ALBERT

Description: Background: Several studies have suggested that genetic variability related with single nucleotide polymorphisms (SNPs) of the BER system, DNA synthesis and folate-metabolizing pathway genes could modulate DNA repair capacity. Moreover, these genes are supposed to be related to cancer risk. However, the prognostic impact of the association of individual and/or combined genetic variants in patients with myelodysplastic syndromes (MDS) remains undetermined. Methods: We genotyped 113 MDS patients, 54 with IPSS low/int-1 receiving only best supportive care (BSC group) and 59 with IPSS int-2/high treated with azacitidine (AZA-group), for the following polymorphisms: XRCC1 194 and 399, APE1 148, XRCC3 241, TS5'-UTR (2R/3R and G/C) and 3'-UTR (6bp+/6bp-), MTHFR 677 and 1298. Genomic DNA was analyzed by High Resolution Melting assay and restriction digests of PCR products. Overall survival (OS) was calculated using the Kaplan-Meier estimate probabilities, and differences between survival curves were analyzed by the log-rank test. Multivariate analyses were performed using the Cox method. Results: For all the target genes, the distribution of genotypes was consistent with the Hardy-Weinberg equilibrium. Among the baseline characteristics analyzed (age, sex, diagnosis according to WHO, hemoglobin) there was no statistically significant difference in the genotype distribution of studied polymorphisms. In the BSC group, the variants XRCC1 399 GG [Hazard ratio (HR)=7.07; p=0.02], -6/-6 of TS3'-UTR (HR=4.65; p=0.05), 2R/3G, 3C/3G, 3G/3G of TS5'-UTR (HR=11.44; p=0.02) and TT of MTHFR 677 (HR=67.12; p

Description: Abstract 2928 Introduction. The recent development of a safe and efficient once daily oral iron chelator (Deferasirox, ExjadeÒ) made possible regular chelation therapy in transfusion dependent MDS patients. However in this category of patients the reported clinical experience is limited to selected populations. For this reason the GIMEMA group developed a phase IIIb prospective trial to test safety and efficacy of Deferasirox in a large population of patients comparable to general MDS population. Methods. One hundred and fifty-nine transfusion dependent IPSS low-intermediate1 risk MDS patients were enrolled. Analysis has been performed on 123 patients who had completed the planned year of treatment. Baseline characteristics were the following (data are expressed as median with upper and lower quartile unless specifically indicated): median age was 72 years (range 24 – 87); 48 were IPSS low risk and 75 Intermediate1; duration of transfusion dependency before treatment was 20 months (12-36) corresponding to 38 (22-70) packed red blood cells transfusions received. Baseline serum ferritin was 2000 ng/ml (1471-3000). Baseline Charlson and CIRS comorbity scores were 1 (0-1) and 0.2 (0.1-0.4), respectively. Patients started treatment with the standard 20 mg/kg Deferasirox dose but dose adjustments on clinical indications were allowed. Results. 61 patients (49%) prematurely interrupted the study (drop out), 62 (51%) patients completed the planned year of treatment. In logistic model for drop out rate high Charlson co-morbidity score showed a trend as significant risk factors (p=0.06). Drops out were related to: ten patients (8%) had progression to acute leukemia during the study; twenty patients (16%) experienced MDS related clinical problem (three had cardiac failure, seven had severe infectious diseases, four had severe bleeding, three died at home, three presented others MDS related problems); five patients underwent hemopoietic stem cell transplantation and thirteen discontinued treatment for unrelated problems. Drug related toxicity was drop out cause in 13 patients (11% of the entire population). Main causes of toxicity related drops out were increase of creatinine and gastro-intestinal disturbance. Out of 123 patients analyzed for adverse events only 4 (3%) presented grade 3–4 drug related adverse events. Severe adverse events with suspected relationship with study drug were diarrhea and increase of liver enzymes. Serum ferritin was monthly recorded in the 62 patients who completed the protocol with a statistically significant decrement during the 12 months follow up: median baseline value 2000 ng/ml (interquartile range 1471–3000), median final value 1550 ng/ml (interquartile range 775–2200) P 〈 0.001, Friedman test analyzing the entire study period. Analysis of quality of life is ongoing. One patient showed a complete erythroid response to Deferasirox treatment acquiring transfusion independence that is still ongoing after 18 months. Discussion. Preliminary results from the GIMEMA MDS0306 study confirmed feasibility of Deferasirox therapy in transfusion dependent MDS patients. Drop out rate, toxicity related drop out and severe side effects were similar to those reported in other trials even if the present population presented clinical characteristics of more advanced disease and age. The rate of progression is coherent with prolonged disease story. Serum ferritin behavior confirms Deferasirox efficacy. The serum ferritin reduction was more evident in the more heavily overloaded population indicating successful iron depletion in this group of patients as clinically requested. ClinicalTrial.gov identifier NCT00469560. Disclosures: Angelucci: Novartis: Honoraria. Saglio:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria.

