Salvage therapy for acute myeloid leukemia with fludarabine,cytarabine, and idarubicin with or without gemtuzumab ozogamicin and with concurrent or sequential G‐CSF

The current salvage therapies for relapsed/refractory acute myeloid leukemia (AML) are unsatisfactory. Over the past 7 years, we have used two salvage regimens: fludarabine, cytarabine, and idarubicin with (FLAG‐IM) or without gemtuzumab ozogamicin (GO) (9 mg/m² on Day 8) (FLAG‐I) in relapsed/refractory AML. Three‐quarters of patients also received concurrent G‐CSF. Seventy‐one patients were treated, 23 with FLAG‐I and 48 with FLAG‐IM. The median duration of follow‐up was 30.6 months. The treatment groups were well balanced with median ages of 48 years (range 18–70) and 47 years (range 20–68), unfavorable cytogenetics in 57% and 35%, prior allogeneic stem cell transplant in 43% and 42%, and CR1 duration <1 year in 60% and 67%, respectively, for FLAG‐I and FLAG‐IM. The complete remission (CR) rate in the FLAG‐I group was 39% with an additional 13% achieving a CRp [overall response rate (ORR) 52%]; the CR rate in the FLAG‐IM group was 29% with an additional 27% achieving a CRp (ORR 56%). The median duration of response (DOR; 16.8 vs. 8.3 months), event‐free survival (EFS; 7.4 vs. 4.1 months), and overall survival (OS; 8.8 vs. 5.0 months) trended to favor FLAG‐I over FLAG‐IM. The patients who received G‐CSF concurrent with chemotherapy had superior overall response rate (ORR; 62% vs. 29%, P = 0.026), median EFS (6.2 vs. 3.4 months, P = 0.010), and OS (8.8 vs. 3.9 months, P = 0.004) when compared with those who sequentially received G‐CSF and chemotherapy, regardless of chemotherapy regimen. The addition of GO, at this dose and schedule, to FLAG‐I failed to improve the outcomes in patients with relapsed/refractory AML. The patients who received G‐CSF concurrently with chemotherapy had improved outcomes. Am. J. Hematol., 2009. © 2009 Wiley‐Liss, Inc.     

High feasibility and antileukemic efficacy of fludarabine,cytarabine, and idarubicin (FLAI) induction followed by risk‐oriented consolidation: A critical review of a 10‐year,single‐center experience in younger,non M3 AML patients

About 105 consecutive acute myeloid leukemia (AML) patients treated with the same induction‐consolidation program between 2004 and 2013 were retrospectively analyzed. Median age was 47 years. The first induction course included fludarabine (Flu) and high‐dose cytarabine (Ara‐C) plus idarubicin (Ida), with or without gemtuzumab‐ozogamicin (GO) 3 mg/m² (FLAI‐5). Patients achieving complete remission (CR) received a second course without fludarabine but with higher dose of idarubicin. Patients not achieving CR received an intensified second course. Patients not scheduled for early allogeneic bone marrow transplantation (HSCT) where planned to receive at least two courses of consolidation therapy with Ara‐C. Our double induction strategy significantly differs from described fludarabine‐containing regimens, as patients achieving CR receive a second course without fludarabine, to avoid excess toxicity, and Ara‐C consolidation is administrated at the reduced cumulative dose of 8 g/m² per cycle. Toxicity is a major concern in fludarabine containing induction, including the recent Medical Research Council AML15 fludarabine, cytarabine, idaraubicin and G‐CSF (FLAG‐Ida) arm, and, despite higher anti‐leukemic efficacy, only a minority of patients is able to complete the full planned program. In this article, we show that our therapeutic program is generally well tolerated, as most patients were able to receive subsequent therapy at full dose and in a timely manner, with a 30‐day mortality of 4.8%. The omission of fludarabine in the second course did not reduce efficacy, as a CR rate of 83% was achieved and 3‐year disease‐free survival and overall survival (OS) were 49.6% and 50.9%, respectively. Our experience shows that FLAI‐5/Ara‐C + Ida double induction followed by risk‐oriented consolidation therapy can result in good overall outcome with acceptable toxicity. Am. J. Hematol. 91:755–762, 2016. © 2016 Wiley Periodicals, Inc.     

