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Haematological Malignancies Parikh_EU Haematology 03/03/2010 12:51 Page 43 Haematological Malignancies Clinical Management of Relapsed/Refractory Acute Myeloid Leukaemia Sameer A Parikh1 and Stefan Faderl2 1. Fellow; 2. Associate Professor of Medicine, Department of Leukemia, University of Texas MD Anderson Cancer Center DOI: 10.17925/EOH.2010.04.0.43 Abstract Conventional chemotherapy for patients with relapsed/refractory acute myeloid leukaemia (AML) remains unsatisfactory, with median survival ranging from 18 weeks following first relapse to six weeks in those with a second or higher relapse. The only potentially curative therapy is stem cell transplantation. Duration of first complete remission (CR) is the best predictor of response to salvage therapy. Novel therapies directed against a number of molecular aberrations associated with AML are being developed, including anti-CD33 monoclonal antibodies, FMS-like tyrosine kinase (FLT3) inhibitors, nucleoside analogues, hypomethylating agents and histone deacetylatase inhibitors, among others. Clinical trials combining novel agents with conventional chemotherapy are of particular interest, and definition of dose, schedule and combination partners remains an area of intense research. Keywords Acute myeloid leukaemia (AML), salvage therapy, chemotherapy, targeted therapy, nucleoside analogues, FLT3 inhibition, epigenetic therapy Disclosure: Sameer A Parikh has no conflicts of interst to declare. Stefan Faderl receives research funding from Genzyme Oncology and has been a member of advisory board meetings conducted by Genzyme Oncology. He is also a member of the speaker’s bureau of Eisai Inc. Received: 22 September 2009 Accepted: 23 February 2010 Citation: European Haematology, 2010;4:43–6 Correspondence: Stefan Faderl, Department of Leukemia, Unit 428, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, US. E: [email protected] Although the outcome of patients with acute myeloid leukaemia (AML) duration more than six months, second CR duration more than six has improved with cytarabine and anthracycline-based chemotherapy months, first salvage therapy not including SCT, non-inversion 16 regimens in addition to advances in supportive care, relapse remains AML, platelet count <50x109/l and white blood cell (WBC) count frequent and constitutes the leading cause of mortality. >50x109/l. Duration of first remission was the most important predictor of response to salvage therapy. In a study of 243 patients with relapsed/refractory AML by Keating et al., 33% patients obtained a complete remission (CR), 24% died prior to Conventional chemotherapy for relapsed/refractory AML has largely achieving a response and 43% were resistant to their first salvage been unsatisfactory and most patients do not achieve long-term regimen.1 The median survival was 18 weeks and five-year survival was durable remissions. The only potentially curative option remains SCT, only 5%. Whereas prior therapy with cytarabine or stem cell transplant but effective regimens are necessary to control AML relapse prior to (SCT) did not influence prognosis, duration of first remission was transplant. With the advent of molecular studies and better insights into significantly associated with subsequent outcome. the pathogenesis of AML, more specific, mechanism-driven, targeted drugs are being developed. The following sections describe a number In a recent article, Breems et al. defined a prognostic score for of new drugs that have been tested in clinical trials for patients with patients with AML in first relapse based on the following variables: relapsed/refractory AML (see Table 1). relapse-free interval from first CR, cytogenetics at diagnosis, age at first relapse and SCT before first relapse.2 Three prognostic Gemtuzumab Ozogamicin subgroups were identified. Eighty-five per cent achieved CR in the Gemtuzumab ozogamicin (GO) is an anti-CD33 monoclonal antibody favourable group compared with 60 and 34% in the intermediate- bound to its cytotoxic conjugate calicheamicin.4 Following attachment and poor-risk groups, respectively. The five-year survival rates were to the surface of myeloid blasts, it becomes rapidly internalised and 46, 18 and 4% in these three groups. The prognostic impact of these releases calicheamicin. In an open-label, single-arm phase II study variables was independent of salvage therapy, and hence was most involving 277 patients with relapsed AML, GO was administered at likely attributed to intrinsic disease (e.g. cytogenetics) and host 9mg/m2 as a two-hour intravenous (IV) infusion in two doses separated characteristics. Giles et al. reported results of 594 patients who by two weeks.5 Thirty-five patients (13%) achieved CR and another 13% underwent second salvage therapy for