scholarly journals Clofarabine added to intensive treatment in adult patients with newly diagnosed ALL: the HOVON-100 trial

2021 ◽  
Author(s):  
Anita W Rijneveld ◽  
Bronno van der Holt ◽  
Okke de Weerdt ◽  
Bart J Biemond ◽  
Arjan A Van de Loosdrecht ◽  
...  
Keyword(s):  
Older Patients ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Serious Adverse Events ◽  
Hematopoietic Stem ◽  
Improve Outcome ◽  
Phase Iii Study

Clofarabine (CLO) is a nucleoside analogue with efficacy in relapsed/refractory acute lymphoblastic leukemia (ALL). This randomized phase III study aimed to evaluate whether CLO added to induction and consolidation would improve outcome in adults with newly diagnosed ALL. Treatment for younger (18-40 years) patients consisted of a pediatric inspired protocol and for older patients (41-70 years) of a semi-intensive protocol was used. 340 patients were randomized. After a median follow up of 70 months, 5-year EFS was 50% and 53% for arm A and B (CLO arm). For patients ≤40 years, EFS was 58% vs 65% in arm A vs B, while in patients >40 years EFS was 43% in both arms. CR rate was 89% in both arms and similar in younger and older patients. Minimal residual disease (MRD) was assessed in 200 patients (60%). Fifty-four of 76 evaluable patients (71%) were MRD negative after consolidation 1 in arm A vs 75/81 (93%) in arm B (p=0.001). Seventy (42%) patients proceeded to allogeneic hematopoietic stem cell transplantation in both arms. Five years OS was similar in both arms, 60% vs 61%. Among patients achieving CR, relapse rates were 28% and 24%, and non-relapse mortality was 16% vs 17% after CR. CLO treated patients experienced more serious adverse events, more infections, and more often went off-protocol. This was most pronounced in older patients. We conclude that, despite a higher rate of MRD-negativity, addition of CLO does not improve outcome in adults with ALL, which might be due to increased toxicity. The trial is registered at www.trialregister.nl as NTR2004.

Two Years Follow-up Results of Graspall/Graall-SA2–2008 Study: L-Asparaginase-Loaded Red Blood Cell Combined with Standard EWALL Chemotherapy in Older Patients with Newly Diagnosed Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (Ph-ALL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1473-1473 ◽  
Author(s):  
Mathilde Hunault-Berger ◽  
Thibaut Leguay ◽  
Françoise Huguet ◽  
Stéphane Leprêtre ◽  
Eric Deconinck ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Older Patients ◽  
Residual Disease ◽  
Remission Rate ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
High Dose ◽  
Newly Diagnosed

