scholarly journals Combined Treatment of Bortezomib, Continuous Low-Dose Cyclophosphamide and Dexamethasone Followed By One Year of Maintenance Treatment for Refractory or Relapsed Multiple Myeloma Patients: A Prospective Phase II Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4733-4733
Author(s):  
Esther GM Waal de ◽  
Linda Munck de ◽  
Gerhard Woolthuis ◽  
Annet velden Van Der ◽  
Yvonne Tromp ◽  
...  
Keyword(s):  
Overall Survival ◽  
Maintenance Therapy ◽  
Research Funding ◽  
Low Dose ◽  
Progression Free Survival ◽  
Free Survival ◽  
First Relapse ◽  
Grade 3 ◽  
One Year

Abstract Introduction: Combination therapy for longer periods but at low dose, also called metronomic scheduling, might be an effective manner to treat patients with relapsing myeloma. In particular if the used agents attack the malignant clone in an alternative manner. Therefore we used the combination of bortezomib, dexametasone and daily low dose of oral cyclophosphamide as an induction regimen followed by one year of maintenance therapy consisting of bortezomib and cyclophosphamide. Methods: Relapsing myeloma patients, bortezomib naïve, were treated with three cycles of 1.3 mg/m2 bortezomib at day 1, 4, 8 and 11, cyclophosphamide 50 mg daily, and 20 mg dexamethasone at day 1, 2, 4, 5, 8, 9, 11 and 12 followed by three cycles of bortezomib 1.6 mg/m2 (day 1, 8, 15 and 2), cyclophosphamide (50 mg) daily and dexamethasone (20 mg) at day 1, 2, 8, 9, 15, 16, 22 and 23. Maintenance therapy consisting of bortezomib 1.3 mg/m2 every two weeks and daily dose of 50 mg cyclophosphamide for one year was applied to patients in partial or complete remission. Primary endpoints were toxicity during re-induction and maintenance therapy. Secondary endpoints were response to treatment and progression free and overall survival. Results: 59 patients with relapsing multiple myeloma were included of whom 69% were in first relapse (Table 1). The upfront treatment consisted mainly of thalidomide-based and vincristine-based chemotherapy and 40% of the patients have been treated with an autologous stem cell transplantation. All 6 cycles of induction chemotherapy could be given in 49% of the patients. Premature discontinuation before starting maintenance therapy was due to toxicity (31%), progressive disease (7%), death (7%) or other reasons (6%). Myelosuppression was the most common side effect with WHO grade 3-4 in 31% of the patients. Neuropathy grade 3-4 was observed in 16% of patients, partially due to the fact that bortezomib was given intravenously during the first 2 yrs of the protocol which included 76% of the patients. Maintenance therapy was started in 47% of the patients with a median duration of 7.3 months (range 0.36.-13.4). Grade 3-4 toxicity was observed in 25% of the patients including infections (n=3) and myelosuppression (n=3) which did not resulted in discontinuation of therapy. Median follow up time was 29 months with an overall response of 62%, and a very good partial response (VGPR), complete remission (CR) in 21% and 7% of the patients respectively. During the maintenance phase an improvement in responsiveness was observed in 25% of the patients. The CR rate increased with 9% to a total of 16%. VGPR rate was 20% and 16% of the patient had a PR. At end of the maintenance therapy 50% of patients started with maintenance had stable disease. The median progression free survival (PFS) was 17.2 months (range 0.13 – 43.5) as depicted in figure 1. and the median overall survival was 21.6 months (range 0.46-54.4, figure 2). During follow up 33 % of the patients died due to progression of MM. Conclusion: The present study demonstrates that combination therapy with bortezomib, continuous low dose cyclophosphamide and dexamethasone is an effective and manageable regimen. Adding a year of maintenance was feasible with limited side effects and an increase in CR rate. Table 1: patient characteristics Patients (%) Age, mean (min,max) 69 (46-86) Sex Male 56 Female 44 Relapse number First relapse 75 Second relapse 20 Third relapse 5 Performance status 0 65 1 29 2 5 M-protein heavy chain IgA 18 IgG 65 Light chain disease 18 Polyneuropathy No 61 Yes 39 Figure 1: Progression free survival Figure 1:. Progression free survival Figure 2: Overall survival Figure 2:. Overall survival Disclosures Waal de: Jansen Cilag: Research Funding. Munck de:Jansen Cilag: Research Funding. Woolthuis:Jansen Cilag: Research Funding. velden Van Der:Jansen Cilag: Research Funding. Tromp:Jansen Cilag: Research Funding. Hoogendoorn:Jansen Cilag: Research Funding. Vellenga:Jansen Cilag: Research Funding. Hovenga:Jansen Cilag: Research Funding.

