Preliminary Results of a Prospective Multicenter Phase III Trial Comparing High-Dose and Standard-Dose Daunorubicin for Induction of Complete Remission (CR) in Acute Myeloid Leukemia (AML).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1833-1833
Author(s):  
Je-Hwan Lee ◽  
Young-Don Joo ◽  
Jae-Hoo Park ◽  
Hun Mo Ryoo ◽  
Myung Soo Hyun ◽  
...  
Keyword(s):  
Risk Group ◽  
Standard Dose ◽  
Disease Free Survival ◽  
Phase Iii ◽  
High Dose ◽  
Dose Intensification ◽  
Free Survival ◽  
Transfusion Requirements ◽  
The Impact ◽  
Different Doses

Abstract The effectiveness of anthracycline dose intensification for induction of CR in AML has not been studied in a randomized fashion. We conducted a prospective randomized trial to compare the therapeutic efficacy and toxicity of two different doses of daunorubicin in combination with cytarabine in AML. This study began on August 2001 and 293 adult patients (younger than 60 years) with newly diagnosed AML except M3 have been enrolled. Fourteen patients were removed from the study and the remaining 279 patients were analyzed. After random assignments, 135 patients received standard-dose daunorubicin (SD-DN, 45 mg/m2/d × 3 d) and 144 patients received high-dose daunorubicin (HD-DN, 90 mg/m2/d × 3 d) in addition to cytarabine (200 mg/m2/d × 7 d) for induction of CR. Patients with persistent leukemia received the second attempt of induction chemotherapy, consisting of standard-dose daunorubicin (2 d) plus cytarabine (5 d). Patients who attained CR received 4 cycles of high-dose cytarabine (3 g/m2 × 6 doses) and 2 cycles of daunorubicin (1 d) plus cytarabine (5 d). For patients in intermediate- or high-risk cytogenetic groups, allogeneic hematopoietic cell transplantation was performed if there was a suitable donor. CR was induced in 98 of 135 patients (72.6%) in SD-DN arm and 119 of 144 (82.6%) in HD-DN arm (P = 0.044). The impact of daunorubicin dose intensification on the CR rates were different by cytogenetic risk group: the CR rates for SD-DN vs. HD-DN arm were 24/25 (96.0%) vs. 35/36 (97.2%) for good-risk group, 63/88 (71.6%) vs. 64/83 (77.1%) for intermediate-risk group, and 10/20 (50.0%) vs. 19/24 (79.2%) for poor-risk group. With a median follow-up of 596 days for surviving patients, the 4-year probabilities of overall survival, disease-free survival, and relapse-free survival were similar between SD-DN and HD-DN arm. Two different doses of daunorubicin (SD-DN vs. HD-DN) showed similar toxicity profiles regarding recovery times from myelosuppression, transfusion requirements, severe toxicities (grades III to IV) classified by NCI-CTC ver 2.0 including cardiac toxicities, and duration of antibiotics administration. In conclusion, high-dose daunorubicin showed higher CR rates in AML patients of intermediate- and poor- cytogenetic risk groups without increase of toxicities compared to standard-dose daunorubicin.

Outcomes in CCG-2961, a Children’s Cancer Group Phase III Trial for Untreated Acute Myeloid Leukemia (AML).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 169-169 ◽  
Author(s):  
Beverly J. Lange ◽  
Franklin O. Smith ◽  
Patricia A. Dinndorf ◽  
Carola A.S. Arndt ◽  
Dorothy R. Barnard ◽  
...  
Keyword(s):  
De Novo ◽  
Interleukin 2 ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Remission Induction ◽  
High Dose ◽  
Free Survival ◽  
Cancer Group ◽  
De Novo Aml

