Similar Efficacy and Toxicity Profile for Idarubicine and Mitoxantrone in Induction and Intensification Treatment of Children with Acute Myeloid Leukemia (AML) or Myelodysplasia (MDS): Long-Term Results of the EORTC-CLG Randomized Phase III Trial 58921

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2615-2615 ◽  
Author(s):  
Barbara De Moerloose ◽  
Stefan Suciu ◽  
Martine Munzer ◽  
Caroline Piette ◽  
Karima Yakouben ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Late Onset ◽  
Standard Dose ◽  
Phase Iii ◽  
Long Term Results ◽  
High Dose ◽  
Sibling Donor ◽  
Significant Difference ◽  
Grade 3 ◽  
To Receive

Abstract Abstract 2615 Background: The first EORTC-CLG AML pilot study (58872) demonstrated the efficacy of Mitoxantrone (MTZ), substituted for daunorubicin, in the treatment of childhood AML. The subsequent trial (58921) aimed to compare MTZ and Idarubicin (IDA), an anthracycline with a favorable pharmacokinetic profile (such as good CSF penetration) and suggested to be more efficacious than daunorubicin in adult AML trials performed in the last two decades. Methods: Between March 1993 and December 2002, 227 eligible patients (pts) <18y of age with newly diagnosed AML (N=216) or high risk MDS (RAEB & RAEBt, N=11) were randomized in the EORTC phase III 58921 trial to receive either IDA or MTZ in induction and 1st intensification course, each at a dose of 10 mg/m2/d for 3 days in both courses. Concomitant chemotherapy consisted of standard dose Cytarabine (AraC) and Etoposide (Eto) in induction and high-dose AraC (18–36 g/m2) in 1st intensification. Allogeneic stem cell transplantation after 1st intensification was recommended for pts who achieved CR and had an HLA-identical sibling donor. Patients in CR without donor had to receive a 2nd (DCTER = continuous infusion of standard dose AraC, Daunorubicin 4x 20 mg/m2/d, Eto, Dexamethasone, 6-thioguanine) and 3rd intensification course (high dose AraC 12 g/m2 + Eto), followed by maintenance therapy (6-Thioguanine daily + AraC 4 days/month) for 12 months. CNS irradiation after the 3rd intensification for patients with initial WBC counts >=70×10E9/L was abandoned from November 1994 on. Randomization was done centrally. The primary endpoint was EFS; secondary endpoints were OS, CR rate after induction/1st intensification, DFS and toxicity. Intention-to-treat analysis was used. Results: A total of 112 and 115 eligible pts were randomly assigned to receive IDA and MTZ, respectively. The rate of CR after two courses was 79.5% (IDA) vs 85.2% (MTZ). At an overall median follow-up of 9.9 y (range 0.25–16 y), there were 65 vs 59 events in the IDA vs MTZ group: failure to achieve CR (23 vs 17), relapse (35 vs 40), and death without relapse (7 vs 2). The 5-year EFS rate was 42.0% (SE 4.7%) in the IDA group and 48.4% (SE 4.7%) in the MTZ group (hazard ratio (HR) = 1.20, 95% CI 0.84–1.71, 2-sided log rank p=0.29). The 5-year OS rate was comparable in both treatment arms: 59.8% (SE 4.6%) in the IDA group and 57.5% (SE 4.7%) in the MTZ group (HR = 1.03, 95% CI 0.70–1.54, 2-sided log rank p=0.87). In CR patients with (N=46/187) or without (N=141/187) an HLA-identical sibling donor, the 5-year DFS rate from CR was 65.1% (SE 7.1%) and 51.5% (SE 4.2%) respectively (HR=0.65, 95% CI 0.37–1.11, 2-sided log rank p=0.11) and the 5-year OS rate 78.0% (SE 6.1%) and 60.7% (SE 4.1%) respectively (HR=0.53, 95% CI 0.28–1.01, 2-sided log rank p=0.048). This advantage for patients with a donor remained important regarding both DFS (HR=0.60, p=0.07) and OS (HR=0.49, p=0.03), even after adjustment for WBC count at diagnosis, age, cytogenetic features and randomized arm. The interval between start of induction and start of 1st intensification was similar in both arms (median 5.2 weeks). Grade 3–4 infection following the induction course was 37.5% (IDA) vs 25.4% (MTZ); incidence of fever grade 3–4 was 25% (IDA) vs 22.8% (MTZ). In this trial, the cumulative anthracycline dosage (conversion factor 5) was 380 mg/m2. Acute and late-onset cardiotoxicity was comparable in both treatment arms. Conclusion: There was no significant difference in efficacy and in toxicity between the two randomized treatment groups, IDA versus MTZ, although grade 3–4 infection rate following the induction course was slightly higher in the IDA arm. Patients who reached CR and who had a HLA compatible sibling donor had a longer DFS and OS than pts without a donor. Disclosures: No relevant conflicts of interest to declare.