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.     

Autologous transplantation gives encouraging results for young adults with favorable-risk acute myeloid leukemia, but is not improved with gemtuzumab ozogamicin

We report the results of a prospective, randomized phase 3 trial evaluating the use of gemtuzumab ozogamicin (GO) in an intensive consolidation approach in 657 patients 17-60 years of age. Patients in first complete remission (CR1) after cytarabine and standard- or high-dose daunorubicin induction received 2 cycles of consolidation with high-dose cytarabine followed by peripheral blood progenitor cell collection. The 352 patients who entered consolidation were randomized to receive GO (n = 132) or not (n = 138) and then proceeded to autologous hematopoietic cell transplantation (HCT). GO was given to 67 patients. Median follow-up was 50.9 months. Results of the intention-to-treat analysis demonstrated a 4-year disease-free survival (DFS) of 33.6% versus 35.9% (P = .54) and an overall survival (OS) of 41.3% versus 41.9% (P = .52) for those randomized to receive GO versus no GO, respectively. Patients with favorable- and intermediate-risk acute myeloid leukemia (AML) treated with high-dose daunorubicin and autologous HCT had 4-year DFS rates of 60% and 40% and OS rates of 80% and 49.3%, respectively. For younger AML patients in CR1, autologous HCT should be considered in favorable- and intermediate-cytogenetic risk patients who do not have an allogeneic donor. The addition of a single dose of GO in this setting did not improve outcomes.     

Complex karyotype,older age,and reduced first‐line dose intensity determine poor survival in core binding factor acute myeloid leukemia patients with long‐term follow‐up

Approximately 40% of patients affected by core binding factor (CBF) acute myeloid leukemia (AML) ultimately die from the disease. Few prognostic markers have been identified. We reviewed 192 patients with CBF AML, treated with curative intent (age, 15–79 years) in 11 Italian institutions. Overall, 10‐year overall survival (OS), disease‐free survival (DFS), and event‐free survival were 63.9%, 54.8%, and 49.9%, respectively; patients with the t(8;21) and inv(16) chromosomal rearrangements exhibited significant differences at diagnosis. Despite similar high complete remission (CR) rate, patients with inv(16) experienced superior DFS and a high chance of achieving a second CR, often leading to prolonged OS also after relapse. We found that a complex karyotype (i.e., ≥4 cytogenetic anomalies) affected survival, even if only in univariate analysis; the KIT D816 mutation predicted worse prognosis, but only in patients with the t(8;21) rearrangement, whereas FLT3 mutations had no prognostic impact. We then observed increasingly better survival with more intense first‐line therapy, in some high‐risk patients including autologous or allogeneic hematopoietic stem cell transplantation. In multivariate analysis, age, severe thrombocytopenia, elevated lactate dehydrogenase levels, and failure to achieve CR after induction independently predicted longer OS, whereas complex karyotype predicted shorter OS only in univariate analysis. The achievement of minimal residual disease negativity predicted better OS and DFS. Long‐term survival was observed also in a minority of elderly patients who received intensive consolidation. All considered, we identified among CBF AML patients a subgroup with poorer prognosis who might benefit from more intense first‐line treatment. Am. J. Hematol. 90:515–523, 2015. © 2015 Wiley Periodicals, Inc.     

Fractionated gemtuzumab ozogamicin and standard dose cytarabine produced prolonged second remissions in patients over the age of 55 years with acute myeloid leukemia in late first relapse