Abstract CCG-2961 tested an intensively timed induction therapy consisting of cytarabine (AC), etoposide, thioguanine, dexamethasone, idarubicin and daunorubicin. Patients in remission after induction were randomized to a second induction course (Arm A) or a 3-drug combination of fludarabine, AC, and idarubicin (Arm B). Course 3 for patients with related donors was bone marrow transplantation (BMT); for those without donors, high dose AC/l-asparaginase. After Course 3 patients without donors were randomized to 14 infusions of Interleukin 2 (IL2) over 18 days or follow-up. CNS prophylaxis was intrathecal AC. Eligibility included all subtypes of de novo AML except acute promyelocytic leukemia and AML in patients with Down syndrome. CCG-2961 opened in Oct.1996 and closed in Dec. 2002. The DSMC suspended the study between Oct. 1999 and May 2000 while the 2961 Committee developed supportive care policies to reduce treatment-related mortality (TRM). CCG-2961 enrolled 900 de novo patients aged 3 days to 21 years, with 495 and 405 patients accruing pre-and post suspension respectively. Remission induction rate is 88.5%. With median follow-up of 3.6 years (range: 0 – 8.1 years), event-free survival (EFS) at 3 years is 44±3% and survival (OS) 57±3%. Disease-free survival (DFS) following Course 2 Arms A and B are not different, although relapse is significantly higher in Arm A (7.3% .vs. 3.1% P=0.018) and TRM more common in Arm B (7.9% vs.4.2% P=0.059), despite 7 less days of neutropenia in Arm B (P<0.001). DFS is 65±9% for patients with a donor versus 50±5% for patients without a donor (P=0.005); respective OS, 74±8% and 66±5% (P=0.221). However, among 98 patients in CR1 with t(8;21) or inv(16) cytogenetics, outcomes in those without and with a donor were no different: DFS (61±12% vs. 72±18%, P = 0.49) and OS (78±10% vs. 77±17%, l P= 0.85). DFS with and without IL2 is 55±9% and 60±8%(P=0.606). Outcomes improved progressively over time. EFS pre- and post-suspension are 41±4% and 47±5%(P=0.038); OS, 52±5% and 63±5%(P=0.005); TRM is 17±3% pre- and 12±3% post-suspension (P=0.039). Factors predictive of inferior EFS are age >17 years, Afro-American and Hispanic ethnicity, body mass index <10th or >95th percentile for age, absence of related marrow donor, WBC > 50,000/mm3, karyotype with −7/7q, −5/5q- or > cytogenetic 5 abnormalities, FLT3/ITD, >15 % morphologic blasts on day 14 or >0.5% immunologically detectable blasts at the end of induction. CCG-2961 confirms the efficacy and high TRM of intensively timed therapy. Neither fludarabine nor IL2 increases DFS or OS, and availability of a donor does not improve outcomes in those with favorable cytogenetics.

Efficacy of dose intensification in induction therapy for localized Ewing sarcoma: Italian Sarcoma Group (ISG) and Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP) ISG/AIEOP EW-1 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11501-11501
Author(s):  
Roberto Luksch ◽  
Giuseppe Maria Milano ◽  
Francesco Barretta ◽  
Alessandra Longhi ◽  
Emanuela Palmerini ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Ewing Sarcoma ◽  
Phase Iii ◽  
Secondary Outcome ◽  
Poor Responders ◽  
High Dose ◽  
Type I ◽  
Tumour Site ◽  
Dose Intensification ◽  
The Impact

