A phase 1 clinical trial of vorinostat in combination with decitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome

Patients with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) may respond to treatment with epigenetic‐modifying agents. Histone deacetylase inhibitors may synergize with hypomethylating agents. This phase 1 dose‐escalation study was designed to determine the maximum tolerated dose, recommended phase 2 dose, safety and tolerability of vorinostat plus decitabine in patients with relapsed/refractory AML, newly‐diagnosed AML, or intermediate‐ to high‐grade MDS. Thirty‐four patients received concurrent therapy with decitabine plus vorinostat and 37 received sequential therapy with decitabine followed by vorinostat. Twenty‐nine patients had relapsed/refractory AML, 31 had untreated AML and 11 had MDS. The target maximum administered dose (MAD) of decitabine 20 mg/m² daily for 5 d plus vorinostat 400 mg/d for 14 d was achieved for concurrent and sequential schedules, with one dose‐limiting toxicity (Grade 3 QTc prolongation) reported in the sequential arm. Common toxicities were haematological and gastrointestinal. Responses were observed more frequently at the MAD on the concurrent schedule compared with the sequential schedule in untreated AML (46% vs. 14%), relapsed/refractory AML (15% vs. 0%) and MDS (60% vs. 0%). Decitabine plus vorinostat given concurrently or sequentially appears to be safe and well‐tolerated. Concurrent therapy shows promising clinical activity in AML or MDS, warranting further investigation.     

Rituximab plus hyper‐CVAD alternating with MTX/Ara‐C in patients with newly diagnosed mantle cell lymphoma: 15‐year follow‐up of a phase II study from the MD Anderson Cancer Center

Intensive chemotherapy regimens containing cytarabine have substantially improved remission durability and overall survival in younger adults with mantle cell lymphoma (MCL). However, there have been no long‐term follow‐up results for patients treated with these regimens. We present long‐term survival outcomes from a pivotal phase II trial of rituximab, hyper‐fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with methotrexate and cytarabine (R‐HCVAD/MA) . At 15 years of follow‐up (median: 13·4 years), the median failure‐free survival (FFS) and overall survival (OS) for all patients was 4·8 years and 10·7 years, respectively. The FFS seems to have plateaued after 10 years, with an estimated 15‐year FFS of 30% in younger patients (≤65 years). Patients who achieved complete response (CR) after 2 cycles had a favourable median FFS of 8·8 years. Six patients developed myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML) whilst in first CR. The 10‐year cumulative incidence of MDS/AML of patients in first remission was 6·2% (95% confidence interval: 2·5–12·2%). In patients with newly diagnosed MCL, R‐HCVAD/MA showed sustained efficacy, with a median OS exceeding 10 years in all patients and freedom from disease recurrence of nearly 15 years in almost one‐third of the younger patients (≤65 years).     

A phase I/II study of oral clofarabine plus low‐dose cytarabine in previously treated acute myeloid leukaemia and high‐risk myelodysplastic syndrome patients at least 60 years of age

Outcomes for older adults with acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) are generally poor, and new effective therapies are needed. We investigated oral clofarabine combined with low‐dose cytarabine (LDAC) in patients aged 60 years and above with relapsed or refractory AML or high‐risk MDS in a phase I/II trial. A 3 + 3 dose escalation of oral clofarabine was followed by a phase II expansion with the aim of obtaining a complete response (CR) rate ≥30%. We identified 20 mg/d for 5 d as the maximum tolerated dose (MTD) of oral clofarabine. A total of 35 patients, with a median age of 72 years, were treated. Of 26 patients enrolled at the MTD, 4 had treatment‐related grade 3–4 non‐haematological toxicities, but none died within 28 d. The observed CR rate and median survival were 34% [95% confidence interval (CI), 18–50%] and 6·8 months overall and 38% [95% CI, 19–57%] and 7·2 months at the MTD. The median disease‐free survival was 7·4 months. Fifty‐two percent (23/44) of cycles administered at the MTD were done without hospital admission. This combination of oral clofarabine and LDAC demonstrated efficacy with a CR rate of >30% and acceptable toxicity in older patients.     

