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/m
2
) 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
AC220
are seen in 25–35% of patients with predominantly diploid AML. Of
DNA Azacitidine Induction of hypomethylation
the >20 molecules with inhibitory activity against FLT3,
12
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/
Refractory Acute Myeloid Leukaemia
reductions in bone marrow and peripheral blood blasts. A phase II
trial testing the efficacy of midostaurin in 20 patients with
relapsed/refractory AML demonstrated a >50% reduction in
Study Number Median Agents Used CR/CRp Median
Age (Years) with GO (%) Survival
peripheral blasts in 14 patients.
14
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, 28/6 5.4
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
response rates and durability of responses. However, a phase III study
GO = gemtuzumab ozogamicin; CR = complete remission; CRp = CR with incomplete
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 these agents have not yet been carried out.
A number of trials exploring the combination of GO with other
chemotherapeutic regimens in relapsed AML have been published Epigenetic Therapy
(see Table 2). The most notable among these results is a study by In contrast to altering the sequence of base pairs in genes, epigenetic
Chevallier et al. that reported a CR rate of 50% and CRp rate of 13%, modifications affect gene expression by two mechanisms: DNA
leading to an overall response (OR) of 63% in patients treated with a hypermethylation and histone modification. Both alter gene expression
combination of IV GO 9mg/m
2
over two hours on day four, cytarabine via architectural remodelling of chromatin and are pharmacologically
1g/m
2
every 12 hours IV over two hours on days one to five and reversible. DNA-demethylating agents and histone deacetylase
mitoxantrone (MIDAM) 12mg/m
2
/day IV over 30 minutes on days one inhibitors (HDACis) induce re-expression of tumour suppressor and
to three.
11
Grade 3–4 neutropenia and thrombocytopenia occurred in proapoptotic genes, and are now widely used in patients with
all patients and 55% patients had documented bacterial sepsis. Grade myelodysplastic syndrome (MDS). Recent reports also suggest that they
3–4 hyperbilirubinaemia was observed in 16% patients and SOS in 3%. may be of therapeutic benefit for patients with AML.
Whereas single-agent therapy with GO appears to have limited Decitabine and azacitidine are hypomethylating agents approved by
activity in relapsed/refractory AML, combinations with chemotherapy the FDA for clinical use in patients with MDS. Some of these patients
are more promising and are being actively investigated. Caution with a French–American–British (FAB) diagnosis of refractory anaemia
should be exercised when GO is used with other hepatotoxic agents with excess blasts in transformation (RAEB-T) were reclassified as
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EUROPEAN HAEMATOLOGY
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