Nonmyeloablative Allogeneic Transplantation With Post-Transplant Cyclophosphamide for Acute Myeloid Leukemia With IDH Mutations: A Single Center Experience

IntroductionMutations in the IDH1 or IDH2 genes are detected in approximately 20% of cases of acute myeloid leukemia (AML). Few studies have examined the impact of IDH mutations in AML on allogeneic bone marrow transplant (alloBMT) outcomes.Patients and MethodsIn this single center study, alloBMT outcomes for 61 patients with IDH-mutated (mIDH) AML were compared to those for 146 patients with IDH-wildtype (wtIDH) AML.ResultsPatients with mIDH AML had a 2-year overall survival (OS) of 85% (95% CI 76%-95%), 2-year relapse free survival (RFS) of 71% (95% CI 59%-85%), 1-year cumulative incidence of relapse (CIR) of 14% (95% CI 5%-23%) and a 1-year cumulative incidence of transplant related mortality (CITRM) of 3% (95% CI 0%-8%). Patients with wtIDH had a 2-year OS of 61% (95% CI 53%-70%), 2-year RFS of 58% (95% CI 50%-67%), 1-year CIR of 27% (95% CI 20%-35%), and a 1-year CITRM of 9% (95% CI 5%-14%). In a univariate analysis cox-proportional hazard model, mIDH was associated with significantly better OS (HR 0.52, 95% CI 0.29-0.96) and a trend toward better RFS (HR 0.60, 95% CI 0.35-1.01). After controlling for donor age, diagnosis, and ELN risk category, mIDH was associated with a nonsignificantly improved OS (HR 0.54, 95% CI 0.29-1.01) and RFS (HR 0.67, 95% CI 0.39-1.15).ConclusionAmong patients with mIDH AML, patients who received a peritransplant IDH inhibitor had improved OS (P = .03) compared to those who did not, but there was no detectable difference for RFS (P = .29).     

Cladribine in the Treatment of Acute Myeloid Leukemia: A Single-Institution Experience

BackgroundDespite advances in novel therapeutics, supportive care, and postremission therapy, the outcome of high-risk and elderly patients as well as those with relapsed/refractory acute myeloid leukemia (AML) remains poor. There is likely still room for improvement through optimizing conventional chemotherapy.Patients and MethodsThrough a pharmacy database search we identified all patients with AML treated at Washington University with cladribine-based regimens.ResultsTwenty-four patients were identified that were treated with 2 cladribine-based regimens: CLAG (cladribine [5 mg/m² days 1-5], cytarabine [2 g/m² days 1-5] and granulocyte colony-stimulating factor [G-CSF; 300 μg subcutaneously (s.c.) days 0-5]) and CLAM (cladribine [5 mg/m² days 1-5], cytarabine [2 g/m² days 1-5], G-CSF [300 mg s.c. days 0-5] and mitoxantrone [10 mg/m² days 1-3]). Complete responses were achieved in 53% of patients given induction chemotherapy and 44% of those given salvage chemotherapy. The regimens were well tolerated with minimal extramedullary toxicity.ConclusionThese data suggest that cladrabine-based regimens should be further explored in both the salvage and first-line setting and might offer an attractive backbone on which to add novel therapies.     

Clofarabine plus low-dose cytarabine followed by clofarabine plus low-dose cytarabine alternating with decitabine in acute myeloid leukemia frontline therapy for older patients

BACKGROUND:

Standard therapy for older patients with acute myeloid leukemia (AML) has a poor outcome. The authors have designed a combination of clofarabine plus low‐dose cytarabine followed by a prolonged consolidation alternating with decitabine.

METHODS:

Sixty patients with a median age of 70 years (range, 60‐81 years) with newly diagnosed AML were included. They received clofarabine 20 mg/m² intravenously daily for 5 days plus cytarabine 20 mg subcutaneously twice daily for 10 days. Responding patients continued for up to 17 courses of consolidation therapy including decitabine.