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 ◽  
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.

Alemtuzumab Plus Oral Dexamethasone, Followed by Alemtuzumab Maintenance or Allogeneic Transplantation in Ultra High-Risk CLL: Interim Analysis of a Phase II Study of the GCLLSG and fcgcll/MW

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2854-2854 ◽  
Author(s):  
Stephan Stilgenbauer ◽  
Florence Cymbalista ◽  
Véronique Leblond ◽  
Alain Delmer ◽  
Dirk Winkler ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Response Rates ◽  
Long Term Results ◽  
High Dose ◽  
Significant Difference ◽  
Ultra High Risk ◽  
Grade 3 ◽  
The Impact

Abstract Abstract 2854 Alemtuzumab (A) proved to be efficacious in CLL patients (pts) with very poor prognosis, either due to fludarabine (F) refractoriness or due to unfavorable cytogenetics (17p-). However, rate and duration of remissions still remain unsatisfactory. Therefore, the French and German CLL study groups jointly embarked on this trial, trying to achieve higher overall response rates (ORR) by adding high-dose dexamethasone (D) to A and, simultaneously, investigating the consolidation effect of prolonged A maintenance or allogeneic stem-cell transplantation (allo-SCT), respectively. Induction treatment consisted of subcutaneous A 30 mg weekly × 3 for 28 days, combined with oral D 40 mg on days 1–4 and 15–18, and prophylactic pegfilgrastim 6 mg on days 1 and 15. Depending on the remission status, pts were treated for up to 12 weeks. If CR was documented at 4 or 8 weeks, or at least SD was achieved at 12 weeks, consolidation was scheduled with either allo-SCT or A maintenance with 30 mg every 14 days for up to 2 years (y), at the discretion of pt and physician. Between January 2008 and July 2011, 124 pts were recruited at 26 centers, 120 of whom were eligible. Pts were generally subdivided into three cohorts: 55 pts were refractory (i.e. no response or relapse within 6 months) to regimens containing F or a similar drug (i.e. pentostatin, cladribine, bendamustine). Non-refractory pts all exhibited 17p- and had either untreated (n=39) or relapsed CLL (n = 26) requiring therapy. The median age was high with 66/64/66 y in 17p- 1st line, 17p- relapse, and F-refractory pts, respectively. The three cohorts had 46/54/75% Binet C disease, 41/35/27% B symptoms, 38/42/53% reduced performance status (ECOG 1/2), median thymidine kinase levels of 35/49/24 U/L, median ß2MG levels of 3.8/5.5/4.6 mg/L, and IGHV was unmutated in 89/96/87%. In the F-refractory group, 53% exhibited 17p deletion and 22% had 11q deletion. Pretreated patients had received a median of 3 (F-refractory) or 2 prior lines (17p- relapse). 5 pts had previously undergone autologous and 1 pt allo-SCT. Treatment and efficacy data are currently available for 87 pts who completed induction therapy :17p- 1st-line (n=30), 17p- relapse (n=17), and F-refractory (n=40). Of these, 80/53/55% received the full induction of 12 weeks. ORR (best observed status) was generally high with 97/76/70%. CR was achieved in 20/0/5%. After a median follow-up of 11.8 months (mo), median progression-free survival (PFS) was 16.9/10.4/8.4 mo. Deaths are recorded in 13/27/36% of pts, with median overall survival (OS) not yet reached (>24 mo) in the 17p- 1st line group, and 15/12 mo in 17p- relapse/F-refractory pts. Consolidation treatment was performed as maintenance A (median duration 32 weeks, range 2 – 89) in 34%, and allo-SCT in 30%, with a median age of 66 and 61 y in these subgroups. The main reasons for going off-study without consolidation were death due to infection (14%, n=11, of these 6 without response, and 10 in the F-refractory cohort), CLL progression (12%), and other toxicity (5%). Among the 28 pts not receiving consolidation, there were 19 (68%) deaths, 15 of them in the F-refractory cohort. When comparing A maintenance and allo-SCT for consolidation, there were 9 (35%) and 7 (30%) PD events, respectively and there was so far no significant difference in PFS (median 17 mo in both groups) or OS. During induction, grade 3/4 hematotoxicity consisted of anemia in 28%, neutropenia in 47%, and thrombopenia in 44%. Grade 3/4 non-CMV infection occurred in 29% of 17p- 1st-line, 15% of 17p- relapsed, and 56% of F-refractory pts. CMV reactivation was observed in 54/25/40%, without severe sequelae recorded. During A maintenance, grade 3/4 toxicity consisted of neutropenia in 39% pts and thrombopenia in 4% pts with 6 SAEs (ITP, diarrhea, infection, erythema, tachycardia, and thrombosis). Conclusions: The combination of A and D shows high response rates in ultra high-risk CLL, with promising preliminary findings for PFS and OS, despite the high median age of the pts. The results compare favorably to ORR/CR of 68%/5%, and median PFS of 11.3 mo in the 17p- subgroup of the CLL8 study treated with FCR, consisting of younger pts (median 61 y). In F-refractory CLL however, when compared to the preceding CLL2H study with single agent A, the improved initial response by adding dexamethasone does not seem to translate into improved long-term results. More mature follow-up is needed, especially with respect to the impact of allo-SCT. Disclosures: Stilgenbauer: Amgen: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding. Off Label Use: Alemtuzumab in 1st line CLL treatment. Cymbalista:Roche (d) Mundipharma (e) Genzyme (e): Honoraria, Research Funding. Hinke:WiSP (CRO): Employment.

