Breakthroughs in Acute Myeloid Leukemia

Acute myeloid leukemia (AML), sometimes called acute granulocytic leukemia, is the most common of the four major types of leukemia which also include chronic myeloid leukemia (CML) and both acute and chronic lymphocytic leukemia (ALL and CLL). The acute portion of AML refers to the speed at which it progresses vs CML. Without treatment, AML is often deadly within a few months. Many of the symptoms of the disease are nonspecific and could include symptoms related to anemia, unexplained bleeding or bruising, weight loss, unexplained neurologic complaints like headache, and a marked reduction in CBC cell counts.

This is a cancer that is rarely seen before age 45 with the average age of onset around 65. The American Cancer Society (ACS) estimates that around 21,380 Americans will have received a new diagnoses of AML in 2017 which is about 1.3% of all new cancer diagnoses. Although the economic burden of AML is not well studied, a 2016 study found that each case of AML can cost between $14,014 to $352,682 depending on treatment and need for a stem cell transplant.

Treatment for AML can vary based on a number of factors, but in general the first-line therapy consists of induction therapy with cytarabine and an anthracycline (often daunorubicin). Other chemo agents may be used in place of this regimen based on specific patient characteristics such as comorbid conditions or biomarkers for targeted therapy. Usually a couple of weeks after the induction phase, a bone marrow biopsy helps the provider determine if the patient is a candidate for consolidation therapy which may include, among other options, several cycles of high-dose cytarabine, allogeneic stem cell transplant, or autologous stem cell transplant. If only chemotherapy is needed, the total drug costs are relatively low hovering around $3000 to $5000 with the majority of the treatment cost stemming from related services and treatments.

The ACS estimates that about two-thirds of patients who undergo standard induction therapy will achieve remission. About half of patients who achieve remission and undergo consolidation will achieve long-term remission. While those are pretty good odds for remission compared to many other types of cancer, it does leave many who need further options for treatment.

This year has brought two new FDA approvals for the treatment of AML; Idhifa (enasidenib; Celgene) and Vyxeos (daunorubicin/cytarabine; Jazz) as well as a reintroduction of Mylotarg (gemtuzumab ozogamicin; Pfizer). Idhifa has an approved indication for the treatment of adult patients with relapsed or refractory AML with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA-approved test. The prevalence of the IDH2 mutation has been estimated to be about 10% of AML cases.

 Idhifa is a is a small molecule inhibitor of the IDH2 enzyme. The drug is taken orally once daily until disease progression is seen with a caveat that it should be given for a minimum of 6 months to allow for clinical response. In the drug’s pivotal clinical trials, complete remission was seen in 19% of patients with a median duration of response of 8.2 months. While this therapy seems to offer hope for qualifying patients, a list price of $29,846 per month will make it interesting to monitor the speed of uptake of therapy.

Vyxeos is a fixed-dose combination of daunorubicin and cytarabine which given separately has been the standard of care as mentioned previously. It has received an FDA-approved indication for the treatment of adults with newly-diagnosed therapy-related AML or AML with myelodysplasia-related changes. These forms of AML are thought to be complications related to previous cytotoxic therapy and has been found to have a prevalence of 0.8% to 6.3% in patients at 20 years post-cytotoxic therapy. Vyxeos was studied head-to-head against the standard cytarabine + daunorubicin therapy. The median overall survival for patients in the Vyxeos arm was 9.6 months compared to 5.9 months in the standard treatment arm (P = .005). Complete remission was seen in 38% of Vyxeos patients compared to 26% in the standard treatment arm (P=0.036). With an AWP of $62,000 for an average size patient needing just one round of induction and consolidation, there is some thought that uptake may be slow among some providers despite the FDA approved first-line indication.

Mylotarg has received FDA approval for reintroduction to the US market for the treatment of both newly-diagnosed and relapsed/refractory CD33-positive AML. Mylotarg is antibody-drug conjugate directed at CD33. It was originally approved in 2000 at a higher dose and in 2010 was voluntarily removed from the market after clinical trial data showed increased risk of fatal toxicity with no improvement in response. The drug remained available overseas and was studied at lower doses in multiple clinical studies. These additional studies revealed an event-free survival of 17.3 months for Mylotarg patients compared with 9.5 months in chemotherapy only patients newly diagnosed with AML. For patients with relapsed AML, a complete response rate of 26% was seen in another clinical trial. The AWP cost of therapy for patients receiving Mylotarg on top of standard chemotherapy will be about $39,360.

A search on clinicaltrials.gov shows high interest in the continuation of research for additional therapies for AML. There are over 400 phase 2 or phase 3 trials currently recruiting or underway for the treatment of AML. Of therapies currently in phase 3 clinical research, a few have been granted either orphan disease status or a breakthrough therapy designation by the FDA including gilteritinib ( FLT3 Inhibitor; Astellas), Venclexta (venetoclax; Abbvie), and volasertib (Plk enzyme inhibitor; Boehringer Ingelheim). It is exciting to see so many drugs with distinct mechanisms of action being studied or recently approved. While dates of possible FDA review for these three drugs have not been made public, we are likely to see the trend of new AML treatment approvals continue into 2018.

With two new drug approvals, one reintroduction to market, and over 400 clinical trials underway in the treatment of AML, it is apparent that there is quite a bit of interest in producing new treatment options for AML. This brings new hope to patients who cannot receive traditional therapies, or who have relapsed despite receiving traditional therapy already. It will be interesting to monitor the impact new therapies will have on the market considering the high cost of treatment with the new therapies and the relatively high success of lower cost traditional chemotherapy for those eligible for treatment.