RESULTS:

Forty of 59 evaluable patients responded (66%). Complete remission rate was 58%. Median relapse‐free survival (RFS) was 14.1 (95% confidence interval [CI], 6.9 to not estimable), and median overall survival (OS) was 12.7 months (95% CI, 8.8 to not estimable). Median OS of responding patients (complete response [CR]/CR with platelet count <100 × 109/L) was 24.2 months (95% CI, 17 to not estimable). Compared with a historical group of patients who received clofarabine plus low‐dose cytarabine with a shorter consolidation, RFS was not statistically different. Induction mortality was low (7% at 8 weeks) and toxicities manageable.

CONCLUSIONS:

Clofarabine plus low‐dose cytarabine alternating with decitabine in consolidation is active in older patients with newly diagnosed AML. The benefits of a prolonged consolidation remain unproven. Cancer 2012. © 2012 American Cancer Society.     

中剂量阿糖胞苷用于老年急性髓系白血病患者巩固强化治疗的临床观察

目的 分析初治老年急性髓系白血病(AML)患者诱导缓解后应用中剂量阿糖胞苷(MDAC)巩固治疗的临床效果及不良反应.方法 61例2个疗程内达完全缓解(CR)的老年AML(M3除外)患者,分别应用MDAC和常规剂量阿糖胞苷(SDAC)进行巩固强化治疗,对其临床资料进行回顾性分析.结果 MDAC组26例,SDAC组35例,MDAC组与SDAC组的无复发生存(RFS)时间分别为42.7和16.0个月(P=0.002),总生存(OS)时间分别为44.6和18.2个月(P=0.004),累积复发率分别为26.9%(7/26)和54.3%(19/35)(x2=4.567,P=0.033),3年生存率分别为23.1%(6/26)和8.6%(3/35)(x2=2.496,P=0.114).两组不良反应发生率差异均无统计学意义(均P>0.05).结论 老年AML患者应用MDAC巩固强化治疗,可延长早期达CR患者的RFS及OS时间,不良反应发生率与SDAC相似.     

Characteristics and Outcomes of Secondary Acute Myeloid Leukemia and Acute Myeloid Leukemia With Myelodysplasia-Related Changes: Multicenter Study From the Thai Acute Leukemia Study Group

BackgroundSecondary acute myeloid leukemia (sAML) and AML with myelodysplasia-related changes (AML-MRC) both result in dismal outcomes. This retrospective study aimed to determine whether these features are poor prognostic factors independent of older age and adverse cytogenetics, which are commonly associated with a poor prognosis.MethodsThe characteristics and real-world outcomes of sAML and AML-MRC from the Thai AML registry database were investigated.ResultsFrom a total of 992 newly diagnosed AML patients, 315 (31.8%) patients were classified into sAML or AML-MRC subtypes. Older age, low white blood cell (WBC) count, low bone marrow blast, and adverse cytogenetic risk were commonly present in sAML and AML-MRC compared to de novo AML. Complete remission after 7 + 3 induction therapy occurred in 42.3% of patients with sAML or AML-MRC and 62.4% of de novo AML (P < .001). The median overall survival (OS) of sAML, AML-MRC, and de novo AML were 6.9, 7.0, and 12.2 months, respectively (P < .001). The independent prognostic factors for inferior OS were older age, intermediate-risk or adverse-risk cytogenetics, WBC count > 100 × 10⁹/L, poor performance status, and a subgroup of AML-MRC with the morphologic criteria of multilineage dysplasia (AML-MRC-M). In addition, sAML, AML-MRC, and a WBC count > 100 × 10⁹/L were pre-treatment prognostic factors associated with poor relapse-free survival (P = .006, P = .017, and P < .001, respectively).ConclusionBoth sAML and AML-MRC are independently associated with poor outcomes in Thai patients. Our study supports AML-MRC-M as an adverse prognostic factor for OS.     