Randomized Comparison of Standard Induction with Daunorubicin (DNR) for 3 Days vs Idarubicin (IDA) for 3 or 4 Days in AML pts Aged 50 to 70 and of Maintenance with Interleukin 2. Final Analysis of the ALFA 9801 Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 162-162 ◽  
Author(s):  
Cecile Pautas ◽  
Xavier Thomas ◽  
Fatiha Merabet ◽  
Emmanuel Raffoux ◽  
Jean Henri Bourhis ◽  
...  
Keyword(s):  
Interleukin 2 ◽  
Final Analysis ◽  
Risk Groups ◽  
Salvage Chemotherapy ◽  
Phase Iii ◽  
High Dose ◽  
Duration Of Hospitalization ◽  
High Doses ◽  
Grade 3 ◽  
To Receive

Abstract Background: For many years the ALFA Group has used high dose DNR, i.e 80 mg/m2/day for 3d as part of the induction regimen for untreated adult AML pts. As the equivalence of DNR and Ida is not known we conducted a phase III study to compare high dose DNR to Ida. We also tested the effect of IL2 for maintenance. Methods: Newly diagnosed AML, aged 50 to 70 years, were randomized to receive AraC 200 mg/m2/day IV x 7 d with either DNR: 80 mg/m2/d x 3 d (arm 1) or Ida: 12 mg/m2/d x 3 d (arm 2) or x 4 d (arm 3). Pts who failed could receive a salvage course with Mitoxantrone x 2 d and AraC1g/m2 12 hrs x 4d. Response was assessed after induction+/− salvage chemotherapy. CR pts received 2 consolidation courses according to the induction arm with DNR: 80 mg/m2 or Ida:12 mg/m2 for 1 day (first course) or 2 days (2nd course) and AraC:1g/m2/12 hrs x 4 days. Pts in CCR after the two consolidation courses were randomized to receive or not a maintenance immunotherapy with IL2: 5.106/m2 for 5 days monthly for12 months. Results: From 2001 to 2006, 468 pts were included (median age: 60 years). The 3 treatment arms were well matched for pretreatment characteristics. CR was achieved in 360/468 pts (77%): 109 (70%) pts arm 1, 129 (83%) arm 2, 122 (78%) arm 3 (p=0.02).70 pts, (45%) pts in the DNR arm reached CR after 1 course vs 97 (62%) and 90 (57%) in Ida arms (p= 0.006). Pts in Ida arms experienced more grade 3 or 4 mucositis (p=0.004) but no differences were observed between the 3 arms for duration of hospitalization, time to PMN or plts recovery, incidence of grade 3 or 4 infectious episodes and treatment related mortality. 3 year cumulative incidence of relapse was 69%, 63%, 62% resp in arms 1,2,3 (p=NS). 3 year EFS was 19%, 30%, 26% resp (p=0.06 for arm 1 vs arms 2 and 3). 3 year OS was 31%, 40% 41% resp in arms 1,2,3 (p=NS). Age (&lt; or &gt;60 years), sex, initial WBC counts, initial LDH (nl or &gt;nl), DNR or Ida arms, need for a salvage course were not predictive for relapse, while 2yCIR was 43%, 64%, 77% among respectively fav, intermediate and unfav cytogenetic risk groups resp (p=0.0046). Of the 219 pts alive in CR after consolidations, 161 (73%) were randomized for maintenance. Only 22 of the 77 pts randomized for IL2 completed the 1 year treatment. 32 and 23 pts stopped IL2 resp because of relapse or intolerance. There were no differences in relapse or OS in both maintenance arms. Conclusion: Ida treatment even when compared to high doses of DNR yields higher CR rate and more CR after one course. This effect translated in slightly better EFS but not better CIR or OS. IL2 maintenance treatment at least as scheduled in this trial was difficult to apply and showed no impact on disease course.

