Predicting Induction Toxicity with 7+3: Analysis of SWOG Trial S1203

Abstract Background: Prior work has shown that multivariable models can have reasonably high accuracy in predicting early deaths (deaths within 28 days of starting induction, defined as treatment-related mortality [TRM]) following intensive AML chemotherapy. These models can be used to derive a TRM score reflective of the probability of TRM with intensive AML therapy, and such scores can be used to make informed treatment decisions and as explicit eligibility criteria in AML protocols. The degree to which non-fatal toxicities can be predicted is unknown. It is also not known which patient characteristics are most strongly associated with occurrence of non-fatal toxicities following induction chemotherapy. Here, we examined these questions using data from the most recent SWOG Phase III with a 7+3 arm. Patients and Methods: We analyzed 260 eligible patients randomized to the 7+3 arm SWOG trial S1203 who received the first cycle of protocol therapy. 7+3 was per contemporary standard when the trial was opened in 2012: 100mg/m2 cytarabine on days 1-7 and 90mg/m2daunorubicin on days 1-3. Toxicities were reported using CTCAE version 4.0. We used logistic regression models to model toxicity incidence and evaluated the predictive accuracy of the models with the area under the receiver operating characteristic curve (AUC). We note that AUC of 0.5 is what would be expected with random chance or using a coin flip to make a decision, while an AUC of 1 denoted perfect prediction. We evaluated the following baseline covariates (modeled quantitatively unless otherwise specified): age at study registration, gender, Zubrod performance status (0-1 versus 2-3), pre-study white blood cell counts (WBC), pre-study platelets, pre-study marrow blasts, secondary vs. de novo AML, cytogenetic risk, and NPM1+ and FLT3-ITD- versus other NPM1/FLT3-ITD status. For toxicities with lower incidence, the number of covariates included in multivariable models was proportionate to one covariate per 10-15 patients with a toxicity. Toxicities were reported using the contemporary CTCAE version 4.0. Only toxicities observed during the first cycle of induction are analyzed below. Results: We evaluated the incidence grade 3 or higher thrombocytopenia (n=180, 70%), infection (n=166, 64%), anemia (n=159, 61%), neutropenia (n=145, 56%), lymphopenia (n=92, 35%), electrolyte abnormalities (n=66, 25%), liver abnormalities (n=37, 14%), cardiovascular abnormalities (n=20, 8%), constitutional symptoms (n=19, 7%), skin abnormalities (n=18, 7%), mucositis (n=17, 7%), GI tract abnormalities (n=16, 6%), pulmonary abnormalities (n=14, 5%), pain (n=13, 5%), endocrine abnormalities (n=12, 5%), bleeding (n=12, 5%), neurologic abnormalities (n=10, 4%), nausea/vomiting (n=7, 3%), kidney abnormalities (n=4, 2%). In univariate models no individual covariate was a strong predictor of toxicity. Only 3 pairs of toxicity/covariate had an AUC > 0.65 [indicating modest predictive ability]: older age predicting increased risk of endocrine abnormalities (OR=1.08 [per year], p=0.06, AUC=0.67), higher baseline WBC predicting increased risk for bleeding (OR=1.26 per 1,000, p=0.36, AUC=0.67), and higher baseline HGB predicting increased risk of neurologic toxicity (OR=1.33 per g/dL, p=0.10, AUC=0.69). As incidence allowed, we evaluate multivariable models. Multivariable models had increased AUC compared to univariate models, but no multivariable model had an AUC larger than 0.70. Conclusion: These findings indicate that with the baseline covariates evaluated, we have a poor ability to predict commonly occurring grade 3 and higher toxicities that occur during the first cycle of 7+3 induction therapy for AML. These findings support the claim that randomization is necessary to compare toxicities between standard and investigational regimens. Moreover, assuming that trial eligibility criteria are often stringent in an attempt to minimize the occurrence of treatment toxicities in study participants, the lack of strong association between individual baseline characteristics and toxicities could be used to argue for less-stringent study inclusion criteria. Support: NIH/NCI grants CA180888 and CA180819 Disclosures Walter: Aptevo Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Amphivena Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Covagen AG: Consultancy, Other: Clinical Trial Support, Research Funding; Seattle Genetics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Pfizer, Inc: Consultancy; Amgen Inc: Other: Clinical Trial Support, Research Funding; Actinium Pharmaceuticals, Inc: Other: Clinical Trial support , Research Funding; Boehringer Ingelheim Pharma GmbH & Co. KG: Consultancy.

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A multisite clinical trial of spectroscopic MRI-guided radiation dose escalation for newly-diagnosed glioblastomas.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2018 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2018-2018

Author(s):

Hui-Kuo George Shu ◽

Eric Albert Mellon ◽

Lawrence Kleinberg ◽

Saumya S Gurbani ◽

Karthik K Ramesh ◽

...

Keyword(s):

Clinical Trial ◽

Dose Escalation ◽

Idh1 Mutation ◽

Resonance Spectroscopy ◽

Newly Diagnosed ◽

Eligibility Criteria ◽

Normal Appearing White Matter ◽

Increased Risk ◽

Grade 3 ◽

Poor Outcomes

2018 Background: Glioblastoma (GBM) is the most common adult primary malignant brain tumor. These pts have poor outcomes [median overall survival (OS) ̃ 16 months] despite radiation therapy (RT) to 60 Gy and temozolomide (TMZ). Magnetic resonance spectroscopy (MRS) measures levels of specific metabolites in the brain including choline (Cho) and N-acetyl aspartate (NAA). Previously, we found that high Cho/NAA ratios can aid in localizing regions of brain at high risk for GBM recurrence that may not be appreciated on standard contrast-enhanced (CE) MRI. Based on this finding, we conducted a clinical trial to assess the feasibility and safety of using an advanced volumetric MRS technique termed spectroscopic MRI (sMRI) to guide RT dose escalation for newly-diagnosed GBMs. Methods: Our clinical trial (NCT03137888) funded by the NCI (RO1CA214557) enrolled pts at 3 institutions (Emory U, U Miami, Johns Hopkins U) from 5/2017 to 4/2019. This study was approved by the IRB at each respective institution. Eligibility criteria included newly-diagnosed GBM pts ≥ 18 years of age with a tumor site that could be adequately imaged by sMRI. Cho/NAA ratio was normalized to the contralateral normal appearing white matter (NAWM). For RT planning, standard gross tumor volumes (GTV1 & 2) were defined based on T2-FLAIR and T1 CE MRIs and 5 mm margins were added to generate clinical tumor volumes (CTV1 & 2). GTV3 ( = CTV3, sMRI-defined) was generated by the union of residual CE tumor and Cho/NAA ≥ 2x NAWM. To remain eligible, CTV3 was required to be ≤ 65 cc. Planning target volumes (PTVs) were generated by applying a 3 mm margin around CTVs. 50.1, 60 and 75 Gy in 30 fractions were prescribed to PTV1, PTV2 and PTV3, respectively. All pts received standard concurrent/adjuvant TMZ. Survival curves were generated by the Kaplan-Meier method. Toxicities were assessed according to CTCAE v4.0. Results: 30 pts met eligibility and were treated on study. Mean/median ages were 56.4/58.9 years. 9 pts (30%) were MGMT methylated; 2 pts (6.7%) harbored an IDH1 mutation. With median followup of 21.4 months in censored pts, median OS was 23.0 months. 11 of 30 pts were documented to have experienced grade 3 or greater toxicities that were at least possibly due to their treatment. Of the 7 pts who experienced these by 9 months post-RT, most were attributable to TMZ (thrombocytopenia x 4, thrombocytopenia/neutropenia x 1, transaminitis x 1) and only one case (headaches/fatigue x 1) could potentially be ascribed to RT. Increased risk of pseudoprogression or radiation necrosis, especially beyond 3 months post-RT, was noted but these were clinically manageable and did not result in toxicity ≥ grade 3. Conclusions: Dose-escalated RT to 75 Gy guided by sMRI appears feasible and safe for pts with newly-diagnosed GBMs. OS outcome is also quite promising and warrants additional testing. Based on these results, a phase II randomized trial is planned at ECOG-ACRIN (EAF211). Clinical trial information: NCT03137888.