Description: Abstract 257 The AML-12 randomized phase III trial of EORTC-LG and GIMEMA assessed the efficacy and toxicity of HD-AraC (3 g/sqm/12 hrs for 4 days) combined with daunorubicin (50 mg/sqm/d for 3 days) and etoposide (50 mg/sqm/d for 5 days) vs SD-AraC (100 mg/sqm/d for 10 days) with the same drugs, in previously untreated AML 〈 61 year old patients (APL excluded). Patients (pts) in complete remission (CR) had to receive consolidation consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin. Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability and age. A 2nd randomization had to be done after evaluation of consolidation in pts without a donor: auto-SCT followed or not by low dose IL-2. The aim of the trial was to detect an 8% treatment difference (from 35% to 43%) in the 5-yr overall survival (OS) rate, corresponding to a hazard ratio (HR) of 0.80 (alpha=5%, power=95%); secondary endpoints were response to induction, toxicity, disease-free survival (DFS) from CR. Randomization was performed centrally; the 1st randomization was stratified for age ( 45 yrs), performance status, WBC and center. Intent-to-treat analysis was done. From 9/1999 till 1/2008, 2005 pts from 68 centers were randomized. Due to insufficient reporting, 3 centers, who recruited 63 patients, have been excluded from the analysis. The remaining 1942 pts (872 pts entered by EORTC-LG and 1070 by GIMEMA) 969 were randomized in SD-AraC and 973 in HD-AraC arm; among them 25 and 28, respectively, were ineligible, but kept in the analysis. Both arms were comparable with respect to gender, age (median=45 yrs), disease history, initial leukocyte count, PS, FAB and cytogenetics. At a median follow up of 6 yrs, 1114 pts had died. Results: After 1 or 2 courses of induction, CR was achieved in 1430 pts (73.6%); 684 (71.9%) pts (SD-AraC group) vrs 746 (78.7%) pts (HD-AraC group): p=0.002. Resistance was documented in 173 (18.2%) vrs 123 (13%), and death during induction in 85 (8.9%) vrs 71 (7.5%) pts, respectively. Induction toxicity profile and grade was similar in the 2 arms except for conjunctivitis grade 3: HD-AraC〉SD-AraC. CR rates for pts45 yrs 66.4% (SD-AraC) and 71.8% (HD-AraC). 634 pts (SD-AraC and 686 (HD-AraC) received a consolidation cycle. Among 765 CR-pts45NoD). In the 45NoD group 244 underwent an auto-SCT and 12 a MUD-SCT. Comparisons of treatments arm regarding OS from randomization, DFS and Survival (S) from CR are indicated in the Table. The impact of age on the treatment difference regarding OS was almost significant (p=0.06). In pts 〉45 who reached CR, the decrease in the relapse rate in the HD-Ara-C arm vrs SD-Ara-C arm (45.5% vs 49.4%) was counterbalanced by an increase in the death in CR rate (18.4% vs 13.2%). Conclusion: The final evaluation of the EORTC-GIMEMA AML-12 trial shows that, with a median follow-up of 6 years, HD-AraC in the induction treatment leads to a significantly higher CR rate than SD-Ara-C and results in improvement in overall survival but only in pts under the age of 46 years. Disclosures: Muus: Amgen: Membership on an entity's Board of Directors or advisory committees. Beksac:Janssen Cilag: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau.