Gemtuzumab ozogamicin (fGO), a humanized anti‐CD33 monoclonal antibody linked to calicheamicin in combination with intensive chemotherapy gives high response rates in adult acute myeloid leukemia (AML) patients in relapse. However, reduced intensity chemotherapy in combination with fractionated GO has not been tested in aged relapsing patients. Patients from our institution with CD33+ AML aged 55 years or more in first late relapse (≥6 months) were proposed participation in a GO compassionate use program. Induction therapy consisted in fractionated GO (fGO; 3 mg/m², days 1, 4, 7) with standard‐dose cytarabine (200 mg/m²/day, 7 days). Patients were consolidated with two courses of GO and intermediate dose cytarabine. Twenty‐four patients (median age 68 years) received fGO with cytarabine. Median follow‐up was 42 months. The response rate was 75%, including complete remission (CR) in 16 patients and CR with incomplete platelet recovery (CRp) in two patients. Two‐year overall survival (OS) was 51% (95% CI: 28–69) and 2 years relapse‐free survival (RFS) was 51% (95%CI: 25–72). Duration of second CR (CR2) was longer than first CR (CR1) in 9 out of 18 patients. Minimal residual disease (MRD) was negative in evaluable patients in CR2, particularly in NPM1 mutated cases. Toxicity was in line with that of the same fractionated single agent GO schedule. Fractionated GO with low intensity chemotherapy produced high response rates and prolonged CR2 in aged AML patients in first late relapse. Am. J. Hematol. 89:399–403, 2014. © 2013 Wiley Periodicals, Inc.     

Outcome of older patients with acute myeloid leukemia in first relapse

To provide data for future drug evaluation, we analyzed the outcome of 393 patients aged 50 years or older (median, 64 years) with AML in first relapse after treatment in recent ALFA trials. Salvage options were retrospectively classified as follows: best supportive care (BSC), low‐dose cytarabine (LDAC), gemtuzumab ozogamicin (GO), intensive chemotherapy (ICT), or ICT combined with GO. Second complete remission (CR2) rate was 31% and median post‐relapse survival was 6.8 months (0, 17, 42.5, 53, and 80% and 3.2, 5.6, 8.9, 9, and 19.8 months in BSC, LDAC, GO, ICT, and ICT + GO subsets, respectively). Age, performance status, WBC, CR1 duration, and favorable AML karyotype, but not other cytogenetic or molecular features, influenced post‐relapse outcome. Multivariate adjustment and propensity score matching showed that intensive salvage (ICT/ICT+GO/GO versus LDAC/BSC) was associated with longer post‐relapse survival, at least in patients with CR1 duration ≥12 months (P = 0.001 and 0.0005, respectively). Of interest, GO appeared to be as effective as standard ICT, and ICT + GO combination more effective than standard ICT. In conclusion, older patients with CR1 duration ≥12 months appeared to benefit from intensive salvage and results observed with GO‐containing salvage suggest that GO combination studies should be actively pursued in this setting. Am. J. Hematol. 88:758–764, 2013. © 2013 Wiley Periodicals, Inc.     

Fractionated gemtuzumab ozogamicin combined with intermediate-dose cytarabine and daunorubicin as salvage therapy in very high-risk AML patients: a bridge to reduced intensity conditioning transplant?

Outcome of patients with primary refractory/relapsed (R/R) acute myeloid leukemia (AML) remains dismal. Herein, we present a retrospective monocentric study of 24 very high-risk AML patients who received a combination of fractionated gemtuzumab ozogamicin (GO) with intermediate-dose cytarabine and daunorubicin as salvage therapy. Median age was 55.3 years. Diagnostic was secondary AML for 33% of them. Seven patients had favorable risk, 8 had intermediate-1 or intermediate-2, and 6 had unfavorable risk of AML according to the European LeukemiaNet prognostic index. Complete remission was achieved in 50% of cases (46% in refractory and 55% in relapsed AML) without excessive toxicity. Thirteen patients could be referred for transplant. Only allogeneic hematopoietic stem cell transplantation provided a benefit in this patient cohort with a 1-year overall survival of 50.7 versus 18.1% in the absence of transplantation. Patients treated with reduced intensity conditioning (RIC) showed a longer survival as compared to those undergoing myeloablative conditioning regimen mainly because of decreased toxicity.Our data suggest that salvage therapy with fractionated GO combined with intermediate-dose cytarabine and daunorubicin in very high-risk patients may serve as a potential bridge therapy to RIC transplant.     

