Final Analysis of the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 Trial: All-Trans Retinoic Acid (ATRA), Intravenous Arsenic Trioxide (ATO) and Idarubicin (IDA) As Initial Therapy for Acute Promyelocytic Leukemia (APL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 375-375 ◽  
Author(s):  
Harry J Iland ◽  
Marnie Collins ◽  
Mark S Hertzberg ◽  
Michael Seldon ◽  
Andrew P Grigg ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Adverse Events ◽  
Arsenic Trioxide ◽  
Final Analysis ◽  
Risk Category ◽  
Cutaneous Toxicity ◽  
Free Survival ◽  
Increased Risk ◽  
Grade 3

Abstract BACKGROUND The combination of ATRA and anthracycline-based chemotherapy has traditionally been regarded as the gold standard for induction and consolidation in previously untreated APL patients (pts), with ATO usually reserved for relapse. Recent data in Sanz low-risk (LR) and intermediate-risk (IR) APL indicate ATRA + ATO is superior to ATRA + chemotherapy (N Engl J Med 2013), but the optimal therapy for high-risk (HiR) pts remains unclear. In an attempt to improve anti-leukemic efficacy whilst limiting reliance on anthracyclines for all risk categories of APL, the ALLG incorporated ATO into an ATRA + reduced chemotherapy backbone, and the results of an interim analysis with a median follow-up of 2 years (yr) have been published (Blood 120:1570, 2012). Herein, we report results of the protocol-specified final analysis, conducted when all surviving pts had been followed for at least 2 yr after completion of consolidation. METHODS As published, APML4 protocol treatment comprised: (i) induction with ATRA (45 mg/m2 d1-36), IDA (12 mg/m2 d2,4,6,8), ATO (0.15 mg/kg d9-36), prophylactic prednisone (1 mg/kg d1-10) and aggressive hemostatic support; (ii) consolidation with ATRA and ATO (continuous in cycle 1, intermittent in cycle 2); (iii) 2 yr oral maintenance with ATRA, 6-mercaptopurine and methotrexate. Between 2004-2009, 124 evaluable pts were accrued, and median follow-up by the censor-reversing Kaplan-Meier method in this final analysis is 4.2 yr. RESULTS Median age was 44 (3-78) yr, median white cell count was 2.4 x 109/L (0.1-85.8), and median platelet count 22 x 109/L (2-173). Risk groups were 33 LR, 67 IR, 23 HiR, 1 unknown. FLT3 mutations were present in 44%, and 11% had ≥ 2 additional cytogenetic abnormalities (2+ACA). There were 4 (3.2%) deaths during induction (myocardial infarction d1, cerebral hemorrhage d3 and d7, cerebral edema and seizures d30). Grade 3-4 non-hematological adverse events included differentiation syndrome in 14%, and frequent but reversible biochemical hepatic and gastrointestinal toxicity. Q-Tc prolongation > 500 msec occurred in 14%, but there were no cases of ventricular arrhythmias or torsades de pointe. Significant neurological and cutaneous toxicity were infrequent. After induction, 118 pts (95%) achieved hematological complete remission; 112 commenced consolidation, and all were in molecular remission after cycle 2. A total of 5 relapses and 3 deaths have occurred post-induction, but none of the deaths were attributable to protocol therapy. Severe adverse events were less common during the chemotherapy-free consolidation cycles, especially cycle 2. The frequency of grade 3-4 neutropenia was 62% in cycle 1 and 27% in cycle 2, but there was no grade 3-4 thrombocytopenia. The following table lists event-free survival (EFS), disease-free survival (DFS), overall survival (OS) and cumulative incidence of relapse (CIR): Table All pts LR IR HiR 2 yr 5 yr 2 yr 5 yr 2 yr 5 yr 2 yr 5 yr EFS 92% 90% 97% 97% 93% 89% 83% 83% DFS 97% 95% 100% 100% 97% 93% 95% 95% OS 94% 94% 97% 97% 96% 96% 87% 87% CIR 3% 5% 0% 0% 3% 7% 5% 5% In univariate analysis, 2+ACA predicted for inferior DFS (P = .04), whereas age > 70 was associated with increased risk of early death (ED, P = .02), inferior EFS (P = .0002), and inferior OS (P = .001). Neither Sanz risk category nor FLT3 mutation status was significantly correlated with these outcome endpoints (all P > .05). In multivariate analysis, the significant associations of 2+ACA (P = .04 for DFS) and age > 70 (P = .0002 for EFS, P = .005 for OS) were retained. In addition, Sanz risk category was correlated with EFS (P[trend] = .003) and OS (P[trend] = .02). When compared with our previous ALLG APML3 trial (ATRA + IDA for induction and consolidation without ATO; Haematologica 2012), treatment with APML4 was associated with substantial and statistically significant improvements (see Figure) in EFS (P = .002), DFS (P = .001) and OS (P = .02). The significance of trial assignment was retained in multivariate analysis when APML3 and APML4 data were combined. CONCLUSIONS APML4 is a potent anti-leukemic regimen with manageable toxicity and a low ED rate. EFS and OS remain impressive with mature follow-up, and were influenced primarily by advanced age and Sanz risk category. The CIR was 5%, and was only associated with 2+ACA. Our results support the inclusion of ATO in induction and consolidation as front-line therapy for APL whilst simultaneously limiting cumulative anthracycline exposure. Figure 1 Figure 1. Disclosures Off Label Use: Arsenic trioxide is currently only registered in the US, Europe and Australia for the treatment of relapsed APL. This report includes its use in the initial treatment of APL.