A phase I study of lenalidomide plus chemotherapy with idarubicin and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome

Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have poor outcomes and hematopoietic cell transplantation (HCT) is the only curative treatment. New targeted therapies improved survival in select patients with specific mutations, however management of patients without these molecular alterations is an unmet need. We conducted a phase one study of lenalidomide in combination with cytarabine/idarubicin salvage chemotherapy in patients with R/R AML and high-risk myelodysplastic syndromes. A total of 33 patients were enrolled in the study (30 AML, 3 MDS), and treated at three dose levels with 3 + 3 design. Dose-limiting toxicity (DLT) was seen in eight patients, including four hematologic DLTs. The most commonly observed non-hematologic serious adverse events were febrile neutropenia, rash, sepsis and renal injury. Dose level −1, consisting of 25 mg/d lenalidomide D1-21, 1 g/m² cytarabine D5-8, and 8 mg/m² idarubicin D5-7 was determined to be the maximum tolerated dose. Note, 15/33 (45%) of patients were able to receive pre-planned 21 days of lenalidomide. Overall, 18 patients achieved complete remission (CR) (n = 14) or CR with incomplete count recovery (CRi) (n = 4) with total CR/CRi rate of 56%. The 1-year and 2-year overall survival (OS) were 24% and 10%, respectively. Among responders, 10/18 underwent allogeneic HCT and had a 1-year OS of 40%. There was no molecular pattern associated with response. These data demonstrate that the combination had clinical activity in R/R AML. This regimen should be further investigated for patients who relapsed after HCT, and as a bridge therapy to HCT. ( ClinicalTrials.gov identifier: NCT01132586).     

Elevated fetal haemoglobin is a predictor of better outcome in MDS/AML patients receiving 5‐aza‐2′‐deoxycytidine (Decitabine)

Although azanucleoside DNA‐hypomethylating agents (HMAs) are routinely used for the treatment of myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML), very few outcome predictors have been established. Expression of the β‐like globin gene locus is tightly regulated by DNA methylation, is HMA‐sensitive in vitro, and fetal haemoglobin (HbF) expression is under study as a potential biomarker for response of MDS patients to azacitidine. We determined HbF expression in 16 MDS and 36 AML patients receiving decitabine (DAC). Pre‐treatment HbF was already elevated (>1·0% of total haemoglobin) in 7/16 and 12/36 patients, and HbF was induced by DAC in 81%/54% of MDS/AML patients, respectively. Elevated pre‐treatment HbF was associated with longer median overall survival (OS): 26·6 vs. 8·6 months for MDS (hazard ratio [HR] 8·56, 95% confidence interval [CI] 1·74–42·49, P = 0·008, with similarly longer progression‐free and AML‐free survival), and 10·0 vs. 2·9 months OS for AML (HR 3·01, 95% CI 1·26–7·22, P = 0·014). In a multivariate analysis, the prognostic value of HbF was retained. Time‐dependent Cox models revealed that the prognostic value of treatment‐induced HbF induction was inferior to that of pre‐treatment HbF. In conclusion, we provide first evidence for in vivo HbF induction by DAC in MDS/AML, and demonstrate prognostic value of elevated pre‐treatment HbF, warranting prospective, randomized studies.     

A prognostic model for survival after salvage treatment with FLAG‐Ida +/− gemtuzumab‐ozogamicine in adult patients with refractory/relapsed acute myeloid leukaemia

The combination of fludarabine, cytarabine, idarubicin, and granulocyte colony‐stimulating factor (FLAG‐Ida) is widely used in relapsed/refractory acute myeloid leukaemia (AML). We retrospectively analysed the results of 259 adult AML patients treated as first salvage with FLAG‐Ida or FLAG‐Ida plus Gentuzumab‐Ozogamicin (FLAGO‐Ida) of the Programa Español de Tratamientos en Hematología (PETHEMA) database, developing a prognostic score system of survival in this setting (SALFLAGE score). Overall, 221 patients received FLAG‐Ida and 38 FLAGO‐Ida; 92 were older than 60 years. The complete remission (CR)/CR with incomplete blood count recovery (CRi) rate was 51%, with 9% of induction deaths. Three covariates were associated with lower CR/CRi: high‐risk cytogenetics and t(8;21) at diagnosis, no previous allogeneic stem cell transplantation (allo‐SCT) and relapse‐free interval <1 year. Allo‐SCT was performed in second CR in 60 patients (23%). The median overall survival (OS) of the entire cohort was 0·7 years, with 22% OS at 5‐years. Four independent variables were used to construct the score: cytogenetics, FLT3‐internal tandem duplication, length of relapse‐free interval and previous allo‐SCT. Using this stratification system, three groups were defined: favourable (26% of patients), intermediate (29%) and poor‐risk (45%), with an expected 5‐year OS of 52%, 26% and 7%, respectively. The SALFLAGE score discriminated a subset of patients with an acceptable long‐term outcome using FLAG‐Ida/FLAGO‐Ida regimen. The results of this retrospective analysis should be validated in independent external cohorts.     