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A Phase III PETHEMA/GEM Study of Induction Therapy Prior Autologous Stem Cell Transplantation (ASCT) In Multiple Myeloma: Superiority of VTD (Bortezomib/Thalidomide/Dexamethasone) Over TD and VBMCP/VBAD Plus Bortezomib

Blood ◽

10.1182/blood.v116.21.307.307 ◽

2010 ◽

Vol 116 (21) ◽

pp. 307-307 ◽

Cited By ~ 12

Author(s):

Laura Rosiñol ◽

María Teresa Cibeira ◽

Maria Victoria Mateos ◽

Joaquin Martinez ◽

Albert Oriol ◽

...

Keyword(s):

High Risk ◽

Induction Therapy ◽

Research Funding ◽

Progression Free Survival ◽

Phase Iii ◽

Eligibility Criteria ◽

Advisory Committees ◽

Intention To Treat ◽

Grade 3

Abstract Abstract 307 Introduction: In April 2006, the Spanish Myeloma Group (PETHEMA/GEM) activated a randomized phase III trial comparing TD vs. VTD vs. VBMCP/VBAD/Bortezomib (VBMCP/VBAD/B) in patients 65 years-old or younger with newly diagnosed symptomatic MM followed by ASCT with MEL-200. Primary end points: response rate after induction and after ASCT and time to progression. Patients and Method: TD consisted of thalidomide 200 mg daily (escalating doses in the first cycle) and dexamethasone 40 mg on days 1–4 and 9–12 at 4-week intervals for 6 cycles. The VTD regimen was identical to TD plus bortezomib 1.3 mg/m2 on days 1,4,8,11 of each cycle. Combination chemotherapy plus bortezomib consisted of 4 cycles of VBMCP/VBAD on an alternating basis followed by 2 cycles of bortezomib (1.3 mg/m2 on days 1,4,8, and 11 every 3 weeks). The duration of the induction therapy was 24 weeks in all arms. From April 6, 2006 to August 5, 2009 the 390 planned patients entered the study. Four patients failed the eligibility criteria. 386 patients (median age: 56 yrs; M: 207, F: 179; IgG: 233, IgA: 85, light chain: 57, IgD: 9, Ig M: 2) were analyzed. The stage according to the ISS was I in 147 patients, II in 160, III in 75 and unknown in 4 and 66 patients (17%) had extramedullary soft-tissue plasmacytomas (EMP). Seventy out of the 330 patients (21%) with cytogenetic studies had high-risk cytogenetics (t(4;14), t(14;16), and/or 17p deletion). One-hundred and thirty patients were allocated to VTD, 127 to TD and 129 to VBMCP/VBAD/B. Prognostic factors, including cytogenetics, were similar in the 3 arms. Response, survival and toxicity were evaluated on an intention-to-treat basis. Responses reported by investigators were centrally reassessed. Result: The IFE negative CR rate was significantly higher with VTD (35%) compared to TD (14%) and VBMCP/VBAD/B (22%) (p=0.0001 and p=0.01, respectively). The progressive disease (PD) rate during induction was significantly lower with VTD than with TD (7% vs. 23%, p=0.001). In patiens with high-risk cytogenetics, the CR rate was significantly greater with VTD when compared with TD (35% vs. 0%, p=0.002) and with VBMCP/VBAD/B (35% vs. 22%, p=0.02). The CR rate to VTD in patients with 17p deletion was 58% while none of the patients with this cytogenetic abnormality responded to TD or to VBMVP/VBAD/B (p=0.03 and p=0.02, respectively). Of interest, the CR rate in patients with t(11;14) was significantly lower than in patients lacking this abnormality (11% vs. 27%, p=0.01). This low CR rate in patients with t(11;14) was similar in the 3 arms. In the overall series, PD was significantly higher in patients with EMP (24% vs. 11%, p=0.01) with a significantly higher PD rate for TD as compared to VTD (40% vs. 12%, p=0.02). The incidence of thrombotic events was 2%, 6% and 5% for VTD, TD and VBMCP/VBAD/B, respectively (p=NS). The frequency of grade ≥ 3 peripheral neuropathy was 12% with VTD compared to 1% in both the TD and the VBMCP/VBAD/B arms (p= 0.0002). Treatment was discontinued due to toxicity en 16 patients (VTD:9, TD:4, VBMCP/VBAD/B:3). Nine patients died during the induction period (3 in each arm). On an intention to treat basis, the post-ASCT CR rate was higher in the VTD arm compared with TD (46% vs. 24%, p=0.004) and VBMCP/VBAD/B (46% vs. 38%, p=0.1). The estimated overall survival (OS) at 4 years was 76% with no significant differences among the 3 arms. After a median follow-up of 27 months, the progression-free survival (PFS) was not reached with VTD while it was 27 and 38 months with TD and VBMCP/VBAD/B, respectively (p=0.006). In the overall series, patients with high-risk cytogenetics had a significantly shorter OS (p=0.00007) and PFS (p=0.004). In addition, when compared with the good-risk group, patients with high-risk cytogenetics showed a trend towards a shorter PFS either after induction with VTD (median not reached vs. 17 months, p=0.05) and with TD (median 28 vs. 15 months, p=0.09). Conclusion: Induction with VTD resulted in a significantly higher CR rate in both the overall series and in patients with high-risk cytogenetics. The post-ASCT CR rate was also significantly higher with VTD than with TD and there was a trend when compared with VBMCP/VBAD/B. Finally, VTD resulted in a significantly longer PFS. However, longer follow-up is required to establish whether or not VTD will overcome the poor prognosis of patients with high-risk cytogenetics. Disclosures: Rosiñol: Janssen-Cilag: Honoraria; Celgene: Honoraria. Off Label Use: Bortezomib and Thalidomide are not approve for first line in Spain. Cibeira:Janssen-Cilag: Honoraria; Celgene: Honoraria. Mateos:Janssen-Cilag: Honoraria; Celgene: Honoraria. Oriol:Janssen-Cilag: Honoraria; Celgene: Honoraria. García-Laraña:Janssen-Cilag: Honoraria; Celgene: Honoraria. De La Rubia:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sureda:Janssen-Cilag: Honoraria; Celgene: Honoraria. Díaz-Mediavilla:Janssen-Cilag: Honoraria. Alegre:Janssen-Cilag: Honoraria; Celgene: Honoraria. Lahuerta:Janssen-Cilag: Honoraria; Celgene: Honoraria. San Miguel:Janssen-Cilag: Honoraria; Celgene: Honoraria, Speakers Bureau. Blade:Janssen-Cilag: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

