Acute myeloid leukaemia: Hope for new treatments

Acute myeloid leukaemia (AML), also known as acute myeloblastic or myelogenous leukaemia, is a malignant disease in which the bone marrow makes abnormal myeloblasts, red blood cells or platelets. The disease manifests in two forms: acute or chronic leukaemia. In the acute stage, the disease advances rapidly, while with chronic leukaemia the progression is slower. Of the 2,400 new diagnosed cases of acute leukaemia in England and Wales each year, 1,800 are AML. Around 20,000 new AML patients are reported annually in the USA. While it can affect both children and adults, its incidence peaks in patients over the age of 50 years. Progress in treatment of AML has been slow, with little change in available therapies for the past three decades; primary options have been chemotherapy or radiation therapy. The result is that prognosis has not been good – AML treatment currently offers a 5-year overall survival (OS) rate of 40–50% for younger patients and a median OS of less than one year for older (>60 years) patients.

For those who can tolerate it, standard treatment for newly diagnosed patients is the "7+3" chemotherapy regimen, involving seven days of standard-dose cytarabine and three days with an anthracycline (daunorubicin or idarubicin), sometimes followed by high-dose cytarabine or stem cell transplant. However, the chemotherapy treatment regime is highly toxic; common side effects include bone marrow suppression, vomiting, diarrhoea, liver problems, rash, oral apthous ulcers and bleeding. More serious side effects include loss of consciousness, lung disease and allergic reactions. While chemotherapy effectively induces remission in most patients with AML, the risk of relapse is high. Meanwhile older patients who are less able to tolerate the 7+3 regimen can receive single-agent chemotherapy or a hypomethylating agent.

Several other drugs have been used in AML treatment over the last decade or so. For example, the immunostimulator sargramostin (Leukine; Genzyme/Sanofi) was first approved in the 1990s to reduce the incidence of infections following induction chemotherapy in older adults with AML – often resulting in high mortality. In addition, azacytidine (Vidaza; Celgene) is a nucleoside metabolic inhibitor indicated for the treatment of adult patients who are not eligible for haematopoietic stem cell transplantation with 20–30% blasts and multi-lineage dysplasia. Azacytidine has become a generic in the USA.

Approved in the EU in 2008, histamine dihydrochloride (Ceplene; Immune Pharmaceuticals) is useful for remission maintenance and prevention of relapse in combination with interleukin-2 drugs. It helps immune cells destroy malignant cells, but was not accepted for approval in the USA as the data did not show overall survival benefit in its Phase III trials. Finally, decitabine (Dacogen; Otsuka/Eisai/J&J/Janssen Cilag) was approved in the EU in 2012 (but not the USA) to treat patients with newly diagnosed AML who are not eligible for initial treatment with standard chemotherapy.

Next generation treatments

One advance on the conventional 7+3 cytarabine and daunorubicin treatment regimen as first-line therapy in older patients with high-risk AML is a formulation called Vyxeos (cytarabine and daunorubicin; Celator/Jazz Pharma). This uses a 5:1 ratio of cytarabine:daunorubicin packaged in liposomes and delivered intravenously, offering an approach that could improve efficacy and mitigate side-effects. Trial results look promising; recent phase III data demonstrated a significant improvement in overall survival, with median OS for patients treated with Vyxeos at 9.56 months compared to 5.95 months for patients receiving 7+3. Vyxeos was accepted for rolling submission in the USA in 2016, with the submission due for completion in 2017.

Approximately one-third of patients with AML – those with FLT-3 receptor tyrosine kinase mutations, which can result in faster disease progression, higher relapse rates and lower rates of survival than other forms of AML – could benefit from midostaurin (Rydapt; Novartis). This drug was filed on both sides of the Atlantic and has been recently approved by the FDA. It is an oral inhibitor of a spectrum of FLT-3 receptor tyrosine kinase mutations, and has shown a 23% improvement in overall survival with drug versus standard therapy in phase III trials. In addition, median OS for patients in the midostaurin treatment group was 74.7 months versus 25.6 months for patients on placebo. If trials are successful, this drug could offer FLT3-mutated patients a new standard of care with an effective maintenance therapy option, an important step since there is still no clear consensus on the efficacy of maintenance therapy in AML [Reference 1].

On the horizon

There are a number of therapies currently in phase III trials. Like midostaurin, AC 220 (quizartinib; Daiichi Sankyo) is an FLT3-kinase inhibitor. Phase II data for AC 220 have shown a remission rate of 44%, and median overall survival of 23 weeks in FLT3-ITD mutant patients who were relapsed or refractory to 2nd line treatment.

