ASH 2018: 'Amazing Developments' in AML Treatment

Hello. I am Jorge Cortes, deputy chair of the leukemia department at MD Anderson Cancer Center in Houston, Texas. Welcome to Medscape Oncology Insights, coming to you from the 2018 American Society of Hematology (ASH) Annual Meeting in San Diego, California. Today we will be discussing some of the highlights of the leukemia sessions at the meeting.

This has been a particularly important meeting and a particularly important year in the leukemia field. I am going to focus specifically on acute myeloid leukemia (AML), because after many years with little progress in this disease, we have seen amazing developments in the past few years. Many of these developments have been presented at this meeting.

Venetoclax

I will start with venetoclax. Venetoclax has been a very hot drug in AML. We know about the data in lymphoid malignancies. About a year and a half ago, we started learning about the combination of venetoclax with hypomethylating agents and low doses of cytarabine. We saw the recent approval of venetoclax with these two types of drugs in the United States. At ASH 2018, we are seeing updates of the results that have led to this approval and a few other studies that have supported the benefit of these combinations.^[1,2]

In the approval, venetoclax combinations are meant for older patients who are not fit enough to receive standard chemotherapy, although their fitness is only vaguely defined. The response rate in the salvage setting is very high. In combination with hypomethylating agents, it is around 70%,^[1] which is a very, very high response rate. With low-dose cytarabine, we see a similar response rate.^[2]

Of importance, some of the longer follow-up data, including the survival data, have been presented at this meeting. The median survival for these patients has been around 16-17 months.^[1,3,4] That is very good for this patient population. Remember, these are patients who are 75 years old or older and are not fit for chemotherapy. These are not controlled studies, but typically we would expect a median survival of about 9-12 months at best, probably less than 9 months.

The results are very similar with low-dose cytarabine. We do have an untreated patient population that has also been presented. A couple of studies show this response rate. In one, response rates are in the high 80% range, and in the other that rate is 100%. Of course, 100% will probably come down, but it just tells you how powerful this combination is.

It is important to recognize that this treatment results in prolonged myelosuppression. The patients need to receive prophylactic antibiotics and be monitored for infections and the need for transfusion, both of which need to be promptly addressed. There is also the risk for tumor lysis syndrome (TLS), but what has been presented here and what has been approved is a gradual escalation of the venetoclax dose, which mostly prevents and eliminates TLS as a significant problem. Otherwise, the drug is quite safe.

This is an important combination and we will see much more happening in the near future, extending this treatment to other patient populations and adding other agents.

IDH Inhibitors

We also heard follow-up on trials with the IDH inhibitors. The IDH1 and IDH2 inhibitors have also been approved recently. In the salvage setting, we have seen complete response (CR) and CR with partial hematologic recovery (CRh) results in the 40% range, with the single-agent inhibitor corresponding to the IDH mutation.^[5]

IDH mutations occur in about 8%-12% of patients.^[6] They are not the most common mutations in AML, but a significant number of patients have them and they do very well with this treatment. It is an oral medication and very well tolerated. One complication that needs to be recognized is the differentiation syndrome, which can happen in between 10% and 20% of the patients.^[5] This differentiation syndrome is sometimes, but not always, associated with an increase in the white blood cell count and an increase in the [myelo]blasts, and if it occurs, that could be a warning that differentiation syndrome is occurring. Other patients may present only with fluid retention, shortness of breath, and some renal dysfunction. Those patients need to be monitored carefully. Patients respond well to steroids and treatment interruption.

An interesting study looked at the use of these drugs as initial therapy, resulting in about a 40% response rate with the single agent.^[7] Considering that it is a single agent, that response rate is very good. It remains to be seen which patients you would consider giving this particular agent to as a single agent and as initial therapy—perhaps older patients for whom you want to avoid any more myelosuppressive therapy. This was not a controlled study. It is valuable, but the benefits need to be further defined.

Glasdegib, Gilteritinib, and Quizartinib

Other important developments included the recent approval of glasdegib as a combination therapy with low-dose cytarabine. Some studies presented in the poster sessions during this meeting show the benefit of this drug, with a significant survival advantage compared with low-dose cytarabine.^[8] Again, this is for patients who are older than 75 years and unfit, who have cardiac dysfunction, renal dysfunction, liver dysfunction, and so on. The combination is very well tolerated, and again, with a significant improvement in response rate, providing at least a doubling in the survival.

Some of the data presented here show that this applies across all of the different mutations we see in leukemia. We see benefit even in patients who have not responded to therapy, which is very valuable. There is a reduction in the transfusion requirements in these patients. This is all valuable information about a drug that is now available.

An interesting study looked at treatment with gilteritinib as a single agent or in combination with azacitidine.^[9] That becomes quite valuable, because again, just as ASH 2018 was beginning, we heard about the approval of gilteritinib as an FLT3 inhibitor in patients with refractory or relapsed AML. There are not much data, however. The pivotal trial is not being presented at this meeting, but it is included in the prescribing information label, and the response rate, the CR plus CRh, is around 20%.^[10]

There was a presentation on quizartinib, another FLT3 inhibitor that is undergoing review for approval. The pivotal trial is being presented at this meeting,^[11] a randomized controlled study of quizartinib versus standard chemotherapy in patients with refractory or relapsed AML. The response rate—and most important, the survival, which was a primary endpoint—was significantly better for patients treated with quizartinib.

We have midostaurin already approved; gilteritinib very recently approved; and quizartinib very soon to be approved, we hope. These drugs will be very valuable for patients with FLT3 mutation.

Monoclonal Antibodies

Other drugs that are worth monitoring include monoclonal antibodies which, as a class, are an important family of drugs, and trials with many of these were presented during this meeting. Gemtuzumab ozogamicin is one that is already approved but was recently reapproved by the US Food and Drug Administration (FDA) in combination with chemotherapy.

The French group that led the study that resulted in the reapproval of the drug presented some follow-up.^[12] There have been some concerns about the possibility of veno-occlusive disease (VOD) and how that may affect the outcome after transplant. The ALPHA study looked at combining gemtuzumab with 3 + 7 and found no significant increase in the risk for VOD with a schedule that they pioneered: 3 mg/m² on days 1, 4, and 7. This dosing schedule did not affect the outcome of the transplant. The survival was similar after transplant for patients who received gemtuzumab and patients who did not receive gemtuzumab. That should alleviate some of the concerns we had in the past when we were using different schedules with this agent.

Some new monoclonal antibodies are under development, including antibody drug conjugates and immunotoxins that are like gemtuzumab, one targeting CD33 and the other targeting CD123, with a different kind of toxin showing some responses.^[13,14] Some patients developed VOD. So far they have not yet reached a maximum tolerated dose. Early results but attractive.

Other, bispecific monoclonal antibodies, again directed at CD33 and CD123, are showing early evidence of activity.^[15] Some patients have developed cytokine release syndrome. That is one of the issues that must be monitored and addressed with these bispecific antibodies, just as we know with blinatumomab in acute lymphocytic leukemia. These drugs are under development. I think they will be very useful. None of them have yet been approved by the FDA.

Overall, we can say that 2018 has been a very exciting year and ASH 2018 has been a very exciting meeting for AML, with many more tools available and many more drugs that have been approved. I believe that we will have many more ways to treat our patients and offer them a better outcome with all of these tools.

With that, I will conclude. Thank you for joining me. I am Jorge Cortes, reporting from the ASH annual meeting, 2018, in San Diego, California.

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