11501 Background: The role of dose intensification of chemotherapy in Ewing sarcoma (ES) is under evaluation in prospective trials. This is a controlled, randomized phase III study evaluating the impact on event-free survival (EFS) of two arms at different intensity of induction therapy in localized ES at onset. Methods: Newly diagnosed localized ES patients aged 2-40 were eligible. They were randomized to receive 4-courses induction therapy - 1 every 21 days - either with a standard arm (arm A) as per ISG/SSGIII protocol (Ferrari S, et at, Ann Oncol. 2011;22(5):1221) or with an intense arm B, consisting of vincristine 1,5mg/sqm+ doxorubicin 80mg/sqm+ifosfamide 9g/sqm for each course. After induction, patients underwent surgery and/or radiotherapy,followed by an adaptive treatment. Good responders received standard courses chemotherapy: arm A pts received 9 courses, while arm B pts received 5 courses. Poor responders in both arms received 4 courses followed by high-dose busulfan/melphalan+autologous stem cell rescue. The primary outcome measure was EFS for the 2 arms in the intention-to-treat population. Kaplan-Meier curves compared with log-rank test and Cox model were performed to assess differences between study arms. A secondary outcome was toxicity differences, assessed by means of the Fisher’s exact test. Initial sample size was 230 pts, type I error rate 5%, power 80%. Results: Between 2009 and 2019, 234 patients were randomized (arm A-115; arm B-119). M:F ratio was 1.8; median age 14 years (range 2-40); tumour site extremity in 55%, axial/pelvis in 45%; tumour volume < 200ml in 31% and ≥200ml in 69%. A good response was obtained in 56% in arm A and 60% in arm B. Median follow-up was 68 months. EFS was not significantly different between arms; HR: 0.85; 95% CI: 0,51-1,41, 5-year EFS (95% CI) was 73% (64-82%) in arm A and 75% (67-83%) in arm B ( p = 0.526). Good responders in arm A and in arm B and poor responders in arm B had comparable results: 5-year EFS (95% CI) was 80% (71-91%), 77% (67-88%), and 72% (59-86%), respectively, while poor responders in arm A showed a worse, not statistically significant (p = 0.164) performance (63%; 50-78%). Subgroup analyses showed similar outcome for age, tumour site and volume in both arms. Hematological, gastrointestinal, and cardiovascular grade ≥3 toxicities were more pronounced in arm B (p < 0.05). Conclusions: Intense induction therapy with arm B did not improve 5-year EFS when compared with the standard arm A. The higher toxicity observed in arm B than in arm A was counterbalanced, in good responders, by a similar outcome with a shorter treatment plan. For poor responders, with almost 30 patients per arm event-free and with < 48-month FUP, better 5-year EFS in arm B than in arm A was observed but needs further observation. Clinical trial information: NCT02063022.

BiovaxID™ Vaccine Therapy of Follicular Lymphoma in First Remission: Long-Term Follow-Up of a Phase II Trial and Status of a Controlled, Randomized Phase III Trial.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2441-2441 ◽  
Author(s):  
Carlos Santos ◽  
Lee Stern ◽  
Laura Katz ◽  
Thelma Watson ◽  
Gause Barry
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Disease Free Survival ◽  
T Cell Response ◽  
Phase Iii ◽  
Patient Specific ◽  
Free Survival ◽  
The Impact ◽  
Disease Free

Abstract Malignant B-cells in Follicular Non-Hodgkin’s Lymphoma expresses a clonal idiotype immunoglobulin which can serve as the basis for a patient-specific anti-idiotype vaccine. In a previous single-arm Phase II study by Bendandi, et al (Nature Med5:1171–1177, 1999), we evaluated the ability of tumor-specific idiotype (Id) conjugated to keyhole limpet hemocyanin (KLH) administered concurrently with granulocyte-monocyte colony-stimulating factor (GM-CSF) adjuvant to induce complete remissions and molecular remissions in treated patients. The vaccine formulation induced a tumor-specific cytotoxic CD8+ and CD4+ T-cell response in patients in first complete remission after standard chemotherapy, as well as achieved molecular remissions in 8 of 11 of these patients. Data available at the time of this abstract for the 20-patient cohort, indicates a median follow-up of 9.167 years. 9 patients (45 %) remain in continuous first CR at their most recent follow-up (either in 2004 or 2005), and overall survival is 95%. The data further indicates the median disease free survival for the cohort is 96.5 months (8.04 years). To date there have been no additional reported mortalities in this cohort. As of August 2005, we report the progress of the Phase III clinical trial for this vaccine, opened in January 2000 by the NCI to evaluate the impact of this hybridoma-based Id vaccine on disease-free survival in a group of up to 375 previously untreated patients who have attained a CR or CRu from PACE [Prednisone, Doxorubicin, Cyclophosphamide, and Etoposide (ProMACE without methotrexate)] chemotherapy, and who are randomized to receive either vaccine or control. To date, 187 patients have been accrued onto the study. Of those patients, 145 (77.5%) achieved a CR or Cru and are being followed in this ongoing clinical trial.