Post-remission therapy in acute myeloid leukemia: Are we ready for an individualized approach?

Recent advances in remission induction treatment strategies for acute myeloid leukemia (AML) have improved the rates of complete remission (CR) and overall survival (OS), owing to a concerted effort to tailor therapies toward specific AML subtypes. However, without effective post-remission therapy, most patients will relapse. The extent to which post-remission therapies is individualized in the current paradigm is quite varied. Core binding factor (CBF) AML is typically treated with post-remission high-dose cytarabine (HiDAC) without allogeneic hematopoietic stem cell transplantation (HSCT), whereas those with intermediate or adverse-risk cytogenetics are treated with post-remission cytarabine followed by allogeneic HSCT in CR1 when feasible. A lack of clarity regarding the proper dosing of post-remission cytarabine has made consensus building on dosing and schedule a challenge. CBF AML benefits most from high-dose cytarabine (HiDAC), and dasatinib appears promising as an adjunct for those for KIT-mutated CBF AML. Other than series using CPX-351 or lomustine in older adults, multiagent chemotherapy approaches have resulted in excess toxicity without a survival benefit. Neither hypomethylating agents nor gemtuzumab ozogamicin have shown a material OS benefit. Targeted agents such as FLT3 inhibitors and IDH1/IDH2 inhibitors show potential for the patients who harbor these druggable targets, but few data are available. Many studies evaluating post-remission strategies to target AML in the MRD-positive state are already underway, and these remain a promising area of investigation.     

Outcomes of elderly de novo acute myeloid leukemia treated by a risk‐adapted approach based on age,comorbidity, and performance status

Several criteria to define fitness for induction chemotherapy in elderly acute myeloid leukemia (AML) have been proposed; however, no studies have reported outcomes according to the application of a risk‐adapted approach. We treated 256 consecutive patients with elderly AML (≥60 years) with a risk‐adapted approach based on age, comorbidity score (CS), and performance status (ECOG). Eighty‐five low‐risk patients (age ≤ 65 years and ECOG 0–1 with CS < 2), 86 intermediate‐risk patients (age > 65 years or ECOG = 2 with CS < 2), and 85 high‐risk patients (ECOG > 2 or CS ≥ 2) were treated with induction chemotherapies, including standard intensive regimens, abbreviated‐scheduled regimens, and modified low‐dose cytarabine with oral etoposide (mLDAC), respectively. Overall response rates (ORR; complete response and complete response with incomplete recovery) for these three groups were 71.8%, 60.5%, and 41.2%, respectively, without a significant difference in early death rate (17.6%, 25.6%, 23.5%, P = 0.415). Among three abbreviated‐scheduled regimens, a gemtuzumab ozogamicin (GO)‐containing regimen (n = 43) showed a similar ORR rate (72.1%) to the intensive regimen. After achieving remission, 142 patients went on postremission treatments, including reduced‐intensity allogeneic transplantation (RIC, n = 41), standard consolidation (n = 71), and repeated mLDAC (n = 30) according to donor availability, age, ECOG, and CS. Multivariate analyses revealed that not only RIC, but also repeated mLDAC, resulted in significantly superior survival outcomes to standard consolidation independent of age, ECOG, and CS. Clinical benefits of mLDAC for high‐risk patients and abbreviated induction with GO for intermediate‐risk patients should be confirmed with further studies. Our results also suggest that RIC should be actively considered in elderly AML as a postremission treatment. Am. J. Hematol. 88:1074–1081, 2013. © 2013 Wiley Periodicals, Inc.     

