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Published on 16 September 2009

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Clinical management of difficult acute leukaemias

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Clofarabine improves the response to treatment in leukaemias in all age groups, experts concluded at a Genzyme symposium at the European Haematology Association Congress held in Berlin in June

Laurence A
Goldberg
FRPharmS

Age has long been regarded as one of the most important prognostic factors in patients treated for acute leukaemia, said Herve Dombret (chief, Clinical Haematology and Immunology
Department and Adult Leukaemia Unit, Hospital Saint-Louis, Paris). Disease characteristics differ with age, and older patients generally receive less intensive therapy because of reduced tolerance, he continued.

Teenagers and young adults with acute lymphoblastic leukaemia (ALL) have often been considered poor risk in paediatric trials but good risk in adult trials. Recently, intensified paediatric-inspired approaches have been associated with impressive gains in eventfree and overall survival in these young patients-this exemplifies how treatment intensity can interfere with other risk factors, some of which (including age) have become relatively outmoded compared with new criteria such as response to initial therapy.

The selection process for deciding which older patients with acute myeloblastic leukaemia (AML) to treat with standard intensive chemotherapy has been a matter of debate for some time. The sensitivity of any selection is limited by the overall severity of the disease at that age. In addition to age, other independent factors, including cytogenetics, white blood cell
count, performance status and antecedent haematological
factors, affect treatment results. “It is difficult to recommend precise age cut-offs for clinical decision-making,” said Professor Dombret. Weighted prognostic score formulae have been developed, such as the score used in the British AML 11 study:

0.675 x cytogenetics) + (0.169 x WBC) + (0.138 x PS)
+ (0.166 x age) + (0.344 x AML type)

ALL in children
The final outcome of paediatric patients with ALL who experience leukaemia reoccurrence remains unsatisfactory, said Franco Locatelli (professor of paediatrics, University of Pavia, Italy). In particular, for children with isolated bone marrow relapse occurring within the first 18-24 months of diagnosis and for those with T-cell ALL, the probability of a five-year leukaemia-free survival does not exceed 30%, even when they receive (0.675 x cytogenetics) + (0.169 x WBC) + (0.138 x PS)
+ (0.166 x age) + (0.344 x AML type) allogeneic haematopoietic stem cell transplantation (HSCT). The most frequent cause of failure for children with relapsed ALL is resistance to second-line therapy or subsequent bone marrow relapse. In the light of this very poor prognosis, innovative treatment strategies based on the use of novel antileukaemic agents are needed.

Clofarabine, a next-generation purine nucleoside analogue, has similar efficacy to its predecessors, fludarabine and cladrabine, but is less toxic. It is authorised in Europe as a single agent for treatment of ALL in paediatric patients who have relapsed or are refractory to at least two prior regimens and where there is no other treatment option anticipated to result in a durable response.

A phase 1 study in paediatric patients with relapsed/refractory ALL reported a 30% response rate, with a median survival of 66.6 weeks, compared with just 7.6 weeks for the non-responders. Patients received daily infusions for five days repeated every two to six weeks depending on toxicity and response.

As clofarabine inhibits DNA repair mechanisms, it is logical to consider administering it together with agents that can damage DNA, such as cyclophosphamide or etoposide, explained Professor Locatelli. A recent study of 25 patients (median age 12.5 years) examined the effects of a single course of combination therapy using clofarabine, cyclophosphamide and etoposide in children with relapsed/refractory ALL. Patients received daily infusions of all three drugs for five days. The results showed that the overall remission rate was 56%; 13 patients achieved complete remission and one patient achieved complete remission without platelet recovery. Children with B-cell precursor ALL had a better probability of responding to treatment than children with T-cell ALL. The 18-month overall survival was 39% in patients who responded to treatment and 0% in patients who did not. These data suggest that this regimen is well tolerated and can induce a clinical response in a relevant proportion of children. In view of its good safety profile and the promising results in this population, further investigation of this regimen is warranted in patients who experience first leukaemia relapse and are at very high risk of treatment failure, concluded Professor Locatelli.

AML in young adults
Treatment of relapsed or refractory AML remains difficult. Most patients have developed resistance by the time of relapse, and effective agents to achieve durable remissions at that stage are lacking, said Stefan Faderl (associate professor of medicines, University of Texas, MD Anderson Cancer Center, Houston, Texas). Furthermore, pretreated patients are highly immunosuppressed, so AML therapy is frequently accompanied
by infectious complications. At the time of relapse, the prognosis depends more on the length of time spent in remission previously and the number of salvage therapies received than on the presence or absence of cytogenetic features (chromosomal structure of the leukemic cell). Cytarabine is the cornerstone for treatment of AML. Its value in older and relapsed patients is significantly diminished, and this has prompted the search for new and better drugs.

Many other new agents of various biological classes are being investigated. These include FLT3 inhibitors, demethylating agents, histone deacetylase (HDAC) inhibitors, farnesyl transferase (FT) inhibitors and anti-CD33 monoclonal antibodies. Approximately 30% of patients with AML have activating mutations in the receptor tyrosine kinase FLT3, and these patients have a significantly worse prognosis than those with wild-type FLT3. One study using the FLT3 inhibitor AC220 (Ambit Biosciences Corporation) has shown promising results, with an overall response rate of 29%.

A study of epigenetic therapy used a combination of azacytidine, valproic acid and all-trans retinoic acid (ATRA) in high-risk AML patients. A response rate of 45% was seen in patients with de-novo AML. A recent report suggests higher remission and survival rates when cladribine is added to a combination of daunorubicin and cytarabine. Clofarabine, a second-generation deoxyadenosine analogue based on the molecular structure of fludarabine and cladribine, has shown efficacy both as a single agent and in combination treatment.

Conditioning prior to transplantation
The overall benefits of myeloblastic allogeneic stem cell transplantation can be reduced by procedurerelated toxicity, morbidity and non-relapse mortality. In most cases the preparatory regimen of chemotherapy and/or radiation accounts for a significant part of the non-relapse mortality. The ideal preparatory regimen should be capable of eradicating malignancy, have tolerable morbidity without mortality and have sufficient immunosuppressant effects to avoid graft rejection, said Mohamad Mohty (professor of haematology and head of stem cell transplantation, Nantes University
Hospital, France).

The recent introduction of clofarabine as an alternative to fludarabine represents a major step forward in optimising reduced-intensity conditioning (RIC) regimens prior to transplantation. Clofarabine combines the most favourable pharmacokinetic properties of fludarabine and cladarabine and has significant antileukaemic activity with acceptable toxicity. An ever-growing body of data suggests that clofarabine-based conditioning regimens can facilitate engraftment whilst minimising the risk of toxicity, Professor Mohty concluded.

AML in elderly patients
“No progress has been made in treating AML in patients over 60 years of age over the past 40 years,” said Hagop Kantarjian (professor of medicine and chair, Department of Leukaemia, University of Texas, MD Anderson Cancer Center, Houston, Texas). Whereas cure rates of 40% are now achieved in younger patients, in older patients the five-year survival remains at about 10%. “We have to think differently for elderly patients,” he said. There are established cytarabine-based drug regimens for patients under 60 years of age, but patients above that age group should be entered into trials with new agents.

Many agents are being investigated in the treatment of AML in patients over the age of 60 years. Clofarabine has shown promise in several trials. In one study clofarabine alone was compared with a combination of clofarabine and cytarabine. The results showed that in the combination arm of the study complete remission was achieved in 63% of patients, compared with 31% who received clofarabine alone.1 This combination is a treatment option for elderly patients who are categorised as “not fit for intensive chemotherapy,” concluded Professor Kantarjian.



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