Sequential RCHOP, Radioimmunotherapy and Rituximab Maintenance Improves Early Outcomes in Advanced Stage Follicular Lymphoma: 5 Year Outcomes from SWOG 0801

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 614-614
Author(s):  
Paul M. Barr ◽  
Hongli Li ◽  
Richard Burack ◽  
Michael LeBlanc ◽  
Sonali M. Smith ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Maintenance Therapy ◽  
Follicular Lymphoma ◽  
Research Funding ◽  
Progression Free Survival ◽  
Advanced Stage ◽  
Secondary Malignancies ◽  
Free Survival ◽  
Grade 3

Abstract Background: Despite an abundance of effective therapeutic options, advanced stage follicular lymphoma (FL) remains incurable. Further, prospective trials consistently demonstrate that 20% of patients relapse within 2 years and ultimately have an inferior survival (Casulo 2015). Maintenace rituximab following chemoimmunotherapy induction is able to delay disease progression but has not demonstrated a benefit in overall survival (Salles 2011). Additionally, radioimmunotherapy (RIT) is one of the most effective single agent options in FL but is not commonly utilized as part of upfront treatment. As such, the role of both remains unclear. Based on results demonstrated with RIT consolidation in SWOG 0016 and the efficacy of rituximab maintenance, SWOG 0801 was designed as a phase 2 single arm trial, conducted to evaluate the utility of consolidative RIT and sequential maintenance rituximab following chemoimmunotherapy induction. Methods: Eligible patients (pts) with treatment naïve stage III/IV or bulky stage II FL received RCHOP for 6 cycles (without rituximab for the last 2 cycles) followed by iodine-131 tositumomab and subsequent rituximab administered every 3 months for up to 4 years. The primary endpoint was progression-free survival (PFS) at 3 years. Secondary endpoints included 5-year overall survival (OS), overall response rate (ORR), and safety. Results: Of 87 pts registered to this study, 85 were deemed eligible following central pathologic review. One additional patient withdrew consent and received no treatment on protocol. Of the 84 evaluable patients, the median age was 52 years (range 29 - 80) ) and 18%, 40%, and 42%had low, intermediate and high risk FLIPI scores, respectively. Seventy-three pts completed RCHOP and I-131 tositumomab. Grade ≥3 AEs occurring ≥5% of pts included neutropenia (57%), leukopenia (40%), thrombocytopenia (20%), febrile neutropenia (17%), fatigue (10%), neuropathy (8%), anemia (7%) and hyperglycemia (5%). Reasons for discontinuation included refusal of tositumumab (6 pts), prolonged myelosuppression (2 pts), ascites (1pt), inability to provide tositumumab (1 pt), and an unrelated lower extremity wound (1 pt). Following induction and RIT, 59 complete responses and 23 partial responses were observed, for a ORR of 99% (95% CI: 93.5%, 99.9%) Sixty nine eligible patients registered to maintenance therapy with 42 completing the 4 year treatment plan. The only grade ≥3 AE that occurred in ≥5% of pts was leukopenia (5%). Twenty-seven pts discontinued maintenance therapy, including 11 in the first 2 years and 16 in the last 2 years, due to the following reasons: infection (8 pts), patient preference (8 pts), deaths (2 pts), treatment delay (2 pts), secondary solid tumors (2 pts), bowel perforation (1 pt), joint pain (1 pt), hepatic transaminase elevation (1 pt), insurance refusal (1 pt), and dose error (1 pt). Four additional secondary malignancies were reported following completion of therapy including solid tumors (3 pts) and AML (1 pt). To date, 9 deaths have occurred due to secondary malignancies (3 pts), unknown etiology (3 pts), cardiac arrest (2 pts) and non-alcoholic cirrhosis (1 pt). After median follow-up of 5.6 years (range 3-7 years), 17 events have occurred including 9 pts experiencing progressive FL resulting in a progression free survival of 90% (95% CI: 81.9%, 95.1%) at 3 years and 84%(95% CI: 74.5%, 90.6%) at 5 years (Figure). Three-year overall survival is 96% (95% CI: 89.3%, 98.8%) and 5-year overall survival is 94% (95% CI: 86.2%, 97.5%). Conclusions: SWOG 0801 demonstrates near universal responses following chemoimmunotherapy and RIT. This sequential therapeutic strategy appears to improve early outcomes as 94% of pts are without disease progression at 2 years, consistent with the best results ever demonstrated for FL in the National Clinical Trials Network. However, the majority of discontinuations occurred during maintenance suggesting that rituximab over a 4-year span is not feasible for many patients due to cumulative toxicity. Future studies investigating precision strategies in high-risk FL may consider an aggressive chemoimmunotherapy induction and RIT consolidation platform to overcome early FL progression given these promising outcomes. Support: NIH/NCI grants CA180888, CA180819, and in part by GlaxoSmithKline. Figure. Progression-Free Survival and Overall Survival Figure. Progression-Free Survival and Overall Survival Disclosures Barr: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy. Smith:Amgen: Other: Educational lecture to sales force; Juno: Consultancy; Pharmacyclics: Consultancy; AbbVie: Consultancy; Portola: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Genentech: Consultancy, Other: on a DSMB for two trials ; TGTX: Consultancy. Gopal:Janssen: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Consultancy. Persky:Merck: Research Funding; Gilead: Speakers Bureau. Press:Roche / Genentech: Consultancy, Research Funding. Fisher:Gilead: Consultancy; Seattle Genetics: Consultancy; Johnson and Johnson: Consultancy. Friedberg:Bayer: Other: Data Safety Monitoring Committee.

scholarly journals Time to Progression Post-Induction Predicts Outcomes of Ixazomib Based Therapy for Relapsed/Refractory Myeloma: Real World Data from a Multi-Site Israeli Registry Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1972-1972
Author(s):  
Yael C Cohen ◽  
Hila Magen ◽  
Noa Lavi ◽  
Moshe E. Gatt ◽  
Evgeni Chubar ◽  
...  
Keyword(s):  
Research Funding ◽  
Overall Response Rate ◽  
Target Organ Damage ◽  
Progression Free Survival ◽  
Organ Damage ◽  
Real World Data ◽  
Free Survival ◽  
Grade 3 ◽  
Indolent Disease

