center Phase 1b, Open-Label, Dose-Finding Pilot Study to Evaluate the Combination of Carfilzomib and Cyclophosphamide with Dexamethasone (CCyD) Prior to Autologous Stem Cell Transplant (ASCT) in Patients with Transplant Eligible Newly Diagnosed Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4739-4739 ◽  
Author(s):  
William I. Bensinger ◽  
Robert Vescio ◽  
Cristina Gasparetto ◽  
Elber S. Camacho ◽  
Rajneesh Nath ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Dose Escalation ◽  
Research Funding ◽  
Autologous Stem Cell Transplant ◽  
Dose Finding ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Open Label ◽  
Advisory Committees

Abstract Background: Carfilzomib is an epoxy ketone, second generation proteasome inhibitor approved for the treatment of relapsed and refractory multiple myeloma. It has shown very high activity when combined with lenalidomide and dexamethasone for the treatment of newly diagnosed patients with multiple myeloma. This is the first reported trial of carfilzomib, cyclophosphamide, and dexamethasone (CCyD) in newly-diagnosed, transplant eligible patients. Methods: This study was a multi-center Phase Ib, open-label, dose-finding study in newly diagnosed transplant eligible multiple myeloma patients (pts) studying the combination of CCyD as induction therapy prior to autologous stem cell transplant (ASCT). Pts could receive a minimum of 4 cycles and up to 6 cycles prior to ASCT. Pts were enrolled into a dose-escalation treatment cohort. A standard 3+3 dose escalation schedule was used with cohorts of carfilzomib 36 (initial), 45 and 56 mg/m2 (administered over 30 minutes on days 1, 2, 8, 9, 15 and 16) combined with 300 mg/m2 of oral cyclophosphamide weekly on days 1, 8, 15 and 40 mg of oral dexamethasone once weekly. Adverse events (AEs) were graded by NCI-CTCAE v4. Response was assessed by the IMWG criteria. Prior therapy was limited to up to 160 mg of dexamethasone or limited field radiation. Results: 28 patients were enrolled from 5 centers. Of 28 patients enrolled, 3 did not complete 4 cycles of therapy (1 proceeded to ASCT after Cycle 3) and are not evaluable for response (pts came off secondary to AE of pulmonary HTN unrelated, secondary to SAE of CHF possibly related, due to PI discretion related to maximum benefit achieved), 8 patients did not undergo ASCT (1 had PD after Cycle 5), 8 patients proceeded to ASCT (1 the aforementioned patient after Cycle 3), 6 patients have completed induction and are still pre-transplant and 4 patients are still on treatment. The median age was 64 years (range 44–74), 57% were male. Cytogenetic abnormalities included 13 patients with del(13), 4 with del(17p), 2 with t(14;16) and 1 with hypodiploidy for a total of 16 patients with high-risk cytogenetics. In the dose-escalation portion of the study, the maximum administered dose tested was 56 mg/m2 carfilzomib. There was one DLT in cycle 1, of Grade 3 dyspnea, at the 56 mg/m2 level. Drug-related AEs occurring in >20% of patients included fatigue (23%) and thrombocytopenia (31%). Thirty-one percent experienced at least one Grade ≥3 AE with dyspnea and nausea as the most common. There were no deaths on study with a median follow-up of 4.9m (range: 1.1 to 13.1m). One pt came off study after Cycle 5 for PD as evidenced by new plasmacytomas. Six patients received 36-45 mg/m2 carfilzomib on the dose escalation portion of this study and 22 patients received the maximum administered dose of carfilzomib at 56 mg/m2. One patient yet to be enrolled to obtain 20 efficacy evaluable pts at the maximum dose. Twenty-three patients were response evaluable. Median of 5.7 cycles of therapy with 2 CR, 9 VGPR, 10 PR, 1 MR and 1 PD for ≥ PR rate of 91%. Of the 12 response-evaluable patients with high risk cytogenetics, 92% were ≥ PR; of the 11 standard risk patients, 91% were ≥ PR. Of 9 patients who underwent stem cell mobilization, all collected adequate stem cells and median number of stem cells collected was 12.58 (5.07-25.31) x106 CD34+ cells/kg. Conclusions: The combination of CCyD given to untreated, symptomatic patients with myeloma was well tolerated and highly active with an 87% RR and a 48% ≥ VGPR after 4 to 6 cycles. This study compares favorably with other regimens used for induction prior to transplant for the management of newly diagnosed multiple myeloma. Disclosures Bensinger: Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Carfilzomib for use in front-line tx of multiple myeloma . Vescio:Onyx Pharmaceuticals: Honoraria, Speakers Bureau. Gasparetto:Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nath:Celgene: Consultancy. Shah:Novartis: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding; Array: Consultancy, Research Funding. Durie:Onyx Pharmaceuticals: IRC Other; Millennium Pharmaceuticals: IRC, IRC Other.

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