Highlights in acute myeloid leukemia from the 2012 meeting of the American Society of Hematology

Abstract

2012 American Society of Hematology Annual Meeting

Atlanta, GA, USA, 8–11 December 2012

The American Society of Hematology Annual Meeting includes physicians, scientists, administrators, medical students, graduate students, allied health professionals and exhibitors. This year’s meeting was held in Atlanta, GA, USA. Presentations included a wide variety of topics in benign and malignant hematology.

While there were no studies with clear-cut implications for change in therapeutic practice for the majority of patients with acute myeloid leukemia (AML), a presentation at the American Society of Hematology (ASH) 2012 meeting is likely to lead to a new therapeutic paradigm in acute promyelocytic leukemia (APL), a well-defined AML subtype. In addition to a plenary abstract that suggested a change in the standard of care for patients with non-high-risk APL [1], other research provided useful findings based on retrospective reviews of the treatment of AML patients, depicted some novel targeted therapies and clarified the role of clofarabine in older adults with AML.

APL accounts for about 10% of all patients with AML; this distinctive entity is characterized by a typical presentation with low white cell count and platelet count, as well as with potentially devastating disseminated intravascular coagulopathy, which can lead to severe bleeding or in some cases, thrombosis [2]. The utility of all-trans-retinoic acid (ATRA), first noted in the late 1980s [3], and the more recent studies showing the profound efficacy of arsenic trioxide in treatment of advanced APL [4] led to the combination of each of these drugs with standard chemotherapy. A series of studies over the last 20 years incorporating one or both of these agents into a chemotherapy-based strategy brought us to ASH 2012, in which a regimen consisting of ATRA and arsenic alone was compared with the current standard ATRA/anthracycline approach.

A series of important studies carried out over the past 15 years have shown that the addition of ATRA to chemotherapy is better than chemotherapy alone [5,6]; a high cure rate can be obtained with intensive anthracycline plus ATRA (i.e., without cytarabine [ara-C]) in patients with non-high-risk APL (white count at presentation <10,000) [7]; high-dose ara-C might be useful in high-risk patients [8]; arsenic trioxide used in the postremission setting can improve the outcome compared with chemotherapy plus ATRA in all risk groups of APL [9], and early use of arsenic trioxide with anthracyclines and ATRA can be highly effective [10]. At ASH 2012, Francesco LoCoco (University Tor Vergata of Roma, Rome, Italy) from the Italian GIMEMA group presented a key trial, which also enrolled patients from two German Cooperative Groups (AMLSG and SAL), in adult patients with APL aged up to 70 years who had white counts at diagnosis of less than 10,000. The trial had a noninferiority end point that compared two regimens, one of which was based on the PETHEMA regimen: induction with idarubicin/ATRA, consolidation with three cycles of anthracycline/ATRA and maintenance therapy with oral antimetabolites and ATRA [7]. The other regimen was modeled after the successful use of ATRA and arsenic ‘alone’ at MD Anderson Cancer Center [11], in which patients were induced with a combination of ATRA and arsenic and then received consolidation with ATRA monthly every other month for four cycles simultaneously with ATRA, 2 weeks on, 2 weeks off during this 8-month period; no maintenance therapy was given. The results demonstrated more myelosuppression in the PETHEMA-like arm and a higher degree of hepatotoxicity and QT prolongation in those randomized to the ATRA/arsenic arm. The chemo-free arm was not inferior, and patients randomized to that arm experienced a superior event-free and overall survival (97 vs 86% and 99 vs 91%, respectively) compared with the chemotherapy arm. Although there were some unique toxicities in the ATRA/arsenic arm, non-high-risk APL can be cured at a very high rate with acceptable side effects using a chemotherapy-free approach.

Challenges in APL remain. Will a similar chemotherapy-free approach be applicable to high-risk APL patients (white blood cell count >10,000)? Perhaps the use of minimal chemotherapy (as per the GIMEMA investigators when the white count went up) will be needed. A second problem are early deaths in APL. The early death rate in population-based studies [12] is always higher than early death rate in patients enrolled on clinical trials. Investigators from France looked at all patients from a specific geographic area who developed APL to try to determine if rapid institution of ATRA, which ameliorates the associated coagulopathy, would be effective in reducing the early mortality rate. The early mortality rate (~8% overall) was influenced negatively by increased patient age and non-enrollment on a clinical trial. However, the duration of time between institution of ATRA after the diagnostic marrow or after hospitalization [13] did not improve the early death rate. While ATRA should indeed be started as soon as the diagnosis of APL is suspected, some patients may simply be destined to do poorly.