Abstract Introduction Ixazomib is an orally available proteasome inhibitor, shown to be safe and efficacious in combination with lenalidomide and dexamethasone (IRd regimen) in patients with relapsed and refractory multiple myeloma (RRMM) with 1-3 prior lines, demonstrating a progression free survival (PFS) benefit which was similar across cytogenetic risk groups (Tourmaline-MM1 phase 3 trial). A European real world data analysis of an IRd named patient program (NPP) outcomes in Greece (n=35), UK (n=46) and Check republic (n=57) showed similar favorable outcomes (Terpos et al, Blood 2017 130:3087). We aimed to analyze outcomes of ixazomib combinations among a multi-site cohort in the Israeli Myeloma registry. Overall response rate (ORR) was classified according to IMWG criteria. Primary endpoint was PFS, secondary endpoints included ORR, overall survival (OS), safety and tolerability. Patients A total of 78 patients across 7 sites, who received at least one cycle of ixazomib combination between June 2013 and June 2018 for treatment of RRMM were retrospectively included. Median age was 68 (range: 38-90). Male/Female ratio was 42/36. ISS (rISS) I/II/II was 30%/42%/27% (25%/54%/15%). Patient received between 1 and 7 prior lines of therapy, 66% received ixazomib in 2nd line, 18% in 3rd line. Overall, 89% of patients had been exposed to PIs (bortezomib 86%) prior to IRd, 41% to IMiDs (thalidomide 28% lenalidomide 22% and pomalidomide 6%), and 35% had undergone autologous transplantation (ASCT). Induction treatment was mostly bortezomib based (85%), most frequently VCD (62%). FISH cytogenetics were available for 60 patients, 29 (48%) had high or intermediate risk aberrations (t(4:14) 12 pts, amp 1q21 12 pts, del17p 9 pts). Disease aggressiveness was classified by treating physician as indolent (rapid control to protect from target organ damage not required) vs aggressive (imminent target organ damage) in 63% vs 27%, respectively. 60 (77%) of the 78 patients received ixazomib via a named patient program, the rest via national or private healthcare provider. Results Median time of follow up from first ixazomib dose was 22 months (range: 1-39 months), and 54 months from diagnosis of myeloma. Treatment is ongoing in 44 (56%) patients with a median duration of 19 months (range: 1-29). Among patients who discontinued treatment, the median duration was 9 months (1-31). Ixazomib was combined with lenalidomide, pomalidomide, and daratumumab in 69%, 9% and 4%, respectively. Overall response rate was 88% - CR 10%, VGPR 36%, PR 42%. Progression free survival was 78% and 54% at 12 and 24 months, respectively (fig1a). A worse PFS was found with physician assessment of aggressive vs indolent disease (14.5 vs 25.9 months, p=0.001), and with post induction progression free period (PFS1) ≤ 24 months vs. >24 months (23.9 vs 31.5 months, p=0.038) (fig 1b); age >=65 trended towards a worse PFS (p=0.058). Poor cytogenetic risk, prior exposure to bortezomib, prior auto transplant, and number of prior lines of therapy did not affect PFS or ORR. OS from first ixazomib administration was 90% and 81% at 12 and 24 months, respectively; median OS was not reached (fig1a). Any (grade 3-4) toxicity considered by investigator as related to ixazomib was reported in 70% (18% grade 3-4), including neutropenia 14% (6%), anemia 19% (6%), thrombocytopenia 17% (5%), nausea and vomiting 17% (1%), DVT/PE 4% (1%), neutropenic infection 0 (4%), peripheral neuropathy 14% (3%), diarrhea 14% (3%), rash 10% (4%), pneumonia 5% (3%). There were no ixazomib related deaths. Dose reduction or discontinuation due to toxicity occurred in 28% and 12%, respectively. Conclusion Our data shows ixazomib-based combinations are efficacious and safe regimens for patients with RRMM, achieving ORR of 88%, at 2nd as well as later lines of therapy, regardless to cytogenetic risk. Over a median follow up of almost 2-years, 54% remained progression free at 24 months. An ixazomib based regimen may be particularly attractive for patients who remain progression free for more than 24 months after a bortezomib induction and for patients with a more indolent disease phenotype. Disclosures Cohen: Neopharm Israel: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Medisson Israel: Consultancy, Honoraria, Research Funding. Tadmor:NOVARTIS: Consultancy; PFIEZER: Consultancy; ABBVIE: Consultancy; JNJ: Consultancy; ROCHE: Research Funding.

scholarly journals Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma

2020 ◽  
pp. JCO.20.02259
Author(s):  
Paul G. Richardson ◽  
Albert Oriol ◽  
Alessandra Larocca ◽  
Joan Bladé ◽  
Michele Cavo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Free Survival ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Grade 3

PURPOSE Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class–refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class–refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. CONCLUSION Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class–refractory and extramedullary disease.