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Cost-Effectiveness of Liposomal Cytarabine-Daunorubicin (CPX-351) Compared to Conventional Cytarabine-Daunorubicin Chemotherapy in Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2021-144992 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 113-113

Author(s):

Jan Philipp Bewersdorf ◽

George Goshua ◽

Kishan K Patel ◽

Rory M. Shallis ◽

Nikolai Podoltsev ◽

...

Keyword(s):

Clinical Trial ◽

Cost Effectiveness ◽

Research Funding ◽

Cost Effective ◽

Phase Iii ◽

Sensitivity Analyses ◽

Inpatient Setting ◽

Consolidation Therapy ◽

Phase Iii Trial ◽

Support Research

Abstract Introduction: A randomized phase III trial demonstrated improved overall survival (OS) and event-free survival (EFS) for older patients diagnosed with therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC) treated with a liposomal formulation of daunorubicin-cytarabine (CPX-351) when compared with 7+3 induction and consolidation therapy, a previous standard of care. Based on those results, CPX-351 was approved in 2017 in the United States (US) for adults with newly diagnosed t-AML and AML-MRC irrespective of age. However, the health economic implications of CPX-351 from a US payer perspective are not well-characterized. Methods: We constructed a partitioned survival analysis based on the data from the original phase III trial (Lancet et al. JCO 2018) and subsequent updates (Lancet et al. Lancet Haematology 2021) and post-hoc analyses from the landmark trial (Villa et al. JME 2019). Newly diagnosed AML patients at a median age of 68 years entered the model with active AML and received either CPX-351 or 7+3 induction and consolidation therapy followed by allogeneic hematopoietic cell transplant (allo-HCT) for some patients. Parametric survival distributions were fitted using patient-level data recreated from the Kaplan-Meier curves and at-risk tables for EFS and OS for both study arms. Log-logistic distributions demonstrated the best fit and were chosen for this model. Frequency and setting (inpatient vs outpatient) of re-induction and consolidation therapy were used as outlined in the original study. Costs and practice patterns of salvage therapy, receipt of allo-HCT, supportive care, and incidence of complications were derived from the original trial or published literature (Table). If available, costs for the Medicare population rather than commercially insured patients were used. For the CPX-351 arm, the maximum new technology add-on payment granted by the Centers for Medicare & Medicaid Services for fiscal year 2020 was added to the costs of inpatient induction and consolidation therapy in the 7+3 arm. Costs were adjusted for inflation to 2020 US dollars using the personal consumption expenditure health index. Previously published utilities were used and measured in quality-adjusted life years (QALYs). Costs and utilities were discounted by 3% annually (range 3-5% in one-way sensitivity analysis) and modelled over a 10-year time horizon. Model outputs were used to calculate the incremental cost-effectiveness ratio (ICER) for CPX-351 over 7+3. A willingness-to-pay (WTP) threshold of $150,000/QALY gained was used to determine cost-effectiveness. One-way sensitivity analyses were performed with utility values varied with a 10% range and all other variables across a 50% range. In probabilistic sensitivity analyses using 10,000 Monte Carlo simulations, beta distributions were used to describe probabilities and utilities, while gamma distributions were used for costs. Results: CPX-351 and 7+3 were associated with lifetime costs of $371,482 and $256,415, respectively, for an incremental cost of $115,066 with CPX-351. CPX-351 resulted in an incremental gain of 0.49 QALYs compared to 7+3 (CPX-351: 1.11 QALYs vs 7+3: 0.62 QALYs) resulting in an ICER of $231,563/QALY gained in the base case analysis. In one-way sensitivity analyses our model was most sensitive to the probability of receiving allo-HCT in either arm (Figure). In threshold analyses, a reduction of the CPX-351 add-on charge in the inpatient setting by 70.4% (from $47,353 to $14,004) would lower the ICER below the WTP threshold of $150,000/QALY. Probabilistic sensitivity analysis yielded a median ICER of $222,894 (95% credible interval: $142,863 - $313,289) with 7+3 favored in 96.4% of 10,000 iterations at a WTP threshold of $150,000. Conclusion: Use of CPX-351 under the current pricing model is unlikely to be cost-effective for most older patients with t-AML/AML-MRC who resemble those enrolled in the clinical trial. A reduction by 70.4% for the CPX-351 add-on charge in the inpatient setting would be necessary to lower the ICER below the conventional WTP threshold of $150,000/QALY. Higher rates of allo-HCT and outpatient consolidation with CPX-351 did not lead to gains in clinical utility or cost reductions substantial enough to make CPX-351 cost-effective. The implications of a potential outpatient administration of CPX-351 induction on its cost-effectiveness require additional studies. Figure 1 Figure 1. Disclosures Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Podoltsev: PharmaEssentia: Honoraria; Blueprint Medicines: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; CTI BioPharma: Honoraria; Bristol-Myers Squib: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Huntington: Bayer: Honoraria; Thyme Inc: Consultancy; Servier: Consultancy; Novartis: Consultancy; SeaGen: Consultancy; AstraZeneca: Consultancy, Honoraria; Genentech: Consultancy; TG Therapeutics: Research Funding; Flatiron Health Inc.: Consultancy; DTRM Biopharm: Research Funding; AbbVie: Consultancy; Pharmacyclics: Consultancy, Honoraria; Celgene: Consultancy, Research Funding. Zeidan: Astex: Research Funding; Amgen: Consultancy, Research Funding; Epizyme: Consultancy; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Aprea: Consultancy, Research Funding; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; AstraZeneca: Consultancy; Janssen: Consultancy; Daiichi Sankyo: Consultancy; Jasper: Consultancy; Astellas: Consultancy; Genentech: Consultancy; Geron: Other: Clinical Trial Committees; Agios: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; BioCryst: Other: Clinical Trial Committees; Pfizer: Other: Travel support, Research Funding; Kura: Consultancy, Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; BeyondSpring: Consultancy; Gilead: Consultancy, Other: Clinical Trial Committees; Ionis: Consultancy; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; ADC Therapeutics: Research Funding; Jazz: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Acceleron: Consultancy, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding.