Ten Year Follow up Analysis of the OSHO Phase III Trial (AML 96) Comparing Different Application Modes of AraC in Patients below 60 Years with Acute Myeloid Leukemia (AML): No Impact of AraCApplication Mode on Remission Rate, Toxicity, Disease-Free Survival or Overall Survival

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2966-2966
Author(s):  
Cornelia Becker ◽  
Rainer Krahl ◽  
Antje Schulze ◽  
Georg Maschmeyer ◽  
Christian Junghanß ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factors ◽  
Cox Regression ◽  
Disease Free Survival ◽  
Phase Iii ◽  
High Dose ◽  
Event Free Survival ◽  
Free Survival ◽  
Significant Difference

Abstract Clinical trials on different cytarabine doses for treatment of AML provide evidence of a dose response effect, but also for increase toxicity after high dose AraC (HDAC). Pharmacokinetic measurements of cytarabine-triphosphate (AraC-CTP), which is the most relevant cytotoxic metabolite of AraC, have revealed its formation in leukemic cells to be saturated with infusion rates above 250 mg/m2/h, this being significantly lower than used in HDAC schedules. Methods: Based on a pharmacological model and encouraging results of a phase II study we conducted a prospective randomized multicenter clinical trial comparing the effects of two different application modes of AraC in patients up to 60 years with untreated newly diagnosed AML. Patients were randomized to receive AraC at two different infusion rates (IR) during induction and consolidation treatment: arm A/experimental: 1 × 2 g/m2/d AraC over 8 hours (IR 250 mg/m2/h) arm B/standard: 2 × 1 g/m2/d AraC over 3 hours (IR 333 mg/m2/h). Induction and first consolidation consisted of AraC (days 1, 3, 5, 7) in combination with an anthracycline (Idarubicine 12 mg/m2 or Mitoxantrone 10 mg/m2, days 1–3). The final dosage points (AraC day 7 and anthracycline day 3) were excluded from the second consolidation. The third consolidation consisted of either allogeneic or autologous stem cell transplantation or of chemotherapy identical to second consolidation. Results: From 02/97 to 04/02 419 patients were enrolled in the study. The present analysis is based on 361 eligible and evaluable patients with a median follow up of 7 years. CR was reached in 249/361 (69%; 95%CI: 65%–74%) patients. No statistically significant differences were detected between arms A and B with regard to CR-rate (69% vs 69%) or early death rate (11% vs 8%). Hematological recovery of median white blood cell count (WBC) &gt; 109/l and median platelets (plt) &gt; 50 × 109/l revealed no difference between arms A and B after induction (WBC day 22 vs 22, p=0,68; plt day 25 vs 26, p=0,41) and consolidation (WBC day 28 vs 27, p=0,07; plt day 42 vs 40, p= 0,58). The event free survival (EFS) after 5 years is 0,25 ± 0,03 % for all patients with an overall survival of 0,31 ± 0,03 % after 5 years. For the purposes of analysis, the 83 transplant patients (23 allogeneic MRD, 14 allogeneic MUD and 46 autologous) were censored at time of transplant. No statistically significant difference between arms A and B in regard to EFS (0,25 ± 0,04 vs 0,25 ± 0,04, p=0,99), relapse incidence (0,63 ± 0,06 vs 0,60 ± 0,06, p=0,89), overall survival (0,32 ± 0,04 vs 0,30 ± 0,04, p=0,44) and therapy associated mortality (0,18 ± 0,04 vs 0,17 ± 0,03, p=0,95) were detectable after adjustment of prognostic factors. An analysis of risk factors by multivariate cox regression model confirmed cytogenetics at diagnosis to be the most important risk factor for CR rate (p&lt;10−6) and for EFS (p&lt;10−6). Other significant prognostic factors for EFS evaluated in the multivariate analysis were de novo vs secondary AML (p=0,0001), WBC (continuous) (p=0,001), LDH (&gt;1–4 × vs other ULN) (p=0,008) and FAB classification (FAB M0,6,7 vs FAB M1,2,4,5) (p=0,0005). EFS after 5 years shows a significant correlation to cytogenetics (p&lt;10−6) with 0,71±0,1, 0,27±0,05, 0,20±0,06 and 0,03±0,03 for favorable, normal, other and unfavorable cytogenetic karyotype, respectively. Conclusion: We conclude that the application of AraC at the presumptive saturating infusion rate of 250 mg/m2/h results in comparable remission rates, toxicity, event free survival and overall survival as compared to the standard IR with 333 mg/m2/h.