Retrospective studies in a large number of patients treated with AML suggested that treatment-related mortality is declining over time, probably due to improvements in supportive care [14]. While patients in the specific trials examined were younger and more fit over time, the treatment-related mortality decrease was not explained by these better patient characteristics based on a multivariate analysis. A registry study performed in Sweden including all patients diagnosed with AML provided data concerning the population-based incidence of secondary AML. Therapy-related AML and AML after antecedent hematological abnormality accounted for 8 and 19%, respectively, of all AML in Sweden. Patients with therapy-related AML had a worse outcome compared with AML after an antecedent hematologic abnormality. Both were independent risk factors for poor outcomes, even when controlling for cytogenetics, age and gender [15]. Thus, the previously held notion that patients with favorable cytogenetics do well even if they have secondary disease [16] may not be always correct.

Clofarabine (single-agent therapy for 5 days) led to a relatively high (46%) remission rate in a Phase II US trial in which patients not deemed likely to benefit from standard induction chemotherapy were enrolled [17]. However, clofarabine (albeit at a lower dose than in the US trial) did not lead to a superior survival than standard low-dose ara-C in older adults with AML not deemed to be fit for chemotherapy by British physicians, according to the nonintensive randomized Phase III part of the AML 16 UK trial [18]. For older adults who were deemed fit for chemotherapy, substitution of clofarabine for ara-C in combination with daunorubicin did not lead to improved outcomes [19]. Despite clofarabine being an active drug in AML (and indeed being associated with a higher complete response rate than low-dose ara-C in the ‘unfit’ MRC trial), it does not have a clear role in the older patient population.

The realm of targeted therapy, specifically with regard to FLT3 inhibition, received a major boost at ASH 2012. The length or internal tandem duplication (ITD) mutation of FLT3, a transmembrane tyrosine kinase, occurs in about 25% of AML patients and results in ligand-independent constitutive activity. A series of prior trials with single-agent putative FLT3 inhibitors have led to a fairly modest complete remission rate [20]. Quizartinib (AC220) a nonprotein-bound selective FLT3 ITD inhibitor was associated with a high response rate in two subcohorts of a large trial for relapsed/refractory patients with AML. In the older cohort of patients, who were in first relapse or refractory to primary treatment, the overall response rate in FLT3 ITD patients was 53% [21]. In a younger cohort of patients who had failed two lines of therapy, the response rate was similar [22]. Very few of the responses were complete remissions since normal hematopoiesis did not resume, possibly because quizartinib inhibited c-kit. QT prolongation was also noted. However, the blast reduction did allow this drug to serve as a ‘bridge to transplant.’ In both these trials, there were responses in FLT3 wild-type patients, albeit at a lower level. Whether or not quizartinib will be approvable as a single agent for FLT3-positive AML is unclear.

FLT3 inhibitors may be useful in combinations with other antileukemia agents. Another encouraging study was the so-called SORAML trial from Germany in which younger adults with AML were given standard chemotherapy with placebo or sorafenib, a multitargeted kinase inhibitor that inhibits FLT3 ITD [23]. There was an improvement in event-free but not overall survival (both FLT3 and wild-type mutant patients were included with the addition of sorafenib, although there was an attempt to perform allogeneic hematopoietic stem cell transplantation in most patients). Another FLT3 inhibitor, crinolanib, inhibits both ITD and the tyrosine kinase domain point mutations [24]; the latter type of mutation has emerged in patients developing quizartinib resistance. Andreeff et al. showed that the addition of the CXCR4 inhibitor plus granulocyte-colony stimulating factor to sorafenib may lead to a higher response rate in FLT3 ITD patients than with sorafenib alone, potentially due to the mobilization of leukemic stem cells from their protected marrow environment [25].

In summary, ASH 2012 provided an important practice-changing trial in APL and some hope in the area of FLT3 inhibition in AML.

Financial & competing interests disclosure

RM Stone serves as an ad hoc consultant for Teva, Ltd, Celgene, Ltd, Amgen, Inc. and Sunesis Pharmaceuticals, Inc. and has received research support from Novartis, Ltd. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.