Abstract Abstract 1473 Introduction: L-asparaginase-loaded red blood cells (GRASPA®) has been shown to be a new available option for combining L-asparaginase with standard chemotherapy in different ALL population, including older patients with the disease. Tolerability and preliminary results of efficacy of GRASPA® in GRASPALL/GRAALL-SA2–2008 study have already been presented. We report below the 2-year follow-up efficacy results of this study. Methods: GRASPALL/GRAALL-SA2–2008 study aimed at determining optimal dose of GRASPA® that could be combined with standard EWALL chemotherapy backbone in patients aged >55y with newly diagnosed Ph-ALL. It was an open label Phase II dose escalation study. Primary endpoint combined tolerance and efficacy (asparagine depletion ≥7 days). Three doses of L-Asparaginase-Loaded Red Blood Cells (50, 100 and 150 IU/kg), infused twice during induction cycles, were investigated. EWALL backbone consisted of dexamethasone prephase followed by induction-1 (dexamethasone d1–2/8–11, vincristine d1,8, and idarubicine d1–2/8–9) and induction-2 (cyclophosphamide d15–17 and cytarabine d16–19/23–26). Consolidation consisted of 6 monthly alternating cycles with methotrexate (d1) / E.coli asparaginase (d2) and high-dose cytarabine (d1, 3, 5). Maintenance included mercaptopurine, methotrexate and vincristine/dexamethasone pulses for 2 years. Hematological and molecular Ig/TCR minimal residual disease (MRD) response rates, survival were secondary endpoints. Results: Between March 2009 and October 2010, 30 patients were recruited in 20 centres in France by the GRAALL network. The 50, 100 and 150 dose levels included 3, 13 and 14 patients, respectively. Median age was 67 years (range 59–77). No differences in baseline characteristics were observed across the 3 dose level groups. The tolerability with L-Asparaginase-related side effects is reported below: Overall L-asp expected adverse events tended to be lower in the 100 UI/kg group. Regarding the efficacy and benefit/risk, asparagines depletion, remission rate, EFS and OS are reported below: Three patients received the dose of 50 UI/kg but this dose was insufficient to reach a 7-day asparagine depletion. Survival analysis showed that the dose of 100IU/kg was associated with median OS of 15.6 months an absolute value that compared favorably with historical controls: 8,8 mo (Rousselot et al. Drugs Aging,2011) and 10,5 mo (Hunault et al. Haematologica,2011) Conclusion: GRASPA® at a dose of 100 UI/kg appears to be a safe and active manner to introduce L-asparaginase during initial induction chemotherapy of older patients with Ph- ALL with a sustained asparagine depletion and a good efficacy/safety profile. Disclosures: Godfrin: ERYTECH Pharma: COO Other.

scholarly journals Fractionated Inotuzumab Ozogamicin Combined with Low-Intensity Chemotherapy Provides Very Good Outcome in Older Patients with Newly Diagnosed CD22+ Philadelphia Chromosome-Negative B-Cell Precursor Acute Lymphoblastic Leukemia: First Results from the EWALL-INO Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 511-511
Author(s):  
Patrice Chevallier ◽  
Thibault Leguay ◽  
Michael Doubek ◽  
Francoise Huguet ◽  
Cyril Salek ◽  
...  
Keyword(s):  
B Cell ◽  
Older Patients ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Newly Diagnosed ◽  
Cell Precursor ◽  
Inotuzumab Ozogamicin ◽  
Low Intensity