ASP 2215 (gilteritinib; Astellas) is also in phase III. This oral drug inhibits the enzymes FLT3, STK1, FLK2, AXL (UFO or JTK11) and anaplastic lymphoma kinase (ALK or CD246). Phase II trials show a 53% overall response rate (ORR), regardless of prior therapy. Additionally, a 56% ORR was observed in patients who had an FLT3-ITD mutation, and 48% ORR was observed in patients who were treated with a tyrosine kinase inhibitor prior to the study.

Also in phase III trials is CY 682 (sapacitabine; Cyclacel Pharmaceutical). This drug acts through a dual mechanism, interfering with DNA synthesis by causing single-strand DNA breaks and inducing arrest of cell cycle progression, mainly at G2-Phase. If successful, it would be the first orally-administered drug offered to elderly patients with the potential to serve as induction, consolidation and maintenance treatment of this life-threatening disease. In the pivotal SEAMLESS trial, CY 682 failed to meet its primary endpoint, but some patient groups exhibited improvements in overall survival.

Combination therapies are also under investigation. For example, a combination of venetoclax (Venclexta/Venclyxto) with azacytidine (Vidaza), (AbbVie, Celgene and Genentech/Roche) has now moved into phase III trials. Early trials demonstrated a tolerable safety profile and induced rapid responses with no reported relapses in elderly treatment-naïve patients. The combination also appears to be effective. venetoclax combined with azacitidine (or decitabine) has demonstrated a complete response rate of 71% and an ORR of 76%. This compares with standard therapies such as azacytidine or decitabine that historically result in response rates of about 28%.

SGN CD33A (vadastuximab talirine; Seattle Genetics) is also in trials, both alone and with azacytidine or decitabine in older patients with newly diagnosed AML. SGN CD33A is a humanized anti-CD33 monoclonal antibody conjugated to a potent DNA-crosslinking toxin, and may offer a benefit over other AML drugs by targeting CD 33 (expressed in about 90% of AML patients and usually not affected by subtype, cytogenic abnormality or underlying mutations). A recent FDA hold on trials due to risk of toxicity has now been lifted and enrolment is continuing in the phase III CASCADE trial in older AML patients.

Finally, there is vosaroxin (Qinprezo; Sunesis Pharma). This cytotoxic drug has been filed in the EU, and is in a multicentre phase III trial in combination with cytarabine. Though it did not meet its primary endpoint, it demonstrated improved outcomes in older patients. The CHMP expressed reservations about the data, and Sunesis has withdrawn its EU application.

Over the horizon

PF-04449913 (glasdegib) is an investigational oral therapy that inhibits the SMO receptor. Developed by Pfizer, it is currently in phase II trials combined with ARA-C, decitabine, daunorubicin, or cytarabine for the treatment of AML. Glasdegib is the first SMO inhibitor to show clinical benefit in a patient population which was ineligible for intensive chemotherapy.

Antibodies with promise for the treatment of AML include anti-CD33 and anti-CD123. Despite early problems with anti-CD33 gemtuzumab ozogamicin (Mylotarg; Pfizer) which was cancelled in the EU and USA due to high toxicity, new trials with this drug at lower doses are looking positive. As a combination treatment with standard chemotherapy it significantly improves event-free survival and relapse-free survival in adults compared to chemotherapy alone.

In addition, blinatumomab (Blincyto), a bispecific antibody to CD19 and CD3 has also been evaluated in Phase I and II trials for leukaemia with promising results in CD19-expressing lymphoid malignancies. This may prove effective in AML. Another bispecific hopeful is AMG 330 (Amgen), an antibody to CD33 and CD3 that has demonstrated significant anti-leukaemia activity in preclinical experiments in subjects with relapsed/refractory AML. Such new antibody constructs may represent an important tool against AML in future.

References

Rashidi A, Walter RB, Tallman MS et al. Maintenance therapy in acute myeloid leukemia: an evidence-based review of randomized trials. Blood 2016 128:763-773.

Hills RK, Gammon G, Trone D et al. Quizartinib Significantly Improves Overall Survival in FLT3-ITD Positive AML Patients Relapsed after Stem Cell Transplantation or after Failure of Salvage Chemotherapy: A Comparison with Historical AML Database (UK NCRI data). Blood 2015 126:2557

Horne GA, Kinstrie R, Copland M. Novel drug therapies in myeloid leukemia. Pharm Pat Anal. 2015;4(3):187-205.

Kadia TM, Ravandi F, Cortes J et al. New drugs in acute myeloid leukemia. Ann Oncol (2016) 27 (5): 770-778.