Decitabine Versus Intensive Chemotherapy for Elderly Patients With Newly Diagnosed Acute Myeloid Leukemia

BackgroundElderly patients with acute myeloid leukemia (AML) have generally had a poor prognosis with unfavorable clinical and biologic disease features. Hypomethylating agents have shown potential for treating medically unfit and elderly patients with AML.Patients and MethodsWe compared the outcomes of elderly patients with AML treated with decitabine and intensive chemotherapy (IC).ResultsThe data from 107 patients with newly diagnosed AML aged ≥ 65 years were analyzed. The overall response rate was 38.6% and was significantly greater in the IC group than in the decitabine group (65.6% vs. 26.1%; P < .001). With a median follow-up duration of survivors of 14.8 months, the median overall survival (OS) and event-free survival were 12.3 months (95% confidence interval [CI], 10.0-14.7) and 2.0 months (95% CI, 2.0-2.0), respectively, which were not different between the 2 treatment groups. The FLT3-internal tandem duplication mutation (hazard ratio [HR], 2.637; 95% CI, 1.379-5.043; P = .003), complex karyotype (HR, 2.513; 95% CI, 1.258-5.020; P = .009), and peripheral blood blast percentage at diagnosis (HR, 1.983; 95% CI, 1.148-3.422; P = .014) were analyzed as independent prognostic factors for OS. A subgroup analysis for OS showed that IC was superior to decitabine for patients with the FLT3-internal tandem duplication mutation (P = .025) and poor risk cytogenetics, except for −7/del(7q) (P = .005), and decitabine was associated with longer OS for patients with −7/del(7q) (P = .077).ConclusionDecitabine showed a similar OS to IC, despite the lower response rate in patients. The clinical outcomes of specific subgroups seemed to differ with different treatment options. Optimal therapeutic approaches for elderly patients with AML should be further examined.     

Effects of Obesity on Overall Survival of Adults With Acute Myeloid Leukemia

BackgroundThe role of obesity in prognosis of acute myeloid leukemia (AML) is debatable. Our retrospective study aimed to determine the effect of obesity on overall survival (OS) in AML.Patients and MethodsAML patients diagnosed at University of Nebraska Medical Center were divided into 3 groups according to body mass index (BMI): normal (18.5-25 kg/m²) or underweight (< 18.5 kg/m²); overweight (25-30 kg/m²); and obese (≥ 30 kg/m²). Chi-square test, Kruskal-Wallis test, and ANOVA were used to examine the association of BMI with baseline characteristics. Mann-Whitney test was used for pairwise comparisons of hematopoietic cell transplantation (HCT) comorbidity index. Bonferroni correction was used to adjust P values. OS, defined as time from diagnosis to death from any cause, was determined by the Kaplan-Meier method; comparisons of survival curves were done using log-rank test. Cox regression analysis was performed to detect the effect of BMI on OS.ResultsOf 314 patients, 38% were obese, 68% received intensive chemotherapy, and 30% underwent HCT. Patient characteristics for all BMI groups were similar except greater HCT comorbidity index in obese patients. Actual body weight was used to calculate the chemotherapy dose in 92% of obese patients. The rates of receipt of HCT in normal, overweight, and obese groups were 33%, 32%, and 25%, respectively (P = .6). One-year OS values for normal/underweight, overweight, and obese groups was 42%, 45%, and 39%, respectively (P = .31). On multivariate analysis, obesity was associated with worse OS compared to normal-weight (hazard ratio = 0.6; 95% confidence interval, 0.4-0.9; P = .03) but not overweight patients.ConclusionObesity confers worse prognosis in AML. Differences in OS were not the result of differences in chemotherapy dose or receipt of HCT.     

Prognostic Impact of Extramedullary Infiltration in Pediatric Low-risk Acute Myeloid Leukemia: A Retrospective Single-center Study Over 10 Years

BackgroundThe impact of extramedullary infiltration (EMI) on the clinical outcomes of pediatric patients with acute myeloid leukemia (AML) are controversial.Patients and MethodsA total of 214 pediatric patients with low-risk AML were classified as having EMI (central nervous leukemia [CNSL] and/or myeloid sarcoma [MS]) and not having EMI. Patients with isolated MS before AML diagnosis by bone marrow examination were confirmed with histopathologic examination. For patients diagnosed with AML by bone marrow examination, a thorough physical examination and radiologic imaging were used to confirm MS.ResultsMale gender, a high white blood cell count, the FAB-M5 subtype, t(8;21) and t(1;11) abnormalities, and c-KIT mutations were associated with EMI. The presence of MS was associated with a low complete remission rate (63.6% vs. 79.4%; P = .000) and poor 3-year relapse-free survival (RFS) (62.6% ± 7.5% vs. 87.0% ± 2.8%; P = .000) and 3-year overall survival (73.5% ± 7% vs. 88.8% ± 2.6%; P = .011). Multivariate analysis revealed that MS was a poor prognostic factor for RFS and overall survival. Bone infiltration was an independent risk factor for inferior RFS with MS. Patients with CNSL had a low complete remission rate (58.3% vs. 77.2%; P = .045); however, CNSL did not significantly affect the survival of low-risk patients with AML.ConclusionMS should be considered an independent risk factor to guide stratified treatment.     