Phase II study of targeted therapy with temozolomide in acute myeloid leukaemia and high‐risk myelodysplastic syndrome patients pre‐screened for low O6‐methylguanine DNA methyltransferase expression

Resistance to temozolomide is largely mediated by the DNA repair enzyme O⁶‐methylguanine DNA methyltransferase (MGMT). We conducted a prospective multicentre study of patients with previously untreated acute myeloid leukaemia (AML) or high‐risk myelodysplastic syndrome (MDS) who were not candidates for intensive therapy. Patient selection was based on MGMT expression by Western blot. Patients with MGMT:ACTB (β‐actin) ratio <0·2 were eligible to receive temozolomide 200 mg/m²/d ×7 d. Patients achieving a complete response (CR) could receive up to 12 monthly cycles of temozolomide ×5/28 d. Of 166 patients screened, 81 (49%) demonstrated low MGMT expression; 45 of these were treated with temozolomide. The overall response rate was 53%; 36% achieved complete clearance of blasts, with 27% achieving a CR/CR with incomplete platelet recovery (CRp). Factors associated with a trend toward a higher response rate included MDS, methylated MGMT promoter and standard cytogenetic risk group. Induction and post‐remission cycles were well‐tolerated and most patients were treated on an outpatient basis. Patient who achieved CR/CRp had a superior overall survival compared to partial or non‐responders. In conclusion, targeted therapy based on pre‐selection for low MGMT expression was associated with a higher response rate to temozolomide compared to previous reports of unselected patients.     

Comparative clinical effectiveness of azacitidine versus decitabine in older patients with myelodysplastic syndromes

The hypomethylating agents (HMAs) azacitidine and decitabine are both approved for treatment of myelodysplastic syndromes (MDS) in the USA. In Europe, decitabine is not approved due to lack of survival advantage in randomized trials. The two drugs have not been compared in clinical trials. We identified patients diagnosed with MDS between 2004 and 2011 from the Surveillance, Epidemiology, and End Results (SEER)‐Medicare linked database in the USA who received ≥ 10 doses of either HMA. We estimated survival from HMA initiation with Kaplan–Meier methods and used multivariate Cox proportional hazards models to adjust for covariates. Analyses controlled for histological subtype and we conducted a subset analysis limited to patients with refractory anaemia with excess blasts (RAEB). In 2025 HMA‐treated patients, median survival was 15 months with no difference in survival based on the HMA received in adjusted analysis (decitabine versus azacitidine, hazard ratio = 1·06, 95% confidence interval: 0·94–1·19, P = 0·37). For RAEB patients (n = 523), median survival was 12 months, with no significant difference based on HMA received. No significant survival difference was found between azacitidine and decitabine in patients with MDS, including RAEB. Importantly, population‐based survival of azacitidine‐treated RAEB patients was substantially shorter than in the AZA‐001 clinical trial (11 versus 24·5 months).     

Safety and clinical activity of 5‐aza‐2′‐deoxycytidine (decitabine) with or without Hyper‐CVAD in relapsed/refractory acute lymphocytic leukaemia

To test the safety and activity of 5‐aza‐2′‐deoxycytidine (decitabine) in patients with relapsed/refractory acute lymphocytic leukaemia (ALL), we conducted a phase 1 study with two parts: administering decitabine alone or in combination with Hyper‐CVAD (fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high‐dose methotrexate and cytarabine). Patients participated in either part of the study or in both parts sequentially. In the initial part, decitabine was administered intravenously at doses of 10–120 mg/m² per d for 5 d every other week in cycles of 28 d. In the combination part, patients were treated on the first 5 d of Hyper‐CVAD with intravenous decitabine at 5–60 mg/m² per d. A total of 39 patients received treatment in the study: 14 in the first part only, 16 sequentially in both parts and 9 in the second part only. Decitabine was tolerated at all doses administered, and grade 3 or 4 toxic effects included non‐life‐threatening hepatotoxicity and hyperglycaemia. Induction of DNA hypomethylation was observed at doses of decitabine up to 80 mg/m². Some patients who had previously progressed on Hyper‐CVAD alone achieved a complete response when decitabine was added. Decitabine alone or given with Hyper‐CVAD is safe and has clinical activity in patients with advanced ALL.     