Maintenance Therapy with Low-Dose Subcutaneous 5-Azacitidine in Older Patients with AML in 1st Remission.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1029-1029
Author(s):  
Jeffrey E Lancet ◽  
Rami S. Komrokji ◽  
HuiYi Lin ◽  
Carlos M. de Castro ◽  
David A. Rizzieri ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Maintenance Therapy ◽  
Older Patients ◽  
Research Funding ◽  
Low Dose ◽  
Disease Free Survival ◽  
Free Survival ◽  
Grade 3 ◽  
Disease Free ◽  
Risk Categories

Abstract Abstract 1029 Poster Board I-51 Background: Elderly patients with AML have a poor outcome, with low complete response (CR) rates and durations of CR that are typically less than 1 year, highlighting the need for more effective post-remission therapy. 5-azacitidine (AZA) is a nucleoside analogue/DNA methyltransferase inhibitor approved for use in all FAB subtypes and risk categories of myelodysplastic syndromes (MDS). In higher-risk patients with MDS, including those with AML (former RAEB-T subtype), AZA improves overall survival and delays the time to leukemia transformation. We undertook a phase 2 pilot study of low-dose subcutaneous (SC) AZA in older adult patients with AML in 1st CR or CR with incomplete platelet recovery (CRp) following standard induction therapy. Methods: Study objectives included the following: 1) determine the one year disease-free survival in elderly patients with acute myeloid leukemia (AML) in first CR/ CRp treated with low-dose SC AZA as post-remission therapy. 2) determine safety and tolerability of SC AZA administered in the post-remission setting. 3) investigate the relationship between bone marrow genomic promoter methylation with 1-year disease-free survival. Eligibility included age ≥ 60 with AML in 1st CR/ CRp following 1-2 cycles of induction chemotherapy and 1-2 cycles of consolidation therapy, ECOG PS 0-2, adequate end-organ function. AZA was administered subcutaneously on 1 of 2 different dosing schedules: A) 50 mg/m2/d x 5d (d 1-5), or B) 50 mg/m2/d x 7d (d 1-5, 8-9). Cycles were repeated every 4 weeks, and up to 12 cycles. Results: As of August 2009, 16 patients have been enrolled on the study and 15 are currently evaluable. Nine patients received dosing schedule A and 6 received schedule B. Median age was 69 years (range 62-81); M/F was 13/2; baseline cytogenetic risk categories at initial diagnoses: poor (6), intermediate (8), and unknown/not done (1). Two of 15 patients had a history of antecedent MDS. Nine of 15 patients (60%) required 2 cycles of induction chemotherapy to achieve CR/CRp. The median time from achievement of CR/CRp to AZA initiation was 13.6 weeks (range 7 – 21.9 weeks). To date, the median number of AZA cycles received was 4, ;5 patients have received ≥ 6 cycles, 2 of whom have received the 12 planned cycles and another who remains on-study after 11 cycles. Median duration of CR/CRp was 54.8 weeks (95% CI: 28.1-96.4 weeks) estimated using the Kaplan-Meier method. Only 2 of 15 (13%) patients developed grade 3-4 non-hematologic adverse events (colitis, headache). Six of 15 (40%) patients developed reversible grade 3-4 neutropenia or thrombocytopenia, but only 3 required dose reduction. No patients discontinued AZA due to toxicity, and there were no deaths that occurred on-study. Criteria for early stoppage, based upon toxicity, have not been reached. Methylation array analyses are ongoing. SC AZA administered as maintenance therapy in older patients with AML in 1st CR/CRp appears feasible and safe. Extended treatment was possible in a high proportion of patients, with encouraging early signs of durable remissions. Accrual to this trial is ongoing and updated results will be presented. Disclosures: Lancet: Celgene: Research Funding. Komrokji:Celgene: Research Funding, Speakers Bureau. de Castro:Celgene: Speakers Bureau. Rizzieri:Celgene: Research Funding, Speakers Bureau. List:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Cyclophosphamide, Adriamycin, Vincristine and Prednisone Plus Rituximab (CHOP-R) in Fludarabine (F) Refractory Chronic Lymphocytic Leukemia (CLL) or CLL with Autoimmune Cytopenia (AIC) or Richter's Transformation (RT): Final Analysis of a Phase II Study of the German CLL Study Group

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2860-2860
Author(s):  
Petra Jenke ◽  
Barbara Eichhorst ◽  
Raymonde Busch ◽  
Nadine Anheier ◽  
Ulrich Duehrsen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Phase Ii ◽  
Research Funding ◽  
Progression Free Survival ◽  
Response Rates ◽  
Median Number ◽  
Response Evaluation ◽  
Free Survival ◽  
Richter's Transformation ◽  
Grade 3