Abstract On behalf of the GRAALL group, the Czech Republic ALL group, the Finland ALL group and the EWALL group. Introduction. Treatment of older patients (pts) with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains an unmet medical need. Inotuzumab ozogamicin (INO), an anti-CD22 antibody conjugated to calicheamicin, is approved for the treatment of relapsed/refractory BCP-ALL in adults, sinusoidal obstruction syndrome (SOS) being the major adverse event associated with INO. A previous first line study conducted by the MDACC in pts 60 years or older successfully used INO in combination with a lower intensity version of the hyper-CVAD (mini-hyper-CVD). Due to the occurrence of SOS, the total doses were fixed at 1.3 mg/m² for cycle 1 followed by 3 cycles at 1 mg/m² (Kantarjian H et al. Lancet Oncol, 2018). Here, we aimed to assess the activity and safety of fractionated INO at a reduced dosage in combination with low-intensity chemotherapy as frontline therapy for older pts with CD22+ Philadelphia chromosome-negative (Ph-neg) BCP-ALL. Methods. EWALL-INO is a single arm prospective phase 2 multicentric study conducted in European centers belonging to the EWALL group. Eligibility criteria were pts aged 55y or older, performance status ≤2, and newly diagnosed CD22+ (20% or more of positive blast cells) Ph-neg BCP-ALL without central nervous system involvement. After a prephase including 5 days (D) of dexamethasone (DEX) 10mg per D and a single intrathecal injection (IT), the induction regimen was begun and split in 2 parts. Induction part I (Induc1) consisted of one triple IT, vincristine (VCR) 2 mg (1 mg over 70y) D1 D8 D15 D22 and DEX 20 mg D1D2 D8D9 D15D16 D22D23 combined with 3 injections of INO (0.8 mg/m² D1, 0.5 mg/m² D8 and D15). Induction part II (Induc2) was offered to pts in CR or CRp (CR with platelets < 100 G/l) after Induc1 or as salvage therapy. Induc2 consisted of DEX 20mg D1D8, cyclophosphamide (CY) 300 mg/m² D1 to D3, one triple IT D2 and 2 injections of INO (0.5 mg/m² D1 and D8). Pts in CR/CRp were programmed to receive 6 blocks of consolidation (Ara-C 1.5g/m²/12h adapted to renal clearance D1D2 and DEX 10mg/12h D1D2, cycles 1 and 4; Methotrexate (MTX) 1.5 g/m² over 24h D1, VCR 1 or 2 mg D1, one triple IT D2 and 6-mercaptopurin (6-MP) D1 to D7, cycles 2 and 5; CY 500 mg/m² D1D2, VP16 75 mg/m² D1D2, one triple IT D2 and MTX 25 mg/m² D1, cycles 3 and 6) followed by a POMP maintenance (VCR, 6-MP, MTX, DEX) during 18 months. Allograft was allowed after at least 3 blocks of consolidation at the discretion of the investigators. The evaluable population was pts who received at least 1 dose of INO. Analyses were by modified intention to treat and performed JUN 28, 2021. All pts gave informed consent. The study is registered at ClinicalTrials.gov under the NCT number: NCT03249870. Results. Between DEC 29, 2017 and JUN 22, 2021, 115 pts (out of 130 planned pts) were enrolled including 6 pts with screen failure. The first 90 eligible pts (up to MAR 1, 2021) were considered for this analysis to obtain a minimum of 4 months follow-up. Median age was 69y (range 55-84) and median follow-up for alive pts was 1.18 years (range 0.3-3.5). At time of analysis, 90 and 88 pts had started induc1 and induc2, respectively. Treatment related mortality was 2.2% (2/90) and CR/CRp rate was 85.5% (77/90, 6 CRp) after induc1. Three cases relapsed between induc1 and induc2 and 5 pts were salvaged by induc2 allowing to a CR/CRp rate of 87.7% (79/90, 8 CRp) after induc2. One pts died from refractory disease during induc2. One, 2, 3 4 and 5 injections of INO were administered to 2 (2.2%), 2(2.2%), 11 (12.2%), 2 (2.2%) and 73 pts (81.1%) respectively. Only 6 pts were allografted. One-year OS was estimated to be 78.5% (95%CI 68-85.9) and median OS was not reached. One-year relapse free survival was 74.5% (95CI 63.5-82.6) (Figure 1). Grade 3-4 liver toxicity was observed in 8 pts (8.8%) during the study including 3 pts (3.3%) developing SOS, 2 related to INO during induc1 and one occurred after transplant. Twenty-nine pts died during the follow-up, 16 from relapses (overall incidence 18%) and 13 from adverse events (overall incidence 14.4%), including one COVID19 fatal infection during consolidation. Conclusion. Fractionated inotuzumab ozogamicin at reduced doses (0.8/0.5/0.5/0.5 mg/m²) combined with low-intensity chemotherapy is a very active and well tolerated frontline therapy for older patients with CD22+ Ph-neg BCP-ALL. Figure 1 Figure 1. Disclosures Doubek: Janssen-Cilag, AbbVie, AstraZeneca, Amgen, Gilead, Novartis: Honoraria, Research Funding. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Raffoux: ABBVIE: Consultancy; PFIZER: Consultancy; CELGENE/BMS: Consultancy; ASTELLAS: Consultancy. Boissel: CELGENE: Honoraria; Servier: Consultancy, Honoraria; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; PFIZER: Consultancy, Honoraria; JAZZ Pharma: Honoraria, Research Funding; SANOFI: Honoraria. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. OffLabel Disclosure: Inotuzumab ozogamicin as first line therapy in newly diagnosed CD22+ Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia

Imatinib Mesylate and Hyper-CVAD (IM-HCVAD) for Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4103-4103
Author(s):  
Martha Arellano ◽  
Disni Muringampurath-John ◽  
Pareen J. Shenoy ◽  
Elliott F. Winton ◽  
Beverly Bryan ◽  
...  
Keyword(s):  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Allogeneic Transplantation ◽  
Newly Diagnosed ◽  
Small Cohort ◽  
Cytogenetic Remission ◽  
Lost To Follow Up ◽  
Disease Free

Abstract Abstract 4103 Introduction The addition of IM to hyper-CVAD led to higher rates and longer duration of complete remissions in Ph+ ALL. The purpose of this study is to report single institution experience with IM-HCVAD followed by maintenance IM or allogeneic transplantation in newly diagnosed adult Ph+ ALL treated between 10/02 and 08/08. Methods IRB-approved retrospective analysis of the institutional hematological database. Results Thirty-three patients, median age 51 (22-72), with 8 (24%) older than 60, presented with a median WBC of 24,000/mm3 (range, 2-200) and LDH of 2.6 ULN (1.3-11). Four (12%) had extra-medullary/CSF leukemia. Patients received a median of 7 (range, 1-8) cycles of IM-HCVAD followed by maintenance IM +/- POMP as tolerated (Blood 2004;103:4396-4407). After 2 cycles, 1 patient had primary refractory disease and expired, and 32 (97%) achieved complete hematological and cytogenetic remission. Twenty-four of 32 (75%) subsequently achieved complete molecular remission (CMR). Among those who achieved CMR, 6/24 relapsed with preceding loss of CMR in 4. Four of 8 who did not achieve CMR relapsed. One patient in CR was lost to follow-up after induction. Thirteen (39%) were allografted in CR1 using TBI-based myeloablative (9) or non-myeloablative (4) conditioning and 18 received maintenance IM-based therapy. With a median follow-up of 18.3 months (range, 4.4-76), 10 patients (32%) relapsed (1 post-transplant and 9 during IM maintenance) and received salvage therapy leading to CR2 in 4, of which 1 was successfully allografted, and 3 remain in CR2 with a follow-up of 20, 36, and 60 months. Eleven patients died (6 from GVHD/infection, and 5 from relapsed refractory leukemia). For the 13 allograft recipients in CR1 disease-free (DFS) and overall survival (OS) were 15, and 18 months; and 15 months and 20 months for the 18 IM maintenance patients, respectively (Figure). WBC > 30,000/mm3 and residual disease detected by flow cytometry after 2 cycles were associated with decreased OS (p < 0.03). A trend for lower survival was noted among African American patients (p= 0.07). Conclusion The addition of IM to hyper-CVAD is associated with high rates of CR (97%) in newly diagnosed Ph+ ALL. In this relatively small cohort with a short follow-up, peripheral blood PCR did not predict outcomes. Ph+ALL patients are candidates for novel maintenance regimens. Disclosures: Off Label Use: Imatinib combined with the hyper-CVAD chemotherapy. Khoury:Novartis Oncology: Honoraria.

Fludarabine, Cytarabine, Daunoxome Plus Dasatinib Has High Efficacy with an Acceptable Toxicity Profile As Either Consolidation or Salvage Regimen in Adult Philadelphia Positive Acute Lymphoblastic Leukemia Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4908-4908 ◽  
Author(s):  
Giordana Pastori ◽  
Fabio Guolo ◽  
Daniela Guardo ◽  
Paola Minetto ◽  
Marino Clavio ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
The Other ◽  
Consolidation Therapy ◽  
Toxicity Profile ◽  
Newly Diagnosed ◽  
Salvage Regimen ◽  
Minimal Residual