High-dose cytarabine induction is well tolerated and active in patients with de novo acute myeloid leukemia older than 60 years

BACKGROUND:

High‐dose cytarabine (HiDAC) is safe and very effective in younger patients with acute myeloid leukemia (AML), but it generally is not well tolerated in the elderly.

METHODS:

The authors explored the safety and tolerability of a modified HiDAC induction regimen consisting of 6 daily doses of cytarabine at 2 g/m² in combination with 3 daily doses of daunorubicin at 45 mg/m² in 59 consecutive patients aged >60 years who had de novo AML diagnosed between July 1996 and February 2005.

RESULTS:

The median patient age was 68 years (range, 60‐86 years). The regimen was well tolerated. Infections were common and occurred in 39% of patients, but cerebellar toxicities occurred in only 7% of patients and were reversible. The day‐30 induction‐related mortality rate was 10%. Overall, 69% of patients achieved complete remissions (CR), and 80% received up to 3 consolidations with HiDAC. The median follow‐up for surviving patients was 53 months (range, 17‐114 months). The median overall survival was 15.3 months (range, 1‐114 months), and the relapse‐free survival was 13.8 months (range, 1‐113 months). Survival for patients who achieved CR was 27 months (range, 2‐114 months).

CONCLUSIONS:

The modified HiDAC regimen was well tolerated in patients aged >60 years with AML and was associated with low induction mortality and high rates of CR. Nevertheless, these high remissions still were associated with poor overall outcomes. Cancer 2011;. © 2011 American Cancer Society.     

Comparison of Autologous Hematopoietic Cell Transplantation and Chemotherapy as Postremission Treatment in Non-M3 Acute Myeloid Leukemia in First Complete Remission

IntroductionA number of randomized trials in patients with AML in CR1 have been conducted and they showed that auto-HCT improves RFS but not OS, compared with chemotherapy. However, because these trials have had compliance problems, the value of auto-HCT still has not been clearly established.Patients and MethodsUsing a database of 2518 adult patients with AML in CR1, we retrospectively analyzed the outcome of auto-HCT and compared it with intensive nonmyeloablative chemotherapy using landmark analyses.ResultsIn 103 auto-HCT recipients, OS and RFS at 3 years from treatment were 65% and 57%, respectively. Multivariate analysis showed that unfavorable risk cytogenetics and entry into CR1 after 2 courses of induction treatment predicted a poor outcome. Because the median time interval between CR1 and auto-HCT was 153 days, landmark analyses at 5 months after CR1 were performed to compare 1290 patients who received chemotherapy alone (median age, 52 years; range, 16-70) with 103 who received auto-HCT (median age, 48 years; range, 16-67). Auto-HCT improves 3-year RFS (58% vs. 37%; P < .001) but not OS compared with chemotherapy alone. Among patients with unfavorable risk cytogenetics or those who required 2 courses to reach CR1, there was no significant difference in RFS between the 2 groups.ConclusionAuto-HCT can be considered as a postremission therapy for AML patients with favorable or intermediate risk cytogenetics who achieve CR1 after a single course of induction treatment.     