Long-term follow-up of previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) treated with ofatumumab (OFA) and chlorambucil (CHL): Final analysis of the phase 3 COMPLEMENT 1 trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7528-7528
Author(s):  
Fritz Offner ◽  
Tadeusz Robak ◽  
Ann Janssens ◽  
Govind Babu Kanakasetty ◽  
Janusz Kloczko ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Final Analysis ◽  
Lymphocytic Leukemia ◽  
Primary Analysis ◽  
Free Survival ◽  
Anti Cancer ◽  
Long Term Follow Up ◽  
Grade 3

7528 Background: Previously in the COMPLEMENT 1 study, treatment with OFA and CHL in pts with untreated CLL had shown a significant improvement in the progression-free survival (PFS) compared with CHL alone, and was well tolerated. Here, we report the final overall survival (OS) analysis of the 5-year (y) follow-up, updated investigator-assessed PFS and safety from the study. Methods: Untreated pts, not fit for fludarabine-based therapy (due to advanced age or co-morbidities) were randomized 1:1 to OFA+CHL or CHL alone. Pts in OFA+CHL arm received OFA (Cycle 1: 300 mg day (d) 1, 1000 mg d8; subsequent cycles: 1000 mg d1) in addition to CHL (10 mg/m2, d1-7) for 3 to 12 cycles of 28 d each. Pts in CHL arm received CHL only. Results: Overall, 447 pts were randomized to OFA+CHL (n = 221) or CHL (n = 226); 168 (76%) and 164 (73%) pts completed the scheduled treatments, respectively. Baseline characteristics were similar in both arms. The investigator-assessed median PFS was 23.4 months (mos) in the OFA+CHL arm and 14.7 mos in the CHL arm (HR: 0.61 [95% CI 0.49, 0.76], p < 0.001). Median OS could not be estimated for the OFA+CHL arm and was 84.7 mos for the CHL arm (HR: 0.88 [95% CI 0.65, 1.17], p = 0.363). Estimated OS rate (95% CI) at 5 y was 68.5% (61.5%, 74.5%) in the OFA+CHL arm, and 65.7% (58.6%, 71.9%) in the CHL arm. Post-treatment anti-cancer therapy after discontinuation was received by a greater proportion of pts in the CHL (66%) vs. OFA+CHL (56%), and started earlier in the CHL arm (486 d) vs. OFA+CHL (743 d) arm. Overall, 84 (39%) pts in the OFA+CHL, and 99 (44%) pts in the CHL arms died during the study with 5 on-treatment deaths in each group. Grade ≥3 adverse events were seen in 64% and 48% of pts in the OFA+CHL vs. CHL arms, respectively, most common being (≥5% in either arm) neutropenia (26% vs. 15%), thrombocytopenia (5% vs. 10%), pneumonia (9% vs. 5%), and anemia (5% vs. 5%). Conclusions: This 5-y survival follow-up analysis supported the results from primary analysis with an estimated 12% (not significant) and 39% risk reduction in OS and PFS, respectively, in the OFA+CHL arm compared with the CHL arm. No new safety concerns were observed in the OFA+CHL arm. Clinical trial information: NCT00748189.