Clinical outcome of treatment with a combined regimen of decitabine and aclacinomycin/cytarabine for patients with refractory acute myeloid leukemia

We conducted a clinical trial of low-dose decitabine plus aclacinomycin/cytarabine (AA) treatment (DAA) for 20 patients with refractory/relapsed de novo acute myeloid leukemia (AML) or AML transformed from myelodysplastic syndrome (MDS/AML) in order to examine its efficacy and tolerability. Additionally, P15^ink4b methylation status was analyzed (for 15 patients) pre- and post-DAA treatment, and in vitro drug sensitivity tests were performed for seven patients (AA or AA?+?decitabine) to explore the role of decitabine in this combination treatment regimen. A total of 11 patients (55.0?%) achieved complete remission (CR) after DAA treatment, including 7 of whom reached CR after only one treatment course. The other two patients achieved partial remission. The median overall survival (OS) was 10?months for all 20 patients. The median OS for those who achieved CR was significantly longer than that of patients with no response (NR; P?=?0.01). The treatment regimen was well tolerated, and there was no treatment-related mortality. The mean levels of P15^ink4b methylation decreased significantly in six patients who achieved CR, whereas very few changes in P15 ^ink4b methylation were detected for the five patients with NR following DAA treatment. The data from the methyl thiazolyl tetrazolium assays showed that the inhibition rates of AA and DAA for tumor cells were identical. We conclude that induction therapy with DAA for refractory/relapsed de novo AML or MDS/AML achieved high levels of CR and improved OS and demonstrated adequate tolerance. Moreover, the decitabine component of DAA may function through a demethylation effect.     

G‐CSF Priming,clofarabine, and high dose cytarabine (GCLAC) for upfront treatment of acute myeloid leukemia,advanced myelodysplastic syndrome or advanced myeloproliferative neoplasm

Prior study of the combination of clofarabine and high dose cytarabine with granulocyte colony‐stimulating factor (G‐CSF) priming (GCLAC) in relapsed or refractory acute myeloid leukemia resulted in a 46% rate of complete remission despite unfavorable risk cytogenetics. A multivariate analysis demonstrated that the remission rate and survival with GCLAC were superior to FLAG (fludarabine, cytarabine, G‐CSF) in the relapsed setting. We therefore initiated a study of the GCLAC regimen in the upfront setting in a multicenter trial. The objectives were to evaluate the rates of complete remission (CR), overall and relapse‐free survival (OS and RFS), and toxicity of GCLAC. Clofarabine was administered at 30 mg m^?2 day^?1 × 5 and cytarabine at 2 g m^?2 day^?1 × 5 after G‐CSF priming in 50 newly‐diagnosed patients ages 18–64 with AML or advanced myelodysplastic syndrome (MDS) or advanced myeloproliferative neoplasm (MPN). Responses were assessed in the different cytogenetic risk groups and in patients with antecedent hematologic disorder. The overall CR rate was 76% (95% confidence interval [CI] 64–88%) and the CR + CRp (CR with incomplete platelet count recovery) was 82% (95% CI 71–93%). The CR rate was 100% for patients with favorable, 84% for those with intermediate, and 62% for those with unfavorable risk cytogenetics. For patients with an antecedent hematologic disorder (AHD), the CR rate was 65%, compared to 85% for those without an AHD. The 60 day mortality was 2%. Thus, front line GCLAC is a well‐tolerated, effective induction regimen for AML and advanced myelodysplastic or myeloproliferative disorders. Am. J. Hematol. 90:295–300, 2015. © 2014 Wiley Periodicals, Inc.     