Abstract Abstract 2860 Introduction: In the last decade, important progress has been achieved in the treatment of CLL through the use of purine analog-based chemoimmunotherapies. Several conditions remain a challenge, often with a poor outcome. Amongst these therapeutic problems are Richter's transformation (RT), refractoriness to F-based therapies (Fref), and the occurrence of AIC, which are sometimes induced by F. Fref and RT pts have a very poor prognosis with an estimated overall survival (OS) of only 10 and 8 months (mos), respectively. Therefore, therapeutic alternatives are urgently warranted. CHOP-R has improved the outcome of pts with aggressive non-Hodgkin's lymphoma. To test the efficacy and tolerability of the CHOP-R regimen in CLL patients with RT, Fref, or AIC, the GCLLSG initiated a prospective phase II trial. Material and Methods: 62 patients were included in the study. Due to protocol violations, 2 patients were excluded. Within the group of Fref pts, the medical review detected 11 patients who had received pre-treatment with F (Fpret), but were not refractory according to the updated guidelines (Hallek et al., Blood 2008). Thus, 26 pts were classified as Fref/pret, 19 pts as AIC and 15 pts as RT. All patients received CHOP every 3 weeks (cyclophosphamide 750mg/m2, adriamycin 50mg/m2 and vincristine 1, 4mg/m2 d1; prednisone 100mg/m2 d1–5). Rituximab was added starting with the 2nd cycle (375mg/m2 on each d0, and 21 days after the last CHOP-R). RT pts received up to 8, Fref/pret and AIC up to 6 courses of CHOP-R. In case of PD after 3 cycles, pts went off-study. The primary endpoints were remission rate, quality and duration of response. Results: 79%, 73%, and 40% of AIC, Fref/pret, and RT pts were male, respectively. The median age was 65 years (y) for Fref/pret-pts, 66y in the AIC and 69y in the RT group. Binet stages for Fref/pret pts were: A: 8%; B: 27% C: 65 %. All but 3 AIC pts were at Binet stage C. Initial RT stages according to Ann Arbor were: II: 13%, III: 13%, IV 73%. The median number of previous therapies were 3 for Fref/pret, 2 for AIC and 2 for RT. A total of 314 cycles were administered, with a median number of 3 cycles for AIC and Fref pts and a median number of 4 cycles for the RT group. Due to toxicity 73% of cycles in the Fref/pret group, 66% in the AIC and 87% in the RT group were dose-reduced. 69% of Fref/pret-pts and 58% of AIC-pts received full 6 cycles of therapy and only 40% of RT-pts completed 8 cycles of therapy. Treatment was stopped in 6 pts because of PD. Due to treatment related toxicity treatment was stopped in 16 pts (27%). Treatment related mortality was 3% (2 pts). Treatment toxicity was reported according to NCI common toxicity criteria (CTC) version 2.0. Adverse events grade 3 or 4 for anemia, neutropenia and thrombocytopenia were documented in 75%, 55% and 65% of patients, respectively. Infections were the most common non-hematologic toxicity and occurred in 67%; severe infections CTC grade 3 or 4 occurred in 28%. All 26 Fref/pret-pts were available for response evaluation. CHOP-R achieved 54% PR, 35% SD and 12% PD. The median progression-free survival (PFS) and median treatment-free survival (TFS) were 11 and 14 mos. OS was 27 mos with a significant difference concerning F-ref (n=15) and F-pret (n=11) pts (17 vs. 35m; p=0.05). We evaluated the response of all 15 RT-pts with 60% PR, 7% CR, 13% SD and 20% PD. The PFS was 15 mos, TFS was 17 mos and OS 27 mos. 17 AIC pts were available for response evaluation with 82% PR, 6% SD and 12% PD. The PFS and TFS were only 14 and 16 mos. The OS was 50 mos. The population had a high incidence of unfavourable genetic markers: deletion of chromosome 17p [del(17p)] was detected in 24%, del(11q) in 34% and unmutated IGHV in 70%. 85% had high levels of serum thymidine kinase (sTK > 10 U/l), and 49% had high levels of ß2-microglobulin (ß2M > 3.5 mg/l). Patients with del(17p) had an unfavourable response rate and achieved significant less a PR or CR (36% vs. 76%; p=0.03). Multivariate analyses showed that del(17p) and ECOG performance status had a negative prognostic impact on OS (p<0.0001). Moreover the presence of a del(17p) predicted a short PFS (6 vs. 16.9 mos; p=0.001). Conclusion: CHOP-R achieves promising response rates in CLL patients with Fref and RT and very good response rates in patients with AIC. However, the progression-free survival and overall survival remain unsatisfactory. Therefore, CHOP-R might be used as induction therapy prior to allogeneic stem cell transplantation in physically fit patients. Disclosures: Eichhorst: Hoffmann La Roche: Honoraria, Research Funding, Travel Grants; Mundipharma: Research Funding, Travel Grants; Gilead: Consultancy. Dreyling:Roche: Research Funding, Scientific advisory board, Speakers Bureau. Bergmann:Celgene: Honoraria. Stilgenbauer:Hoffmann La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel Grants. Fink:Hoffmann La Roche: travel grants. Fischer:Hoffmann La Roche:. Wendtner:Hofmann-La Roche: Consultancy, Honoraria, Research Funding. Hallek:Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Honoraria.

Patient Outcomes with Proteosome Inhibitor Bortezomib in Multiple Myeloma at an English District General Hospital

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5745-5745
Author(s):  
Anil Vaikunth Kamat ◽  
Tariq Shafi ◽  
Raphael A. Ezekwesili
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Progression Free Survival ◽  
Second Primary ◽  
Second Line ◽  
First Line ◽  
Free Survival ◽  
Grade 3 ◽  
Second Primary Malignancies