125I Brachytherapy for Localized Prostate Cancer: A Single Institution Experience

2013 ◽  
Vol 99 (1) ◽  
pp. 83-87 ◽  
Author(s):  
Alessia Guarneri ◽  
Angela Botticella ◽  
Andrea Riccardo Filippi ◽  
Fernando Munoz ◽  
Giancarlo Beltramo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Multivariate Analysis ◽  
Early Stage ◽  
Disease Free Survival ◽  
Localized Prostate Cancer ◽  
Free Survival ◽  
Genitourinary Toxicity ◽  
Grade 3 ◽  
Disease Free

Aims and background To evaluate the clinical outcome of a cohort of localized prostate cancer patients treated with 125I permanent brachytherapy at the University of Turin. Methods and study design A retrospective analysis was carried out on 167 consecutive patients with early stage prostate adenocarcinoma who underwent 125I brachytherapy between January 2003 and December 2010. A minimum follow-up of ≥12 months was mandatory for inclusion. Biochemical disease-free survival (defined on the basis of the ASTRO definition and the ASTRO-Phoenix definition) was chosen as the primary end point. Secondary end points were gastrointestinal and genitourinary toxicity (acute and late, defined according to the RTOG scale). Results With a median follow-up of 42 months (range, 13.5–90.7), biochemical disease-free survival at 3 and 5 years was respectively 91.1% and 85.7%, according to the ASTRO definition and 94.5% and 85.1% according to ASTRO-Phoenix definition (for statistical purposes, only the ASTRO definition was used). Hormone treatment and nadir PSA (cutoff of 0.35 ng/ml) were the only factors affecting biochemical disease-free survival both on univariate ( P = 0.02 and P = 0.001, respectively) and multivariate analysis (HR 0.024; P = 0.021 and HR 21.6; P = 0.006, respectively). Only 3.6% of patients experienced ≥grade 3 acute urinary toxicity and 5% ≥grade 3 late urinary toxicity. Prior transurethral prostate resection was the only independent predictor of grade 3 late urinary toxicity on multivariate analysis (HR 0.13; P = 0.009). Conclusions This mono-institutional series confirmed that brachytherapy is an effective and safe treatment modality for localized prostate cancer, with acceptable short- and long-term morbidity rates.

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

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

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

scholarly journals Analysis of cardiovascular and arteriothrombotic adverse events in chronic-phase CML patients after frontline TKIs

2019 ◽  
Vol 3 (6) ◽  
pp. 851-861 ◽  
Author(s):  
Preetesh Jain ◽  
Hagop Kantarjian ◽  
Prajwal C. Boddu ◽  
Graciela M. Nogueras-González ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Adverse Events ◽  
Myeloid Leukemia ◽  
Regression Models ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Increased Risk ◽  
Prospective Trials ◽  
Grade 3 ◽  
New Onset

Abstract Cardiovascular or arteriothrombotic adverse events (CV- or AT-AEs) are reported in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs). The incidence and characteristics across different TKI have not been systematically analyzed. We analyzed 531 patients treated with frontline TKIs in different prospective trials: imatinib 400 mg (n = 71) and 800 mg (n = 203), nilotinib (n = 108), dasatinib (n = 106), and ponatinib (n = 43). Characteristics and incidence of new-onset CV-AEs and AT-AEs were analyzed. Poisson regression models assessed factors associated with AE incidence. Median follow-up was 94 months (range, 2-195). Overall, 237 patients (45%) developed CV-AEs and 46 (9%) developed AT-AEs. Hypertension was the most common AE seen in 175 patients (33%; grade 3/4 in 17%). CV-AE and AT-AE incidence ratios (IRs) with 95% confidence intervals (CIs) were 8.6 (7.6-9.8) and 1.7 (1.2-2.2) per 100 person-years. Among the TKIs, ponatinib showed the highest IR (95% CI) for CV-AEs and AT-AEs at 40.7 (27.9-59.4) and 9.0 (4.1-20.1). In multivariate analysis, ponatinib therapy was associated with increased incidence rate ratio (IRR) for CV-AEs (4.62; 95% CI, 2.7-7.7; P &lt; .0001) and AT-AEs (6.38; 95% CI, 1.8-21.8; P &lt; .0001) compared with imatinib 400. In summary, there is an increased risk of CV-AEs (except hypertension) and AT-AEs in CML patients treated with newer TKIs, particularly with ponatinib. Patients on TKIs must be informed and closely monitored for vascular AEs. These studies were registered at www.clinicaltrials.gov as #NCT00048672, #NCT00038649, #NCT00050531, #NCT00254423, #NCT00129740, and #NCT01570868.

