November 2018 Edition Vol.11, Issue 11

Acute Myeloid Leukemia: Progress toward Sustained Remissions

After more than a decade with hardly any advances being made, seven drugs have received regulatory approval over the last two years for the treatment of acute myeloid leukemia (AML). Furthermore, several additional drugs that have demonstrated efficacy in phase 3 trials for the treatment of AML are currently under regulatory review; and candidates with unique mechanisms of action are also showing promise at earlier stages of clinical testing.

Relative to the 7+3 cytotoxic chemotherapy regimen of cytarabine and an anthracycline, which has been the AML induction standard, many of the newer therapies are designed to inhibit specific disease pathways.1

In this summary of recent AML drug development, a review and explanation of the emerging targetable molecular pathways provide an outline for the increasing opportunities for personalized AML treatment.

Brief History

AML, the most common type of acute leukemia in adults, is the result of disturbances in maturation of myeloid cells.2 Progress in characterizing the cytogenetic abnormalities and downstream molecular aberrations that drive AML provides the basis for most of the new therapeutic options. While these advances have the potential to expand options in the induction, consolidation, maintenance, and refractory/relapsed settings, older patients may benefit the most.

In a disease for which the median age at diagnosis is 70 years, less than 10% of those 60 years and older are alive at five years.3 In younger patients, who can tolerate aggressive chemotherapy and hematopoietic stem cell transplant (HSCT), the five-year survival rate is estimated to be approximately 40%.4 Many of the new treatment options have low relative rates of toxicity, circumventing the limitation of the 7+3 standard in patients unable to tolerate aggressive therapy.

Except for CPX-351, a fixed liposomal combination of cytarabine and daunorubicin, which showed an efficacy advantage over the 7+3 standard and is one of the recently approved AML therapies, several pathways targeted by the new agents are specific to AML subtypes and require molecular profiling.

Due to the specificity of action of many newer agents, molecular profiling will play an increasingly important role in optimal selection and sequencing of treatment options. The goal of upfront regimens with curative potential is eradication of AML and clonal evolution, but chemotherapies, targeted therapies, and immunotherapies employed in an optimal sequence offer the prospect of extended periods of disease control for a malignancy that is currently fatal in the majority of cases.

Midostaurin and Gilteritinib: FLT3 Kinase Inhibitors

The era of targeted therapies in AML therapies was initiated with the approval of midostaurin April 28, 2017. Midostaurin targets a point mutation in FLT3—a cell surface receptor known to regulate survival and proliferation of progenitor cells. FLT mutations, which are found in about 30% of patients with AML, is associated with an aggressive AML phenotype as well as rapid resistance to 7+3 therapies.5

The approval of midostaurin, which inhibits FLT as well as several other kinases, was based on a phase 3 trial of patients with newly diagnosed FLT-positive AML.6 In that study, 51% of patients receiving midostaurin plus daunorubicin were alive at four years compared with 44.3% of those receiving placebo plus daunorubicin (P=0.009).

Another FLT3 inhibitor, gilteritinib, joined midostaurin when it was approved for AML November 28, 2018. Unlike midostaurin, which has an indication as a first-line induction therapy when combined with 7+3 and as a consolidation therapy when combined with cytarabine in patients with FLT3-positive AML, gilteritinib is approved only in the relapsed or refractory setting in FLT3-positive AML patients. Other FLT3 inhibitors, such as quizartinib, which was recently granted breakthrough status and is now under review by the FDA, are coming. As drugs in this class do not necessarily have the same specificity or inhibitory effect on FLT3, they might not have the same spectrum of activity.

Gemtuzumab and other Anti-CD33 Monoclonal Antibodies

The anti-CD33 monoclonal antibody (MAB) gemtuzumab was approved September 2, 2017 in patients with relapsed or refractory CD33-positive AML. CD33 is expressed in varying degree in approximately 90% of cases of AML7 but the story of gemtuzumab ozogamacin, an anti-CD33 antibody conjugate, underscores the importance of individualized therapy.

Initially approved in 2000, gemtuzumab ozogamacin, which binds to the CD33 receptor to deliver a cytotoxic agent, was subsequently withdrawn due to lack of efficacy. It was reapproved in 2017, when several clinical trials, such as the phase 3 trial conducted in Europe,8 demonstrated activity in patients with CD33-positive AML.

Several treatment strategies in AML are now being pursued on the basis of CD33-positive disease, including other conjugates, such as IMGN779,9 which combines a CD33 MAB with different anti-cancer payloads. Strategies also include agents that bind simultaneously to CD33, or other cell surface receptors, and T cell receptors, such as CD3. AMG330 is an example of a bi-specific T cell engager (BITE) strategy,10 currently being tested in a phase 1 trial.