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Prospective, Multi-Center, Phase I Clinical Trial of PLX-R18 Placental Expanded Adherent Stromal Cells in Subjects with Incomplete Hematopoietic Recovery after Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood-2018-99-116239 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3379-3379 ◽

Cited By ~ 1

Author(s):

Hillard M Lazarus ◽

Leland Metheny ◽

Tsila Zuckerman ◽

Carolina Escobar ◽

Joseph P. McGuirk ◽

...

Keyword(s):

Clinical Trial ◽

Bone Marrow ◽

Cell Transplantation ◽

Stromal Cells ◽

Research Funding ◽

Hematopoietic Cell Transplantation ◽

Eligibility Criteria ◽

Acute Radiation Syndrome ◽

Hematopoietic Recovery ◽

Grade 3

Abstract Background: Successful engraftment remains a challenge in hematopoietic cell transplantation (HCT) for some patients. Salvage approaches, including use of recombinant hematopoietic growth factors, cytokine therapy, CD34+-selected progenitor cell boosts, or second or subsequent HCT, are successful only in a minority of patients, and patients are exposed to prolonged blood products transfusions. With our successful pre-clinical rodent and Rhesus Macaques total body irradiation injury-induced marrow failure models (Metheny, Front Med 2018; Sher, Cell Transplantation 2018; Sher, Blood 2017), this prospective, multi-center, phase I clinical trial is evaluating the safety of PLX-R18 cells used to improve peripheral blood counts in patients who have experienced incomplete hematopoietic recovery after HCT. PLX-R18 cells are human placental-derived adherent stromal cells that are predominantly of fetal origin, expressing CD105, CD73 and CD29, and lacking surface expression of CD45, CD34, CD14, CD19, HLA-DR, CD31 (endothelial marker) and GlyA (erythrocyte cell marker). PLX-R18 also do not express HLA class II molecules (HLA-DP, DQ, and DR) and co-stimulatory markers (CD80, CD86, and CD40). PLX-R18 cells secrete MCP-1, IL-6, and IL-8 and had been shown to stimulate migration of bone marrow cells in vitro. Cells are grown ex vivo, under GMP conditions, using a 3-dimensional system, and are administered as several intramuscular (IM) injections. PLX-R18 cells already are approved for treatment of acute radiation syndrome (ARS) under an IND. Methods: This is a multi-center, open label, dose-escalation, phase 1 trial (ClinicalTrials.gov: NCT03002519). Eligibility criteria include patients age ≥18 years who underwent either an autologous (auto) or an allogeneic (allo) HCT but had incomplete hematopoietic recovery at 4 months post-transplant, defined as failure to maintain either hemoglobin (Hb) >8 g/dL and/ or neutrophil count (ANC) >1,000/µL and/or platelet count (Plt) (unsupported) >50,000/µL. Other eligibility criteria include ECOG performance status of 0-2, no evidence of underlying malignancy at time of enrollment, no active infection, and no evidence of grade 3-4 acute or severe chronic GvHD. The PLX-R18 cells, cryopreserved in DMSO and human serum albumin in Plasma-Lyte, are thawed and injected IM in multiple locations - half into the gluteus medius muscle on one side and half to the thigh muscles on the contralateral side. A total of 24 subjects are planned to be enrolled into 3 dose escalating cohorts: low (n=3) given 1 million cells/kg; intermediate (n=6) at 2 million cells/kg and high (n=15) dosed at 4 million cells/kg each. The assigned dose is given twice, 1 week apart; cohorts are recruited sequentially and progression to the next cohort is based on the safety assessment of its predecessor. Adverse event is graded using the CTCAE criteria of the NCI. As of July 2018, all 3 patients of cohort 1 were treated (with sufficient follow-up), as well as 3 out of the 6 subjects planned for the 2nd cohort, and data of the first cohort are presented herein. Results: Cohort 1 (low-dose) - 3 subjects (ages 43, 48 and 55 years old) who had an allo (n=2) or auto (n=1) HCT received two IM administrations of PLX-R18, 1 million cells/kg each within a 1-week interval. 67 Adverse Events (AEs) were recorded. 64.3% of the AEs were grade 1, 30.9% were grade 2, 3.6% were grade 3 and 1.2% were grade 4. One patient suffered from 3 Serious AEs (immune thrombocytopenic purpura, bacteremia and migraine), all assessed as not related to treatment. Most frequent related AE was transient injection site pain, experienced by all 3 patients. See patients' details and blood counts in the table and graphs. Conclusions: Treatment with PLX-R18 generally was well-tolerated and most frequent adverse events were injection site reactions, which were all reversible without sequelae. The trial continues to accrue patients and the next dosing cohort (intermediate dose) is at 2 million cells/kg. Upon completion, a larger phase II trial will be considered in the same indication using the optimal dose. Other potential uses include PLX-R18 therapy in Acute Radiation Syndrome, Bone marrow failure, and in HCT as a "pan" cytokine for rapid count recovery. Figure. Figure. Disclosures Lazarus: Pluristem Ltd.: Consultancy. Zuckerman:Cellect Biotherapeutics Ltd: Consultancy. McGuirk:Novartis Pharmaceuticals Corporation: Honoraria, Other: speaker, Research Funding; Fresenius Biotech: Research Funding; Kite Pharma: Honoraria, Other: travel accommodations, expenses, speaker ; Gamida Cell: Research Funding; Astellas Pharma: Research Funding; Pluristem Ltd: Research Funding; Bellicum Pharmaceuticals: Research Funding. Rosen:Pluristem: Employment.

