General AML,   FLT3,  IDH1/2,  NPM1

Five new powerful weapons against AML

It has taken around 40 years – from cytarabine and anthracyclines through the “3 + 7 regimen” – to develop effective drugs for the treatment of Acute Myeloid Leukemia (AML). Even if it was a rocky road and was fraught with difficulties, in the year of 2017, four new drugs have been approved by the US Food and Drug Administration (FDA), and several more ongoing studies will support new promising treatments for AML.

In a recent issue of Blood, Andrew H. Wei, chair of the AGP Rest of the World Steering Committee, and Ing S. Tiong, both from The Alfred Hospital, Melbourne, Australia, wrote a review about the clinical impact and challenges associated with the newly approved drugs in AML, including midostaurin, enasidenib, CPX-351 and gemtuzumab ozogamicin (GO). They also discussed promising data from clinical studies of venetoclax in combination with low-dose cytarabine (LDAC) in patients with AML.

Midostaurin,  a multi-targeted protein kinase inhibitor with Fms Like Tyrosine Kinase 3 (FLT3) inhibitory activity,  was the first discussed by the review authors.

After successful preclinical and phase II trials, midostaurin in combination with conventional induction and consolidation therapies was found to significantly prolong survival of FLT3-mutated AML patients, compared to placebo, in the randomized phase III clinical trial (RATIFY). Based on the findings of this phase III study, midostaurin was approved by the FDA and European Medicines Agency on the 28th of April and 20th September 2017 respectively, for the treatment of adult patients with newly diagnosed FLT3 positive AML, in combination with chemotherapy.

Despite this success, several questions on the findings of the RATIFY study were raised by Wei & Tiong. Firstly, the benefit and optimal duration of midostaurin maintenance therapy in AML is still debatable. The authors highlighted that in the phase III RATIFY study, the main benefit of midostaurin was derived at the beginning of treatment, as the median exposure of patients was only 42 days. Further investigation would be required to demonstrate the optimal duration of midostaurin as maintenance therapy after completion of chemotherapy, which the authors suggested would require more patients and time. They also suggested that a practicable objective of midostaurin maintenance therapy would be to effectively eliminate Minimal Residual Disease (MRD) and prolong relapse free survival.  

Secondly, although the RATIFY study was not powered for sub-analysis, it was observed that male patients with FLT3-TKD and female with FLT3-ITD did not appear to derive OS benefit from midostaurin. The authors suggested that these contrasts require further studies to confirm and disclose enigmas. Lastly, in the RATIFY study, post-transplant survival was better in patients receiving prior midostaurin and transplanted in first remission. future investigation should confirm whether midostaurin brings more patients to transplant in first remission without MRD and also determine the effect on survival of the addition of FLT3 inhibitors in the transplant setting. t

Enasidenib is an orally administered inhibitor of Isocitrate Dehydrogenase 2 (IDH2), which effectively suppresses the production of 2-hydroxyglutarate. . In August 2017, the FDA granted approval to enasidenib for patients with Relapsed or Refractory (R/R) IDH2 mutated AML. The approval was on results from the phase I/II AG-221 AML-001 study (NCT01915498). In this study, the efficacy of enasidenib, was assessed in R/R AML patients (median age = 68 years) with mutant IDH2. Patients were orally administered enasidenib at a starting dose of 100 mg daily until disease progression or unacceptable toxicity. Complete remission (CR) and CR with incomplete hematologic recovery (CRi) rates were reached in 26.6% of the patients, with12% of patients achieving partial remission or morphologic leukemia-free state leading to an overall response rate of 38.5%.

More importantly, the median duration of response to enasidenib was 5.6 months, which is longer than standard AML therapies (approximately 3 months). The authors noted that waiting for a clinical response with prolonged therapy with IDH inhibiors in patients with persistent AML would be difficult for both patients and clinicians; they suggested that further research is needed in order to identify predictive biomarkers of IDH inhibitor response.

CPX-351, a liposomal formulation of  daunorubicin plus cytarabine co-encapsulated at a molar ratio of 1:5, was recently approved by the FDA in August 2017 for adult patients with newly diagnosed therapy related AML (t-AML) or AML with Myelodysplasia-related changes AML-MRC. The approval was based on clinical data from the pivotal phase III study (NCT01696084), which evaluated the safety and efficacy of CPX-351 compared to cytarabine and daunorubicin (7+3) in patients with newly diagnosed t-AML and AML-MRC.  The results of the phase III study demonstrated that CPX-351 improved the survival of older patients with AML.