Abstract Bortezomib is a targeted proteosome inhibitor licensed & approved for in multiple myeloma both as first line and in relapsed setting. This is a retrospective non experimental cross sectional quantitative comparative group study using clinical case notes, laboratory & pharmacy records for patients treated with Bortezomib in 2011 & 2012. Outcomes studied included remission status, adverse events, progression free survival and overall survival at follow up. The study also looked at the comparative responses of cohort of patients administered Bortezomib through intravenous & subcutaneous route. The cohort consisted of 33 patients, 21 male, 11 female, median age 71 years, first line 10 patients, second line 23 , median number of cycles in 2011 & 2012 – first line 3 & 8 , second line 5 & 4, respectively. In 2011, 8 received intravenous treatment, 9 were switched from intravenous to subcutaneous route whilst all patients from 2012 received subcutaneous Bortezomib. The most frequently used regimen was Bortezomib Dexamethasone ( VD). The overall response rate ( ORR >/= Minor Response) was: First line 70% (7/10) ; Second line 47.8% ( 11/23); median PFS ( Figure 1) 6 months ( First line: 7 months ; Second line : 6 months) and median overall survival ( Figure 2) at follow up: 9 months ; 39.4 % ( 13/33) First line 8.5 months, Second line 11 months. Subcutaneous Bortezomib was equivalent to intravenous Bortezomib in terms of efficacy & tolerance. Of 33 patients, there were 12 dose reductions. Adverse events reported included: peripheral Neuropathy - grade 3 - 6% ( all grades 27.3%); Diarrhoea - grade 3 - 3% (all grades 6%); Nausea / Vomiting - grade 3 - 3% ( all grades 6%) and Second Primary Malignancies - 12% ( 4 of 33). Mortality at follow up was 20 patients from cohort of 33 ; causes included disease progression in 11, second primary malignancy with disease progression in 4, COPD 2, Systemic Amyloidosis 2, Tuberculosis 1 , Multiple co morbidities 1 and Asthma with mechanical failure in single patient. Second primary malignancies ( 4/33) included Prostate carcinoma ( 1), Renal Cell Carcinoma (1), Neuroendocrine tumour ( 1 ) and Unknown Primary in single patient. Beyond second line treatment, majority (14 of 23 patients; 60.9 %) did not have further active treatment. These data indicate that patient outcomes were modest compared to published data from VISTA and APEX trials. Majority of patients did not have further active treatment beyond second line which suggests the most effective treatment strategy should be used upfront as patients may not be fit to have further lines of therapy despite availability of recently introduced novel targeted agents. A higher percentage of second primary malignancies were noticed in this cohort which should be an area of further clinical research. Figure 1: Progression free survival with Bortezomib as first line & second line in multiple myeloma Figure 1:. Progression free survival with Bortezomib as first line & second line in multiple myeloma Figure 2: Overall survival with Bortezomib as first line & second line in multiple myeloma Figure 2:. Overall survival with Bortezomib as first line & second line in multiple myeloma Disclosures No relevant conflicts of interest to declare.

Nivolumab (NIVO) + low-dose ipilimumab (IPI) as first-line (1L) therapy in microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Two-year clinical update.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4040-4040 ◽  
Author(s):  
Heinz-Josef Lenz ◽  
Sara Lonardi ◽  
Vittorina Zagonel ◽  
Eric Van Cutsem ◽  
M. Luisa Limon ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Low Dose ◽  
Objective Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Free Survival ◽  
Duration Of Response ◽  
Therapy Option ◽  
Grade 3

4040 Background: In the phase 2 CheckMate 142 trial, NIVO + low-dose IPI had robust, durable clinical benefit and was well tolerated as 1L therapy for MSI-H/dMMR mCRC (median follow-up 13.8 months [mo; range, 9–19]; Lenz et al. Ann Oncol 2018;29:LBA18). Longer follow-up is presented here. Methods: Patients (pts) with MSI-H/dMMR mCRC and no prior treatment for metastatic disease received NIVO 3 mg/kg Q2W + low-dose IPI 1 mg/kg Q6W until disease progression or discontinuation. The primary endpoint was investigator-assessed (INV) objective response rate (ORR) per RECIST v1.1. Results: In 45 pts with median follow-up of 29.0 mo, ORR (95% CI) increased to 69% (53–82) (Table) from 60% (44.3–74.3); complete response (CR) rate increased to 13% from 7%. The concordance rate of INV and blinded independent central review was 89%. Median duration of response (DOR) was not reached (Table). Median progression-free survival (PFS) and overall survival (OS) were not reached, and 24-mo rates were 74% and 79%, respectively (Table). Nineteen pts discontinued study treatment without subsequent therapy. An analysis of tumor response post discontinuation will be presented. Ten (22%) pts had grade 3–4 treatment-related adverse events (TRAEs); 3 (7%) had grade 3–4 TRAEs leading to discontinuation. Conclusions: NIVO + low-dose IPI continued to show robust, durable clinical benefit with a deepening of response, and was well tolerated with no new safety signals identified with longer follow-up. NIVO + low-dose IPI may represent a new 1L therapy option for pts with MSI-H/dMMR mCRC. Clinical trial information: NTC02060188 . [Table: see text]

Bortezomib-Melphalan-Prednisone-Thalidomide Followed by Maintenance With Bortezomib-Thalidomide Compared With Bortezomib-Melphalan-Prednisone for Initial Treatment of Multiple Myeloma: Updated Follow-Up and Improved Survival

2014 ◽  
Vol 32 (7) ◽  
pp. 634-640 ◽  
Author(s):  
Antonio Palumbo ◽  
Sara Bringhen ◽  
Alessandra Larocca ◽  
Davide Rossi ◽  
Francesco Di Raimondo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Response Rate ◽  
Complete Response Rate ◽  
Progression Free Survival ◽  
Complete Response ◽  
Free Survival ◽  
Grade 3 ◽  
To Receive