Oxaliplatin Combined With Weekly Bolus Fluorouracil and Leucovorin As Surgical Adjuvant Chemotherapy for Stage II and III Colon Cancer: Results From NSABP C-07

2007 ◽  
Vol 25 (16) ◽  
pp. 2198-2204 ◽  
Author(s):  
J. Philip Kuebler ◽  
H. Samuel Wieand ◽  
Michael J. O'Connell ◽  
Roy E. Smith ◽  
Linda H. Colangelo ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Disease Free Survival ◽  
Stage Ii ◽  
Phase Iii ◽  
Wall Thickening ◽  
Free Survival ◽  
Significant Difference ◽  
Grade 3 ◽  
The Impact ◽  
Disease Free

Purpose This phase III clinical trial evaluated the impact on disease-free survival (DFS) of adding oxaliplatin to bolus weekly fluorouracil (FU) combined with leucovorin as surgical adjuvant therapy for stage II and III colon cancer. Patients and Methods Patients who had undergone a potentially curative resection were randomly assigned to either FU 500 mg/m2 intravenous (IV) bolus weekly for 6 weeks plus leucovorin 500 mg/m2 IV weekly for 6 weeks during each 8-week cycle for three cycles (FULV), or the same FULV regimen with oxaliplatin 85 mg/m2 IV administered on weeks 1, 3, and 5 of each 8-week cycle for three cycles (FLOX). Results A total of 2,407 patients (96.6%) of the 2,492 patients randomly assigned were eligible. Median follow-up for patients still alive is 42.5 months. The hazard ratio (FLOX v FULV) is 0.80 (95% CI, 0.69 to 0.93), a 20% risk reduction in favor of FLOX (P < .004). The 3- and 4-year disease-free survival (DFS) rates were 71.8% and 67.0% for FULV and 76.1% and 73.2% for FLOX, respectively. Grade 3 neurosensory toxicity was noted in 8.2% of patients receiving FLOX and in 0.7% of those receiving FULV (P < .001). Hospitalization for diarrhea associated with bowel wall thickening occurred in 5.5% of the patients receiving FLOX and in 3.0% of the patients receiving FULV (P < .01). A total of 1.2% of patients died as a result of any cause within 60 days of receiving chemotherapy, with no significant difference between regimens. Conclusion The addition of oxaliplatin to weekly FULV significantly improved DFS in patients with stage II and III colon cancer. FLOX can be recommended as an effective option in clinical practice.

Incorporating Target Immunotherapy into Standard Conditioning Regimen Prior to Autologous Stem Cell Transplantaion (ASCT) Improves the Transplant Outcome for Pateints with Relapsed/Refractroy B Cell Non-Hodgkin Lymphoma (B-NHL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1911-1911
Author(s):  
Mohamed I. Farhat ◽  
Reem Karmali ◽  
Stephanie A. Gregory ◽  
Parameswaran Venugopal ◽  
Mohamad Kassar ◽  
...  
Keyword(s):  
Stem Cell ◽  
Disease Progression ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Cell Transplant ◽  
Free Survival ◽  
The Impact ◽  
Disease Free

Abstract Background: Refractory or relapse B-NHL has a poor prognosis with conventional chemotherapy. Autologous stem cell transplant (ASCT) preceded by high dose chemotherapy has been the preferred therapeutic choice for such patients. The majority of the treatment failures occur within one to two years post transplant with disease progression after transplant accounted for most of the failures. The incorporation of targeted immunotherapy (rituximab) into the upfront and relapse setting is becoming of the standard of care for patients with B-NHL. The objective of this study is to evaluate the impact of rituximab (R) on disease free survival (DFS) when added to a standard conditioning regimen -- BEAM (carmustine, cytarabine, etoposide, and melphalan) prior to ASCT. Methods: A single institution retrospective analysis of 53 patients (pts), whom were heavily pre-treated, underwent ASCT between 08/98 & 07/06. All pts received rituximab in combination with high dose cytoxan for stem cell mobilization. 37 pts received R-BEAM and 16 received BEAM prior to ASCT. Actuarial rate for DFS was estimated from the day of SCT using the Kaplan-Meier method. Results: The group was predominantly men, 73% and 78%, with a median age of 57 years for both the R-BEAM and BEAM group. With a median follow up of 15.7 months, 13/37 (32%) and 11/16 (64%) pts who received R-BEAM and BEAM respectively developed disease progression after ASCT. The 2-yr actuarial disease-free survivals (figure1) were 60% and 21% for the R-BEAM and BEAM arm respectively (p=0.006). Conclusion: In this study, the outcome of pts who received R-BEAM compares favorably to those who receive BEAM alone with significant improvement in disease-free survival. Thus, incorporating target immunotherapy into standard conditioning regimen may have altered the natural history of the disease for pts undergoing ASCT for relapsed/refractory B-NHL. Disease Free survival Disease Free survival

