New and Emerging Strategies in the Treatment of Patients with Higher risk Myelodysplastic Syndromes (MDS)

Transcription

1 Welcome to Managing Myelodysplastic Syndromes. My name is David Steensma. I am an Associate Professor of Medicine at Harvard Medical School and a faculty member in the Adult Leukemia Program at Dana Farber Cancer Institute here in Boston, Massachusetts. Today, I will be discussing new and emerging strategies in the management of patients with higher risk myelodysplastic syndromes. 1

2 What exactly do we mean by higher risk myelodysplastic syndromes? Given that MDS shortens lives, that progression is unpredictable, that it affects quality of life, is there really any lower risk patient? 2

3 To illustrate that I made this graphic. What if we were to imagine all of the patients diagnosed with MDS in the U.S. this year as 100 people? We think there are probably about 30,000 patients with MDS diagnosed each year. What actually happens to those patients? 3

4 Well, it is an older patient population. So, many of the patients die with MDS but not from MDS. They die from other geriatric related conditions. Secondly, about a quarter to a third of patients will go on to progress to acute myeloid leukemia. A few of those patients, the younger ones, may be able to receive intensive chemotherapy followed by stem cell transplant with a reasonable outcome, but for most patients, the life expectancy after such a transformation is only a few months at best. Patients with MDS are anemic and repeated transfusions lead to iron overload, and although the MDS is not often attributed to the congestive heart failure or the myocardial infraction or stroke that takes the patient s life, the anemia can be a contributing factor. The most common cause of non leukemogenic death in patients with MDS is infection resulting both from neutropenia and from neutrophil dysfunction. Number two is hemorrhage. Patients die either of a bleeding complication or of bleeding complicating some other problem, and finally, a small subset of patients, currently about 6%, with MDS in the United States and Western Europe will go on to get allogeneic stem cell transplant. Of them, about 30%, 2 out of 6, will be cured. About 15 20% will die of immediate short term complications such as infection. The others will either die from more chronic complications such as chronic graft versus host disease or from relapsed disease after transplant. So, as you can see, MDS in any of its forms is a dangerous disease. 4

5 However, when we are talking about which patients are at highest risk, we use prognostic tool such as this 2012 Revised International Prognostic Scoring System or the IPSS R. The IPSS R takes into account the patient s blast proportion in the marrow, the karyotype, and the number and depth of cytopenias to generate a score between 0 and 10 points. 5

6 That score is then transformed into one of five risk groups ranging from very low, where the median survival is just above 8 years, to the very highest risk where the median survival is less than 1 year. Collectively, patients with very low and low risk are referred to as lower risk. Those with high and very high risk are referred to as higher risk. The intermediate risk, we do not really have a good category for. The old IPSS was a little bit cleaner with respect to risk groups because there were four. So, the lower two were lower risk, the upper two were higher risk, but this introduction of a fifth category, intermediate, has made that classification of lower versus higher a little bit messier, and it may be that there are other disease features that will help us know which patients in this intermediate risk group are really at higher risk than the IPSS R would predict. Importantly, these figures for median survival are for patients managed primarily with supportive care, and disease modifying therapies, such as azacitidine or stem cell transplant,can modify the patient s outcomes. 6

7 One thing that we know is that somatic genetic mutations are important prognostic factors, independent of IPSS and IPSS R. These are routinely obtained now on patients with myelodysplastic syndromes. There are a number of companies and reference laboratories that provide genetic panels and next generation sequencing, and they are relatively inexpensive. In my own institution for instance, we can do a panel of 95 genes for about $800 which is cheaper than either karyotyping or the conventional hematopathology. One of our former fellows, Rafael Bejar, published 5 years ago in the New England Journal of Medicine that one of five mutations, TP53, ETV6, ASXL1, EZH2, or RUNX1, if present, effectively increases the patient risk group by one. So, for instance, the patient with IPSS intermediate 1 risk disease who has an ASXL1 mutation behaves more like a patient with IPSS intermediate 2 risk disease. 7

8 Rafael is now extending this analysis with collaborators in many countries in the hope of developing an IPSS Rm, a Molecular Prognostic Scoring System that takes into account both clinical and pathological variables and genetic mutation testing. 8

9 More than 3,500 patients have been accrued to this thus far. Follow up data are present on more than 3,000, and more than 1,000 have already undergone genetic sequencing. 9

10 Rafael has sequenced 17 genes in 1,996 patients to date and found that in a univariate analysis, 16 of them had adverse prognostic importance, whereas one, SF3B1, which is often linked with ring sideroblast morphology, was more favorable. 10

11 However in a multivariable analysis taking into account other IPSS risk factors, the SF3B1 remained favorable, but all but four of the other unfavorable mutations fell out. The p53 mutations are prognostically the highest risk in MDS followed by RUNX1, EZH2, and NRAS. The others did not have IPSS independent effects on prognosis. 11

12 So, what about treatment? 12

13 I made this slide in 2006 and have made very few changes since. The platelet growth factors which are an off label use are increasing in their utilization in myelodysplastic syndromes, but we have not had a new drug approval since May 2006 for MDS. Hopefully, in the near future, there will be another drug approved, but that agent, luspatercept, which is currently undergoing a registration trial is for lower risk disease and not higher risk. So, we have three drugs that have a specific MDS approval, azacitidine and decitabine, the DNA methyltransferase inhibitors, and we have the immunomodulatory drug lenalidomide which is approved for patients with lower risk disease and del(5q). Iron chelators are approved for transfusion related hemosiderosis which commonly occurs in MDS. The red cell growth factors are actually the most commonly used drugs, but they do not currently have a specific label for MDS. Their approval is in chemotherapy associated anemia, renal failure, and other indications. 13