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Long Term Outcome of Lenalidomide-Dexamethasone (Rd) Vs Melphalan-Lenalidomide-Prednisone (MPR) Vs Cyclophosphamide-Prednisone-Lenalidomide (CPR) As Induction Followed By Lenalidomide-Prednisone (RP) Vs Lenalidomide (R) As Maintenance in a Community-Based Newly Diagnosed Myeloma Population: Updated Analysis of EMN01 Phase III Study

Blood ◽

10.1182/blood.v130.suppl_1.901.901 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 901-901

Author(s):

Sara Bringhen ◽

Massimo Offidani ◽

Pellegrino Musto ◽

Anna Marina Liberati ◽

Giulia Benevolo ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Phase Iii ◽

Cell Transplant ◽

Newly Diagnosed ◽

Community Based ◽

Advisory Committees ◽

Risk Of Death ◽

Grade 3 ◽

To Receive

Abstract Introduction : Rd and MPR showed to be effective combinations in elderly newly diagnosed multiple myeloma (NDMM) patients (pts). Cyclophosphamide is a less toxic alkylating alternative agent. EMN01 is the first trial to formally compare these three different Lenalidomide-based combinations. Maintenance with Lenalidomide has been recently approved in patients eligible for autologous stem cell transplant (ASCT). Few data are available about the best combination as maintenance in patients not eligible for ASCT. Methods : 662 pts with NDMM were randomized to receive 9 28-day cycles of Rd (lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15 and 22 in pts 65-75 years old and 20 mg in those >75 years), MPR (lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in pts 65-75 years old and 0.13 mg/Kg in >75 years pts; prednisone 1.5 mg/Kg for 4 days) or CPR (lenalidomide 25 mg/day for 21 days; cyclophosphamide orally 50 mg/day for 21 days in pts 65-75 years old and 50 mg every other day in >75 years pts; prednisone 25 mg every other day). After induction, pts were randomized to receive maintenance with lenalidomide alone (R; 10 mg/day for 21 days) or with prednisone (RP; R, 10 mg/day for 21 days and P, 25 mg every other day), until disease progression. Results : Pts characteristics were well balanced in all groups; 217 pts in Rd, 217 in MPR and 220 in CPR arms could be evaluated. After a median follow-up of 63.7 months, median PFS was 23.2 months in MPR, 18.9 months in CPR and 18.6 months in Rd (MPR vs CPR p=0.02; MPR vs Rd p=0.08). Median overall survival (OS) was 79.9 months in MPR, 69.4 months in CPR and 68.1 months in Rd (MPR vs CPR p=0.98; MPR vs Rd p=0.64). The most common grade ≥3 adverse event (AEs) was neutropenia: 64% in MPR, 29% in CPR and 25% in Rd pts (p<0.0001). Grade ≥3 non hematologic AEs were similar among arms. At the end of induction, 402 pts were eligible for maintenance, 198 in the RP and 204 in the R groups. PFS from start of maintenance was 22.2 months in the RP group and 17.6 in the R group, with 20% reduced the risk of death/progression for pts receiving RP maintenance (HR 0.81, p=0.07; Figure 1). A subgroup analysis was performed to determine the consistency of RP vs R treatment effect in different subgroups using interaction terms between treatment and cytogenetic abnormalities, ISS, age, sex, induction treatment and response before maintenance (Figure 1). No difference in OS was observed (HR 1.02, p=0.93) but the OS analysis was limited by the low number of events. Median duration of maintenance was 23.0 months in RP pts and 20.5 months in R pts, 14% and 13% of pts discontinued due to AEs, in RP and R groups, respectively. Conclusion : This phase III trial compared 2 different Lenalidomide-containing induction regimens and 2 different Lenalidomide-containing maintenance regimens in an elderly community-based NDMM population. MPR prolonged PFS by approximately 5 months, yet the higher incidence of hematologic toxicity should be carefully considered. The addition of low-dose prednisone to standard lenalidomide maintenance reduced the risk of death/progression by 20%, with a good safety profile. Updated results will be presented at the meeting. Disclosures Bringhen: Mundipharma: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; Karyipharm: Membership on an entity's Board of Directors or advisory committees. Offidani: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Musto: Celgene: Honoraria; Janssen: Honoraria. Gaidano: Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. De Sabbata: Celgene: Membership on an entity's Board of Directors or advisory committees. Palumbo: Sanofi: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Binding Site: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Genmab A/S: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Employment, Equity Ownership, Honoraria, Research Funding. Hájek: Amgen, Takeda, BMS, Celgene, Novartis, Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; Pharma MAR: Consultancy, Honoraria. Boccadoro: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

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A phase III multicenter randomized clinical trial to compare cisplatin plus fluorouracil with or without docetaxel as the first-line induction chemotherapy for locoregionally advanced nasopharyngeal carcinoma: Long-term outcomes update.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.6032 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 6032-6032

Author(s):

Wang Fang FangZheng

Keyword(s):

Clinical Trial ◽

Nasopharyngeal Carcinoma ◽

Induction Chemotherapy ◽

Phase Iii ◽

Karnofsky Performance Score ◽

Long Term Outcomes ◽

First Line ◽

Grade 3

6032 Background: A phase III multicenter prospective randomized controlled trial was conducted to compare cisplatin plus 5-fluorourcil with or without docetaxel as first-line induction chemotherapy in the patients with locoregionally advanced nasopharyngeal carcinoma (LANPC). Here, we report on the long-term outcomes and late toxicities of the trial (NCT01536223). Methods: Patients with newly diagnosed LANPC, stage III-IV disease, Karnofsky performance score≥70, without metastasis were eligible and randomly assigned 1:1 to TPF versus PF for three cycles. The primary end point was progression-free survival; local control, OS and advent events were important key secondary end points. The Kaplan-Meier method and the log-rank test were used to conduct and compare the survival curves in this study. Results: Two hundred ninety-nine patients were enrolled. 276 patients (138 TPF and 138 PF) were evaluable. Baseline characteristics were well-balanced between two groups, and the median age was 48 (range, 18-60 years). The ORR rates after induction chemotherapy and chemoradiotherapy were 90.6% and 9797.8% in TPF group and 87.0% (P > 0.05) and 97.8% (P > 0.05), respectively. The median follow-up was 99 months. For all patients, the 5- and 8-year OS and PFS were 76.9% and 74.9%, 72.3% and 69.1%, respectively. PF was associated with a similar PFS versus TPF ( 5-year PFS of 72.4% versus 73.2%, P =.747), and an equivalent OS at 5 years ( 79.2% and 79.1%, P = 0.519). Treatment-related grade 3 to 4 advent events were less frequent with PF compared with TPF. Conclusions: With prolonged follow-up, the survival outcomes in the PF group were not non-inferiority to those in the TPF group, but grade 3 to 4 advent events were less frequent. Clinical trial information: NCT01536223.

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Bortezomib Added to CVP-R Is Safe and Effective for Previously Untreated Advanced Stage Follicular Lymphoma: A Phase II Study by the NCIC Clinical Trials Group.

Blood ◽

10.1182/blood.v114.22.407.407 ◽

2009 ◽

Vol 114 (22) ◽

pp. 407-407

Author(s):

Laurie H. Sehn ◽

David A Macdonald ◽

Sheldon H. Rubin ◽

Guy Cantin ◽

Morel Rubinger ◽

...