Effect of Venous Thrombotic Events on Overall Survival in Multiple Myeloma: Analysis of Thrombotic Events Occurring in E4A03A Randomized Trial of Lenalidomide Plus High-Dose Dexamethasone (RD) Versus Lenalidomide Plus Low-Dose Dexamethasone (Rd) in Newly Diagnosed Multiple Myeloma, a Trial Coordinated by the Eastern Cooperative Oncology Group (ECOG).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1740-1740 ◽  
Author(s):  
Susanna Jacobus ◽  
Shaji Kumar ◽  
Natalie Scott Callander ◽  
Rafat Abonour ◽  
Rafael Fonseca ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Low Dose ◽  
Standard Dose ◽  
Eastern Cooperative Oncology Group ◽  
Phase Iii ◽  
High Dose ◽  
Newly Diagnosed ◽  
Serious Adverse Events ◽  
The Impact

Abstract Background: Venous thrombotic events (VTE) are a common complication of therapy with the lenalidomide plus dexamethasone regimen. The incidence of VTE with RD is approximately 20%, and can be lowered with the use of effective thromboprophylaxis, avoidance of erythropoietin, and the use of lower doses of dexamethasone. The goal of this study was to determine the impact of VTE on overall survival of patients with newly diagnosed myeloma by studying events occurring in ECOG E4A03 phase III trial of lenalidomide plus high (standard) dose dex (RD) versus lenalidomide plus low dose dex (Rd) in newly diagnosed myeloma (MM). Methods: Pts with untreated, symptomatic MM were eligible. Pts in the RD arm (Arm A) received lenalidomide 25 mg/day PO days 1–21 every 28 days plus dex 40 mg days 1–4, 9–12, and 17–20 PO every 28 days; pts in the Rd arm (Arm B) received lenalidomide at the same dose plus dex 40 mg days 1, 8, 15, and 22 PO every 28 days. The trial initially did not mandate routine thromboprophylaxis, but recommended that such treatment be considered. After the first 264 patients were enrolled the trial was amended to require mandatory thromboprophylaxis of aspirin for all patients, with a recommendation to use stronger thromboprophylaxis with either warfarin (target INR 2–3) or low molecular weight heparin among patients in the RD arm. Results: 445 pts (median age, 65 yrs) were accrued; 223 randomized to RD, 222 to Rd. Median follow-up time is 30 months. Overall VTE including deep vein thrombosis (DVT) and pulmonary embolism (PE) occurred in 18.5% of patients; 25.6% in Arm A and 11.4% in Arm B. Rates for the first 4 cycles of treatment were 20.2% in Arm A and 8.2% in Arm B, P&lt;0.01. Rates did not change substantially before and after the prophylaxis amendment. A partial response (PR) or higher was seen in 82.1% of pts who experienced VTE compared with 74.6% of pts who did not experience VTE, P=0.19. Overall VGPR rates also were not inferior. Pts who had VTE, however, had significantly higher other grade 3–5 toxicities such as hyperglycemia (14.6% vs 7.5%, P=0.051), cardiac ischemia (4.9% vs 0.8%, P=0.002), non-neuropathic weakness (13.4% vs 6.4%, P=0.039), infection/pneumonia (17.1% vs 11.1%, P=0.138) and fatigue (18.3% vs 10.5%, P=0.060). In a Cox PH model, VTE status as a time-varying covariate was marginally significant: HR 1.54 95%CI (0.96–2.47), P=0.074, suggesting patients that develop VTE have a higher hazard of death. Conclusions: The occurrence of VTE may adversely affect the survival of patients with newly diagnosed myeloma receiving Rev-Dex. VTE was associated with a higher frequency of other serious adverse events. Prevention of VTE events is a priority. Besides lowering the dose of dexamethasone, studies investigating optimum thromboprophylaxis are needed.

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.