Single Versus Tandem High Dose Therapy (HDT) Supported with Autologous Blood Stem Cell (ABSC) Transplantation Using Unselected or CD34-Enriched ABSC: Long-Term Results of a Two by Two Designed Randomized Trial in 225 Young Patients with Multiple Myeloma (MM). for the Group “Myelome-Autogreffe”, Caen, Creteil, Limoges, Paris, Strasbourg, France.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2320-2320 ◽  
Author(s):  
Jean-Paul Fermand ◽  
Kristell Desseaux ◽  
Jean Pierre Marolleau
Keyword(s):  
Randomized Trial ◽  
Disease Progression ◽  
Conflicts Of Interest ◽  
Autologous Blood ◽  
Prospective Trial ◽  
Early Death ◽  
Long Term Results ◽  
High Dose ◽  
Significant Difference

Abstract Abstract 2320 Poster Board II-297 In 1996, we initiated a multicenter prospective trial where patients aged under 56 with newly diagnosed symptomatic MM were randomly assigned up-front to receive either a single HDT (HDT1) or two sequential HDT (HDT2). In addition, all patients were independently randomized to be transplanted with unselected ABSC (unselected arm) or CD34-enriched ABSC (CD34 arm). We presented here updated data of this factorial 2*2 design trial, based on a median follow-up of 123 months.In all cases, patients first received one or 2 courses of high dose steroid containing regimens and ABSC were thereafter mobilized by cytoxan (CTX) (4 g/m2) and lenograstim (10 mg/kg/d). When appropriate (CD34 arm), part of collected ABSC were selected using the Isolex®300i system. The selection procedure resulted in a median purity of 95% (65-100) and in a more than two log tumor cell depletion. In the HDT1 arm, HDT was preceded by 3 monthly courses of a VAD-like regimen and combined a multi-drug regimen (carmustine, etoposide, melphalan 140 mg/m2 (MLP 140) and CTX 60 mg/kg) with a TBI (12 grays in 6 fractions). Patients treated in the HDT2 arm received MLP 140 alone (always supported by unselected ABSC) followed 2 to 3 months later by a second MLP 140 combined with etoposide (30 mg/kg) and 12-gray TBI. In both arms, TBI including HDT were supported with unselected or CD34 enriched ABSC. Two hundred and twenty-five patients were included in the study. Baseline characteristics of the four groups were close. All analyses were performed in intent to treat basis. In HDT groups, treatment completion rates were satisfactory, with 6/112 transplants not performed in the HDT1 group (allotransplant n=1, refusal n=1, mobilisation failure n=1, early death due to disease progression n=3) and 9/113 second transplant not performed in the HDT2 group (allotransplant n=2, mobilisation failure n=3, relapse post first transplant n=1, early death due to disease progression n=3). In the HDT1 and HDT2 groups, median time to TBI-including transplant was 4 months and 4.5 months, respectively.Present analysis did not show any significant difference in terms of early mortality, disease response and outcome of patients included in the two HDT groups. Early death rates (within 9 months post randomization, including toxic deaths and fatal progressive diseases) were 12% and 7% in the HDT1 and the HDT2 arms, respectively. At one year post-randomization, 32 (35 %) patients in the HDT1 and 32 (37 %) patients in the HDT2 groups were still in unmaintained CR or VGPR. The 2 OS curves were not statistically different (p= 0.60 by the log rank test), neither the EFS curves (p= 0.61). There was no significant interaction between selection CD34 and HDT in terms of outcomes. There was no evidence for benefit of CD34 selection as compared to the use of unselected ABSC. Of note, in the CD34 selected group, incidence of severe infections was increased. In conclusion, with a 10-years median follow-up, results of this randomized trial did not show any significant benefit of single HDT versus tandem HDT. Disclosures: No relevant conflicts of interest to declare.

A Retrospective Real-Life Analysis of Chronic Myeloid Leukemia Patients in Suboptimal Response to Imatinib

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4446-4446
Author(s):  
Dario Ferrero ◽  
Elena Crisà ◽  
Marco Cerrano ◽  
Mario Boccadoro ◽  
Francesca Pirillo ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Standard Dose ◽  
Real Life ◽  
Significant Risk ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
High Dose ◽  
Significant Difference ◽  
Response Detection