Outcome of Adolescents and Young Adults Compared With Pediatric Patients With Acute Myeloid and Promyelocytic Leukemia

BackgroundStudies on the outcome of adolescents and young adults (AYAs) with acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL) are limited.MethodsWe compared the outcome of AYA (19-30 years) patients with AML and PML and pediatric (0-18 years) patients with AML (pAMLs) and APL (pAPLs) utilizing the Surveillance Epidemiology and End Results-18 registry. Early mortality rate (EMR), defined as mortality within 1 month of diagnosis, was used as a surrogate for treatment-related mortality. Survival statistics were computed using the Kaplan-Meier method. Multivariate analysis was done using logistic regression and the Cox proportional hazard regression model.ResultsA total of 6343 patients with AML were identified; 44.7% were AYAs. pAMLs had lower EMR (6.2% vs. 9.2%; P < .01) and higher overall survival (OS) (1-year, 70.3% vs. 62.1%; 5-year, 48.2% vs. 36.4%; P < .01). Nine hundred twenty patients with APL were also identified; 59.5% were AYAs. No statistically significant difference was found between AYAs with APL and pAPLs in EMR (11.4% vs. 14.1%; P = .23) and OS (1-year, 83.8% vs. 81.2%; P = .31 and 5-year, 68.2% vs. 73.1%; P = .11]. Comparing all patients with AML and APL, AYAs with APL and pAPLs had higher EMR (11.4% and 14.1% vs. 6.2% and 9.2%; P ≤ .01) but better OS than AYAs with AML and pAMLs (5-year OS, 68.2% and 73.1% vs. 48.2% and 36.4%; P ≤ .01).ConclusionOur analysis shows AYAs with AML have worse EMR and OS compared with pAMLs. AYAs with APL and pAPLs have similar outcomes. To our knowledge, this is the first study reporting outcomes of AYAs with APL and pAPLs using a large population-based registry and their comparison with same age patients with AML.     

A Post Hoc Sensitivity Analysis of Survival Probabilities in a Multinational Phase III Trial of Decitabine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia

BackgroundIn a multicenter, randomized, open-label phase III study, patients ≥ 65 years with newly diagnosed AML received decitabine 20 mg/m² once daily for 5 days every 4 weeks (n = 242) or treatment choice (supportive care or cytarabine 20 mg/m² once daily for 10 days every 4 weeks; n = 243). Decitabine use demonstrated greater response rates (P = .001) and OS data favored decitabine.Patients and MethodsIn a post hoc sensitivity analysis of mature data of patients in the intent-to-treat population (N = 485), OS at 3, 6, 12, 18, and 24 months after randomization was estimated for each arm using Kaplan-Meier methods. Age, cytogenetic risk, and Eastern Cooperative Oncology Group performance status were used as stratification factors in the Cox regression model to estimate the hazard ratio.ResultsA survival advantage was seen with decitabine at each cutoff time point; hazard ratios for OS for decitabine vs. treatment choice were 0.83, 0.71, 0.83, 0.80, and 0.79 at 3, 6, 12, 18, and 24 months, respectively. A trend toward improved OS with decitabine was observed at fixed time points over 2 years.ConclusionDecitabine should be considered as a treatment option for older patients with AML and poor prognostic risk factors.     

High Response Rate for Treatment With Gemtuzumab Ozogamicin and Cytarabine in Elderly Patients With Acute Myeloid Leukemia and Favorable and Intermediate-I Cytogenetic Risk

BackgroundThe benefit of gemtuzumab ozogamicin (GO) in combination with chemotherapy as frontline therapy in patients with acute myeloid leukemia (AML) is still debated.Patients and MethodsWe evaluated the safety and efficacy of low-dose GO with cytarabine in elderly patients with newly diagnosed AML. Over the past 5 years, we have treated 16 elderly patients with AML (64-82 years) with GO (3 mg/m²) followed by continuous infusion of cytarabine (100 mg/m²) for 7 days.ResultsComplete remission (CR) was achieved in 68.8% of patients; however, this was true only in patients in the favorable or intermediate-I cytogenetic risk groups. Of the 12 patients with AML in the favorable and intermediate-I genetic groups, 11 (91.7%) achieved CR. By comparison, of all 4 patients in the intermediate-II or adverse genetic groups, none of the patients achieved CR (P = .003). The median disease-free survival and overall survival (OS) was 10.9 and 18.8 months, respectively, for patients who achieved CR. The estimated median survival was 15 months in the favorable and intermediate-I cytogenetic groups and only 4.4 months in the intermediate-II and unfavorable risk groups (P = .008).The toxicity profile was also manageable in patients with AML who were mainly older than 70 years with good performance status (PS). The 8-week mortality rate was 6.25%, which is relatively low in this high-risk group of patients. These data are in line with results from 2 randomized trials suggesting that the addition of low-dose GO should be further investigated to reevaluate its role in selected elderly patients with AML and raises the issue of the optimal protocol.     