Abstract BACKGROUND AND AIMS The prognosis of Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) patients has improved since the introduction of tyrosine kinase inhibitors (TKI). The inclusion of TKIs in standard ALL protocols allows a great increase in complete molecular responses, but at the price of non negligible toxicities and high rates of toxic deaths. On the other and TKI monotherapy as induction treatment allows to rapidly achieve complete hematologic remission (CR) but only a minority of patients achieve a complete molecular response with high risk of relapse. On the other hand, In the last years we tested a combination of Fludarabine, Cytarabine, Daunoxome (FLAD) with or without TKIs (mainly Dasatinib) as salvage regimen in relapsed-refractory ALL, with acceptable toxicity and good efficacy. We decided to apply the same schedule in newly diagnosed Ph+ ALL as consolidation treatment after a two months TKI (Dasatinib) monotherapy induction on a minimal residual disease condition. MATERIALS AND METHODS FLAD regimen consisted with a three-days administration of Fludarabine 30 mg/sqm followed four hours later by Cytarabine 2000 mg/sqm and Daunoxome 100 mg/sqm. TKI were suspended during chemotherapy administration and were re-administrated starting from day 5. G-CSF was given to all patients from day 4 to complete hematological recovery. FLAD was administrated for up to two cycles; all patients with available donor proceeded to allogeneic bone marrow transplantation (allo-BMT) after FLAD. Minimal residual disease (MRD) was evaluated in all patients after each FLAD either by RQ-PCR for VDJ rearrangements, multicolor flow cytometry (MFC) and RQ-PCR for BCR/Abl. Ten Ph+ ALL have been treated with FLAD + TKIs from January 2008 to December 2014: six patients received FLAD as salvage regimen, two of them in post allo-BMT setting, whereas four patients were treated frontline, after hematological CR was obtained with Dasatinib + steroids induction. All frontline patients proceeded to allo-BMT after two FLAD. Median age for frontline patients was 50 years (range 29-58), median follow-up was 20 months. RESULTS As salvage regimen, 5/6 patients achieved hematological CR after FLAD, with three patients achieving also MFC MRD negativity and clearance of VDJ and BCR/Abl transcript. All patients who did not receive subsequent BMT relapsed, whereas of the two transplanted patients one is still in CR after a follow-up of 38 months. In the frontline setting, all patients received 70 days induction of Dasatinib + Steroids and achieved CR with complete hematological recovery. BCR/Abl transcript could be detected in all patients on BM samples on day 33 and on day 70 (Fig. 1), two patientshad MFC MRD positivity both on day 33 and on day 70, whereas two patients achieved MFC MRD negativity on day 33. FLAD was very well tolerated, with negligible non hematological toxicity, with a median duration of ANC <500 and PLT <20000 of 7 and 9 days, respectively, slightly higher in the second course. Median time between the beginning of first and second course was 35 days, whereas median time from second course to allo-BM was 44 days. Two patients achieved BCR/Abl negativity after first FLAD. All patients achieved molecular complete response after the second course (Fig. 1). No patient experienced relapse, whereas one patient died in CR on day +289 after allo-BMT due to myocardial viral infection. CONCLUSIONS FLAD has a very good efficacy in adult Ph+ ALL, with an acceptable toxicity profile. Deep responses have been observed in relapsed patients, and all newly diagnosed patients who received FLAD as consolidation regimen had achieved molecular CR before allo-BMT. Achieving complete hematological response with Dasatinib + steroids allowed us to safely administer two FLAD courses. Figure 1. BCR/abl on bone marrow samples at different timepoints for each of the four patients receiving FLAD as consolidation therapy Figure 1. BCR/abl on bone marrow samples at different timepoints for each of the four patients receiving FLAD as consolidation therapy Disclosures Off Label Use: Use of liposomal daunorubicin in the treatment of ALL.