Azacitidine in the ‘real‐world’: an evaluation of 1101 higher‐risk myelodysplastic syndrome/low blast count acute myeloid leukaemia patients in Ontario,Canada

The outcome of myelodysplastic syndrome (MDS) patients with uniformly higher‐risk disease treated with azacitidine (AZA) in the ‘real‐world’ remains largely unknown. We evaluated 1101 consecutive higher‐risk MDS patients (International Prognostic Scoring System intermediate‐2/high) and low‐blast count acute myeloid leukaemia (AML; 21–30% blasts) patients treated in Ontario, Canada. By dosing schedule, 24·7% received AZA for seven consecutive days, 12·4% for six consecutive days and 62·9% by 5‐2‐2. Overall, median number of cycles was 6 (range 1–67) and 8 (range 6–14) when restricted to the 692 (63%) patients who received at least 4 cycles. The actuarial median survival was 11·6 months [95% confidence interval (CI) 10·7–12·4) for the entire cohort and 18·0 months (landmark analysis; 95% CI 16·6–19·1 months) for those receiving at least 4 cycles. There was no difference in overall survival (OS) between the 3 dosing schedules (P = 0·87). In our large ‘real‐world’ evaluation of AZA in higher‐risk MDS/low‐blast count AML, we demonstrated a lower than expected OS. Reassuringly, survival did not differ by dosing schedules. The OS was higher in the 2/3 of patients who received at least 4 cycles of treatment, reinforcing the necessity of sustained administration until therapeutic benefits are realised. This represents the largest ‘real‐world’ evaluation of AZA in higher‐risk MDS/low‐blast count AML.     

Treatment of children with acute myeloid leukaemia who relapsed after allogeneic haematopoietic stem cell transplantation

Despite improvements in diagnosis and treatment, 30–40% of children with acute myeloid leukaemia (AML) experience relapse. For those who relapse after allogeneic haematopoietic stem cell transplantation (allo‐HSCT), the prognosis is particularly poor, with limited reported literature on these patients. We reviewed the clinical course of 49 children with AML (28 males, 21 females) who received allo‐HSCT between 1993 and 2011, and who had subsequently relapsed. Study endpoints included (i) complete remission (CR) rate after intensive chemotherapy, and prognostic factors for CR, (ii) disease‐free survival (DFS) and overall survival (OS) for patients who achieved CR and (iii) OS for recipients of intensive chemotherapy and prognostic factors for OS . Of the 36 patients who received intensive chemotherapy after post‐HSCT relapse, 26 (72%) achieved CR. For patients who achieved CR, 5‐year DFS and OS were 32·6 ± 10·2% and 44·4 ± 11·1%, respectively. For all recipients of intensive chemotherapy, 5‐year OS was 31·6 ± 8·7%. Cumulative incidence of treatment‐related death was 14·4%. All three recipients of second HSCT died. Amongst prognostic factors predicting improved survival, only disease status at HSCT (early first CR vs. others) proved significant in multivariate study (Hazard Ratio 2·42, 95% Confidence Interval 1·02–5·74, P = 0·045). Treatment with curative intent was able to salvage a minor but important subset of children with AML who relapsed post‐allogeneic transplant.     

Idarubicin,cytarabine, and pravastatin as induction therapy for untreated acute myeloid leukemia and high‐risk myelodysplastic syndrome

Previous studies suggest that idarubicin/cytarabine(ara‐C)/pravastatin (IAP) is an active salvage regimen for patients with AML. We therefore investigated this regimen in patients with newly‐diagnosed AML or MDS (≥10% blasts). Patients were eligible if the anticipated treatment‐related mortality (TRM) was <10%. Patients received pravastatin (1,280 mg/day po; days 1–8), cytarabine (1.5 g/m²/day; days 4–7), and idarubicin (12 mg/m²/day, days 4–6). Up to 3 cycles of consolidation with a shortened course was permitted. The primary endpoints were “good CR” rate (CR on day 35 without minimal residual disease) and TRM in the first 28 days. The study was to stop if after each cohort of 5 patients (a) the Bayesian posterior probability was < 5% that the true “good CR rate” was ≥ 70% or (b) the posterior probability was >25% that the TRM rate was ≥5%. Twenty‐four patients were included. Conventional CR was achieved in 15 (63%) patients but only 12 (50%) achieved “good CR”. 4 of 12 (33%) patients with “good CR” relapsed at median of 16 weeks (10.5–19). Five (21%) patients had refractory disease. Survival probability at 1 year was 72% (48.7–64). Two (8.3%) patients died within 28 days from multiorgan failure. The most common grade 3–4 adverse effects were febrile neutropenia (75%) and diarrhea (25%). Based on the stopping rules accrual ceased after entry of these 24 patients. IAP did not meet the predefined efficacy criteria for success. Therefore, we would not recommend this regimen for phase three testing in this patient subset. Am. J. Hematol. 90:483–486, 2015. © 2015 Wiley Periodicals, Inc.     

