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Update on good risk acute myeloid leukaemia

Alan Burnett MD
9 August, 2017  
The median age of patients who develop acute myeloid leukaemia (AML) is 68–70 years. It is well established that, even when given identical chemotherapy, the results are age-dependent, with older patients having a much inferior outcome. Overall, patients under 60 years can be expected to reach a marrow morphological and functional status of complete remission (CR) in about 80% of cases, and of which about 50–55% are cured. In patients >60 years, who received conventional chemotherapy with curative intent, the CR rate will be lower (50–60%) and a three year survival of 15%. This discrepancy is usually attributed to a different proportion of biologically favourable disease as defined by cytogenetic and/or mutation analysis, with the more favourable aggregating in the younger age groups. Older patients tend to withstand chemotherapy less well, and so therapeutic hands tend to be tied. Of considerable importance is that older patients (for example, >70 years), who comprise a substantial proportion of those with the disease, are not exposed to curative-intent treatment, albeit age being only a surrogate for tolerance to treatment. Such patients are offered low-intensity treatment such as a demethylating agent (azacitidine/ decitibine) or low dose cytarabine (Ara-C), which can prolong life but are not curative.
 
The cytogenetics of the leukaemic clone have been universally accepted as strong predictors of outcome. This is now being augmented by additional mutation information. Information from these data, patient age, diagnostic white count, whether the disease was de novo or secondary, and the response to the first induction course are used to inform post-induction treatment. Two cytogenetic entities confer an expectation of a high remission and high cure rate, and are considered to be discrete disease subgroups.
 
Acute promyelocytic leukaemia (APL)
The subgroup is apparently most frequent in younger patients, comprising 10–15% of younger patients with AML. Although proportionately less frequent in the over 60s, there are more patients in that age group (Figure 1), and thus the absolute number of APL cases is important also in older patients, who may not be represented in clinical trials. APL has characteristic morphological appearance with a granulated cytoplasm under microscopy. It is defined by cytogenetics with a balanced translocation of chromosome 15 and 17. This reciprocal translocation results in an abnormal hybrid oncoprotein called PML-RARα where PML is derived from chromosome 9 and RARα from chromosome 17. Sometimes the transposition is between chromosome 11 and 17. The consequences are that these transcripts prevent neutrophil differentiation and apoptosis. Mutations of FLT3 can be found in about 30% of cases. They seem to be closely associated with a higher presenting white blood count (>10 x 104/l), which is the most important prognostic factor and which occurs in 25% of cases, by being associated with early death and increased relapse risk.
 
 
Treatment
APL represents one of a relatively few treatment emergencies in haematology, where prompt diagnosis and therapy are crucial. A senior British haematologist’s mantra was “never let the sun set on an APL”. The reason is that this subtype is associated with severe disruption of coagulation mechanisms that have been triggered by the granular leukaemic blasts. Both fibrinolysis and hypercoagulability can occur. The major risk to the patient at presentation is bleeding, particularly intracranial bleeding. Treatment guidelines emphasis the need to keep the platelet count as near 50 x 109/l and the fibrinogen level >150mg/l.1 Specific treatment must be initiated promptly which, in practice, means oral all-trans-retinoic acid (ATRA). The coagulation abnormalities resolve promptly as the ATRA induces the clone to differentiate. Arsenic, usually as the trioxide (ATO), is arguably more effective than ATRA by targeting the PML component of the transcript, and single agent ATO is an approved treatment for relapsed disease. It has long been known that this disease has a unique sensitivity to anthracyclines. Both ATRA and ATO each induce remissions when given as monotherapy, but the response to ATRA is not durable. 
 
The evolution of treatment has been to add ATRA to standard AML anthracycline-containing chemotherapy, which resulted in a survival improvement from 45% to 75–80%. In recent years, ATO has been added to first-line treatment along with ATRA and anthracycline containing chemotherapy. The most recent development has been to combine ATRA with ATO alone in a ‘chemo-free’ approach. In low-risk disease, the overall survival has reached >90% with long-term follow up indicating that this is durable.2–5 A similar outcome may be achieved irrespective of presenting white count.2 A well established treatment risk is the ‘differentiation syndrome’, which is a consequence of the induced differentiation as a result of ATRA or ATO therapy. This is less likely to happen when chemotherapy is given simultaneously, and is associated with a high- or rising WBC, so vigilance is needed. Suggestive signs include unexplained fever, weight gain, respiratory distress, interstitial pulmonary infiltrates, and pleural or pericardial effusion, with or without hyperleukocytosis. No single sign or symptom itself may be considered diagnostic of the syndrome. However, the earliest suspicious manifestations, for example, unexplained respiratory distress, and prior to the development of a fulminant syndrome, treatment with dexamethasone 10mg IV 12-hourly should be initiated and continued until disappearance of symptoms and signs, and for a minimum of three days.
 