Prognosis and Outcome of Fit Patients with Acute Myeloid Leukemia in Kuwait

PurposeAcute myeloid leukemia (AML) data from the Middle East are limited to single-center studies. We report leukemia-free survival (LFS) and overall survival (OS) of young (≤70 years) patients with AML treated in Kuwait.Patients and MethodsThis study investigated prognostic markers among 172 young and fit patients with de novo nonacute promyelocytic leukemia AML treated with intensive induction protocols from a tertiary cancer center.ResultsThe median age was 44 years (interquartile range, 32-51) and 67% of cases were Arab. A greater proportion of males was found in the 2017 European Leukemia Net-defined unfavorable-risk group (20% vs 9%, respectively; P = .02). Most patients (94%) were treated by a standard 7 × 3 regimen; 72.5% of cases achieved complete remission. The 24-month LFS was 44% (95% confidence interval, 30-65), 36% (95% confidence interval, 26-50), and 23% (95% confidence interval, 10-53) for the favorable-, intermediate-, and adverse-risk groups, respectively (P = .018). The 24-month OS was 70% (95% confidence interval, 60-90), 65% (95% confidence interval, 53-79), and 49% (95% confidence interval, 31-78), respectively (P = .05). Multivariable factor analysis identified male gender (hazard ratio [HR], 1.66; P = .029) and older age (HR, 1.02; P = .05) with poor LFS outcome, whereas favorable-risk classification predicated better outcome (HR, 0.49; P = .03). Favorable-risk classification was the only predictor of OS (HR, 0.39; P = .029).ConclusionFit patients with AML in the favorable-risk group treated with intensive chemotherapy fare well, whereas patients in the adverse-risk group have poor survival.     

Pancreatitis during therapy of acute myeloid leukemia: Cytarabine related?

Background: Acute pancreatitis in acute myeloid leukemia (AML) has been rarely associated with cytarabine therapy. This report attempts to characterize this toxicity.Patients and methods: Criteria for pancreatitis was prospectively defined. Seven patients with pancreatitis were identified from an AML database and a clinical study at two tertiary care centers (n = 134). Their records were retrospectively reviewed.Results: Seven patients with pancreatitis complicating AML therapy were identified. Median age was 36 (range 25–73) years. Median amylase was 184 (range 77–552) U/l and median lipase was 1026 (range 630–6087) U/l. The patients had received high dose bolus cytarabine (2 g/m² i.v. bolus every 12 hours; n = 2), and continuous infusion cytarabine followed by high-dose cytarabine (100 mg/m² i.v. CI days 1–7 then 2 g/m² i.v. bolus every 12 hours days 8–10; n = 2), or standard dose continuous infusion cytarabine (200 mg/m²/d; n = 3) prior to developing pancreatitis. Pancreatitis occurred at a median of 10 days following day one of cytarabine administration with resolution at a median of 11 days after initial diagnosis. Six patients did not suffer major complications. One patient died of causes unrelated to pancreatitis. Five of six patients was rechallenged and all remained free of pancreatitis. One patient subsequently did develop pancreatitis on a later rechallenge.Conclusions: Pancreatitis in the setting of AML therapy may be an infrequent and self-limited toxicity of cytarabine. A schedule dependent toxicity with cytarabine was not identified.     

Differential Implications of CSF3R Mutations in t(8;21) and CEBPA Double Mutated Acute Myeloid Leukemia