Wei & Toing noted that the rationale for benefit in AML-MRC and t-AML remains an unanswered question, with one hypothesis being that liposomal drug delivery may exceed drug resistance.

Interestingly, findings of a randomized phase II study demonstrated that there was no benefit for CPX-351 salvage therapy compared to other salvage regimens in patients in first relapse. Future research is required to confirm the benefit of CPX-351 in the salvage setting as well as in specific cytogenetic subgroups.

GO, an Antibody Drug Conjugate (ADC), is an antibody-targeted chemotherapeutic agent consisting of a humanized murine CD33 antibody. Since it is a humanized anti-CD33 monoclonal antibody, it is highly specific for targeting leukemic blasts. GO binds to, and is internalized by tumor cells expressing CD33. As a result, this ADC can then dispense the anti-tumor antibiotic calicheamicin to CD33-expressing tumor cells.

GO was first approved by the FDA via accelerated review in May 2000 for monotherapy of elderly individuals with relapsed AML, but it was voluntarily withdrawn by the company, Pfizer, from market on October 15th 2010.  On  1st  September 2017, the FDA approved GO for adults with newly diagnosed CD33-positive AML, and adults and children 2 years and older with R/R CD33-positive AML. The approval was based on several studies, which are reported by the AGP in more detail here.

Wei and Tiong emphasized several challenges about the use of GO in the future.  The authors’ first major concern was the risk of Veno-Occlusive Disease (VOD) mainly in patients who received SCT within 3 months. The new dosing schedules seem safer in terms of VOD, but the limited experience with GO requires clinicians to carefully observe their patients and avoid hepatotoxic medications. The authors also stated that GO activity in adverse karyotype AML should be further investigated. Also worthy of note is that current studies are investigating the potential of GO in combination with other novel drugs.

Venetoclax, a BCL-2 inhibitor, in combination with low-dose cytarabine, was granted a breakthrough therapy designation by FDA on 28th July 2017, for treatment-naïve, elderly AML patients unfit for intensive chemotherapy.

The authors discussed data from clinical studies of venetoclax in elderly AML patients. As monotherapy, venetoclax was found to be only modestly effective in R/R AML patients. In spite of this, phase II studies confirmed that venetoclax in combination with either hypomethylating agents or LDAC leads to CR/CRi rates of 54-68% and 1-year survival outcomes of 50-70% in elderly AML patients. At present, there are ongoing studies (NCT02993523 and NCT03069352) which aims to validate the benefit of venetoclax in combination with standard therapies in older AML patients who are unfit for intensive chemotherapy.

Future challenges highlighted by the authors include: venetoclax can be a valuable alternative to other inhibitors in elderly AML without the necessity of preemptive mutation screening which may affect the patient recruitment into registration studies in this particular patient population. When a highly active treatment with superior response rates and 12-month OS for venetoclax/HMA or LDAC becomes available with a low toxicity profile, the differentiation may become irrelevant between “fit” and “unfit” elderly patients when choosing the favorable therapy. Further investigation is required in pediatric and R/R AML patients to assess whether venetoclax is safe with more intensive chemotherapy.

In conclusion, the authors stated that “the majority of AML population may now have treatment outcomes augmented by the addition of a novel drug in the clinic. Additionally, venetoclax is also making solid strides toward a possible drug registration in elderly AML. Although cytarabine and daunorubicin will continue to play an important role in AML, patients and physicians will now have the help of several new recruits in their fight against this lethal blood cancer”.

 

Abstract

In 2017, four new drugs have so far received FDA marketing approval for the treatment of acute myeloid leukemia (AML), including targeted therapies for mutant FLT3 (midostaurin) and IDH2 (enasidenib), a novel liposomal cytarabine-daunorubicin formulation (CPX-351) for therapy-related AML and AML with myelodysplasia-related changes and finally, resurgence of an antibody-drug conjugate designed to target CD33 (gemtuzumab ozogomycin; GO). Promising results also emerged for the BCL-2 inhibitor venetoclax combined with low-intensity therapy in older patients with AML unfit for intensive chemotherapy. This quintet of new drugs is likely to re-shape the therapeutic landscape of AML.

References
  1. Wei H.A., Tiong S.T. Midostaurin, enasidenib, CPX-351, gemtuzumab ozogomycin and venetoclax bring a new hope to AML. Blood. 2017 Oct 19. DOI: 10.1182/blood-2017-08-784066.