Failure to respond to the initial therapy makes the prognosis more complicated, but there is usually an opportunity for additional therapy and for a good response if the patient is in adequate condition. The type of therapy depends on the treatment that was used initially. If standard doses of ara-C were used (or if no ara-C was used) in a younger patient, usually a regimen centered around higher doses of ara-C would be used. If higher doses of ara-C were already used, most commonly in combination with an anthracycline, other combinations can be used. A common one is a combination of mitoxantrone, etoposide and ara-C. There are also many investigational approaches being used. Importantly, a patient who did not respond or lost response to initial therapy, if a remission is achieved with the “salvage” therapy, a stem cell transplant should be a strong consideration.

Stem cell transplant is usually indicated in first remission in patients with the highest risk of relapse, such as patients with high risk cytogenetic abnormalities or with mutations in the FLT3 gene. In these patients a search may be started at the time of diagnosis. Patients who are in second remission (ie, patients who relapsed and then achieved again a remission with chemotherapy) are also good candidates for a stem cell transplant, as well as patients who did not achieve a remission with the first chemotherapy but achieve it with a salvage therapy. In all instances, transplant is considered when patient achieves a remission. Doing a transplant when the patient has still very active disease is associated with low probability of success.

The most common regimen used for AML is a regimen called “3+7”, that is a combination of an anthracycline given daily for 3 days and ara-C (or cytarabine) given daily for 7 days. However, many (including myself) prefer to use higher doses or ara-C which have been associated in some studies with more durable responses. This however is still a controversial issue. The dose of anthracycline is also important and it is important to give these drugs with adequate dose intensity. Increasing the doses may increase the risk of some adverse events, but ultimately improves the probability of long term remissions and cures. There are some subsets of AML that are treated differently. AML associated with favorable prognostic cytogenetic abnormalities such as inv(16) or t(8;21) (also known as core-binding factor AML) are more curable but usually require higher doses or ara-C to improve the chances of cure.

A patient undergoing treatment for AML is monitored closely with the peripheral blood as anemia, thrombocytopenia, and neutropenia, usually profound and sustained, are common during the treatment. Monitoring peripheral blood helps identify timing of transfusions which are required in nearly 100% of patients. It is important also to monitor electrolytes, as well as liver function tests and renal function as abnormalities occur not infrequently from the leukemia, the chemotherapy, or other concomitant medications (eg, antimicrobials used prophylactically or therapeutically). A bone marrow is done, usually around 3-4 weeks after the start of chemotherapy to determine the efficacy of the treatment. To determine that a patient has achieved a remission, the bone marrow has to show <5% blasts and the neutrophil and platelet count should have recovered (to >1x109/L and >100 x109/L, respectively).

A bone marrow aspiration is needed when AML is suspected. Occasionally the diagnosis can be made with peripheral blood, but the bone marrow provides additional information and will be later required to confirm remission. In addition, it is important to do an analysis of chromosomes. Chromosomal abnormalities may be seen in many patients with AML and the type of abnormalities may determine the prognosis and can guide treatment (for example, whether a stem cell transplant is recommended in first remission, or whether it is a core-binding factor AML that benefits from higher doses of ara-C). More recently, molecular abnormalities have been increasingly recognized in patients with AML. They have important prognostic implications. For example, a mutation in FLT3 carries a worse prognosis and may make one think more about stem cell transplant in first remission. Also, drugs somewhat specific for these mutations are being developed although these are still investigational.

There are multiple targets that are being pursued in AML for therapy and multiple targeted drugs being investigated. Perhaps the most advanced are the FLT3 inhibitors. One currently available is sorafenib. Although it is not approved for the treatment of AML, it is a potent inhibitor of FLT3 and several studies have suggested that it may have a role in the treatment of AML, although its precise role and place in the treatment of AML is still being defined. Many other FLT3 inhibitors are being investigated including midostauin, quizartinib, crenolanib, and others. Monoclonal antibodies have also been used and there was a drug called gentuzumab ozogamycin that was available for some time. This was a monoclonal antibody against CD33 attached to a toxin, calicheamycin. It had some activity in the salvage setting given by itself, and recent studies have suggested that, when added to chemotherapy, may improve the outcome of some patients with AML. There are many other targeted drugs being investigated but they are much earlier in their development, including inhibitors of MEK, c-met, etc.

Nearly everybody that is in good health or with only minor ailments can be a bone marrow donor. The main issue to determine whether someone can be a bone marrow donor for a specific patient is whether there is HLA compatibility. A sibling has 25% probability of being a match for a brother or sister. Parents and children are, by definition, 50% identical genetically (called haploidentical), but for a transplant usually we look for a better match. In some instances, however, a 50% identical donor can be considered for a transplant. When no family donor can be identified, one can go to the donor registry to find an identical donor. With increasing numbers of volunteered donors who register, the chances of finding a donor for a given patient have increased significantly. Cord blood is also a good source of stem cells for a transplant. In many instances one cord blood may not be enough for an adult patient, but research has evolved in combining 2 cords or expanding the cord cells in the laboratory to obtain enough cells for a transplant.

A relapse means that the disease has come back. This can sometimes be clearly evident in the blood if there is the emergence of blasts, particularly when these are more than a few. In all instances it would be important to do a bone marrow to confirm the relapse. The bone marrow would show >5% blasts in cases of relapse. The same tests done at diagnosis are done when there is a relapse to characterize the leukemia. That is, cytogenetic analysis and molecular analysis. In addition, a general evaluation of the patient is important to asses whether there may be effects of the prior chemotherapy or the disease itself that may alter the risk of complications with chemotherapy.