relapsed AML.3 Thirteen per achieved CR with incomplete platelet recovery (CRp <100x109/l). All cent achieved CR (median CR duration: seven months), and one-year patients developed grade 3 or 4 neutropenia and thrombocytopenia. survival was 8%. Multivariate analysis revealed the following Grade 3–4 hyperbilirubinaemia was noted in 29% of patients and 0.9% variables as independent adverse prognostic factors: first CR of patients who did not undergo SCT developed sinusoidal obstructive © TOUCH BRIEFINGS 2010 43 Parikh_EU Haematology 03/03/2010 12:51 Page 44 Haematological Malignancies Table 1: Novel Agents in Relapsed/Refractory and within three to four months of SCT to avoid the development Acute Myeloid Leukaemia of SOS. Reduction of doses (3–6mg/m2) in combination therapies has proved safer. Target Drug Mechanism of Action CD33 Gemtuzumab Anti-CD33 monoclonal antibody FMS-like Tyrosine Kinase Inhibitors ozogamicin attached to calicheamicin Mutations of the FMS-like tyrosine kinase (FLT3) gene cause auto- FLT3 Lestaurtinib (CEP701) Inhibition of FLT3 receptor phosporylation of the FLT3 receptor tyrosine kinase, resulting in Midostaurin (PKC412) tyrosine kinase, inhibition of cell proliferation and inhibition of apoptosis. In particular, internal Sorafenib (BAY43-9006) downstream signalling via tandem duplications (ITD) of FLT3 confer an adverse prognosis and Sunitinib (SU11248) MAPK and STAT pathways are seen in 25–35% of patients with predominantly diploid AML. Of AC220 12 DNA Azacitidine Induction of hypomethylation the >20 molecules with inhibitory activity against FLT3, the most hypermethylation Decitabine with re-expression of tumour- widely studied agents in AML include midostaurin (PKC412), suppressor genes sorafenib (BAY43-9006), sunitinib (SU11248), lestaurtinib (CEP701) Histone Vorinostat Induction of histone hyperacetylation, and tandutinib (MLN518) (see Table 3). deacetylase Valproic acid apoptosis and differentiation DNA Clofarabine Inhibition of ribonucleotide A phase I study testing the efficacy of sorafenib in 21 patients reductase, inhibition of DNA with relapsed/refractory AML reported a >50% reduction of the polymerases, induction of apoptosis peripheral blast count in 11 patients.16 Lestaurtinib was evaluated STAT = signal transducers and activators of transcription. in a phase I–II clinical trial of 14 patients with relapsed/refractory AML.13 Five patients had measurable responses, including Table 2: Gemtuzumab Ozogamicin in Relapsed/ reductions in bone marrow and peripheral blood blasts. A phase II Refractory Acute Myeloid Leukaemia trial testing the efficacy of midostaurin in 20 patients with relapsed/refractory AML demonstrated a >50% reduction in Study Number Median Agents Used CR/CRpMedian 14 Age (Years) with GO (%) Survival peripheral blasts in 14 patients. Twelve out of 40 patients showed Cortes 17 55 Cytarabine, 12/NR 8.2 weeks a >50% reduction in peripheral blasts in a phase I trial of tandutinib.15 et al.7 (20–70) topotecan Another novel FLT3 inhibitor, AC220, has been shown to produce Alvarado 14 61 Cytarabine, 21/12 8 weeks objective clinical responses, including six patients achieving CR, et al.8 (34–74) idarubicin with an OR rate of 29% out of 58 patients with relapsed/refractory Apostilodou 11 37 Cytarabine, 9/9 12 weeks AML.18 For all these agents, responses have generally been better in et al.9 (16–67) liposomal those patients with the mutant FLT3 compared with those patients daunorubicin, with the wild-type FLT3. Nausea, vomiting, diarrhoea and fatigue cyclosporine were the most common side effects. Tsimberidou 32 53 Cytarabine, 28/65.4 et al.10 (18–78) fludarabine, months cyclosporine Unfortunately, none of these agents when used as monotherapy has Chevallier 62 55 Cytarabine, 50/13 9.5 led to sustained responses. Therefore, trials are under way to combine et al.11 (21–68) mitoxantrone months these agents with conventional chemotherapy agents to improve GO = gemtuzumab ozogamicin; CR = complete remission; CRp = CR with incomplete response rates and durability of responses. However, a phase III study platelet recovery. of lestaurtinib with either mitoxantrone, etoposide, cytarabine (MEC) or high-dose cytarabine in relapsed FLT3 mutant AML showed similar syndrome (SOS). Based on these data, the US Food and Drug rates of CR and overall survival (OS) in both groups.19 Combination Administration (FDA) approved the use of GO for patients with therapies of other FLT3 inhibitors with chemotherapy are ongoing. In relapsed AML who are >60 years of age and who are considered unfit vitro data also suggest synergism between these agents and histone for conventional cytotoxic therapy.6 deacetylase and mammalian target of rapamycin (mTOR) inhibitors.20,21 Clinical trials combining
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