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SECOND THOUGHTS FROM SEKERES: ASH 2012—Research That Caught My Attention in MDS and AML

Sekeres, Mikkael A. MD, MS

doi: 10.1097/01.COT.0000426450.75710.06
MIKKAEL SEKERES, MD, MS, OT's Clinical Advisory Editor for Hematology/Oncology, is Director of the Leukemia Program and Chair of the Hematology/Oncology Pharmacy & Therapeutics Committee at the Cleveland Clinic Taussig Cancer Institute; and Chair of the FDA Oncologic Drugs Advisory Committee

MIKKAEL SEKERES, MD, MS, OT's Clinical Advisory Editor for Hematology/Oncology, is Director of the Leukemia Program and Chair of the Hematology/Oncology Pharmacy & Therapeutics Committee at the Cleveland Clinic Taussig Cancer Institute; and Chair of the FDA Oncologic Drugs Advisory Committee

Let's face it: Conferences like the American Society of Hematology and the American Society of Clinical Oncology Annual Meetings are overwhelming, with multiple simultaneous sessions, huge conference centers, and overlapping sessions even in boutique disease areas like the ones in which I specialize. It's a challenge to attend all of the interesting sessions, never mind synthesize the material in a way that can change your practice, or modify the information you impart to patients. So, here's my take on some of the presentations that jumped out to me in myelodysplastic syndromes and acute myelogenous leukemia, and will likely influence my patient care in the next year.

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Nothing Gets Between Me and My (Calvin Klein) Genes

With apologies for the reference to Brooke Shields. As techniques such as whole exome sequencing and single nucleotide polymorphism (SNP) or comparative genomic hybridization (CGH) arrays become more sophisticated and, frankly, cheaper, more disease-specific, and possibly disease-defining, lesions have been identified.

Last year, the SF3B1 mutation that has now been associated with the refractory anemia with ring sideroblasts subtype of MDS and with chronic lymphocytic leukemia was all the rage. This year, attention is focused on the SETBP1 abnormality.

This is a curious one. As a constitutional abnormality, it is associated with a rare congenital syndrome, Schinzel-Giedion syndrome (SGS), characterized by bone, muscle, and cardiac abnormalities; neuroepithelial neoplasms; and mental retardation.

In a plenary presentation, Makishima and colleagues from Cleveland Clinic, Japan, Baltimore, and Los Angeles (Abstract #2) reported on 734 patients (283 with MDS, 106 with secondary AML, 167 with MDS/myeloproliferative neoplasm [MPN] overlap syndromes, 138 MPN, and 146 with primary AML). A total of 52 mutations were detected in 52 patients (7.1%), with 15 percent in patients with secondary AML and chronic myelomonocytic leukemia.

Clinically, the mutation was associated with higher age, chromosome 7 abnormalities, shorter survival, and importantly, with evolution from MDS to AML in paired samples. The investigators also determined that the SETBP1 mutation was associated with gain of function activity via RUNX1.

In a late-breaking abstract (Abstract #LBA-2), Gambacorti-Passerini and colleagues from Italy, Germany, and the United Kingdom also described this lesion in 24 percent of patients with atypical chronic myeloid leukemia. Other genes that were either presented or validated for their prognostic import in MDS, MDS/MON, or secondary AML include PRPF8, CSMD1, U2AF2, IDH2, PPFIA2, SF3B1, TP53, and NRAS (Abstracts #307 and #311).

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Fortune Tellers and Soothsayers

This summer, the revised International Prognostic Scoring System (IPSS-R) for MDS was published in the journal Blood by Greenberg and colleagues (doi: 10.1182/blood-2012-03-420489). It is no surprise that a number of groups presented research at ASH validating the system in their own patient cohorts, and on the whole it appears to be standing up fairly well.

One important presentation by Ades and colleagues reported on the application of the IPSS-R to 282 patients treated with azacitidine under the compassionate use program in France (Abstract #422). The investigators found that the system did have strong prognostic value for survival in this treated population. This is extremely important—there is an inherent paradox to the way we have used the IPSS in MDS patients.

While both the classic IPSS and the IPSS-R were developed and (in the case of the IPSS-R) validated in MDS patients who were by and large untreated, the scoring systems are often applied in practice and for determining clinical trial eligibility in patients who have received therapy previously or are about to. This is the first study, then, to show that the IPSS-R can be used with confidence in patients receiving this disease-modifying therapy.

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Chemotherapy, You have Met Your Match in Acute Promyelocytic Leukemia

There are few areas within the world of adult acute leukemias where we can claim the successes of our pediatric colleagues. One shining example of how understanding disease biology can have radical therapeutic implications is within acute promyelocytic leukemia (APL), in which combining classic cytotoxic chemotherapy with differentiation agents has led to long-term disease-free survival rates of 80 percent. But perhaps even including chemotherapy in induction regimens for APL is overkill.

In another plenary session, Lo-Coco and colleagues from Italy and Germany (Abstract #6) report results from a phase 3 trial of 162 non-high risk APL patients (all with white blood cell counts less than 10 × 109/L) who were randomized to receive induction chemotherapy with idarubicin and the differentiation agent all-trans retinoic acid (ATRA), followed by anthracycline-based post-remission therapy, vs. ATRA combined with another differentiation agent, arsenic trioxide (ATO), followed by post-remission therapy with ATO.

Both two-year event-free and overall survival were superior in patients randomized to the dual-differentiation agents (ATRA + ATO), at 97 percent vs. 87 percent (p = 0.03), and 99 percent vs. 91 percent (p = 0.03), respectively.

These results at the very least imply that it may be time to retire chemotherapy in patients with non-high risk APL.

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Flat-out FLT3 Responses

The FLT3 story in AML has been maddening. A lesion is detected in up to one-third of AML patients that confers a terrible prognosis (particularly in the absence of an NPM1 mutation), yet is targetable. Attempts to treat patients who have the FLT3 internal tandem duplication abnormality have yielded reductions in blasts percentages when drugs have been given as monotherapy, and no clear response advantages when given in combination with cytotoxic regimens.

In an oral presentation by Cortes and colleagues from Philadelphia, Baltimore, Seattle, France, Germany, and the United Kingdom (Abstract #48), the investigators report on 134 patients with relapsed or refractory acute myeloid leukemia enrolled onto a phase 2 study of the FLT3 inhibitor quizartinib (AC220); 69 percent had FLT3 mutations, and the patients' median age was 70 years. The composite complete remission rate for FLT3-positive patients (which included complete remission [CR], CR with incomplete platelet recovery, and CR with incomplete hematologic recovery) was 54 percent, of whom almost all had a complete remission with incomplete hematologic recovery.

This was accompanied by a response duration of 12.7 weeks. Among the entire population, eight percent of patients went on to receive a hematopoietic stem cell transplantation. Another phase 2 study of quizartnib presented by Levis and colleagues reported on 137 relapsed or refractory AML patients (Abstract #673). The composite CR rate for FLT3+ patients was 44 percent, and for FLT3- patients, was 34 percent—again, almost entirely comprised of CR with incomplete hematologic recovery.

So, we aren't quite there yet with these drugs as monotherapy, and we need to come to some consensus over whether altering the definition of CR is appropriate in AML. What is encouraging is that this type of response rate may be “good enough” to transition patients topotentially curative therapy—and that will have an impact in a desperate population.

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More ‘Second Thoughts’!

Check out all the previous articles in Mikkael Sekeres' award-winning column in this collection on the OT website:

© 2013 Lippincott Williams & Wilkins, Inc.
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