BackgroundFew data are available exploring mutations of the colony-stimulating factor 3 receptor (CSF3R) in acute myeloid leukemia (AML) in an all-round and systematic manner. The purpose of this study was to analyze the CSF3R mutations (CSF3R_mut) in AML with recurrent genetic abnormalities for potential synergistic pathomechanism.Patients and MethodsWe retrospectively screened 1102 adult de novo AML patients with available next-generation sequencing (NGS) information on 132 genes related to hematologic disorders. The χ², Mann-Whitney U tests were used to analyze their associations with clinicopathologic characteristics, and a propensity score matching (PSM) followed by Kaplan-Meier method was applied to measure their prognostic effects.ResultsOverall, CSF3R_mut were detected in 40 (3.6%) of 1102 patients with adult de novo AML. CSF3R_mut were predominantly enriched in AML with the CEBPA double mutations (CEBPA_dm) (16/122, 13.1%), t(8;21) (12/186, 6.5%) and mutated RUNX1 (3/50, 6.0%), respectively. The CSF3R_mut loci and types differed according to AML subtypes, with frameshift-indels and premature stop confined in the t(8;21) AML [10/12 (83.3%)], and missense recurrently aggregated in the CEBPA_dm AML [16/16 (100%)]. Cases with CSF3R_mut had a lower WBC count versus those with CSF3R wild-type (CSF3R_wt) in the t(8;21) AML cohort, with a borderline significance [median 5.45 (range 0.94-20.30) × 10⁹/L) vs. 8.80 (range 0.96-155.00) × 10⁹/L, P = .046]. CSF3R_mut were non-significantly associated with higher WBC counts [median 33.6 (range 6.8-287.6) × 10⁹/L vs. 18.1 (range 1.7-196.0) × 10⁹/L, P = .156] and significantly with lower immunophenotypic CD15 positivity [0/8 (0%) vs. 44/80 (55%), P = .009] as compared to CSF3R_wt in the CEBPA_dm AML cohort. After propensity score matching followed by Kaplan-Meier analysis, CSF3R_mut cases had comparable disease-free survival (DFS) and overall survival (OS) to those with CSF3R_wt (P = .607 and P = .842, respectively) in the t(8;21) AML cohort. By contrast, CSF3R_mut showed an inclination towards inferior DFS compared to CSF3R_wt in the CEBPA_dm AML cohort [median DFS 19.8 (95%CI 3.1-36.5) months vs. not reached (NR), P = .086]. No significant difference was found for OS between CSF3R_mut and CSF3R_wt cases (P = .943).ConclusionWe concluded that CSF3R_mut were frequently enriched in patients with t(8;21) and CEBPA_dm subtypes among AML, but showed divergent clinicopathologic features, mutation loci and types and differing prognostic aspects.     

Adding Oral Pioglitazone to Standard Induction Chemotherapy of Acute Myeloid Leukemia: A Randomized Clinical Trial

BackgroundThe hypothesis of an effect by thiazolidinedione on leukemia cells was proposed 2 decades ago, but there is little clinical evidence regarding its efficacy. We evaluated the safety and efficacy of adding pioglitazone to standard induction chemotherapy in patients with acute myeloid leukemia (AML).Patients and MethodsIn this randomized clinical trial, newly diagnosed AML patients were randomized to 1 of 2 groups. Patients in both groups received cytarabine (100 mg/m² per day for 7 days) and daunorubicin (60 mg/m² per day for 3 days). Patients in the pioglitazone group additionally received oral pioglitazone (45 mg per day). The 2 groups were compared according to remission rate, laboratory findings, and adverse events during treatment.ResultsForty patients were evaluated, 20 patients in each group. The complete remission rate was 20% more in the pioglitazone group compared to the control group (P = .202). Complications due to pioglitazone discontinuation were observed in 2 cases. The mean serum alanine aminotransferase in the fourth treatment week was significantly more in pioglitazone group compared to the control group (65.5 vs. 33.6 mg/dL, P = .039). The mean serum creatinine in all treatment phases was significantly higher in the pioglitazone group compared to the control group (P < .05). There were no significant differences between the 2 groups regarding other laboratory findings (P > .05).ConclusionAdding pioglitazone to cytarabine and daunorubicin increased the remission rate in AML patients compared to control subjects. Although this difference in remission rate between the 2 groups was not statistically significant, it could be important in the clinical setting. Pioglitazone may provide benefits as an adjuvant therapy for AML patients without causing serious adverse events.     

Clofarabine combinations as acute myeloid leukemia salvage therapy

BACKGROUND.

Outcome of patients with relapsed acute myeloid leukemia (AML) remains unsatisfactory. Clofarabine is a nucleoside analog with activity in adult AML. Combinations with cytarabine in AML are feasible and effective. Idarubicin is another active AML drug, which has not yet been tested with clofarabine.

METHODS.