Keyword(s):

Follicular Lymphoma ◽

Phase Ii ◽

Research Funding ◽

Standard Dose ◽

Phase Iii ◽

High Risk Population ◽

Low Grade ◽

Grade 3 ◽

To Receive ◽

Experienced Grade

Abstract Abstract 407 Background: Bortezomib, the first-in-class proteasome inhibitor has demonstrated promising efficacy as a single agent in heavily pretreated patients (pts) with follicular lymphoma (FL). This is the first study to evaluate the safety and efficacy of the addition of bortezomib to cyclophosphamide, vincristine, prednisone and rituximab (CVP-R), one of the most commonly used regimens in untreated patients. Methods: This is a phase II multi-centre open-label trial adding bortezomib (1.3 mg/m2 day 1&8) to standard dose cyclophosphamide (750 mg/m2), vincristine (1.4 mg/m2, capped at 2 mg), prednisone (40 mg/m2 × 5) and rituximab (375 mg/m2) for up to 8 cycles in pts with newly diagnosed stage III/IV FL requiring therapy. Response was assessed following 4 and 8 cycles. The two co-primary endpoints were complete response rate (CR/CRu) and incidence of grade 3/4 neurotoxicity. Following the final response assessment, patients were permitted to receive maintenance rituximab at the discretion of the treating physician according to local practice. Results: Between March 2007 and February 2009, 95 patients were enrolled. Median age was 56.6 years (range 29.5 – 83.6 years). 48% percent were male and 63% had stage IV disease. FLIPI score at study entry: low 11%, intermediate 43%, high 46%. Safety data was availabel on all patients. Overall, the combination of bortezomib and CVP-R was extremely well tolerated. No pts have developed grade 4 neurotoxicity and only 6/95 (6.3%) have developed grade 3 neurotoxicity (five sensory neuropathy and one neuropathic pain). The incidence of grade I and II neuropathy was 65.3% and 36.8% respectively. Neurotoxicity was largely reversible. Five pts discontinued therapy prematurely (three refused further treatment, one pt was found to have Hodgkin lymphoma as well as FL and one pt was removed from study for non-compliance). 84% of planned bortezomib treatments and 85% of vincristine treatments were administered without dose reduction. Five pts experienced grade 3/4 anemia and 3 pts experienced grade 3/4 thrombocytopenia. Only 4 episodes of febrile neutropenia occurred and 2 grade 3 infections were noted. No grade 4 infections were reported. No serious adverse events were reported. One patient died due to progressive disease. At present, 78/95 patients are evaluable for response. 37/78 (47%) achieved a CR/CRu (95% CI 36.4, 58.5), and 29/78 (37%) achieved a PR with an ORR of 84.6% (95% CI 76.6, 96.6). An additional 5/78 pts had stable disease, while 7/78 progressed on therapy. Complete efficacy data as well as information on quality of life will be availabel within the next few months. Forty-one of 70 pts (58.6%) with availabel follow-up information went on to receive maintenance rituximab. Conclusions: The addition of bortezomib to standard dose CVP-R is feasible and well tolerated with minimal associated toxicity. Neurotoxicity is primarily low grade and reversible and does not limit delivery of either bortezomib or vincristine. The complete remission rate in this high risk population compares favorably to historical results of patients receiving CVP-R. Based on these encouraging results, a phase III trial of CVP-R with or without bortezomib is currently being planned. Disclosures: Sehn: Johnson and Johnson Ortho Biotec: Honoraria. Off Label Use: Velcade for is not yet approved for follicular lymphoma. Chen:Johnson and Johnson Ortho Biotec: Research Funding. Djurfeldt:Johnson and Johnson Ortho Biotec: Research Funding. Shepherd:Johnson and Johnson Ortho Biotec: Research Funding. Crump:Johnson and Johnson Ortho Biotec: Honoraria.

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A Randomized Phase III Trial of ABVD Vs. Stanford V +/− Radiation Therapy In Locally Extensive and Advanced Stage Hodgkin's Lymphoma: An Intergroup Study Coordinated by the Eastern Cooperatve Oncology Group (E2496)

Blood ◽

10.1182/blood.v116.21.415.415 ◽

2010 ◽

Vol 116 (21) ◽

pp. 415-415 ◽

Cited By ~ 12

Author(s):

Leo I Gordon ◽

Fanxing Hong ◽

Richard I Fisher ◽

Nancy L. Bartlett ◽

Joseph M. Connors ◽

...

Keyword(s):