Prevalence and Prognostic Significance of KIT Mutations in Pediatric Core Binding Factor AML Patients Treated with Gemtuzumab Ozogamicin: Results from the Randomized Phase III Children's Oncology Group Trial AAML0531

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 800-800
Author(s):  
Jessica Pollard ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Yi-Cheng Wang ◽  
Jason Joaquin ◽  
...  
Keyword(s):  
Prognostic Significance ◽  
Disease Free Survival ◽  
Gemtuzumab Ozogamicin ◽  
Phase Iii ◽  
Study Entry ◽  
Prognostic Impact ◽  
Core Binding Factor ◽  
Free Survival ◽  
Binding Factor ◽  
The Impact

Abstract Mutations of KIT (KIT +) occur in children and adults with core binding factor (CBF) acute myeloid leukemia (AML) and cluster within exons 8 and 17. We previously reported a 19% prevalence of KIT mutations in pediatric CBF AML and lack of prognostic significance in serial pediatric cooperative trials. We also determined that gemtuzumab ozogamicin (GO) improves outcomes for a subset of CBF AML patients with higher CD33 expression enrolled on AAML0531, a randomized trial of conventional chemotherapy with or without GO. Thus, in this study, we determined whether the clinical outcome of patients with KIT + CBF AML is affected by GO treatment. COG AAML0531 enrolled 1022 eligible pediatric de novo AML patients of which 247 had CBF AML [137 t(8;21) and 110 inv(16)/t(16;16)] based on central cytogenetic review. Of these 247 patients, 218 had evaluable samples for KIT mutational analysis. Analysis included PCR amplification of exons 8 and 17 and fragment length analysis and direct sequencing to identify all missense and size mutations. Mutations were detected in 55 patient samples (25%); 27 (49%) involved exon 8, 26 (47%) involved exon 17 and 2 (4%) involved both exons. Breakdown by exon and CBF translocation type demonstrated exon 8 mutations in 12/121 (10%) t(8;21) samples and 17/97 (18%) inv(16)/t(16;16)patient samples. Exon 17 mutations were found in 18/121 (15%) t(8;21) and 10/97 (10%) inv(16)/t(16;16) patient samples. Overall outcome analysis among the 218 CBF AML samples analyzed for KIT mutations revealed similar complete remission (CR) rates after induction I for KIT + vs. KIT- patients (83% vs. 82%, p=0.796). Five-year event-free survival (EFS) from study entry for KIT + vs. KIT- was 54% and 70%, respectively (p=0.029) with a corresponding overall survival (OS) of 76% vs. 83% (p=0.380). Notably, KIT + patients who achieved CR had a relapse risk (RR) of 45% vs. 23% for KIT- patients (p=0.010). Disease-free survival (DFS) for KIT + vs. KIT- was 51% and 72%, respectively (p=0.021). We also compared the clinical impact of exon 8 vs. exon 17 mutations. Outcomes of CBF AML patients with exon 8 mutations were similar to CBF AML patients without these mutations (OS 90% vs. 80%, p=0.277, EFS 55% vs. 68%, p=0.224, DFS 58% vs. 68%, p= 0.419, RR 42% vs. 26%, p= 0.112). In contrast, outcomes of patients with exon 17 mutations were inferior to those CBF AML patients without exon 17 mutations [OS 64% vs. 84%, p=0.035; DFS 43% vs. 70%, p=0.016) and higher RR was observed (48% vs. 26%, p=0.057). The impact of GO treatment on outcome was subsequently evaluated. KIT + CBF AML patients who did not receive GO had inferior OS and EFS from study entry compared to KIT-patients (OS 64% vs. 86%, p= 0.034, EFS: 46% vs. 69%, p=0.037). Higher RR (55% vs. 31%, p= 0.046) and inferior DFS (45% vs. 66%, p= 0.094) were also observed. In contrast, KIT + and KIT-patients receiving GO treatment had comparable outcomes (OS 88% vs. 80%, p=0.393; EFS 62% vs. 72%, p=0.438) as well as RR (33% vs. 15%, p=0.103) and DFS (57% vs. 77%, p=0.109). Analysis by mutation subtype revealed that outcomes of patients with exon 8 mutations were similar to exon 8 wild-type (WT) patients when treatment did not include GO (OS 81% vs. 80%, p=0.910; EFS 50% vs. 65%, p= 0.185). DFS and RR were also similar (DFS 57% vs. 62%, p= 0.752, RR 43% vs. 36%, p= 0.632). Treatment of exon 8 mutations with GO resulted in significant improvement in OS at 5 years from study entry compared to those without exon 8 mutations (100% vs. 80%, landmark p value <0.001) but other outcome parameters were not significantly improved (EFS 62% vs. 71%, p= 0.707; DFS 58% vs. 75%, p=0.382; RR 42% vs. 16%, p=0.056). For patients with exon 17 mutations, treatment without GO resulted in inferior outcomes when compared to CBF AML patients without exon 17 mutations (OS 56% vs. 85%, p= 0.019; EFS 44% vs. 66%, p=0.154; DFS 33% vs. 65%, p=0.049; RR 67% vs. 32%, p=0.031). Adding GO abrogated this negative impact. Specifically, OS, EFS, DFS and RR for patients with exon 17 mutations were comparable to that of CBF AML patients with WT exon 17 when treated with GO (OS 77% vs. 83%, p= 0.542; EFS 62% vs. 71%, p=0.516; DFS: 56% vs. 74%, p=0.195; RR 22% vs.19%, p=0.898). This analysis suggests that pediatric KIT + CBF AML has negative prognostic impact within the context of AAML0531. This effect was abrogated, particularly for patients with exon 17 mutations, with GO treatment. CD33-targeted agents may be beneficial, at least for a subset of these patients, in future clinical trials. Disclosures Aplenc: Sigma Tau: Honoraria.