Purpose Bortezomib-melphalan-prednisone (VMP) has improved overall survival in multiple myeloma. This randomized trial compared VMP plus thalidomide (VMPT) induction followed by bortezomib-thalidomide maintenance (VMPT-VT) with VMP in patients with newly diagnosed multiple myeloma. Patients and Methods We randomly assigned 511 patients who were not eligible for transplantation to receive VMPT-VT (nine 5-week cycles of VMPT followed by 2 years of VT maintenance) or VMP (nine 5-week cycles without maintenance). Results In the initial analysis with a median follow-up of 23 months, VMPT-VT improved complete response rate from 24% to 38% and 3-year progression-free-survival (PFS) from 41% to 56% compared with VMP. In this analysis, median follow-up was 54 months. The median PFS was significantly longer with VMPT-VT (35.3 months) than with VMP (24.8 months; hazard ratio [HR], 0.58; P < .001). The time to next therapy was 46.6 months in the VMPT-VT group and 27.8 months in the VMP group (HR, 0.52; P < .001). The 5-year overall survival (OS) was greater with VMPT-VT (61%) than with VMP (51%; HR, 0.70; P = .01). Survival from relapse was identical in both groups (HR, 0.92; P = .63). In the VMPT-VT group, the most frequent grade 3 to 4 adverse events included neutropenia (38%), thrombocytopenia (22%), peripheral neuropathy (11%), and cardiologic events (11%). All of these, except for thrombocytopenia, were significantly more frequent in the VMPT-VT patients. Conclusion Bortezomib and thalidomide significantly improved OS in multiple myeloma patients not eligible for transplantation.

scholarly journals Impact of Early Switching to Nilotinib As Second Line TKI in Patients with Chronic Myeloid Leukemia Who Were Intolerant to, Suboptimal to and Failed Imatinib: The Thai Multi-Centered Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4267-4267
Author(s):  
Pongtep Viboonjuntra ◽  
Arnuparp Lekhakula ◽  
Kanchana Chansung ◽  
Chittima Sirijerachai ◽  
Pimjai Niparuck ◽  
...  
Keyword(s):  
Overall Survival ◽  
Adverse Events ◽  
Real Life ◽  
Progression Free Survival ◽  
Second Line ◽  
Free Survival ◽  
Kaplan Meier ◽  
Grade 3 ◽  
The Impact

Abstract Introduction : To date, the ELN recommendation and NCCN guidelines are the principle mile stones to follow up the treatment response and to make the decision of TKIs switching. However, in real life practice, many factors influence changing the real switching date from the date had an indication. This study aims to analyze the impact of early switching to second line TKI, nilotinib, in real life practice, for the CML patients who failed, had sub-optimal response or were intolerant to imatinib. Methods : This prospective study was conducted through 7 medical centers in Thailand between 1st of September 2009 and 31st of August 2011. Adult CML patients of age ≥ 18 years old, in chronic and accelerated phase, who had failure, suboptimal response or intolerance to imatinib, based on ELN 2009 guideline, were included and were eligible with nilotinib 400 mg twice daily. Prospective data collection for 24 months of each patient was performed. The main objective was to identify the impact of early switching to nilotinib on major molecular response (MMR). The other objectives were to observe the efficacy of nilotinib including overall survival, progression free survival and the safety. The survival results were presented as Kaplan-Meier survival curves. For the comparison of the treatment groups, the Kaplan-Meier estimator with the corresponding log-rank test for equality of survivor functions across treatment group was applied. Results : The final 108 cases were analysed. The median age was 47 (17-79) years with the proportion of male to female of 1.4:1 respectively. The median duration of the prior imatinib treatment was 18 months (2-142 months). The median duration between the date of indication and the date of real switching was 3.1 months (0-62.8 months) with 50% changing less than 3 months, 26.9% between 3 months and 12 months, and 23.1% changing longer than 12 months. The indication of switching included 63.6% failure to imatinib, 29% intolerance to imatinib and 7.4% suboptimal to imatinib. On the nilotinib switching, 70.4% completed 24 months follow-up, and 29.6% discontinued treatment mostly because of unsatisfactory results or adverse events. Evaluation was made every 3 months based on 2009 ELN recommendation. At 3 months, 57%, 20%, and 8% of the patients achieved CHR, CCyR and MMR, respectively. Those who did not achieve CHR at 3 months never achieved MMR, while 86 % of those who achieved CCyR at 3 months achieved MMR. All CML achieving MMR at 3 months had sustained MMR throughout the study period (24 months). Imatinib suboptimal response had better outcome than imatinib failure and imatinib intolerance groups. A preliminary analysis of BCR-ABL mutation was performed on 90 cases, and mutations were found on 21 cases. Two of them were T315I which were excluded from the study. The cases with mutation had poorer response to treatment than those without mutation. There was one case with initial G250E mutation developing T315I mutation after treatment with nilotinib. At 24 months, one case progressed to accelerated phase and 3 cases progressed to blastic transformation. The 2-year overall survival and 2-year progression-free survival and were 98.9% and 96.9% (figure 1 and 2), respectively. The interquatile analysis was done to identify the groups of cumulative MMR according to the duration between the date of indication and the date of real switching to nilotinib. The patients who switched to nilotinib within 12 months after date of indication could have a greater chance to achieved MMR than those who switched treatment later than 12 months (p(log-rank) = 0.002) (figure 3). Skin rash, musculoskeletal pain, and infection were the three most common non-hematologic adverse events, However, most of them were grade 1-2, except for 4 cases with grade 3-4 infections. Grade 3-4 hematologic adverse events included thrombocytopenia (12%), neutropenia (11%), anemia (5%) and leucopenia (4%), and most of them were manageable. Although biochemical abnormalities were commonly found, most of them were mild. Conclusions : Nilotinib, as a second line treatment showed excellent efficacy and tolerability. Indication for nilotinib treatment, initial mutation status and depth of response at 3 months after treatment can predict outcomes of the patients. However, the patients will have a greater chance to achieve MMR if they switched to nilotinib within 12 months after the date of indication for changing. Disclosures No relevant conflicts of interest to declare.