Description: Background: An unmet medical need persists for elderly patients (pts) with AML who are deemed not to be fit for intensive chemotherapy. Such pts are usually treated with BSC and hydroxyurea or low-dose cytarabine, but outcomes are dismal. The immunoconjugate GO has shown single agent efficacy and tolerability in older pts with relapsed AML. The AML-19 study was designed as a sequential phase II/III trial comparing GO monotherapy to BSC (including hydroxyurea if clinically indicated) in pts age ≥ 61 yrs with previously untreated AML who were considered unfit for intensive chemotherapy (or refused it). Of the two induction schedules of GO (total dose 9 mg/m2 delivered in 2 or 3 fractions over one week) under comparison in the phase II part of the study, the 2-fraction regimen was found to have the best efficacy profile to warrant phase III comparison with BSC (BJH 2010; 149:376). We herein report the final results of the phase III part of the study. Methods: Untreated pts with de novo or secondary AML, adequate renal and hepatic function, and WBC count 30 days in 24.3%) was 56.7%. Of the 30 pts who achieved CR/CRi, 28 later relapsed or died in remission (1 infection, 2 general physical deterioration, 2 unknown cause), and the median disease-free survival (DFS) was 5.3 months with a 1-year DFS of 20%. CR/CRi pts had a median survival from remission of 8.2 months, with 40% alive at 1 year. The 30-day all-cause mortality from randomization was comparable in the GO (10.8%) and BSC (13.5%) arms. Most frequent grade 3+ non-hematologic adverse events (AEs) for GO vs BSC were infection (35.1% vs 34.3%), febrile neutropenia (18% vs 23.7%), bleeding (12.6% vs 12.3%), fatigue (11.7% vs 21%), and cardiac toxicity (6.3% vs 14%). Severe liver dysfunction occurred infrequently (2.7% vs 1.8% for GO vs BSC), and no episodes of VOD were reported. Overall, AEs led to GO discontinuation or death in 27 pts (24.3%). Conclusions: Compared with BSC including hydroxyurea as necessary, single agent GO in the dose/schedule chosen significantly improved OS in elderly AML pts not considered fit for intensive chemotherapy, with an acceptable safety profile. Of note, estimates of the benefit of GO were greater in pts presenting with better-risk cytogenetics, high CD33 expression on blast cells, or secondary disease. Disclosures Off Label Use: Gemtuzumab Ozogamicin in AML.

Description: Background Despite the prediction of a fairly benign clinical course, a subset of patients with low-risk myelodysplastic syndromes (MDS) have a more aggressive disease and shorter overall survival. The DNA repair and folate pathway genes play an important role in prognosis and progression in both solid and hematological cancers, and their expression has been known to be associated with polymorphism of genes. However, the impact of polymorphisms of these genes on MDS patients outcome has not yet been demonstrated. The aim of this study was to investigate the association between the polymorphisms of genes encoding main proteins of BER system (XRCC1, XRCC3 and APE1) and folate-metabolizing enzymes (TS, MTHFR) and survival in IPSS low-intermediate1 MDS patients. Methods the study was designed according to the Schoenfeld design for biomarkers, assuming the presence of an unfavorable pharmacogenetic profile (one or more adverse genotypes) in at least one-third of the study population. Accordingly, 10 events in 54 patients would allow the detection of an Hazard Ratio (HR) 〉6 associated with the group having unfavorable genotypes (80% power and 5% type I error for a two-tailed test). We thus prospectively genotyped 54 MDS patients (median age 75 years) with IPSS low (n=23) or intermediate-1 (n=31) treated with best supportive care only. Genomic DNA was isolated from 1ml of peripheral blood by means of commercially available kits. Polymorphisms were determined by PCR-HRM (High Resolution Melting) assay and restriction digests of PCR products. All samples were analyzed for the following polymorphisms: XRCC1 194 (rs1799782 C/T, Arg/Trp) and 399 (rs25487 G/A, Arg/Gln), XRCC3 241 (rs861539 C/T, Thr/Met), TS5'-UTR (2R/3R and rs183205964 G/C) and 3'-UTR Ins/Del (rs11280056 6bp+/6bp-), MTHFR 677 (rs1801133 C/T, Ala/Val) and 1298 (rs801131 A/C, Gln/Ala), APE1 148 (rs1130409 T/G, Asp/Glu). The characteristics and laboratory features of MDS patients with each polymorphisms were compared using Х2-test and Mann-Whitney test. The associations between polymorphisms status and survival were assessed using Kaplan-Meier method and Log-rank test. For the multivariate survival analysis, Cox proportional hazard models, was used to identify the genotypes fitted as indicator variables. Before performing clinical correlations, genotype frequencies were checked for agreement with those expected under the Hardy-Weinberg equilibrium. Results The frequencies of genotypes of studied gene polymorphisms in patients with low/Int-1 risk are listed in Table 1. At univariate analysis, a significantly shorter survival was associated with XRCC1 399 GG, TS3’-UTR -6/-6, TS5’-UTR 2R/3G, 3C/3G, 3G/3G and MTHFR 677 TT variant alleles. In multivariate analysis, using a stepwise logistic regression model, patients with TS3’-UTR -6/-6, XRCC1-399 GG, TS5’-UTR 2R/3G, 3C/3G, 3G/3G and MTHFR- 677 TT unfavorable genotypes presented with an Hazard Ratios of 4.65, 7.07, 11.44 and 67.12, respectively, if compared to the reference group of variant alleles (P=.058, P=.024, P=.026 and P=.000). Accordingly, we performed an exploratory analysis to investigate the effect on survival arising from the combination of the unfavorable genotypes to each other. As a fact, 3-years OS was 33% for those patients with ≥2 variant alleles, as compared to 62.5%, and 100%, respectively, for those with 2 or 0/1 variant alleles, suggesting that patients with a higher number of variant alleles had a shorter survival. Conclusions The mutational status of BER, TS and MTHFR genes predicts the overall survival of patients with low-Int-1 IPSS MDS treated with best supportive care only. If confirmed on larger series, these polymorphisms could help to identify a subset of low-risk MDS patients with shorter survival, who might benefit from an early therapy with hypometilating agents. Acknowledgments The study was supported in part by AIL Pesaro Onlus. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 791 The AML-12 randomized phase III trial of the EORTC and GIMEMA Leukemia Groups assessed the efficacy and toxicity of HD-AraC (3 g/m2/12 hrs for 4 days) combined with daunorubicin (50 mg/sqm for 3 days) and etoposide (50 mg/sqm for 5 days) vs SD-AraC (100 mg/sqm for 10 days) combined with the same drugs. Patients (pts) in complete remission (CR) received consolidation consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin (50 mg/sqm for 3 days). Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability, cytogenetics and age. A 2nd randomization was performed after consolidation in pts without a donor: auto-SCT followed or not by low dose IL-2 (4-8 × 106 IU s.c. for 5 days per month) during one year. A total of 577 patients were required to be randomized for the 2nd question in order to reach 255 events (relapses or deaths) which would allow to detect a 11.5% increase in the 3-year disease-free survival (DFS) from 50% to 61.5% corresponding to hazard ratio (HR) = 0.70 (2-sided alpha=5%, statistical power=80%). Randomization was performed centrally; the 2nd randomization was stratified for induction treatment, cytogenetic/molecular genetic group, number of courses to reach CR, auto-SCT planned (No/Yes) and center. Intent-to-treat analysis was done. From 9/1999 till 1/2008, 2005 previously untreated AML pts (APL excluded), age