A phase I–II study of plerixafor in combination with fludarabine,idarubicin, cytarabine,and G-CSF (PLERIFLAG regimen) for the treatment of patients with the first early-relapsed or refractory acute myeloid leukemia

Clinical outcomes of patients with acute myeloid leukemia (AML) showing the first primary refractory or early-relapsed disease remain very poor. The Programa Español de Tratamientos en Hematología (PETHEMA) group designed a phase I–II trial using FLAG-Ida (fludarabine, idarubicin, cytarabine, and G-CSF) plus high-dose intravenous plerixafor, a molecule inducing mobilization of blasts through the SDF-1α-CXCR4 axis blockade and potentially leading to chemosensitization of the leukemic cells. We aimed to establish a recommended phase 2 dose (RP2D) of plerixafor plus FLAG-Ida, as well as the efficacy and safety of this combination for early-relapsed (first complete remission (CR/CRi)?<?12 months) or primary refractory AML. Between 2012 and 2015, 57 patients were enrolled, and 41 received the RP2D (median age 52 years [range, 18–64]). Among these patients, 20 (49%) achieved CR/CRi, and 3 (7%) died during induction. CR/CRi rate was 50% (13/26) among primary refractory and 47% (7/15) among early relapse. Overall, 25 patients (61%) were allografted. Median overall and disease-free survivals were 9.9 and 13 months, respectively. In summary, the combination of plerixafor plus FLAG-Ida resulted in a relatively high CR/CRi rate in adult patients with primary refractory or early relapsed AML, with an acceptable toxicity profile and induction mortality rate, bridging the majority of patients to allogeneic stem cell transplantation. ClinicalTrials.gov Identifier: NCT01435343     

Primary treatment of leukemia relapses after allogeneic hematopoietic stem cell transplantation with reduced‐intensity conditioning second transplantation from the original donor

Acute leukemia relapsing after allogeneic hematopoietic stem cell transplantation (HSCT) has dismal outcome. Consecutive consenting patients (acute myeloid leukemia: N = 71; acute lymphoblastic leukemia: N = 37), at a median age of 37 (16–57) years, who had relapsed 7.9 (1.3–132) months post‐HSCT, were treated with three cytarabine‐based intensive regimens as reduced‐intensity conditioning (RIC), followed by infusion of mobilized HSC from the original donors. There were four treatment‐related mortalities (TRMs). Of 104 evaluable cases, 72 patients (67%) achieved complete remission (CR)/CR with incomplete hematologic recovery (CRi). The median overall survival (OS) of the entire cohort was 11.6 months. The OS of patients achieving CR/CRi after the first RIC/HSCT was 18.8 months, as compared with 3.9 months for those not (P < 0.01). For 32 patients with nonremission, 11 received a repeat RIC‐HSCT, leading to CR/CRi in three cases. Therefore, 75/108 (69%) of patients achieved CR/CRi after one or two courses of RIC‐HSCT. Among CR/CRi patients, 48 cases relapsed again after 6.1 (1.0–64.4) months. Thirty cases received a repeat RIC‐HSCT, leading to CR/CRi in 22 patients. Multivariate analyses showed a significant impact of remission duration after initial HSCT (P = 0.026) and the presence of acute graft‐versus‐host disease after RIC‐HSCT (P = 0.011) on CR/CRi. RIC‐HSCT as primary treatment for acute leukemic relapses post‐HSCT induced a high CR rate with low TRM. Optimal postremission treatment remains to be defined. Am. J. Hematol. 88:485–491, 2013. © 2013 Wiley Periodicals, Inc.     

A prospective,multicenter phase II study of continuous infusion of FLAG for patients older than 60 yr with resistant acute myeloid leukemia: a comparison with intensive younger patients’ trial