Risk Factors ◽

Research Funding ◽

Sensory Neuropathy ◽

Stage I ◽

Phase Iii ◽

Significant Difference ◽

Ann Arbor ◽

Intergroup Trial ◽

Grade 3 ◽

Splenic Disease

Abstract Abstract 415 Background: The ability to cure patients (pts) with advanced Hodgkin's Lymphoma (HL) with combination chemotherapy (CC) (MOPP and variants, ABVD and variants) represented a major milestone in oncology research, and CC became a paradigm for other malignancies. Further, the rationale for combined modality therapy (CMT) (radiation (RT) and CC) in HL evolved based on the high frequency of relapse in initially involved sites. As response rates and survival improved, newer treatments such as the combined modality Stanford V regimen were developed to shorten the duration of chemotherapy, add RT to sites of disease and reduce toxicity while maintaining or improving the cure rate. Indeed, the Stanford V regimen was tested and validated in a Phase II co-operative group trial (E1492) (J Clin Oncol 2000; 18:972). In order to investigate this approach against “standard” therapy, we conducted a randomized Phase III Intergroup trial of ABVD vs. the Stanford V regimen for patients with locally extensive or advanced HL. Objectives: The trial was designed to detect a 33% reduction in the failure free survival (FFS) hazard rate with Stanford V compared with ABVD, which corresponds to a difference in five-year FFS of 64% vs. 74%. Method: Patients with locally extensive (defined as clinical Ann Arbor Stage I-IIA/B and bulky mediastinal disease (BMD) (mass > 1/3 maximum intrathoracic diameter on standing postero-anterior chest x-ray or >/−10 cm on computerized tomography) or advanced (Ann Arbor Stage III or IV) HL were randomized to receive either ABVD × 6–8 cycles (C) (51% had 6 C, 35% had 8 C, 14% had <6 C) + 36 Gy (only in pts with BMD) or Stanford V × 12 weeks (95% had 12 weeks) + 36 Gy (for sites >5cm or for macroscopic splenic disease). The log-rank test was used to compare FFS for all eligible patients stratified on extent of disease (locally extensive vs. advanced), and number of International Prognostic Factor Project (IPFP) risk factors (0–2 vs. 3–7). An extended Cox model was also used to address non-proportional hazard between the two arms. Results: 854 pts enrolled from April, 1999 to June, 2006 and 812 were eligible for analysis. 404 pts were randomized to ABVD and 408 to Stanford V. Median age was 33 yrs in both arms (range 16–83). 53% were men and 47% women; 4% had Stage I, 31% had Stage II, 39% had Stage III and 25% had Stage IV disease by Ann Arbor criteria. 35% of pts on ABVD and 35% on Stanford V had BMD. Three % of pts had nodular lymphocyte predominant HL, 77% of pts had nodular sclerosis HL, 14% had mixed cell HL. Age, stage, pathology and risk factors (0–2 vs. 3–7) were similar in both arms. In total, 65% were IPFP score 0–2 and 33% were 3–6. Response rate. There was no difference in response rates (RR) between the two arms (ABVD=72% CR+ CCR, 7.7% PR, 7.9% SD; Stanford V= 69 % CR +CCR, 7% PR and 10 % SD. 8% were not evaluable for response on ABVD and 9% on Stanford V. Toxicity was similar in both groups. The most frequent Grade 3 + 4 toxicity was neutropenia, and was similar between the 2 groups (76% Grade 3 + 4 in ABVD and 70% Grade 3+ 4 in Stanford V). Grade 5 toxicity was <1% in both groups. There was, however, more Grade 3 lymphopenia in Stanford V (78% vs. 42%, p< 0.0001) and more Grade 3 +4 sensory neuropathy in Stanford V (10%) than in ABVD (3%) (p< 0.0001). A total of 26 second primary cancers developed, 12 after ABVD and 14 after Stanford V (p=NS). FFS and OS. For 812 eligible patients, with a median follow up of 5.25 years, 5-year FFS was 73% for ABVD and 71% for Stanford V (p=0.29 by log rank) (Figure left); 5-year OS was 88% for ABVD and 87% for Stanford V (p=0.87 by log-rank, HR=0.97, 95% CI: 0.65 to 1.44) (Figure right) indicating no significant difference in either FFS or OS between the 2 arms. Conclusion: In the largest Phase III intergroup trial of HL in North America, there was no significant difference in RR, FFS, OS, and 5-year toxicity when ABVD (+ RT for BMD) is compared with Stanford V (+RT for nodal sites >5 cm and macroscopic splenic disease). There was more Grade 3 lymphopenia (p< 0.0001) and more Grade 3 + 4 sensory neuropathy (p< 0.0001) on Stanford V. Thus ABVD (plus RT for BMD) remains the standard of care because Stanford V did not meet the objective of 33% improvement in FFS. For some patients, Stanford V, when given as described with RT, remains an acceptable alternative. Disclosures: Friedberg: Genentech: Honoraria. Blum:Seattle Genetics: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Horning:Genentech: Employment.

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Pharmacokinetics (PK), Safety and Overall Response Rate (ORR) Achieved with Subcutaneous (SC) Administration of Rituximab in Combination with Chemotherapy Were Comparable to Those Achieved with Intravenous (IV) Administration in Patients (pts) with Follicular Lymphoma (FL) in the First-Line Setting: Stage 1 Results of the Phase III SABRINA Study (BO22334)

Blood ◽

10.1182/blood.v120.21.1629.1629 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1629-1629 ◽

Cited By ~ 3

Author(s):

Andrew Davies ◽

Francesco Merli ◽

Biljana Mihaljevik ◽

Noppadol Siritanaratkul ◽

Philippe Solal-Céligny ◽

...

Keyword(s):

Follicular Lymphoma ◽

Research Funding ◽

Overall Response Rate ◽

Geometric Mean ◽

Phase Iii ◽

Comparable Efficacy ◽

Grade 3 ◽

Line Setting ◽

Stage 1 ◽

To Receive

Abstract Abstract 1629 Rituximab and chemotherapy induction followed by maintenance rituximab is the backbone of therapy for FL. IV rituximab administration can take several hours; therefore, a SC formulation has been developed which may shorten administration times and increase convenience for pts. Achieving clinically effective rituximab serum concentrations is essential for optimal activity (Yin et al, ASCO 2010, abstract e13108). Therefore, achieving non-inferior Ctrough levels with SC compared with IV dosing is expected to provide comparable efficacy. BO22334 (NCT01200758) is a two-stage, phase III, international, randomized, controlled, open-label study of SC vs IV rituximab combined with up to 8 cycles of CHOP or 8 cycles of CVP chemotherapy followed by maintenance in pts with previously untreated FL. Pts were scheduled to receive 8 cycles of rituximab, regardless of the number of chemotherapy cycles. In the SC arm, rituximab was administered IV (375 mg/m2) for the first cycle, with following cycles administered SC (1400 mg). Stage 1 aimed to confirm that the SC rituximab dose of 1400 mg (dose based on phase I study BP22333; Salar et al, EHA 2012, abstract 0794), resulted in non-inferior Ctrough rituximab levels compared with the 375 mg/m2 IV dose when given as 3-weekly induction therapy combined with chemotherapy. The stage 1 primary endpoint was non-inferiority of the Ctrough,SC:Ctrough,IV ratio (limit for non-inferiority was Ctrough ratio > 0.8) at Cycle 7 of induction. Secondary endpoints included comparisons of SC vs IV: area under the serum concentration–time curve (AUC); end of induction ORR; CR (CR/CRu); and safety. Previously untreated pts with histologically confirmed CD20-positive grade 1, 2, or 3a FL requiring treatment (N = 127) were randomized 1:1 to SC (n = 63) or IV (n = 64) rituximab, stratified by Follicular Lymphoma International Prognostic Index score, chemotherapy, and region. Allocation to R-CHOP or R-CVP was at the investigator's discretion; 40 pts in each arm (63%) received CHOP chemotherapy and the remaining pts (37%) received CVP chemotherapy. The primary PK endpoint was met with a geometric mean of 134.6 μg/mL for the rituximab SC arm (n = 48) and 83.1 μg/mL for the rituximab IV arm (n = 54) resulting in an SC:IV ratio of 1.62 (90% confidence interval [CI]: 1.36, 1.94). The Ctrough achieved with SC rituximab was therefore concluded to be non-inferior to IV administration. The geometric mean ratio of AUCSC:AUCIV (1.378 [90% CI: 1.241, 1.530]) was also non-inferior. After a median follow-up of approximately 9 months, the overall safety profile was as would be expected for IV administration, with no new or unexpected adverse events (AEs). In the SC and IV arms AEs were experienced by 92% (n = 57) and 88% of pts (n = 57), respectively. Grade 3/4 AE were observed in 47% of pts in the SC arm and 46% in the IV arm. The only grade 3/4 AE occurring in > 10% of pts was neutropenia (26% in the SC arm, 22% in the IV arm) which was not associated with increased infection rate (grade 3/4 infections and infestations: 5% SC vs 9% IV). Total administration-related reactions (ARRs; any events occurring during/within 24 hours of drug administration that were considered treatment-related by the study investigator) were higher in the SC vs IV arm (50% vs 32%) with the majority being grade 1/2; there were no grade 4 ARRs. Individual ARRs (all grades) occurring in ≥5% of pts in the SC vs IV arms were: erythema (8% vs 3%), pruritus (6% vs 3%), chills (3% vs 6%), injection site erythema (10% vs 0%), and vomiting (3% vs 6%). Investigator-assessed ORR was 90.5% (95% CI: 80.4, 96.4) in the SC arm and 84.4% (95% CI: 73.1, 92.2) in the IV arm. Complete response (CR/CRu) rates were 46.0% (29/63 pts, 95% CI: 33.4, 59.1) for the SC arm and 29.7% (19/64 pts, 95% CI: 18.9, 42.4) for the IV arm. Stable and progressive disease rates were similar in each arm. An independent review of response assessments is planned. Data demonstrate PK non-inferiority and comparable efficacy for SC (1400 mg) compared with IV (375 mg/m2) rituximab administration, with similar ORR and CR rates in the rituximab SC and IV arms. Overall, SC and IV rituximab AE profiles were similar; ARRs were mostly of mild/moderate intensity. Stage 1 pts are continuing to receive maintenance treatment with SC or IV rituximab. Stage 2 of the study has opened recruitment of an additional 280 pts who will be randomized to receive SC (1400 mg) or IV rituximab. Disclosures: Davies: Roche: Consultancy, Honoraria, Research Funding. Off Label Use: Pharmacokinetics (PK), safety and overall response rate (ORR) achieved with subcutaneous (SC) administration of rituximab in combination with chemotherapy were comparable to those achieved with intravenous (IV) administration in patients (pts) with follicular lymphoma (FL) in the first-line setting. Siritanaratkul:Roche: Research Funding. Solal-Céligny:Roche, France: Consultancy, Honoraria, Research Funding. Boehnke:F. Hoffmann-La Roche: Employment. Berge:Roche: Employment. McIntyre:Roche: Employment. Barrett:Roche: Employment. Macdonald:Roche, Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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A Phase III Study Of ASCT Vs Cyclophosphamide-Lenalidomide-Dexamethasone and Lenalidomide-Prednisone Maintenance Vs Lenalidomide Alone In Newly Diagnosed Myeloma Patients