Abstract Abstract 4446 Life expectancy of CML patients has greatly improved in tyrosine-kynase inhibitor (TKI) era, but still some questions remain about the management of suboptimal responders (SR) to imatinib standard dose. This group of patients appears to be heterogeneous, with significant differences in terms of event-free survival between cytogenetic SR and molecular SR (Alvarado et al, Cancer 2009) European Leukemia Net (ELN) recommendations did not clarify those differences and there isn't a clear agreement on SR: maintaining imatinib at standard or higher dose or switching to another TKI are all considered acceptable options (Baccarani et al, JCO 2009). We retrospectively analyzed 63 CML patients, diagnosed in chronic phase between 1988 and 2011, SR to imatinib 400 mg/d, treated according to the 3 different ELN options. Fifty-two patients received imatinib front line and 11 had been previously treated with an interferon based therapy. Sokal score, evaluable in 44 patients, was high in 7, intermediate in 24 and low in 12, respectively. Twenty-five patients were cytogenetic SR and 38 molecular SR. The median follow-up from diagnosis was 76 months (range 10–292). At suboptimal response detection 47 patients (74%) continued imatinib 400 mg/d (30 of them afterword switched to high dose imatinib or new TKI), 12 patients (19%) increased imatinib dose to 600 mg/d (7) or 800 mg/d (5) (8 of them later changed TKI) and only 4 patients switched immediately to new TKI. Twenty-three percent of the 47 patients who continued imatinib 400 mg/d obtained a stable complete cytogenetic response (CCyR) and major molecolar response (MMR) while 27% underwent to a failure. Globally thirty-tree SR patients increased imatinib dose, 36% at suboptimal response detection and 64% after a median of further 12 months of standard dose treatment (range 3–50): 48% of them obtained a durable CCyR and MMR. Twenty-six evaluable patients switched to new TKI (9 to nilotinib and 17 to dasatinib), 13 after high dose imatinib: 62% of the patients achieved a stable CCgR and MMR. Both high dose imatinib and new TKI were significantly more effective in achieving CCyR and MMR than maintaining imatinib 400 mg/d (p<0,05). Considering separately the subgroup of cytogenetic SR patients, a stable CcyR has been reached by 35% of patients continuing imatinib standard dose, by 50% of the patients who increased imatinib dose and by the totality of the patients treated with new TKI (option significantly superior to the other two, p<0,05). Among molecular SR, 26% of the patients obtained a stable MMR with imatinib 400 mg/d, 52% with imatinib 600 or 800 mg/d and 63% switching to new TKI. The difference was statistically significant between new TKI and imatinib 400 standard dose only (p<0,05). Cytogenetic SR maintained at imatinib 400 mg/d had a higher risk of event (defined as loss of hematologic or cytogenetic response or death) compared to molecular SR (40% vs 5%, p<0,01), although at the last follow-up, after a change in therapeutical strategy, no difference in response rate was detected between cytogenetic and molecular SR (68% vs 71%) in stable CCyR and MMR. Two patients progressed to accelerated phase (clonal evolution) but then obtained an optimal response after switching to new TKI; 2 patients died of unrelated disease. Among the 61 living patients, 71% was in MMR, 26% in CCyR only and 3% didn't reach CCyR (for these patients the efficacy of the therapeutic change is not evaluable yet). In our casistics cytogenetic SR had a higher risk of negative events than molecular SR, as reported in literature, although they obtained similar responses after changing therapeutic strategy. No clear advantage in maintaining imatinib 400 mg/d after suboptimal response was observed, since it led to a few optimal responses and was associated with a significant risk of treatment failure. Imatinib dose increment might represent a more reasonable option, at least for molecular SR. Considering the global casistic no significant difference in response rates were found between new TKI and high dose imatinib even if dasatinib and nilotinib showed a trend towards a superior efficacy in patients mostly unresponsive to the last option, suggesting that an earlier switch to new TKI might further increase the proportion of optimal responders. For cytogenetic SR the switch to new TKI brought better results than those obtained with high dose imatinib: therefore it seems to be the best choice in this subgroup of patients. Disclosures: No relevant conflicts of interest to declare.

Randomized Phase II Evaluation of 6 g/m2 of Ifosfamide Plus Doxorubicin and Granulocyte Colony-Stimulating Factor (G-CSF) Compared With 12 g/m2 of Ifosfamide Plus Doxorubicin and G-CSF in the Treatment of Poor-Prognosis Soft Tissue Sarcoma

2005 ◽  
Vol 23 (1) ◽  
pp. 105-112 ◽  
Author(s):  
Francis P. Worden ◽  
Jeremy M.G. Taylor ◽  
Janet S. Biermann ◽  
Vernon K. Sondak ◽  
Kirstin M. Leu ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Standard Dose ◽  
Disease Free Survival ◽  
High Dose ◽  
First Line Therapy ◽  
Significant Difference ◽  
Outcome Differences ◽  
Grade 3 ◽  
Combination Regimens