Outcomes of previously untreated elderly patients with AML: a propensity score-matched comparison of clofarabine vs. FLAG

The 5-year overall survival (OS) in patients ≥?60 years old with acute myeloid leukemia (AML) remains <?10%. Clofarabine-based induction (CLO) provides an alternative to low-intensity therapy (LIT) and palliative care for this population, but supporting data are conflicted. Recently, our institution adopted the FLAG regimen (fludarabine, cytarabine, and granulocyte colony-stimulating factor) based on data reporting similar outcomes to CLO in elderly patients with AML unable to tolerate anthracycline-based induction. We retrospectively analyzed the efficacy and safety of patients ≥?60 years old with AML treated with FLAG or CLO over the past 10 years. We performed a propensity score match that provided 32 patients in each group. Patients treated with FLAG had a higher CR/CRi rate (65.6 vs. 37.5%, P?=?0.045) and OS (7.9 vs. 2.8 months, P?=?0.085) compared to CLO. Furthermore, FLAG was better tolerated with significantly less grade 3/4 toxicities and a shorter duration of neutropenia (18.5 vs. 30 days, P?=?0.002). Finally, we performed a cost analysis that estimated savings to be $30,000–45,000 per induction with FLAG. Our study supports the use of FLAG both financially and as an effective, well-tolerated high-dose treatment regimen for elderly patients with AML. No cases of cerebellar neurotoxicity occurred.     

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.     

Adding low-dose gemtuzumab ozogamicin to fludarabine, Ara-C and idarubicin (MY-FLAI) may improve disease-free and overall survival in elderly patients with non-M3 acute myeloid leukaemia: results of a prospective, pilot, multi-centre trial and comparison with a historical cohort of patients

We report the final results of a prospective multi-centre trial testing the combination of chemotherapy (fludarabine, cytosine arabinoside and idarubicin; FLAI) followed by low-dose gemtuzumab ozogamicin (GO), for induction treatment of patients with CD33+ acute myeloid leukaemia (AML). Forty-six consecutive patients were treated: the median age was 66 (range: 60-80) years; the karyotype was unfavourable in 12 patients (26%), intermediate in 33 (71%) and favourable in one (3%). Eleven major infectious complications were recorded. There was one early death. Of the 45 evaluable patients, 24 achieved a complete response (CR; 52%), 66% and 33% in good-intermediate/poor karyotype patients. Median duration of CR was 7 (3-24) months. The cumulative incidence of relapse was 37% with an actuarial 2-year survival of 54%. These results were compared with 47 patients matched for age and karyotype who received FLAI, without GO. The proportion of patients achieving CR was comparable. However, patients with de novo AML receiving GO (n = 26) had a significantly lower risk of relapse at 2 years when compared with patients not receiving GO (n = 35) (40% vs. 80%, P = 0.01) and significantly better overall 2-year survival (40% vs. 14%P = 0.02). Patients with secondary AML had comparable outcome whether or not they received GO. This GO-based induction chemotherapy has a good toxicity profile. In keeping with a recent prospective randomised trial, the addition of GO seems to prolong disease-free survival.     

A genome‐wide single‐nucleotide polymorphism‐array can improve the prognostic stratification of the core binding factor acute myeloid leukemia

Core binding factor (CBF) AML with the D816 C‐KIT gene mutation demonstrate inferior treatment outcomes. However, the remaining cases without the D816 C‐KIT mutation imply a requirement of more sophisticated dissection of the patients according to their prognosis. In this study, we analyzed the prognostic value of a single nucleotide polymorphism array (SNP‐A) based karyotyping combined with metaphase cytogenetics (MC) to facilitate further stratification of CBF AML patients. A total of 98 CBF AML patients were included and genome‐wide Human SNP 6.0 Arrays (Affymetrix) were performed using marrow samples taken at diagnosis. Overall, 40 abnormal lesions were identified in 25 patients (26%). Survival of the patients with the abnormal lesion(s) detected by SNP‐A and/or MC was worse than those without lesions in terms of the 2‐year overall survival (OS; 57.5% vs. 76.4%, P = 0.028), event‐free (EFS; 45.7% vs. 66.2%, P = 0.072), and leukemia‐free survival (LFS; 49.0% vs. 77.4%, P = 0.015), specially in the subgroup with inv(16)/t(16;16) (40.9% vs. 80.2% OS, P = 0.040) and in the subgroup without the D816 C‐KIT mutation (61.6% vs. 82.7% OS, P = 0.038). Multivariate analysis confirmed the prognostic impact of the abnormal SNP‐A and/or MC lesion on EFS (HR 2.011, P = 0.047), and LFS (HR 3.231, P = 0.005) in the overall CBF AML. This study suggests that the combined use of SNP‐A with MC in the CBF AML can provide important prognostic value, especially in the inv(16)/t(16;16) subgroup or in the patients without the D816 C‐KIT mutation. Am. J. Hematol., 2012. © 2012 Wiley Periodicals, Inc.     