scholarly journals Effect of Timing and Duration of Maintenance Lenalidomide in Myeloma Patients after Autologous Stem Cell Transplantations

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 194-194
Author(s):  
Idrees Mian ◽  
Denai Milton ◽  
Uday R. Popat ◽  
Nina Shah ◽  
Yago Nieto ◽  
...  
Keyword(s):  
Overall Survival ◽  
Maintenance Therapy ◽  
Research Funding ◽  
Maintenance Treatment ◽  
Progression Free Survival ◽  
Disease Status ◽  
Hazard Ratio ◽  
P Value ◽  
Free Survival ◽  
Late Initiation

Abstract Introduction: Maintenance lenalidomide after autologous hematopoietic stem cell transplantation (auto HCT) has been shown to improve progression free (PFS) and overall survival (OS) in myeloma patients. In this analysis we sought to determine the impact of lenalidomide treatment on achievement of complete remission (CR), survival and the incidence of secondary primary malignancies (SPM). Methods: We retrospectively analyzed all (N=466) consecutive myeloma patients who underwent auto HCT and received maintenance lenalidomide between August 2006 and September 2013 at our institution. Patients received doses of maintenance lenalidomide ranging from 5 mg – 15 mg/day or every other day. We looked at whether lenalidomide improved disease status, specifically CR in patients who had not achieved this before maintenance initiation and the median time to achieve CR. We also analyzed the effects of early initiation (<4-months after auto HCT) of maintenance lenalidomide versus late initiation (≥ 4-months after auto HCT) with regards to PFS and OS using the Kaplan-Meier method. Lastly we assessed if continuation of maintenance therapy beyond 2 and 3-years after auto HCT improved PFS and OS and increased the incidence of SPM. Results: The median follow-up time for all patients was 26.6 months. 173 patients (37%) experienced improvements in their disease status. Of these, 86 patients (50% of those with noted improvements and 19% of total patients assessed) who were not in CR before maintenance achieved CR while on maintenance. The average time to achieve CR in these patients was 12.9 months. Comparing the patients who were started on early maintenance treatment with those who were started on late maintenance therapy, we did not find any difference with regards to PFS (Hazard Ratio [HR]=0.90; p-value=0.57) and OS (HR=0.90; p-value=0.74). However, patients who had been on lenalidomide for > 2 years experienced a significant benefit in OS compared with those on lenalidomide for ≤ 2 years (HR=0.36; p-value=0.0015), although no difference in PFS was observed between the two cohorts (HR=0.77; p-value=0.18). A similar trend in OS was seen for patients who had been on lenalidomide > 3 years compared with those on maintenance treatment ≤ 3 years, though not statistically significant (HR=0.47; p-value=0.10). Again, no difference in PFS was noted between the two groups. Lastly there were only 12 cases of SPM reported in all patients assessed with no statistically significant association to the duration of lenalidomide use. In all 12 cases, lenalidomide was suspended and the mortality among these patients was 50%. Conclusions: Maintenance lenalidomide improves response rates after auto HCT in some patients including the CR rate, however, the median time to achieve CR in these patients is approximately 13 months. The patients who received maintenance therapy for > 2years had a significantly lower risk of death with a trend of improved OS in patients who continued maintenance therapy beyond 3-years. We conclude that the maintenance therapy should be continued for at least 2 years and possibly longer after auto HCT. Table 1 Summary of Survival Outcomes Maintenance Treatment Initiation Measure Early (N=155) Late (N=184) p-value Progression-free survival Hazard ratio (95% CI)a 0.90 (0.63, 1.30) 0.57 Overall survival Hazard ratio (95% CI)a 0.90 (0.49, 1.66) 0.74 Duration of Maintenance Treatment Measure > 2 years (N=115) ≤ 2 years (N=224) p-value Progression-free survival Hazard ratio (95% CI)b 0.77 (0.52, 1.13) 0.18 Overall survival Hazard ratio (95% CI)b 0.36 (0.19, 0.67) 0.0015 > 3 years (N=49) ≤ 3 years (N=290) p-value Progression-free survival Hazard ratio (95% CI)b 0.75 (0.45, 1.26) 0.28 Overall survival Hazard ratio (95% CI)b 0.47 (0.19, 1.15) 0.10 a Cox proportional hazards regression model: measure included as a baseline covariate with the following additional covariates: patient’s cytogenetic risk, creatinine, hemoglobin, B2-microglobulin, ISS stage at diagnosis, disease status at auto HCT, and response prior to auto HCT. b Cox proportional hazards regression model: measure included as a time-dependent covariate with the covariates listed above. Figure 1 Comparison of Overall Survival in Early vs Late initiation of Revlimid Figure 1. Comparison of Overall Survival in Early vs Late initiation of Revlimid Figure 2 Overall Survival – All Patients Figure 2. Overall Survival – All Patients Disclosures Shah: Novartis: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding; Array: Consultancy, Research Funding. Orlowski:Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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