Maintenance chemotherapy with methotrexate and 6-mercaptopurine has traditionally been used. However the recent ‘chemo-free’ results suggest that this is no longer needed, which is also the case if patients are PCR negative at the end of consolidation following ATRA and chemotherapy. 
 
Core binding factor (CBF) leukaemias
Another 10–12% of younger patients have another type of myeloid leukaemia that is regarded as favourable. It is characterised cytogenetically by the presence of the chromosome translocation t(8;21)(q22;q22)/RUNX1-RUNX1T1 or inv(16)(p13q22)/t(16;16)(p13;q22)/CBFB-MYH11. Similar to APL, patients frequently have additional chromosome abnormalities, such as loss of a sex chromosome and del(9q) in the case of t(8;21), and trisomy 22 in inv(16), but these additions do not alter the prognosis. These abnormalities characterise this subgroup, although skilled morphologists can identify these cases morphologically. 
 
 
Treatment
These leukaemias are highly sensitive to standard chemotherapy, but particularly to Ara-C. A remission rate of >90% is expected, with an overall relapse rate of about 40%. A fortunate feature, and unlike most AMLs, is that they remain highly sensitive to re-induction treatment if relapse happens, and can usually be salvaged. In that context, the usual practice it to proceed to transplant if a second remission is achieved. Taken together, this results in an expected survival rate of about 75%. 
 
High-dose Ara-C as consolidation is important, and possibly also in induction. The recent trials of combining the immunoconjugate, gemtuzumab ozogamicin (MylotargTM),6 with induction treatment, has suggested an overall survival of about 85% when combined with high dose Ara-C in consolidation. However this agent is currently only approved in Japan. A total of four courses of chemotherapy appears optimal, although unreported studies may suggest that three courses are adequate. It is well established that about 30% of cases have a mutation of the kit gene, and this is associated with an increased risk of relapse. However, it is less clear that this mutation always brings a poorer survival even although the relapse rate is higher, if either GO or high-dose Ara-C are part of the treatment. There is current interest in adding tyrosine kinase inhibitors with kit-inhibitory effects to chemotherapy, but no randomised data are available so far. Similarly, while the CBF leukaemias would not normally be offered transplant as first remission consolidation, some investigators are exploring transplant in cases with a cKIT mutation.
 
Molecular monitoring
Like APL, an abnormal transcript results from the t(8;21) translocation, which can be monitored by PCR of the resultant AML-ETO oncoprotein. This is often quantitated as a log reduction, where the level of reduction correlates with relapse risk. However if there is only minimal reduction (1 log), subsequent haematological relapse can be so rapid that the therapeutic opportunity is transient. Further log reduction levels are prognostic, but are not completely predictive of relapse, so therapeutic intervention in this context is more  speculative Molecular minimal residual disease (MRD) monitoring has been most extensively studied in APL, in which assays for the PML-RARα fusion are relatively insensitive (typically 1 in 104), but give an accurate indication of impending relapse. In this subtype of AML, MRD assessment is included within the standard response criteria, since achievement of molecular remission in the bone marrow by the end of consolidation is a prerequisite for cure. While the majority of patients (~95%) achieve this milestone, approximately 10–25% will ultimately relapse following ATRA and anthracycline-based protocols. 
 
The majority of relapses can be predicted by re-emergence of PML-RARA transcripts detected in sequential bone marrow MRD monitoring samples, which are usually performed three-monthly taking into account assay sensitivity and kinetics of relapse. Early studies that pre-dated availability of ATO suggested a survival advantage for early treatment intervention for molecular (subclinical) relapse as compared with salvage at frank relapse, due to decreased risk of bleeding and other complications. However, treatment protocols for APL have steadily improved, so for patients with low-risk disease with rapid achievement of molecular remission, there is little benefit for further monitoring. Whereas, currently, sequential MRD monitoring until three years post-treatment is recommended in patients who present with ‘high risk’ disease, due to the 25% risk of relapse CBF leukaemia and APL account for a smaller proportion of AML presenting in older adults, but continue to represent a more favourable group, with a survival of 35% compared with an overall survival of 15–20% in that age group in those treated with intensive chemotherapy. 
 
While these two entities are the traditional favourable groups, the molecular identification of patients with a bi-alleleic mutation of CEBPα, or NPM1  mutation who lack a co-incidental FLT3 mutation predicts a survival of about 70% with standard chemotherapy. Although studies are underway, so far there are no additional non-chemotherapy agents to be recommended. 
 
References
1 Sanz M et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2009;113: 1875–91.
2 Lo-Coco F et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369:111–21.
3 Burnett AK et al. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol 2015;(13):1295–305.  
4 Hu J et al. Long-term efficacy and safety of all-transretinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci USA 2009;106:3342–7.
5 Abaza Y et al. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood 2017;129:1275–83.
6 Hills RK et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol 2014;15:986–96.