Relapsed or refractory acute myeloid leukemia (R/R AML) in elderly (≥60 yr old) patients were eligible. Induction chemotherapy consisted fludarabine and cytarabine (ARAC) as a 24‐hr CI without idarubicin (C‐FLAG), which was compared with the results of C‐FLAG with idarubicin (CI‐FLAG2) in younger patients’ trial. A total of 33 and 68 patients were enrolled in C‐FLAG and CI‐FLAG2, respectively. CR, CRp, and CRi were achieved in 10 (30.3%), 3 (9.1%), and 2 (6.1%), respectively. When comparing outcomes between C‐FLAG and CI‐FLAG2, there were no difference in terms of CR rate (P = 0.572) and objective response rate (ORR; P = 0.899). Favorable predictors on ORR in C‐FLAG were PB WBC ≤ 20K/uL at salvage (P = 0.024) and early evaluation peripheral BLAST = 0% (P = 0.013) on multivariate analysis. The overall survival of patients who achieve CR/CRp/CRi showed significantly prolonged survival compared with patients who did not in C‐FLAG (P < 0.001) and was a favorable predictor of longer survival by multivariate analysis (P = 0.009). Median overall survival was 3.19 (95% CI, 2.05–4.33) months and similar with that of CI‐FLAG2 (P = 0.841). Attenuated salvage regimen C‐FLGA in elderly patients was as effective as more intensive younger patients’ regimen CI‐FLAG2 in terms of response and survival although elderly patients had more unfavorable clinical characteristics.     

Peripheral blood blast rate of clearance is an independent predictor of clinical response and outcomes in acute myeloid leukaemia

The day 14 bone marrow aspirate and biopsy (D14BM) is regularly used to predict achievement of complete remission (CR) with induction chemotherapy in acute myeloid leukemia (AML), however its utility has been questioned. Clearance of peripheral blood blasts (PBB) may serve as an early measure of chemosensitivity. PBB rate of clearance (PBB-RC) was calculated for treatment-naive AML patients (n = 164) undergoing induction with an anthracycline and cytarabine (7+3) and with detectable PBB at diagnosis. PBB-RC was defined as the percentage of the absolute PBB count on the day of diagnosis that was cleared with each day of therapy, on average, until D14 or day of PBB clearance. Each 5% increase in PBB-RC approximately doubled the likelihood of D14BM clearance (OR = 1·81; 95% CI: 1·24–2·64, P < 0·005). PBB-RC was also associated with improved CR rates (OR per 5% = 1·97; 95% CI: 1·27–3·01, P < 0·005) and overall survival (OS) [hazard ratio (HR) per 5% = 0·67; 95% CI: 0·52–0·87]. African American patients had poorer OS adjusted for PBB-RC (HR = 2·18; 95% CI: 1·13–4·23), while race was not associated with D14BM or CR rate. PBB-RC during induction chemotherapy is predictive of D14BM clearance, CR, and OS, and can therefore serve as a prognostic marker for clinical outcomes in AML.     

Genome‐wide DNA methylation profiling predicts relapse in childhood B‐cell acute lymphoblastic leukaemia

Low‐dose decitabine has encouraging activity and tolerability in adults with acute myeloid leukaemia (AML), but paediatric experience is lacking. We report our retrospective experience with decitabine in eight children and young adults (median age 4 years) with refractory/relapsed AML, who had failed multiple regimens or were not candidates for standard retrieval regimens due to prior toxicities. Three of eight patients (38%) had complete response (CR; 1 each of CR, CR with incomplete platelet recovery and CR with incomplete count recovery). Best responses were observed after a median of 2·5 cycles (range 1–4 cycles). Four patients received subsequent allogeneic stem cell transplant, and two remain in long‐term CR.     

Maintenance treatment with azacytidine for patients with high‐risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy

This prospective Phase II study is the first to assess the feasibility and efficacy of maintenance 5‐azacytidine for older patients with high‐risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia and MDS‐acute myeloid leukaemia syndromes in complete remission (CR) after induction chemotherapy. Sixty patients were enrolled and treated by standard induction chemotherapy. Patients that reached CR started maintenance therapy with subcutaneous azacytidine, 5/28 d until relapse. Promoter‐methylation status of CDKN2B (P15 ink4b), CDH1 and HIC1 was examined pre‐induction, in CR and 6, 12 and 24 months post CR. Twenty‐four (40%) patients achieved CR after induction chemotherapy and 23 started maintenance treatment with azacytidine. Median CR duration was 13·5 months, >24 months in 17% of the patients, and 18–30·5 months in the four patients with trisomy 8. CR duration was not associated with CDKN2B methylation status or karyotype. Median overall survival was 20 months. Hypermethylation of CDH1 was significantly associated with low CR rate, early relapse, and short overall survival (P = 0·003). 5‐azacytidine treatment, at a dose of 60 mg/m² was well tolerated. Grade III‐IV thrombocytopenia and neutropenia occurred after 9·5 and 30% of the cycles, respectively, while haemoglobin levels increased during treatment. 5‐azacytidine treatment is safe, feasible and may be of benefit in a subset of patients.