A phase III randomized trial of intensive induction and consolidation chemotherapy ± oblimersen, a pro-apoptotic Bcl-2 antisense oligonucleotide in untreated acute myeloid leukemia patients >60 years old

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7012-7012 ◽  
Author(s):  
G. Marcucci ◽  
B. Moser ◽  
W. Blum ◽  
W. Stock ◽  
M. Wetzler ◽  
...  
Keyword(s):  
Antisense Oligonucleotide ◽  
Performance Status ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Induction Treatment ◽  
High Dose ◽  
Consolidation Chemotherapy ◽  
Free Survival ◽  
Treatment Changes ◽  
And Performance

7012 Background: Overexpression of Bcl-2, an inhibitor of apoptosis, may render AML cells resistant to chemotherapy and has been associated with unfavorable outcome. Genasense is a phosphorothioate 18-mer antisense oligonucleotide directed against the first 6 codons of Bcl-2. In a phase I study of older (≥60 yrs) AML patients (pts) treated with Genasense in combination with cytarabine (Ara-C) and daunorubicin (DNR) induction and with high-dose cytarabine (HiDAC) consolidation, no antisense-related toxicity was reported. Furthermore, overexpression of Bcl-2 at diagnosis and down-regulation of the Bcl-2 target after antisense treatment was shown in pts achieving complete remission (CR). Methods: A phase III trial (CALGB 10201) randomized untreated older AML pts to induction treatment with Ara-C (100 mg/m2/d by CIVI on days 4–10) and DNR (60 mg/m2/d on days 4–6) followed by consolidation therapy with HiDAC (2 g/m2/d on days 4–8) with (Arm A) or without (Arm B) Genasense (7 mg/m2/d CIVI on days 1–10 for induction and days 1–8 for consolidation). The study was powered to identify a survival advantage for pts receiving Genasense. Results: 503 pts enrolled between 12/03 and 10/06; 76 had prior MDS and 24 prior chemoradiotherapy for unrelated cancers. The arms were balanced for age, sex, race, and performance status. No differences in toxicities were observed between the 2 arms. An interim futility analysis performed at 34 months from initiation of the study showed no differences in CR rates (48% vs 52%; p=0.75) or overall survival (OS; p=0.83) between the 2 arms. Estimated OS at 1 yr was 36% for Arm A and 40% for Arm B. Similarly, there were no differences in disease-free survival from date of CR (DFS; p=0.78) or event-free survival (EFS; p=0.77). DFS and EFS rates at 1 yr were 40% and 25% for Arm A, and 43% and 7% for Arm B, respectively. Conclusions: Addition of Genasense to induction and consolidation chemotherapy failed to improve the outcome of older AML pts. Pretreatment levels and post-antisense treatment changes in Bcl-2 expression are now being measured and correlated with outcome. No significant financial relationships to disclose.

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