Enasidenib and Ivosidenib in IDH1 and IDH2 Mutation Suppression

Two of the recently approved therapies for AML, enasidenib and ivosidenib, involve therapies that target isocitrate dehydrogenase (IDH) mutations. IDH-gene regulated enzymes have an important role in several molecular processes that govern myeloid cell development. IDH mutations found in AML as well as other myelodysplastic disorders are implicated in disease pathology.11

Enasidenib, which was approved August 1, 2017, targets IDH2, a mutation that occurs in approximately 12% of patients with AML. In a proof of principle study that contributed to its approval, enasidenib promoted normal maturation of leucocytes and led to complete remissions in approximately 20% of patients with relapsed or refractory disease positive for this target.12

Ivosidenib, which was approved July 20, 2018, targets IDH1 mutations, which are found in 6% to 10% of patients with AML. This agent was largely approved on the basis of an early stage trial, which, in this case, documented a 21.6% complete remission rate in patients with relapsed/refractory IDH1 mutated AML.13 Both of these small-molecule oral inhibitors of mutant IDH were associated with low rates of grade 3 or higher adverse events.

The activity of the IDH inhibitors may prove to be forerunners of other oral agents that target epigenetic mutations, such as TET2 and DNMT3A, to treat AML by preventing abnormal myeloid development. While this strategic approach includes a variety of hypomethylating agents (HMA), some of which, like guadecitabine, are already in clinical testing,14 the efficacy of this and most targeted therapies in development depend on first establishing that AML is positive for the target.

Venetoclax in Bcl-2 Inhibition

Venetoclax, approved November 21, 2018, was one of three approvals for treatments of AML in the last two months of 2018. Venetoclax inhibits the anti-apoptotic B-cell lymphoma (Bcl-2) protein and is indicated for the treatment of newly diagnosed AML in patients ineligible for intensive chemotherapy when combined with the hypomethylating (HMA) agents azacitidine or decitabine. Venetoclax is already approved in chronic lymphocytic leukemia (CLL).

In AML, the complete remission (CR) rate was 73% with venetoclax plus an HMA in patients ineligible for cytotoxic chemotherapy.15 Even in those 75 years of age or older with poor cytogenetics, the CR rate was 60%. These are rates that rival those achieved in fit patients receiving the 7+3 regimen but with a far lower risk of adverse events and in a more difficult-to-treat population.

It is important to emphasize that this therapy, unlike the other targeted therapies coming forward, may be active irrespective of driver mutations, epigenetics, or other disease features that involve first establishing the presence of a specific target. As a result, there is now interest in comparing venetoclax-based regimens to 7+3 in younger patients. Due to the potential for inhibitors of proteins that block apoptosis such as Bcl2 to exert broad anti-cancer activity, this has become an intensive focus of drug development.16

Glasdegib in Hedgehog Pathway Signaling

Glasdegib, which targets the hedgehog pathway was granted approval November 21, 2018 on the basis of a phase II trial in which it almost doubled the median OS relative to low-dose cytarabine alone in patients with newly diagnosed AML ineligible for intensive chemotherapy.17 For enrollment in the trial, there was no requirement to demonstrate activation of the hedgehog pathway. The indication is for treatment of patients 75 years of age or older with newly diagnosed AML and comorbidities that preclude use of intensive induction chemotherapy. The role of this agent relative to other first-line agents in patients ineligible for intensive chemotherapy is still being evaluated.

Active and Promising Immune Therapies

In addition to experimental BITE agents that employ cell surface AML antigens to engage the immune system, recent clinical studies challenge the premise that AML is poorly responsive to checkpoint inhibitors or other immunotherapies.18,19 Clinical trials showing activity with several types of immunotherapy, including chimeric antigen receptor (CAR) T-cells,20 have demonstrated activity in AML. So far, studies have been confined to patients with advanced and refractory disease, but these types of therapies may provide yet another option for prolonging survival in patients no longer responding to agents used in earlier disease stages.

Summary

The rapid expansion of therapeutic options for AML has the potential for meaningful improvements in outcome for both newly diagnosed and late stage disease. Although this increase in options introduces potential uncertainty regarding which therapy should be considered first in the individual patient, clinical trials in well-defined populations, such as those with relapsed/refractory disease, or in patients who have tested positive for specific targets, such as a FLT3 mutation, are guiding clinical indications.

In younger patients with AML who can tolerate intensive chemotherapy, the 7+3 induction regimen remains an effective treatment alone or as a backbone for achieving deep responses and durable remissions. In patients ineligible for intensive chemotherapy or those with refractory or relapsed AML, therapeutic choices will be increasingly personalized according to molecule features, a step made possible by the recent introduction of multiple targeted therapies.

 

References

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