Purpose The relative value of increasing ifosfamide dose in combination chemotherapy for patients with soft tissue sarcoma (STS) is unclear. The purpose of this study was to compare the efficacy and toxicity of doxorubicin with high-dose (HD) ifosfamide or standard-dose (SD) ifosfamide in patients with STS. Patients and Methods Chemotherapy-naive patients with STS were randomly assigned to receive doxorubicin 60 mg/m2 and either SD ifosfamide (1.5 g/m2/d, days 1 through 4) or HD ifosfamide (3.0 g/m2, days 1 through 4) every 21 days. Patients were stratified by the presence or absence of metastatic disease. End points were overall survival (OS), 1-year disease-free survival (DFS), and toxicity. Results The study group consisted of 79 patients (52 patients with localized disease and 27 patients with metastases). Both groups were well-balanced with respect to known prognostic factors. There was no significant difference in 1-year DFS comparing SD ifosfamide with HD ifosfamide (55% v 52%; P = .81). For SD ifosfamide, 2- and 3-year OS were 73% and 52% versus 57% and 49% for HD ifosfamide (P = .34). The incidence of grade 3/4 neutropenia, anemia, and thrombocytopenia were 49%, 23%, and 10%, respectively, on the SD ifosfamide arm, compared with 88%, 58%, and 63%, respectively, on the HD ifosfamide arm. There were five early deaths, all on the HD ifosfamide arm. Conclusion When combined with doxorubicin, HD ifosfamide did not improve 1-year DFS and OS. Toxicity was clearly greater with the HD ifosfamide arm, and lack of outcome differences might be explained by toxicities with HD ifosfamide. These results suggest that HD ifosfamide combination regimens should not be used as first-line therapy for patients with STS.

Phase III Randomized Trial of FOLFIRI Versus FOLFOX4 in the Treatment of Advanced Colorectal Cancer: A Multicenter Study of the Gruppo Oncologico Dell’Italia Meridionale

2005 ◽  
Vol 23 (22) ◽  
pp. 4866-4875 ◽  
Author(s):  
Giuseppe Colucci ◽  
Vittorio Gebbia ◽  
Giancarlo Paoletti ◽  
Francesco Giuliani ◽  
Michele Caruso ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Bolus Injection ◽  
Advanced Colorectal Cancer ◽  
Phase Iii ◽  
Significant Difference ◽  
Duration Of Response ◽  
Phase Iii Study ◽  
The Difference ◽  
Grade 3 ◽  
To Receive

Purpose We performed this phase III study to compare the irinotecan, leucovorin (LV), and fluorouracil (FU) regimen (FOLFIRI) versus the oxaliplatin, LV, and FU regimen (FOLFOX4) in previously untreated patients with advanced colorectal cancer. Patients and Methods A total of 360 chemotherapy-naive patients were randomly assigned to receive, every 2 weeks, either arm A (FOLFIRI: irinotecan 180 mg/m2 on day 1 with LV 100 mg/m2 administered as a 2-hour infusion before FU 400 mg/m2 administered as an intravenous bolus injection, and FU 600 mg/m2 as a 22-hour infusion immediately after FU bolus injection on days 1 and 2 [LV5FU2]) or arm B (FOLFOX4: oxaliplatin 85 mg/m2 on day 1 with LV5FU2 regimen). Results One hundred sixty-four and 172 patients were assessable in arm A and B, respectively. Overall response rates (ORR) were 31% in arm A (95% CI, 24.6% to 38.3%) and 34% in arm B (95% CI, 27.2% to 41.5%; P = .60). In both arms A and B, median time to progression (TTP; 7 v 7 months, respectively), duration of response (9 v 10 months, respectively), and overall survival (OS; 14 v 15 months, respectively) were similar, without any statistically significant difference. Toxicity was mild in both groups: alopecia and gastrointestinal disturbances were the most common toxicities in arm A; thrombocytopenia and neurosensorial were the most common toxicities in arm B. Grade 3 to 4 toxicities were uncommon in both arms, and no statistical significant difference was observed. Conclusion There is no difference in ORR, TTP, and OS for patients treated with the FOLFIRI or FOLFOX4 regimen. Both therapies seemed effective as first-line treatment in these patients. The difference between these two combination therapies is mainly in the toxicity profile.

Improvement in Treatment Outcome and Identification of a New Prognostic Parameter in Down Syndrome Acute Myeloid Leukemia (DS-AML): Results of the Children’s Oncology Group (COG) Phase III AAML0431 Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 278-278 ◽  
Author(s):  
Jeffrey W Taub ◽  
Jason N Berman ◽  
Johann K. Hitzler ◽  
April D. Sorrell ◽  
Norman J. Lacayo ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Residual Disease ◽  
Heart Defects ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Cardiac Complications ◽  
High Dose ◽  
Significant Treatment ◽  
Free Survival ◽  
Grade 3

