Richard M. Stone, MD

Disclosures

December 23, 2011

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Introduction

Hello, I am Dr. Richard Stone, Professor of Medicine at Harvard Medical School, and Director of the Adult Leukemia Program at Dana-Farber Cancer Institute. Welcome to Medscape Oncology Insights on acute myeloid leukemia (AML).

Today, I would like to discuss several of the key studies in AML presented at the American Society of Hematology (ASH) annual meeting in 2011. I will organize my remarks into 3 areas. First, I will discuss the reports of important clinical trials in AML; second, I will mention some of the results of studies in acute promyelocytic leukemia; and third, I will discuss some interesting new drugs that might be used in the future which account for our developmental therapeutic armamentarium.

The Buzz About Gemtuzumab

In terms of clinical studies, certainly the most exciting topic discussed at ASH was the question of whether gemtuzumab ozogamicin should be added to chemotherapy in adults with AML. About 7 years ago, gemtuzumab ozogamicin, an antibody toxin conjugate, was approved for use in the United States for older adults with relapsed AML who expressed CD33 on the surface of their myeloblasts but were not considered candidates for chemotherapy. The drug was voluntarily withdrawn from the market in this country about a year ago when the results of the Southwest Oncology Group trial failed to show a benefit from the addition of gemtuzumab ozogamicin to chemotherapy in newly-diagnosed younger adults with AML. However, at this meeting, gemtuzumab ozogamicin seemed to be making somewhat of a resurgence based on 2 important abstracts.

The first was presented by Dr. Castaigne on behalf of the ALFA [Acute Leukemia French Association].[1] In this study, adults aged 50-70 years were randomly assigned to chemotherapy alone or chemotherapy plus gemtuzumab ozogamicin in the form of 3 relatively low doses, given on days 1, 3 and 5 of induction. The study was powered to see an improvement in event-free survival with the addition of the immunotoxin conjugate. Indeed, event-free survival was significantly improved in patients who received the gemtuzumab, in addition to an overall survival advantage, suggesting that gemtuzumab might be a good drug to add to chemotherapy at least in that subgroup of patients with AML.

Dr. Alan Burnett, on behalf of the Medical Research Council in the United Kingdom,[2] presented an abstract describing a trial in which patients who were deemed fit to receive chemotherapy but were older than age 60 (by and large, some were a little bit younger than that, but most were older than age 60) They were randomly assigned to receive standard induction and post-remission chemotherapy, with the experimental group receiving a low dose of gemtuzumab on day 1 of therapy.

Amazingly, the addition of a single dose of gemtuzumab ozogamicin on day 1 resulted in improvement in event-free survival, less improvement in relapse-free survival, and a sufficiently significant benefit in overall survival -- from a 20% 3-year survival in the control group to 25% in the treated group. This isn't a huge difference in overall magnitude but certainly sufficiently significant. The conclusion from these 2 papers was that gemtuzumab ozogamicin should be added to chemotherapy, at least in adults age 50 or older with AML.

This drug is not available to be given off-label so it remains to be seen what the approval strategy will be for the company that owns the rights to this drug. Right now, this is only of theoretical benefit to patients so we will have to follow that.

Another interesting abstract was presented by the German Leukemia Study Group.[3] They confirmed earlier results of the benefit of using all-trans retinoic acid (ATRA) in the subgroup of AML patients who had an NPM1 mutation but do not have a FLT3 mutation. This is considered to be a genetically-favorable group within the subcategory of patients with normal chromosomes. This study suggested that adding ATRA in this genetically-favorable subgroup would improve the results from what can now be achieved with chemotherapy alone.

APML: Any Room for Improvement?