Description: Abstract 3612 The AML-12 randomized phase III trial of the EORTC and GIMEMA Leukemia Groups assessed the efficacy and toxicity of HD-AraC (3 g/sqm/12 hrs for 4 days) combined with daunorubicin (50 mg/sqm/d for 3 days) and etoposide (50 mg/sqm/d for 5 days) vs SD-AraC (100 mg/sqm/d for 10 days) combined with the same drugs, in previously untreated AML 〈 61 year old patients (APL excluded). Patients (pts) in complete remission (CR) received consolidation consisting of AraC (500 mg/sqm/12 hrs for 6 days) and daunorubicin (50 mg/sqm/d for 3 days). Subsequently an allogeneic (allo-SCT) or autologous stem cell transplantation (auto-SCT) was planned according to donor availability and age. A 2nd randomization was performed after consolidation in pts without a donor: auto-SCT followed or not by low dose IL-2 (4-8 × 106 IU/d s.c. for 5 days per month) during one year. A total of 577 pts were required to be randomized for the 2nd question in order to reach 255 events (relapses or deaths) which would allow to detect a 11.5% increase in the 3-year disease-free survival (DFS) from 50% to 61.5% corresponding to hazard ratio (HR) = 0.70 (2-sided alpha=5%, statistical power=80%). Randomization was performed centrally; the 2nd randomization was stratified for induction treatment, cytogenetic/molecular genetic group, number of courses to reach CR, auto-SCT planned (No/Yes) and center. Intent-to-treat analysis was done in eligible pts. From 9/1999 till 1/2008, 2005 pts were randomized (891 by EORTC-LG and 1114 by GIMEMA). In addition 104 pts (GIMEMA) were registered to receive SD-AraC (+etoposide+daunorubicine) in induction. Due to insufficient reporting, 3 centers, who recruited 63 pts, have been excluded from the analysis. After 1 or 2 courses of induction, CR was achieved in 1500 pts. Between 4/2000 and 5/2008 544 pts have been randomized for the IL-2 question, of whom 528 (222 EORTC, 306 GIMEMA) met the eligibility criteria and were included in the analysis: 263 in IL-2, 265 in Observation (Obs) arm; the remaining pts have not been randomized due to prolonged hypoplasia after consolidation or after auto-SCT, or refusal of the patient or a planned allo-SCT. The two groups were well balanced with respect to the above mentioned stratification factors. Due to prolonged pancytopenia after auto-SCT, severe organ damage or infection after auto-SCT, early relapse or patient refusal, 165 pts actually received IL-2 and 197 pts were adequately documented in the Obs arm. During the first 4 months 82% of the pts in the IL-2 arm received a mean daily dose of 6 × 106 IU and 62% of the pts received the maximally required 20 s.c. injections; the remaining stopped due to relapse (22%) or toxicity (16%). During the second 4 months, out of 103 pts 82% in the IL-2 arm received a mean daily dose of 6 × 106 IU and 76% of the pts received the maximally required 20 s.c. injections; the remaining stopped due to relapse (15%), toxicity/refusal (6%) or other reasons (2%). During the third 4 months, among 79 of the pts in the IL-2 arm 80% received a mean daily dose of 6 × 106 IU and 85% of the pts received the maximally required 20 s.c. injections. Grade 3–4 toxicity was more frequent in the IL-2 compared to Obs arm and consisted of hypersensitivity (3% vs 0%), fatigue (7.9% vs 1%), rigor/chills (6.1% vs 0%), arthralgia/myalgia (3.6% vs 0%). For the total of 528 pts, the median follow-up from the 2nd randomization was 6 years. As of July 2011, a total of 308 events were reported: 150 (IL-2 arm) vs 158 (Obs arm); among them 277 relapses (137 vs 140) and 31 deaths without relapses (13 vs 18). The DFS from 2nd randomization was similar in the 2 groups: the 5-yr DFS rate was 44.2% (IL-2) vs 40.4% (Obs), hazard ratio (HR)=0.95, 95% CI (0.76,1.19), p=0.66. A total of 259 pts died: 128 (IL-2 arm) vs 131 (Obs. arm). The 5-yr overall survival rate was 52.2% (IL-2) vs 50.9% (Obs), HR=0.98, 95% CI (0.77,1.26), p=0.9. The initial remission induction treatment (received/randomized) did not have impact on the results after the 2nd randomization. Conclusion: This study shows that, with a median follow-up of 6 years, low dose IL-2 maintenance does not lead to a prolonged DFS and overall survival in pts with AML in first complete remission treated in the EORTC-GIMEMA AML12 trial. Disclosures: Muus: Amgen: Membership on an entity's Board of Directors or advisory committees. de Witte:Novartis: Consultancy, Honoraria, Speakers Bureau.