QTWIST analysis in the RECOURSE trial.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 698-698 ◽  
Author(s):  
Josep Tabernero ◽  
Eric Van Cutsem ◽  
Atsushi Ohtsu ◽  
Nadia Amellal ◽  
Stéphanie Cadour ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Adverse Events ◽  
Progression Free Survival ◽  
Health State ◽  
Free Survival ◽  
Utility Coefficient ◽  
Grade 3 ◽  
Overall Survival Benefit

698 Background: RECOURSE showed that treatment with trifluridine/tipiracil in patients in patients (pts) with refractory metastatic colorectal cancer was associated with significantly improved survival vs placebo. As quality of life (QoL) was not captured in the trial, other methods were used to evaluate potential impact on QoL. Methods: We used the QTWIST method, i.e. quality-adjusted TWIST (time without symptoms of disease or toxicity), to explore survival adjusted for QoL with trifluridine/tipiracil vs placebo in the RECOURSE population. QTWIST incorporates a trade-off between time spent with treatment-related adverse events versus improvement in progression-free survival, and combines an estimate of the mean duration of each health state (TOX, TWIST, and RELAPSE [REL]), weighted by a utility coefficient, into a global QTWIST score. TOX represents time with grade 3/4 treatment-related adverse events that are expected to impact QoL (i.e. nausea, vomiting, diarrhea, fatigue/asthenia, anorexia, febrile neutropenia) before progression, TWIST represents time without symptoms or toxicity; and REL represents time from progression (as defined in the RECOURSE trial) until death. We applied a utility coefficient of 1 for TWIST and values of 0.5 for TOX and REL. A sensitivity analysis varied the utility coefficients for TOX and REL from 0 to 1. Results: 798 pts (533 trifluridine/tipiracil vs 265 placebo) were included with median follow-up time of 11.8 mo. The between-group difference in the global QTWIST score was 1.5 mo (95% CI, 1.49–1.52) in favor of trifluridine/tipiracil. Using varying utility coefficients for TOX and REL from 0 to 1 as a sensitivity analysis, the between-group difference in the global QTWIST score ranged from 1.3 to 1.7 mo, always in favor of trifluridine/tipiracil. Conclusions: The median overall survival benefit observed with trifluridine/tipiracil vs placebo in RECOURSE was 1.8 months. Consistently, patients' QoL as evaluated by QTWIST showed that quality-adjusted survival with Lonsurf is significantly improved by 1.5 months vs placebo. Clinical trial information: NCT01607957. [Table: see text]

Arsenic trioxide dose capping to decrease toxicity in the treatment of acute promyelocytic leukemia

2021 ◽  
pp. 107815522110247
Author(s):  
Kyle Zacholski ◽  
Bryan Hambley ◽  
Erin Hickey ◽  
Sarah Kashanian ◽  
Andrew Li ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Survival Rates ◽  
Disease Free Survival ◽  
Promyelocytic Leukemia ◽  
Free Survival ◽  
All Trans Retinoic Acid ◽  
Grade 3 ◽  
Disease Free

Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination therapy yields high complete remission and disease-free survival rates in acute promyelocytic leukemia (APL). ATO is dosed on actual body weight and high ATO doses in overweight patients may contribute to increased toxicity. We performed a retrospective, two-center study comparing toxicities in patients who received the Lo-Coco et al ATRA/ATO regimen with capped ATO, ≤10 mg/dose, and non-capped ATO, >10 mg/dose. A total of 44 patients were included; 15 received doses ≤10 mg and 29 received >10 mg. During induction, there was no difference in the incidence of grade ≥3 hepatotoxicity, grade ≥3 QTc prolongation, neurotoxicity, and cardiac toxicity between groups. In consolidation, patients receiving >10 mg/dose experienced a greater incidence of neurotoxicity (66.7% vs 22.2%; p = 0.046). Capping doses saved $24634.37/patient and reduced waste of partially-used vials. At a median follow-up of 27 months, no disease relapses occurred in either group. This represents an opportunity to improve the safety profile of this highly effective regimen.