Use of fludarabine in the treatment of acute myeloid leukemia

Acute myeloid leukemia (AML) is a disease, which when left untreated, is invariably fatal. The disease is more common in elderly people, who also fare worse than younger patients with AML due to a higher rate of unfavorable prognostic factors, such as poor performance status, multiple comorbidities, reduced tolerance to treatment, 'unfavorable' chromosomal abnormalities and multidrug resistant protein-1 expression. While many patients achieve a complete remission, the rate of relapse is high and prognosis after relapse very poor. Promising results have been published in recent years using fludarabine-containing combination therapy for AML, most commonly fludarabine +cytarabine + granulocyte colony-stimulating factor (G-CSF) [FLAG], FLAG + mitoxantrone (FLANG), or FLAG + idarubicin (FLAG-Ida). Such combinations maximize favorable cytotoxic interactions between cytarabine and G-CSF, and between cytarabine and fludarabine. In small studies, such combinations used as second-line therapy have resulted in complete response (CR) rates of 36-59%. Early retrospective analyses suggested higher CR rates in patients with refractory AML than in those with relapsed AML, but this observation has not been confirmed in recent prospective trials. Fludarabine-containing combinations have also been evaluated as first-line therapy in high-risk patients and resulted in CR rates of 34-70%, with median survival from 7 to 16 months. The current large MRC randomized high-risk study will provide further data on the use of fludarabine-containing regimens in patients with poor prognosis AML. Further studies are investigating the use of fludarabine in combination with other agents, such as gemtuzumab ozogamicin and gemcitabine, in patients with AML.     

Fludarabine,cytarabine, and attenuated‐dose idarubicin (m‐FLAI) combination therapy for elderly acute myeloid leukemia patients

We performed a phase II trial to evaluate the efficacy and safety of the modified fludarabine, cytarabine, and attenuated‐dose idarubicin (m‐FLAI) regimen in elderly acute myeloid leukemia (AML) patients. Elderly (≥60 years) AML patients who had not previously received chemotherapy were enrolled in the study. Patients received two consecutive cycles of m‐FLAI chemotherapy as an induction. The m‐FLAI regimen comprised fludarabine (25 mg/m², days 1–4), cytarabine (1,000 mg/m², days 1–4), and attenuated‐dose idarubicin (5 mg/m², days 1–3). The primary end point was complete remission (CR) rate. Secondary end points were overall survival (OS), event‐free survival (EFS), and treatment‐related mortality (TRM). There were 108 patients (median age 68.4 years, M:F = 64:44) enrolled in the study. CR was achieved in 56.5% of patients, and the TRM rate was 21.3%. Median OS and median EFS were 10.2 and 6.6 months, respectively. The mortality at 30 and 60 days was 15 and 21%, respectively. Performance status and comorbidity did not have prognostic value in this patient cohort. Bone marrow expression of CD117 was associated with increased EFS and OS. m‐FLAI is an effective induction regimen for previously untreated AML in elderly patients. In addition, bone‐marrow CD117 expression is an independent favorable prognostic factor in elderly AML patients. (ClinicalTrials.gov number, NCT01247493). Am. J. Hematol. 2013. © 2012 Wiley Periodicals, Inc.     