Abstract Background: DS-AML patients (<4 years of age), have favorable outcomes compared to non-DS AML patients. However, DS patients experience significant treatment-related morbidity and mortality due to infectious and cardiac complications. Blast cells from DS-AML patients reportedly have increased sensitivity to cytarabine (araC) and daunorubicin, suggesting that optimization of drug dosing may improve outcomes and/or reduce toxicity. Objective: The main objectives of the AAML0431 study were to determine whether high-dose (HD)-araC) administered earlier during treatment could improve EFS rates, and whether EFS rates could be maintained despite reducing the cumulative daunorubicin dose and the number of intrathecal treatments. The study also aimed at determining the clinical significance of minimal residual disease (MRD) in this AML subgroup. Methods: AAML0431 consisted of 4 cycles of induction and 2 of consolidation therapy based on a backbone of the previous COG A2971 trial with several modifications including the use of HD-araC for Induction II rather than during Intensification therapy (fifth cycle of therapy), a 25% reduction in the cumulative daunorubicin dose and a decrease in the number of intrathecal treatments from 7 to 2. The recommended criteria for proceeding to each subsequent cycle of therapy was an absolute neutrophil count ≥1,000/µL and platelets ≥100,000/µL. MRD was measured by a multi-parameter flow cytometry assay capable of detecting 0.01% DS AML blasts. Results: Between March 2007 and December 2011, 205 children (106 females, 99 males) with DS or DS mosaicisim were enrolled. Of the 204 evaluable patients, 144 were classified as having AML and 60 myelodysplastic syndrome (MDS); median age at diagnosis was 1.57 years. Sixty two patients (40 AML, 28%; 22 MDS, 37%) had a prior diagnosis of the transient myeloproliferative disorder (TMD) and 6 had received chemotherapy for TMD. Congenital heart defects were present in 90 (44%) patients. Among AML patients, median white blood cell count (WBC) at diagnosis was 6.5 x 103/µL, peripheral blast percentage 7% and platelet count 34 x 103/µL; for MDS patients, these were 4.85. x 103/µL, 0% and 36.5 x 103/µL, respectively. No patient had CNS leukemia at diagnosis. Institutional reporting of morphology was megakaryocytic leukemia in 85 (42%) of cases. Event-free survival (EFS) from study entry for all eligible patients was 90% ± 4.4% at 3 years; overall survival (OS) was 92.7% ± 3.8% at 3 years, with equivalent results for MDS patients. There were 19 treatment failures: 2 induction failures, 14 relapses and 3 non-relapse deaths. MRD data on day 28 of Induction I was available in 149 patients. Three-year disease-free survival among patients who were MRD-negative (blasts <0.01%) after Induction I (93.5% ± 4.8%; n=125) was significantly higher than that of MRD-positive patients (70.6% ± 18.7%; n=24; log-rank P <.001). The OS at 3 years for the 16 patients with refractory/relapse leukemia was 30% ± 23.6%. There were a total of 1045 adverse events (AEs) classified as grade 3 or higher; 66% of these AEs were reported during the Induction II cycle. No life-threatening cardiac toxicities were reported and overall, only 7 cardiac AEs classified as ≥ Grade 3 were identified. Thirteen patients were electively taken off protocol therapy by request from the treating physician (n=6) or parents (n=7) (Induction I, 4; Induction II, 3; Induction IV, 2; Intensification I, 4), primarily due to experiencing significant toxicities. One patient taken off therapy after Induction II, relapsed and died and another had a non-relapse death after stopping therapy post-Induction I. The remaining patients were reported to be alive. The earlier use of HD-araC in AAML0431 resulted in improvements in EFS and OS compared to past COG studies, while a 25% reduction of the cumulative daunorubicin dose (compared to COG A2971) and limited intrathecal chemotherapy treatments did not adversely impact outcome. In addition, MRD analysis performed after Induction I was identified as a prognostic factor for DS-AML patients for the first time. MRD provides a prospective tool for risk stratification for future trials to identify patients who may benefit from a further reduction in therapy intensity (e.g., elimination of HD-araC), as well as identifying patients with resistant disease who require new treatment options (e.g. treatment intensification, new agents). Disclosures No relevant conflicts of interest to declare.

Dacarbazine, Cisplatin, and Interferon-Alfa-2b With or Without Interleukin-2 in Metastatic Melanoma: A Randomized Phase III Trial (18951) of the European Organisation for Research and Treatment of Cancer Melanoma Group

2005 ◽  
Vol 23 (27) ◽  
pp. 6747-6755 ◽  
Author(s):  
Ulrich Keilholz ◽  
Cornelis J.A. Punt ◽  
Martin Gore ◽  
Wim Kruit ◽  
Poulam Patel ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Single Agent ◽  
Interleukin 2 ◽  
Progression Free Survival ◽  
Interferon Alfa ◽  
Phase Iii ◽  
High Dose ◽  
Phase Iii Trial ◽  
Significant Difference ◽  
To Receive