The authors therefore designed a phase I study of clofarabine ± cytarabine, plus idarubicin. Patients with primary refractory or first‐relapse AML were assigned to either clofarabine plus idarubicin (CI) if previously exposed to cytarabine with a response lasting <12 months, or clofarabine and idarubicin plus cytarabine (CIA) for responses ≥12 months, or if never exposed to cytarabine. A standard “3 + 3” phase 1 design was followed to define maximum tolerated dose (MTD). Forty‐four patients were treated (23 CI; 21 CIA).

RESULTS.

Dose‐limiting toxicities were hyperbilirubinemia and hepatic transaminase elevations for CI‐treated patients in addition to mucositis and diarrhea for CIA‐treated patients. MTD for CI was clofarabine 22.5 mg/m² intravenously daily × 5 and idarubicin 10 mg/m² intravenously daily × 3. MTD for CIA was clofarabine 22.5 mg/m² intravenously × 5, idarubicin 6 mg/m² intravenously × 3, and cytarabine 0.75 g/m² intravenously × 5 days.

CONCLUSIONS.

A phase 2 randomized trial is in process to compare activity between treatment arms. Cancer 2008. © 2008 American Cancer Society.     

WT1 Expression in Peripheral Blood at Diagnosis and During the Course of Early Consolidation Treatment Correlates With Survival in Patients With Intermediate and Poor-Risk Acute Myeloid Leukemia

BackgroundUp to 55% of non-APL acute myeloid leukemias (AML) lack a molecular target suitable for standardized disease monitoring. We aimed to evaluate the prognostic significance of WT1 gene expression at early stages of intensive treatment.Patients and MethodsA total of 106 consecutive patients with intermediate and high-risk AML who had WT1 expression at diagnosis >500 copies/10⁴ ABL and who achieved remission after 1 to 2 cycles of induction treatment were analyzed. WT1 expression was measured in peripheral blood using a standardized European LeukemiaNet method. Overexpression was defined as >50 copies/10⁴ ABL. The median follow-up was 30 months.ResultsPatients with normal versus high WT1 expression after 2 cycles of chemotherapy had overall survival (OS) at 3 years of 66% versus 41% (P = .01); event-free survival (EFS) 45% versus 22% (P = .01). Prognostic significance of WT1 expression after 2 cycles of treatment was maintained in the group of patients treated with chemotherapy alone without hematopoietic stem cell transplantation in first line treatment (OS 70% vs. 36%, P = .02; EFS 35% vs. 0%, P = .03). Significant prognostic factors for EFS on multivariate analysis were the achievement of molecular remission (<50 copies of WT1) at any time during treatment (hazard ratio [HR] 0.47, P = .04) and increased WT1 expression after 2 cycles of chemotherapy (HR 2.0, P = .03).ConclusionIncreased WT1 expression after 2 cycles of chemotherapy is a negative prognostic factor for survival. WT1 remains a valuable molecular marker in AML without any leukemia-specific mutation, especially if next generation sequencing and/or digital polymerase chain reaction are not routinely available.     

大剂量阿糖胞苷巩固治疗急性髓系白血病患者的疗效及预后分析

目的:探讨大剂量阿糖胞苷（HDAC）用于急性髓系白血病(AML)患者完全缓解后巩固治疗的安全性及预后分析。方法:回顾性分析2016年03月至2020年03月就诊空军军医大学第二附属医院血液科的49例接受HDAC方案作为巩固治疗的AML患者,观察巩固治疗中三系细胞减少持续时间、输血量及治疗中的不良事件,记录OS及RFS时间,并进行基因突变与预后分析。结果:49例患者共进行121个疗程,中位2.7（1~4）个疗程。巩固化疗期间共发生感染34例次（28.1%）。2年RFS率及OS率分别为64.3%、76.8%。多因素分析结果提示巩固化疗次数和伴有FLT3-ITD基因突变是影响患者复发的独立预后不良因素（P值分别为0.019和0.024）。而复发是影响OS的独立预后不良因素（P=0.008）。结论:HDAC用于AML患者巩固治疗的安全性好。巩固治疗≤2次是导致疾病复发的不良因素,伴有FLT3-ITD基因突变不能从HDAC中获益。