Vincristine (V), dactinomycin (A), and lower doses of cyclophosphamide (C) with or without radiation therapy for patients with newly diagnosed low-risk embryonal rhabdomyosarcoma (ERMS): A report from the Children’s Oncology Group (COG).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 9509-9509 ◽  
Author(s):  
David Walterhouse ◽  
Alberto S. Pappo ◽  
Jane L Meza ◽  
John C. Breneman ◽  
Andrea Anita Hayes-Jordan ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Complete Response ◽  
Low Risk ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Group Iii ◽  
Group I ◽  
Phase Iii Study ◽  
Stage 1

9509 Background: Intergroup Rhabdomyosarcoma Study (IRS) trials showed improved survival with VAC compared with VA for patients with Stage 1 Group III (non-orbit) or Stage 3 Group I/II ERMS (see table). In COG ARST0331, we hypothesized that VA in combination with lower doses of C (total cumulative dose=4.8 g/m2) would produce the benefit of IRS-IV VAC with less toxicity for patients with Stage 1 Group III (non-orbit) or Stage 3 Group I/II low-risk ERMS. Methods: This single arm, non-inferiority, phase III study enrolled newly diagnosed patients with Stage 1 Group III (non-orbit) ERMS or Stage 3 Group I/II ERMS onto Subset 2. Therapy was 4 cycles of VAC followed by 12 cycles of VA over 46 weeks (total cumulative doses: V=54 mg/m2, A=21.6 mg/m2, C=4.8 g/m2). The radiation therapy dose was 36 Gy for Group IIA patients, 41.4 Gy for Group IIB/C patients, and 50.4 Gy for Group III patients. From 2004–2008 girls with Group III vaginal RMS did not receive radiotherapy if a complete response was achieved with chemotherapy with or without delayed resection. The primary endpoint was failure-free survival (FFS), and results were compared with a fixed expected outcome. Results: With a median follow-up of 3.0 yrs, we observed 16 failures vs. 7.8 expected failures. Estimated 3-yr FFS was 63% (95% CI: 46%, 75%) (n=60), and overall survival (OS) was 84% (95% CI: 68%, 93%). Estimated 3-yr FFS was 46% (95% CI: 23%, 67%) for girls with non-bladder genitourinary tract ERMS (n=21) and 75% (95% CI: 53%, 88%) for all other Subset 2 patients (n=39). Conclusions: We observed suboptimal FFS of patients with Subset 2 low-risk RMS using reduced total cyclophosphamide (4.8 g/m2). Results were complicated by the choice of no radiation therapy for girls with vaginal tumors. Future studies for low-risk RMS Subset 2 patients could investigate a dose of C between 4.8 and 26.4 g/m2 with VA and local radiotherapy. [Table: see text]

A single-arm multicenter phase II trial of doxorubicin (Doxo) in combination with trabectedin (Trab) given as first-line treatment to patients with metastatic/advanced uterine (U-LMS) and soft tissue leiomyosarcoma (ST-LMS): Final results of the LMS-02 study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 11506-11506
Author(s):  
Patricia Pautier ◽  
Anne Floquet ◽  
Christine Chevreau ◽  
Nicolas Penel ◽  
Cecile Guillemet ◽  
...  
Keyword(s):  
Overall Survival ◽  
Residual Disease ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Response Duration ◽  
Phase Iii ◽  
Line Therapy ◽  
Phase Iii Study ◽  
Line Setting