Background Based on phase II trial results, chemoimmunotherapy combinations have become the preferred treatment for patients with metastatic melanoma in many institutions. This study was performed to determine whether interleukin-2 (IL-2) as a component of chemoimmunotherapy influences survival of patients with metastatic melanoma. Patients and Methods Patients with advanced metastatic melanoma were randomly assigned to receive dacarbazine 250 mg/m2 and cisplatin 30 mg/m2 on days 1 to 3 combined with interferon-alfa-2b 10 × 106 U/m2 subcutaneously on days 1 through 5 without (arm A) or with (arm B) a high-dose intravenous decrescendo regimen of IL-2 on days 5 through 10 (18 × 106 U/m2/6 hours, 18 × 106 U/m2/12 hours, 18 × 106 U/m2/24 hours, and 4.5 × 106 U/m2 for 3 × 24 hours). Treatment cycles were repeated in the absence of disease progression every 28 days to a maximum of four cycles. Results Three hundred sixty-three patients with advanced metastatic melanoma were accrued. The median survival was 9 months in both arms, with a 2-year survival rate of 12.9% and 17.6% in arms A and B, respectively (P = .32; hazard ratio, 0.90; 95% CI, 0.72 to 1.11). There was also no statistically significant difference regarding progression-free survival (median, 3.0 v 3.9 months) and response rate (22.8% v 20.8%). Conclusion Despite its activity in melanoma as a single agent or in combination with interferon-alfa-2b, the chosen schedule of IL-2 added to the chemoimmunotherapy combination had no clinically relevant activity.

De-intensified chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma based on plasma EBV DNA: A phase 2 randomized noninferiority trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 110-110
Author(s):  
Hai-Qiang Mai ◽  
Xiao Yun Li ◽  
Hao-Yuan Mo ◽  
Guo Ling ◽  
Dong-Hua Luo ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Controlled Trial ◽  
Phase Iii ◽  
Stage Iii ◽  
Phase 2 ◽  
Significant Difference ◽  
Ebv Dna ◽  
Grade 3 ◽  
Cycle Group ◽  
To Receive

110 Background: The cisplatin-based chemoradiotherapy (CCRT), given at a dose of 100 mg/m2 for 3 cycles during radiotherapy, is the major treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). As several retrospective studies showed that receiving a cumulative cisplatin dose of 200 mg/m2 can bring survival benefits to NPC patients, we sought to test the non-inferiority of 2-cycle concurrent cisplatin over 3-cycle in locoregionally advanced NPC with Epstein-barr virus (EBV) DNA levels < 4000 copies/ml. Methods: We did a non-inferiority, phase 2, randomised controlled trial. Patients were enrolled with stage III–IVB NPC, EBV DNA levels < 4000 copies/ml, aged 18–70 and adequate haematological, renal, and hepatic function. Eligible patients were randomly assigned (1:1) to receive 2 or 3 cycles of cisplatin-based CCRT. Patients in the 2-cycle group were scheduled to receive 100 mg/m2 cisplatin given every 3 weeks concurrently with radiotherapy, and patients in the 3-cycle group received 100 mg/m2 cisplatin given every 3 weeks for 3 cycles. Randomization was done by a computer-generated random number code with a block size of six, stratified by clinical stage III or IV. The primary endpoint was 3-year progression-free survival (PFS), with a non-inferiority margin of 10%. This study was registered with ClinicalTrials.gov, ID. NCT02871518. Results: Between September 2016 and October 2018, 342 patients were enrolled, of whom 332 were randomly assigned to receive 2 or 3 cycles of cisplatin. 314 (94.6%) patients completed protocol-defined cycles of chemotherapy. After median follow-up of 33.6 months, 20 (12.0%) patients in the 2-cycle group and 17 (10.2%) patients in the 3-cycle group had tumor progression, and the 3-year PFS rates were 88.0% and 90.4% respectively, with a difference of 2.4% (95%CI -4.3 to 9.1, Pnon-inferiority < 0.001). In the per-protocol analysis, 3-year PFS was 88.5% in the 2-cycle group and 90.6% in the 3-cycle group, with a difference of 2.1% (95% CI –4.7 to 8.9; Pnon-inferiority= 0.001). No significant difference was observed concerning OS, LRRFS and DMFS. The grade 3 or 4 acute adverse events were recorded in 113 (68.1%) patients in the 2-cycle group and 116 (69.9%) patients in the 3-cycle group. Patients in the 3-cycle group was observed to have significantly more hyponatremia. Besides, patients in the 3-cycle group presented with more grade 1 or 2 dry mouth, dysphagia, weight loss, fatigue, constipation, fever, mucositis and dermatitis. More grade 3 or 4 anorexia, mucositis and dermatitis were also recorded in the 3-cycle group. No patients died from treatment-related toxicities. Conclusions: IMRT plus 2 cycles of concurrent 100 mg/m2 cisplatin could be an alternative option for patients with low-risk locoregionally advanced NPC. Further phase III studies are needed to validate the findings of this study. Clinical trial information: NCT02871518.

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