Gemtuzumab ozogamicin for treatment of newly diagnosed acute myeloid leukaemia: a systematic review and meta‐analysis

Evidence regarding the efficacy of gemtuzumab ozogamicin (GO) addition to standard induction chemotherapy in newly diagnosed acute myeloid leukaemia (AML) is conflicting. This systematic review aimed to identify and summarize all evidence regarding the benefits and harms of adding GO to conventional chemotherapy for induction treatment of AML. A comprehensive literature search of two databases (PUBMED and Cochrane) from inception up to November 22, 2012, and 4 years of proceedings from four major haematology/oncology conferences was undertaken. Endpoints included benefits (complete remission, relapse‐free, event‐free, and overall survival), and harms (early mortality and incidence of hepatic veno‐occlusive disease/sinusoidal obstructive syndrome). Seven trials (3942 patients) met all inclusion criteria. Addition of GO showed improved relapse‐free [Hazard Ratio (HR) = 0·84 (95% confidence interval (CI) 0·71–0·99)] and event‐free survival [HR = 0·59 (95%CI 0·48–0·74)] but not overall survival [HR = 0·95 (95%CI 0·83–1·08)]. Addition of GO resulted in higher rate of early mortality [Risk Ratio = 1·60 (95%CI 1·07–2·39)]. Improved overall survival was observed in studies using a lower cumulative GO dose (<6 mg/m²) [HR = 0·89 (95%CI 0·81–0·99)]. Addition of GO to conventional chemotherapy as induction therapy may improve relapse‐free and event‐free survival, but does not impact overall survival and significantly increases early mortality in AML.     

A multicentre, open, non-comparative phase II study of a combination of fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor in relapsed and refractory acute myeloid leukaemia and de novo refractory anaemia with excess of blasts in transformation

The primary objective of this study was to determine the complete remission (CR) rate achieved with the FLAG (fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor) regimen in patients with relapsed or refractory acute myeloid leukaemia (AML) or de novo refractory anaemia with excess of blasts in transformation (RAEB-t). Secondary objectives were to evaluate survival and toxicity. Induction treatment consisted of between one and two courses of FLAG. Patients achieving CR received between one and two courses of consolidation treatment. Eighty-three of the 89 patients entering the study were eligible for assessment. CR rates were: 17 out of 21 (81%) in late relapse AML (Group 1), 13 out of 44 (30%) in early relapse/refractory AML (Group 2), and 10 out of 18 (56%) in de novo RAEB-t (Group 3). Thirty-four of the 40 responders (85%) achieved CR after one induction course. Median survival times were 1.4 years, 3 months and 1.6 years in Groups 1, 2 and 3 respectively. Other than myelosuppression, the FLAG regimen was not generally associated with clinically significant toxicity and was well tolerated by most patients including the elderly. The FLAG regimen offers a very effective alternative treatment for CR induction in poor prognosis adult patients with either relapsed or refractory AML or de novo RAEB-t. FLAG delivers high-dose treatment without increasing overall toxicity, an approach which is of particular value in older patients, who constitute the majority in these diseases. It is therefore an important advance in developing new treatment options for these patients.     

Gemtuzumab ozogamicin as postconsolidation therapy does not prevent relapse in children with AML: results from NOPHO-AML 2004

There are no data on the role of postconsolidation therapy with gemtuzumab ozogamicin (GO; Mylotarg) in children with acute myeloid leukemia (AML). The NOPHO-AML 2004 protocol studied postconsolidation randomization to GO or no further therapy. GO was administered at 5 mg/m(2) and repeated after 3 weeks. We randomized 120 patients; 59 to receive GO. Survival was analyzed on an intention-to-treat basis. The median follow-up for patients who were alive was 4.2 years. Children who received GO showed modest elevation of transaminase and bilirubin without signs of veno-occlusive disease. Severe neutropenia followed 95% and febrile neutropenia 40% of the GO courses. Only a moderate decline in platelet count and a minor decrease in hemoglobin occurred. Relapse occurred in 24 and 25 of those randomized to GO or no further therapy. The median time to relapse was 16 months versus 10 months (nonsignificant). The 5-year event-free survival and overall survival was 55% versus 51% and 74% versus 80% in those randomized to receive GO or no further therapy, respectively. Results were similar in all subgroups. In conclusion, GO therapy postconsolidation as given in this trial was well tolerated, showed a nonsignificant delay in time to relapse, but did not change the rate of relapse or survival (clinicaltrials.gov identifier NCT00476541).