11506 Background: U-LMS and ST-LMS are rare tumors with poor prognosis when locally advanced or metastatic, and with moderate chemosensitivity. Overall response rates (ORR) given in the 1st-line setting do not exceed 50% for U-LMS and 35% for ST-LMS with a mean response duration of 3- 6 months without impact on overall survival (OS). In 2015 we reported very encouraging results of the LMS-02 study (NCT02131480) with ORR of 59.6% in U-LMS, and 39.3% in ST-LMS with manageable toxicity (Pautier; Lancet oncol 2015). Herein, we report the updated results of progression-free survival (PFS) and final results of overall survival (OS). Methods: Patients (pts) received 60 mg/m² intravenous Doxo followed by trabectedin 1.1 mg/m2 as a 3-hour infusion on Day 1 and pegfilgrastim on Day 2, repeated every 3 weeks for up to 6 cycles. Surgery for residual disease was permitted. Patients were stratified into U-LMS and ST-LMS groups. Results: Overall, 108 patients with LMS with a median age of 59 years and mostly metastatic disease (85%) were enrolled. Of those, 77 patients (71.3%) have received all 6 cycles of treatment, and 20 patients (18.5%) had metastasis resection. With a median follow-up of 7.2 years (95% CI: 6.9 - 8.2), the overall median PFS was 10.1 months (95% CI: 8.5 - 12.6), being 8.3 months (95 CI: 7.4 - 10.3) and 12.9 months (95% CI: 9.2 - 14.1) in U and ST group, respectively. Median OS was 34.4 months (95% CI: 26.9 - 42.7), being 27.5 months (95% CI: 17.9 - 38.2) in U-LMS and 38.7 months (95% CI: 31.0 - 52.9) in ST-LMS group. The median OS among the 20 pts with surgery was not reached vs 31.6 months in the population without surgery (95% IC: 23.9 - 35.4). Conclusions: The Doxo +Trab combination is an effective 1st-line therapy for pts with LMS, with promising PFS and OS results and an acceptable safety profile. Merely for comparison, the most recent results of Doxo alone in metastatic LMS, given in 1st-line setting in a phase III ANNOUNCE trial conducted during the same period, reported median PFS of 6.9 months, and median OS of 21.9 months (ASCO 2019 LBA3). Results of the LMS04 trial (NCT02997358), a randomized phase III study comparing this combination vs Doxo alone in 1st-line therapy in metastatic LMS are pending. Clinical trial information: NCT02131480 .

Effect of consolidation with arsenic trioxide (As2O3) on event-free survival (EFS) and overall survival (OS) among patients with newly diagnosed acute promyelocytic leukemia (APL): North American Intergroup Protocol C9710

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2-2 ◽  
Author(s):  
B. L. Powell
Keyword(s):  
Disease Free Survival ◽  
Patient Characteristics ◽  
Phase Iii ◽  
Remission Induction ◽  
Cooperative Groups ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Phase Iii Study ◽  
To Receive

2 Background: This randomized phase III study was designed to evaluate the benefit and toxicity of two 25-day courses of As2O3 as first post-remission therapy for newly diagnosed patients with APL. Methods: Adult patients were randomized to receive 2 courses of As2O3 (0.15 mg/kg/d for 5d each wk for 5 wk) as a first consolidation if they achieved remission (CR or PR) after induction with oral tretinoin (ATRA; 45 mg/m2/d), daunorubicin (50 mg/m2 IV × 4d), and cytarabine (200 mg/m2 CIV × 7d); by study design, all but 2 children were assigned to the non-As2O3 arm. Subsequent consolidation on both arms included 2 courses of ATRA (45 mg/m2 × 7d) + daunorubicin (50 mg/m2 × 3d; 2d for age < 15 yr). CR patients were then randomized to 1 yr of ATRA maintenance (7d repeated every other wk) with or without 6- mercaptopurine (daily) + methotrexate (weekly). Results: 518 adults (15–79 yr) and 64 children (<15 yr; 11%) with untreated APL were enrolled by 5 cooperative groups (CALGB, ECOG, SWOG, COG, NCIC-CTG). Eligibility required demonstration of PML-RARA in one of 3 central labs; 37 adults and 7 children were ineligible and not included in the analyses. Patient characteristics and toxicity data have been reported (ASH 2006; Blood 108:171a). Median follow up is now 29 mos. Overall CR rate for adults was 89% and did not differ by treatment arm; CR rate for children was 89%. There were 41 deaths (8%) within 60 days. EFS, the primary endpoint, was 77% at 3 yrs on the As2O3 arm (median, not reached) compared to 59% at 3 yrs on the standard arm (median, 63 mos; p=0.0013). Overall, 84% of adults were alive at last follow up. OS was 86% at 3 yrs on the As2O3 arm compared to 77% at 3 yrs on the standard arm (medians not reached; p=0.029); EFS and OS for pediatric patients did not differ statistically from the adult arm without As2O3. Among 452 CR pts, there have been only 71 post-CR events (16%) so disease- free survival has not yet been analyzed by treatment arm. Conclusion: The addition of 2 courses of As2O3 consolidation following remission induction significantly improves EFS and OS in adults with APL. No significant financial relationships to disclose.