scholarly journals Survival analysis of afatinib versus erlotinib for individuals with advanced del19 lung adenocarcinoma with asymptomatic brain metastasis after pemetrexed-cisplatin chemotherapy: a retrospective study

2020 ◽  
Vol 48 (8) ◽  
pp. 030006052093709
Author(s):  
Ye Jiang ◽  
Wenli Chen ◽  
Weiguang Yu ◽  
Ning Shi ◽  
Guowei Han ◽  
...  
Keyword(s):  
Brain Metastasis ◽  
Lung Adenocarcinoma ◽  
Primary Outcome ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Free Survival ◽  
Median Progression Free Survival ◽  
Secondary Outcomes ◽  
Grade 3

Objective To evaluate survival following afatinib (AF) and erlotinib (ER) treatment in advanced del19 lung adenocarcinoma (AD19LA) with asymptomatic brain metastasis (ABM) after pemetrexed–cisplatin chemotherapy (PCC). Methods Data were retrospectively analysed from individuals with AD19LA and ABM after PCC who received AF or ER for 2 years or until intolerable adverse events (AEs), withdrawal, or death. The primary outcome was survival; secondary outcomes were AEs. Results The final analysis included 174 AD19LA individuals (AF: n = 86; ER: n = 88) with a median follow-up of 24.2 months (IQR 2.1–28.3). Significant differences in overall survival (16.2 months [95%CI 15.4–17.1] for AF vs 7.2 months [95%CI 6.3–8.1] for ER) (HR 0.50, 95%CI 0.36–0.71, p<0.0001) and median progression-free survival (9.4 months [95%CI 8.5–9.7] for AF vs 5.6 months [4.7–6.2] for ER) (HR 0.66, 95%CI 0.47–0.94, p=0.02) were observed between the groups. Rates of all-grade AEs were 82.5% for AF and 72.7% for ER, and rates of grade ≥3 AEs were 37.2% for AF and 34.0% for ER. Conclusion Compared with ER, AF treatment may be more beneficial in terms of survival in the management of AD19LA after PCC with a tolerable safety profile.

scholarly journals Incidence, Outcomes and Predictors of Acute Kidney Injury Post Allogeneic Stem Cell Transplant

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 16-17
Author(s):  
Kayla Madsen ◽  
Gabrielle Cote ◽  
Karyne Pelletier ◽  
Abhijat Kitchlu ◽  
Shiyi Chen ◽  
...  
Keyword(s):  
Kidney Injury ◽  
Multivariate Models ◽  
Relapse Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Increased Risk ◽  
Grade 3

INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers cure for some patients with hematological diseases but is associated with significant risk of morbidity and mortality. Acute kidney injury (AKI) represents an important cause of post-transplant complications, often multifactorial in the unique setting of allo-HSCT. However, to date, there is limited information on the overall impact of AKI in this patient population. To address this, we retrospectively reviewed the effect of AKI on transplant outcomes at Princess Margaret Cancer Centre (PMCC). METHODS: The study included 408 patients transplanted at PMCC between January 2015-January 2018 for any indication, using either reduced intensity (RIC) or myeloablative conditioning (MAC). Median follow-up time was 23 months. AKI was defined using the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Demographics, clinical characteristics and transplant related variables were extracted from patient records and the institutional allo-HSCT database. Univariate and multivariate Cox proportional hazard models were used to examine associations between AKI and outcomes including overall survival (OS), relapse free survival (RFS), graft versus host disease (GVHD) and relapse-free survival (GRFS). Univariate and multivariate Fine and Gray competing risk models were used to examine the association between AKI and incidence of relapse, treatment related mortality (TRM), grade 2-4 acute GVHD (aGVHD), grade 3-4 aGVHD and moderate-severe chronic GVHD (cGVHD). Multivariate models were used to examine the association of AKI and outcomes of interest, while adjusting for potential risk factors. RESULTS: The overall incidence of AKI at 100 days was 64% (stage 1: 62.6%, stage 2: 22.5% and stage 3: 14.8%). Dialysis was required in 2% of these patients. Mean baseline eGFR in the AKI group was 94.4 mL/min/1.73m2 (IQR 42, 141) vs 96.9 mL/min/1.73m2 (IQR 45.7, 142.9) in the non-AKI group. Patient-related risk factors for development of AKI were age over 60 (p=0.001), male gender (p=0.05), diabetes (p=0.004) and hypertension (p=0.003). Transplant related characteristics associated with AKI were MAC conditioning (p=0.02), veno-occlusive disease (p&lt;0.0001), BK viremia (p=0.01), thrombotic microangiopathy (p=0.009), bacterial infections (p=0.001) and more than two cytomegalovirus (CMV) reactivations (p=0.02). There was no difference in mean cyclosporine levels in the first 100 days between patients who developed AKI and those who did not (p=0.80). AKI was less common in patients who received GVHD prophylaxis with dual T-cell depletion (TCD) with anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) (p&lt;0.001) than those who received alternative GVHD prophylaxis. In the univariate analyses, compared with patients who did not have AKI, those with AKI had inferior 2-y OS: 46% versus 63% (p=0.0004). AKI patients had lower 2-y GRFS (29% vs 45%, p=0.0002), higher 2-y TRM (31% versus 17%, p=0.0003), and higher incidence of day 100 grade 3-4 aGVHD (13% vs 6%, HR 2.18, 95% CI=1.18-4.01, p=0.01). In multivariate analysis, AKI was associated with decreased 2-y OS (HR= 1.36, 95% CI 1.00-1.65, p=0.048), 2-y GRFS (HR= 1.42, 95% CI 1.10-1.82, p=0.006), and increased risk of day 100 grade 3-4 aGVHD (HR= 1.93, 95% CI 1.04-3.58, p=0.03). There was an association between AKI and TRM, specifically in those patients with stage 2 (HR= 1.76, 95% CI 1.06-3.30, p=0.03) and stage 3 AKI (HR= 2.64, 95% CI 1.44-4.83, p=0.002) compared to no AKI. In multivariate models, there was no association between AKI and relapse (p=0.65), grade 2-4 aGVHD (p=0.7) or moderate-severe cGVHD (p=0.81). CONCLUSION: Patients who develop AKI within 100 days of transplant have lower OS, GRFS, and higher grade 3-4 aGVHD and TRM. The use of dual TCD for GVHD prophylaxis is associated with lower risk of AKI, suggesting this may be a favorable regimen for those at increased risk for AKI. Contrary to previously published literature, there was no difference in cyclosporine levels between the non-AKI and AKI groups, suggesting that it may not be a significant cause of AKI post-transplant. AKI was more common in patients who had multiple episodes of CMV reactivation, highlighting the importance of CMV prophylaxis. AKI patients require close follow up, preventative strategies and monitoring for new or progression of chronic kidney disease post transplant. Disclosures Madsen: Jazz Pharmaceuticals: Honoraria. Pelletier:Celgene: Honoraria; International Kidney and Monoclonal Gammopathy: Membership on an entity's Board of Directors or advisory committees. Mattsson:Jazz Pharmaceuticals: Honoraria; ITB: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Mallinkrodt: Honoraria; Gilead: Honoraria.

scholarly journals Ofatumumab maintenance prolongs progression-free survival in relapsed chronic lymphocytic leukemia: final analysis of the PROLONG study

2019 ◽  
Vol 9 (12) ◽  
Author(s):  
Marinus van Oers ◽  
Lukas Smolej ◽  
Mario Petrini ◽  
Fritz Offner ◽  
Sebastian Grosicki ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Lymphocytic Leukemia ◽  
Free Survival ◽  
Median Progression Free Survival ◽  
Third Line ◽  
Grade 3 ◽  
Third Line Treatment