Blood ◽

10.1182/blood.v122.21.763.763 ◽

2013 ◽

Vol 122 (21) ◽

pp. 763-763 ◽

Cited By ~ 16

Author(s):

Antonio Palumbo ◽

Francesca Gay ◽

Andrew Spencer ◽

Francesco Di Raimondo ◽

Adam Zdenek ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Phase Iii ◽

Study Endpoint ◽

Newly Diagnosed ◽

Advisory Committees ◽

Grade 3 ◽

To Receive

Abstract Background High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). The introduction of novel agents challenged the role of ASCT at diagnosis. We conducted a multicenter 2X2 randomized trial comparing conventional chemotherapy plus lenalidomide with ASCT followed by maintenance with lenalidomide-prednisone (RP) or lenalidomide (R) alone in newly diagnosed young MM (NDMM) patients. Methods Eligible patients with NDMM ≤ 65 years were enrolled. All patients received Rd induction (four 28-day cycles of lenalidomide 25 mg day 1–21 and low-dose dexamethasone 40 mg day 1,8,15,22) followed by stem cell mobilization. Patients were randomized to receive consolidation with CRD [six 28-day cycles of cyclophosphamide (300 mg/m2 day 1,8,15), dexamethasone (40 mg days 1,8,15,22) and lenalidomide (25 mg days 1–21)] or MEL200-ASCT (melphalan 200 mg/m2 with stem-cell support). Patients were randomly assigned to receive subsequent maintenance with RP (28-day cycles of lenalidomide 25 mg days 1–21 plus prednisone 50 mg every other day) or R alone (28-day cycles of lenalidomide 25 mg days 1–21). Primary study endpoint was progression-free survival (PFS); secondary endpoints included safety, responses and overall survival (OS). Data cut off was May 30th, 2013. Results Three-hundred and eighty-nine patients were enrolled in the trial. Patient characteristics were well balanced between CRD (n=194) and MEL200-ASCT (n=195), and between R (n=195) and RP (n=194) arms. Median follow-up was 31 months. In the intent to treat (ITT) analysis, the median PFS was not reached with MEL200-ASCT and 28 months with CRD (the respective 3-year PFS was 60% vs. 38%, HR=0.62, 95%CI: 0.49-0.85, P=0.003). Median time from enrolment to maintenance was 14 months. In the population of patients eligible for maintenance, 2-year PFS from the start of maintenance was 73% for RP and 56% for R patients (HR= 0.57, 95%CI: 0.34-0.93; P=0.03). In the subgroup of patients who received MEL200-ASCT, 2-year PFS from the start of maintenance was 83% for patients who received RP and 64% for those who received R alone (HR=0.36 95%CI: 0.15-0.87, P=0.02). In the subgroup of patients who received CRD, 2-year PFS from the start of maintenance was 64% for patients who received RP and 47% for those who received R alone (HR=0.75, 95%CI: 0.40-1.39, P=0.36). At present, no differences in OS were noticed between patients randomised to received CRD or MEL200-ASCT, and between patients who received RP or R maintenance. As expected, the rates of grade 3-4 hematologic (85% vs. 26%, P<0.001) and non-hematologic (35% vs. 19%, P=0.003) adverse events (AEs) were higher in the MEL200-ASCT arm compared with the CRD arm. The main non-hematologic AEs were infections (18% vs. 5%, P=0.001) and gastrointestinal AEs (18% vs. 3%, P<0.001). Rates of grade 3-4 hematologic (8% vs. 7%, P=0.85) and non-hematologic (12% vs. 13%, P=0.88). AEs were similar in the RP and R arms. The main non-hematologic AEs in both RP and R groups were infections (3% vs. 3%). At present, 6 second primary malignancies and 3 cases of cutaneous basalioma have been reported. Conclusions MEL200-ASCT significantly prolonged PFS in comparison with CRD. At present no difference in OS was reported, this may be due to the low number of events and to the length of follow-up. The increase in toxicity with MEL200-ASCT did not adversely impact on efficacy. The addition of prednisone to lenalidomide maintenance significantly reduced the risk of progression in comparison with lenalidomide alone, without increasing the toxicity. Updated data with longer follow-up will be presented at the meeting. Disclosures: Palumbo: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Gay:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Spencer:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Larocca:Celgene: Honoraria. Caravita:Celgene: Honoraria, Research Funding. Petrucci:Celgene: Honoraria. Hajek:Celgene: Honoraria; Celgene: Consultancy. Boccadoro:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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