scholarly journals Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study

2020 ◽  
pp. JCO.20.02529
Author(s):  
Christina Peters ◽  
Jean-Hugues Dalle ◽  
Franco Locatelli ◽  
Ulrike Poetschger ◽  
Petr Sedlacek ◽  
...  
Keyword(s):  
Total Body Irradiation ◽  
Lymphoblastic Leukemia ◽  
Stopping Rule ◽  
Phase Iii ◽  
Unrelated Donor ◽  
Open Label ◽  
Hematopoietic Stem ◽  
Childhood All ◽  
Total Body

PURPOSE Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients. PATIENTS AND METHODS FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients ≤ 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129 ). RESULTS Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; P < .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17; P < .0001) and 0.02 (95% CI, < 0.01 to 0.05; P = .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively. CONCLUSION Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.

A phase III study of VMPT versus VMP in newly diagnosed elderly myeloma patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8515-8515 ◽  
Author(s):  
A. P. Palumbo ◽  
S. Bringhen ◽  
D. Rossi ◽  
S. Berretta ◽  
V. Montefusco ◽  
...  
Keyword(s):  
Chromosomal Abnormalities ◽  
Progression Free Survival ◽  
Total Sample ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Intention To Treat ◽  
Phase Iii Study ◽  
Grade 3 ◽  
To Receive

8515 Background: In MM patients VMP is superior to MP. In relapsed-refractory patients the 4 drug combination VMPT induced a high proportion of complete responses (CR). Methods: 500 newly diagnosed MM patients ≥ 65 years were randomly assigned to receive VMPT (N=247) or VMP (N=253). Patients were treated with nine 5-week cycles of VMPT (bortezomib 1.3 mg/m2 days 1, 8, 15, 22; melphalan 9 mg/m2 days 1–4; prednisone 60 mg/m2 days 1–4 and thalidomide 50 mg days 1–35) or VMP (bortezomib, melphalan and prednisone at the same doses and schedules previously described). Primary end-point was progression-free survival (PFS). Assuming the hazard ratio (VMP vs VMPT) of 1.35, the total sample size is 500 (250/arm) subjects (power 80%, 2-side alpha 0.05). Results: 354 patients (median age 71 years), who received at least 1 cycle were evaluated: 177 VMPT and 177 VMP. Data were analyzed in intention-to-treat. The VGPR rate was 55% in the VMPT group and 45% in the VMP group (p<0.001). After a median follow-up of 14.5 months, the 3-year PFS was 74% in the VMPT group and 70% in the VMP group (HR=0.75, 95% CI 0.45–1.26, p=0.28). The 3-year overall survival (OS) was 88% in the VMPT group and 87% in the VMP group (HR=0.89, 95% CI 0.42–1.87, p=0.75). Subgroup analyses did not show any statistical difference between responses/PFS and either ISS or chromosomal abnormalities (t(4;14) or t(14;16) or del17) in both groups. Age > 75 years was associated with lower VGPR rate (p=0.02) in VMPT but not in VMP. Factors predictive of longer PFS were age ≤ 75 years (p=0.003) and the achievement of VGPR (p=0.0005) in VMPT but not in VMP. The incidence of grade 3–4 adverse events (AEs) was similar in both groups. In the VMPT patients and in the VMP patients, the more frequent AEs were neutropenia (36% vs 31%), thrombocytopenia (20% vs 19%), peripheral neuropathy (18% vs 12%) and infections (14% vs 10%), respectively. Conclusions: VMPT is superior to VMP in terms of response rates. Longer follow-up is needed to assess their effects on PFS and OS. Both regimens appeared to overcome the poor prognosis of ISS and chromosomal abnormalities. An update of these data will be presented. [Table: see text]

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