Description: Abstract 1679 Recent data suggest that second-generation tyrosine-kinase inhibitor (TKI) dasatinib and nilotinib can be responsible for increased non-hematologic adverse events in comparison to imatinib. In particular, there are a few reports of severe peripheral arterial occlusive disease (PAOD) and other vascular occlusive events (infarction) in patients receiving nilotinib. With this in mind we retrospectively evaluated incidence of PAOD or other vascular occlusive events in our cohort including 82 consecutive chronic myeloid leukemia (CML) patients treated at our institution with imatinib alone (n=55) or nilotinib as first-line (n=17) or second-line treatment after imatinib failure (n=10). After a median time of exposition to nilotinib of 24 months (range, 7–34 months) 4 (14.8%) out of 27 patients developed an episode of severe and previously unrecognized PAOD or other vascular occlusive events (2 PAOD, 1 myocardial infarction, 1 ictus). All 4 patients were more than 60 years old and 3 out of 4 were male while obesity was never observed. A history of nicotine abuse could be found in 2 out of 4 patients. The same applied when we looking for the presence of arterial hypertension (2/4) or dyslipidemia (2/4). When 55 patients treated with imatinib were analyzed for PAOD or other vascular occlusive event incidence we detected only one patient who experienced myocardial infarction after 135 months of therapy. We then evaluated the likelihood of developing PAOD in the subset of patients treated only with imatinib and in those who received nilotinib, respectively. The projected 10-year actuarial probability of remaining PAOD-free was 100% in the imatinib group and 67% in the nilotinib group (HR, 14.6; P=0.0008). Interestingly, the two patient cohorts were alike with respect to age (P=0.76), gender (P=0.80), number cardiovascular risk factors (P=0.62) and body mass index (P=0.59). The only difference we observed was a significantly longer exposition to drug among patients treated only with imatinib in comparison to those who received nilotinib (P

Description: Treatment of AML in the elderly remains challenging. In particular, few therapeutic options exist for patients (pts) who are not considered medically fit for intensive chemotherapy. Gemtuzumab ozogamicin (GO), a humanized anti-CD33 monoclonal antibody conjugated to calicheamicin, has demonstrated single agent efficacy in older patients with relapsed AML. In a previous trial we reported a complete response rate of 17% when the licensed dose/schedule of GO was used as frontline monotherapy for older unfit pts with AML, but excess hematologic and liver toxicity suggested changes in both dosing and scheduling to improve feasibility. The AML-19 study was designed as a sequential phase II–III trial in pts of age 61 or over with untreated AML, who could not be considered candidates for, or must have declined, conventional intensive chemotherapy. The primary objective of the phase II study was to investigate whether any of two different schedules of lower dose GO monotherapy (total delivered dose 9 mg/m2 in 2 or 3 fractions over one week) is sufficiently effective and tolerable frontline therapy to continue phase III comparison with best supportive care (BSC). Pts had to have adequate renal and hepatic function, and the WBC count had to be less than 30,000/cmm at the time of registration. Two-thirds of the pts were randomly assigned to receive a single induction course of either GO 3 mg/m2 iv on days 1, 3 and 5 (arm A), or GO 6 mg/m2 iv on day 1 and 3 mg/m2 on day 8 (arm B); the remaining third was assigned to the BSC arm. Randomization was stratified by age, performance status (PS), initial WBC, CD33 expression on marrow blasts, and Institution. Pts with no evidence of objective disease progression were eligible to receive continuation treatment with monthly outpatient infusions of GO at 2 mg/m2 for a maximum of 8 months. Primary end-point of the phase II study was clinical benefit rate (CBR) defined as the number of pts either achieving a remission (CR, CRp, PR) or maintaining a stable disease (SD) in each experimental arm. The arm associated with the highest CBR would be selected for phase III assessment, providing that it is at least 48% (Simon design). Between 06/2004 and 12/2006, 56 pts were randomized in the two experimental arms (arm A 29; arm B 27). The two arms were comparable in terms of age (arm A: median 77 yrs; arm B: median 78 yrs), PS 〉2 (arm A: 7%; arm B: 4%), secondary AML (arm A: 45%; arm B: 37%), and CD33 expression on ≥20% marrow blasts (arm A: 86%; arm B: 85%). In arm A, 6 pts achieved CR, 2 PR, and 3 maintained SD for an overall CBR of 38% (90% CI, 23%–55%); in arm B, 5 pts achieved CR, 1 CRp, and 11 maintained SD for an overall CBR of 63% (90% CI, 45%–78%). Most toxicities were