AbstractWe report the final analysis of the PROLONG study on ofatumumab maintenance in relapsed chronic lymphocytic leukemia (CLL). In all, 480 patients with CLL in complete or partial remission after second- or third-line treatment were randomized 1:1 to ofatumumab (300 mg first week, followed by 1000 mg every 8 weeks for up to 2 years) or observation. Median follow-up duration was 40.9 months. Median progression-free survival was 34.2 and 16.9 months for ofatumumab and observation arms, respectively, (hazard ratio, 0.55 [95% confidence interval, 0.43–0.70]; P < 0.0001). Median time to next treatment for ofatumumab and observation arms, respectively, was 37.4 and 27.6 months (0.72 [0.57–0.91]; P = 0.0044). Overall survival was similar in both arms; median was not reached (0.99 [0.72–1.37]). Grade ≥ 3 adverse events occurred in 62% and 51% of patients in ofatumumab and observation arms, respectively, the most common being neutropenia (23% and 10%), pneumonia (13% and 12%) and febrile neutropenia (6% and 4%). Up to 60 days after the last treatment, four deaths were reported in the ofatumumab arm versus six in the observation arm, none considered related to ofatumumab. Ofatumumab maintenance significantly prolonged progression-free survival in patients with relapsed CLL and was well tolerated.

Oral Melphalan, Prednisone and Thalidomide for Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 779-779
Author(s):  
Antonio Palumbo ◽  
Sara Bringhen ◽  
Pellegrino Musto ◽  
Tommaso Caravita ◽  
Rosanna Capozzi ◽  
...  
Keyword(s):  
Adverse Events ◽  
Response Rate ◽  
Progression Free Survival ◽  
Hazard Ratio ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Grade 3 ◽  
Lost To Follow Up ◽  
To Receive

Abstract In newly diagnosed multiple myeloma (MM) patients, the combination melphalan, prednisone and thalidomide (MPT) induces a fast tumor response with a high response rate, but evidence that this translate into improved outcome is limited. This multicenter trial compared the efficacy and the toxicity of oral MPT with oral melphalan and prednisone (MP) in previously untreated patients. From January 2002 to December 2004, we randomised 255 patients, who were older than 65 years of age (median age 72). Data analysis was performed on July 2005. The MPT regimen included oral melphalan (4 mg/m2 for 7 days) and prednisone (40 mg/m2 7 days) for six four week cycles plus thalidomide (100 mg per day continuously until any sign of relapse or progressive disease) The MP regimen was as MPT without thalidomide. Patients who were not assigned to receive thalidomide were permitted to cross over to receive thalidomide after relapse or disease progression. Patients treated with MPT experienced higher response rates and a longer time to progression (primary end points) than patients who did not receive thalidomide. The overall response rate was 76% for MPT and 48% for MP alone (P&lt;0.0001), and the near complete response rates were 28% and 7%, respectively (P&lt;0.0001). Median progression free survival in the MPT and in the MP groups was 33 months and 14 months, respectively (hazard ratio, 0.47; P&lt;0.001). MPT increase median progression free survival by almost 19 months. The 2-yr survival rate was 82% in MPT patients and 65% in MP patients (hazard ratio, 0.68; P=0.2). In MPT group, 33 patients did not complete the 6 courses because of progression disease (9), toxicity (16), death (2), and withdrawal of consent or lost to follow-up (6). In MP group, 32 patients did not complete the 6 courses because of progression disease (19), toxicity (3), death (3), and withdrawal of consent or lost to follow-up (7). By looking at those patients who completed the assigned 6 cycles in both arms, the 2-yr survival rate was 90% in MPT patients and 71% in MP patients, the difference was statistically significant (hazard ratio, 0.39; P&lt;0.01). Grade 3 or 4 adverse events were reported in 49% of patients treated with MPT and in 25% of those treated with MP: they included thromboembolism (12% versus 2% of patients), infections (10% versus 1%), peripheral neuropathy (10% versus 1%), and hematologic toxicity (22% versus 25%) respectively. In the first 64 patients who received MPT, grade 3–4 adverse events were reported in 58% of patients. In the last 65 MPT patients, the incidence of grade 3–4 adverse events was 40%. By comparing the first cohort with the second one, thromboembolism dropped from 22% to 3% (P&lt;0.01) and neurotoxicity from 13% to 8% (P=NS), respectively. The oral MPT was superior to the standard MP in patients with newly diagnosed myeloma. The adequate mangement of side effects reduced toxicity.

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