Acute promyelocytic leukemia (APML) is a disease for which we happily have established a very high bar -- a cure rate of 70%-80% in adults. Of course APML accounts for 10%-15% of all AML so it's not a common disease, but it's very important to get the treatment right because most patients can be cured. Dr. Douer of Memorial Sloan-Kettering,[4] described a study with a very rare incidence of late relapses. These patients, who have been disease-free for more than 3 years, very rarely relapse, but if they do, they can go into remission and go on to be cured with available therapy. That was good news. Basically, a patient who survives for 3 years after modern therapy for APML is in good shape and very unlikely to relapse.

A German group[5] presented data about treatment of older adults with APML. Frankly, the results were a little disappointing. The event-free survival in the average older adult was 60%-70%. It is likely that with modern therapy (arsenic and ATRA alone), we can do better than that, but we certainly need to look at the studies on APML with an eye toward making sure that older adults are well cared for.

There remains much debate about the best use of chemotherapy in APML. We know that daunorubicin is a very useful drug in this disease, as are other anthracyclines. The question of whether Ara-C (cytarabine) needs to be added is still unanswered. A German group[6] presented data suggesting that high-risk patients benefit from Ara-C but this was in the pre-arsenic trioxide era.

Arsenic trioxide, which is an incredibly useful drug in APML, was the subject of a fascinating presentation by Dr. Vikram Mathews.[7]In this randomized trial conducted in a developing country, patients were induced with arsenic trioxide as the only therapy for their AML, then were given consolidation with either 6 or 12 months of additional arsenic. This was a trial conducted in several cooperative centers throughout the country of India. It turned out that adding 6 extra months of arsenic trioxide was not necessary.

Dr. Bayard Powell, on behalf of the US Intergroup,[8] presented results of the maintenance randomization in CALBG 9710 in which patients with APML were given induction chemotherapy with Ara-C, retinoic acid, and daunorubicin and consolidation with daunorubicin and ATRA, with or without arsenic trioxide. Patients in remission after all that therapy were randomly assigned to 6-mercaptopurine, methotrexate, and retinoic acid or retinoic acid alone. It turned out, especially in the people who received arsenic trioxide during the early post-remission setting, that no benefit was derived from the addition of the antimetabolites. This suggests that patients who are in good shape after receiving all their post-remission therapy, especially if it includes arsenic, don't need to get any maintenance therapy other than retinoic acid. In fact, whether retinoic acid can be dispensed with entirely in those who are molecularly negative at the end of induction and consolidation, is an open question to which we don't have the answer right now.

AML Drugs in Development

In the last couple of minutes, I want to discuss some of the exciting developmental studies presented at ASH 2011 in terms of new drugs in AML. Several of these were early clinical trials. A lot of interest has been expressed in reversing the protective effect exerted by the microenvironment in the bone marrow niche against the leukemic stem cell. Dr. Uy from Washington University in St. Louis[9] presented a trial in which he gave plerixafor plus induction chemotherapy to older adults with AML. This combination seemed to be well-tolerated. Dr. Guillermo Garcia-Manero from MD Anderson[10] presented a trial in which he used the histone deacetylase inhibitor vorinostat in addition to idaurubicin and cytarabine for newly-diagnosed adults, which also seemed to be well-tolerated.

A couple of very early clinical trials were presented, including a phase 1 study with a hedgehog inhibitor by Dr. Jamieson from the University of California-San Diego.[11] Hedgehog is a pathway thought to be very important in maintenance of leukemia stem cell function. Some dramatic results and responses have been observed in patients given fairly low doses of the hedgehog inhibitor. A lot of pre-clinical studies were presented in which various components of the leukemogenic pathway (such as STAT 3) were inhibited, including activated tyrosine kinases and degradation pathways, such as the NEDD8 pathway.

Conclusion

Whether any of these studies that were pre-clinical in nature will make it to the clinic remains to be seen, but there is some hope that our increased understanding of leukemogenic pathways will eventually make therapy for adults with AML much better than it is right now.

I want to thank you for joining me for this edition of Medscape Oncology Insights. This is Richard Stone reporting from ASH 2011 in San Diego, California.

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