FLT3 inhibitors as MRD-guided salvage treatment for molecular failure in FLT3 mutated AML.

Patients with FLT3-mutated AML have a high relapse rate and suboptimal outcomes. Many have co-mutations suitable for measurable residual disease (MRD) monitoring by RT-qPCR and those destined to relapse can be identified by high or rising levels of MRD, called molecular failure.  This provides a window for pre-emptive intervention, but there is little evidence to guide treatment. The use of FLT3 inhibitors (FLT3i) appears attractive but their use has not yet been evaluated.  We identified 56 patients treated with FLT3i at molecular failure.  The FLT3 mutation was an ITD in 52, TKD in 7 and both in 3. Over half of patients had previously received midostaurin. Molecular failure occurred at a median 9.2 months from diagnosis and was treated with gilteritinib (n = 38), quizartinib (n = 7) or sorafenib (n = 11). 60% achieved a molecular response, with 45% reaching MRD negativity. Haematological toxicity was low, and 22 patients were bridged directly to allogeneic transplant with another 6 to donor lymphocyte infusion. 2-year overall survival was 80% (95%CI 69-93) and molecular event-free survival 56% (95%CI 44-72). High-sensitivity next-generation sequencing for FLT3-ITD at molecular failure identified patients more likely to benefit. FLT3i monotherapy for molecular failure is a promising strategy which merits evaluation in prospective studies.

Optimising care for UK patients with acute myeloid leukaemia.

Acute myeloid leukaemia is a rare cancer, with about 3000 cases diagnosed each year in the UK. Diagnosis is based on patient history, blood and bone marrow tests and, in some cases, imaging. Chemotherapy is the mainstay of treatment for acute myeloid leukaemia, with eligible patients also undergoing allogeneic haematopoietic stem cell transplantation, which can be curative. However, patients must be carefully evaluated by the multidisciplinary team before they are put forward for transplant to ensure they are able to tolerate the conditioning therapy required. Improvements in transplant technology have increased donor availability and reduced transplant toxicity. At the same time, greater understanding of the cytogenetics and molecular genetics of acute myeloid leukaemia have helped to ensure that patients receive treatment that gives them the best chance of survival. A recent roundtable discussion considered how current diagnostic and treatment pathways might be adapted or enhanced to leverage good outcomes for the greatest numbers of patients.

Treatment of older patients with acute myeloid leukemia--new agents.

The experience of most collaborative study groups is that the outcome for older patients has, unlike in younger patients, failed to improve over the last two decades. In addition there are a substantial number of older patients who do not enter collaborative group trials because they are not considered suitable for an intensive chemotherapy approach. During this era many combinations of chemotherapeutic agents at different dose levels have been tried. It is clear that novel agents and new approaches must be used to improve the situation, and should include options for patients who are not fit for intensive treatment. Fortunately, the increased understanding of the molecular basis and heterogeneity of the disease has fostered the development of novel agents. Chemo-resistance is a key characteristic of acute myeloid leukaemia (AML) in older patients and a number of randomized trials have now been completed to assess this approach. New possibilities of selectively killing leukemic cells and/or modifying toxicity are in prospect with the development of antibody directed chemotherapy in the form of gemtuzumab ozogamicin (Mylotarg; Wyeth, Philadelphia, PA). New drugs such as clofarabine or cloretazine are being evaluated. Molecular mechanisms, whether recognized or not, have been targeted by the use of FLT-3 and farnesyl transferase (FT) inhibitors. With several new agents to evaluate, novel approaches to trial design aimed at detecting options likely to make a useful impact are needed.

Autoimmune haemolytic anaemia as the presenting manifestation of agnogenic myeloid metaplasia.

We report an unusual case of a 40-year-old female patient with a severe case of direct Coombs positive haemolytic anaemia, moderate hepatomegaly and marked splenomegaly. Her initial response to steroids was transient and was rapidly followed by a relapse. Therefore, she underwent splenectomy both as a therapeutic measure and to rule out an underlying lymphoproliferative disorder. Histopathological examination of the excised spleen, as well a liver biopsy, revealed extensive extramedullary haematopoiesis, while significant marrow fibrosis was noted in a trephine biopsy sample. These findings confirmed the concomitant diagnosis of agnogenic myeloid metaplasia with myelofibrosis.