14 The azacitidine 001 study showed that AZA is the only thing when compared with conventional care, such as best supportive care alone or low dose or high dose cytotoxic chemotherapy, improves survival. The median survival improvement was 9 months in patients who received azacitidine on the AZA 001 study. Importantly, control groups for other trials in a higher risk MDS have not had a median survival of 24 months or even of 15 months, and so, this study probably enrolled a patient subset who were a little bit lower risk than a typical high risk patient. For instance, patients on this trial had been diagnosed with MDS a median of 13 months before enrollment, which is different for other high risk studies. 14

15 In the decitabine D 0007 study, there was not a survival benefit, but those patients appeared to be higher risk as manifested by the median survival in the control group, which was only about 8months. There was a delay to leukemia progression in this patient cohort. 15

16 An algorithm for how patients with MDS are to be approached is seen here, which we published in Blood back in Many patients with MDS, especially those whose cytopenias are milder do not need treatment initially and can be observed for a period of time. However, when treatment is indicated, using a tool such as the IPSS R supplemented by molecular genetic testing allows us to divide patients into lower risk and higher risk disease. We will not talk about lower risk disease today, but that is a group of patients in which lenalidomide, growth factors, immunosuppressive therapy, and sometimes hypomethylating agents are used. In the higher risk patients, the key decision is whether or not patients are candidates for allogeneic stem cell transplant. For those who are candidates, mathematical modeling has shown that getting them two transplants as quickly as possible is beneficial. For those who are not transplant candidates or do not have a donor, this is where really the hypomethylating agents are important. However, as we saw from the azacitidine study with a 24 month median survival, these are not curative agents and eventually all patients will lose response or progress, and we do not have a well established second line therapy for higher risk MDS for whom hypomethylating agents have failed. There have been several attempts to improve the outcomes for patients with higher risk disease. For instance, one strategy is to add a second agent to azacitidine or decitabine and there have been a number of studies adding either deacetylase inhibitors or lenalidomide to azacitidine as upfront therapy for higher risk MDS. Unfortunately, all those studies have been negative. However, this strategy continues to be employed and studies are ongoing looking at Seattle Genetics vadastuximab, a CD33 antibody drug conjugate, and venectoclax or ABT 199, a BCL 2 modulator, in patients with higher risk disease, adding them to the hypomethylating agent backbone. Additionally, there are a number of studies that are adding checkpoint inhibitors to that backbone or adding checkpoint inhibitors or other agents such as the PI3 kinase modulator, rigosertib, as second line therapy, and those in general are the strategies that are being employed in patients with higher risk MDS. 16

17 As mentioned, however, we now have four different studies with HDAC inhibitors, entinostat, vorinostat, pracinostat, and a French study with valproic acid which is an antiepileptic that has weak deacetylase inhibitor activity, and all four of those showed more toxicity and no increase in efficacy in the combination arm compared with azacitidine alone. Two studies have shown that lenalidomide results in more toxicity when added to azacitidine, although there is a small subset of patients who can tolerate this combination, who may do a little bit better than if they got azacitidine alone, but in most patients, this is an unworkable combination. And finally, there was just a study reported of birinapant, a SMAC mimetic, and inhibitor of an inhibitor apoptosis, an industry sponsored study, azacitidine versus azacitidine plus birinapant, that too was a negative trial. 17

18 What about the hypomethylating agent plus venetoclax? Certainly, in acute myeloid leukemia, we saw very exciting data in only 22 patients, with a complete response rate or complete response rate with incomplete count recovery of over 70% with combination therapy; much better than we would expect to see with azacitidine alone. However, the study drug had to be interrupted more than half of the time due to cytopenias. 18

19 What about SGN CD33A or vadastuximab? This was given to patients with AML who were felt to be unfit for chemotherapy as an IV every 4 weeks on the last day of standard hypomethylating agent therapy. These were an older patient group, median age 77 years. There were lots of febrile neutropenia. There were a lot of grade 3 and 4 cytopenias, but 65% of the patients achieved CR or CRI. 19

20 This is a table describing the ongoing checkpoint inhibitor trials in MDS, as you can see both CTLA 4, PD 1, and PDL 1 targeting drugs are being used with either azacitidine or in the case of durvalumab with CC 486, which is oral decitabine. 20

21 We know that once azacitidine or decitabine failed the patient, the outlook is poor. In one study of more than 400 patients for whom azacitidine had failed, the median survival for the cohort was 5.6 months and only 15% of the patients lived for 2 years. A decitabine study from MD Anderson showed similar result. In 87 patients who were failed by decitabine, their median survival was 4.3 months 21

22 There is a subset of patients who after azacitidine fails are in good shape with a relatively good performance status and can go on to get either stem cell transplant or an investigational therapy, and they tend to do a little bit better than those who just get palliative care, but the overall outlook is pretty grim for these patients once azacitidine or decitabine failed. 22

23 Rigosertib, a PI3 kinase and Polo like kinase inhibitor is being compared with best supportive care alone. In a prior randomized trial, almost 300 patients received this drug as a 72 hour infusion with each cycle, 23

24 and patients were stratified by blast count, and as you can see, there was a slight trend toward improved survival on the rigosertib group, but not a statistically significant difference. Rigosertib is now being studied in a more rigorously defined population of very high risk patients for whom HMAs have failed. 24

25 What about other approaches? So, there is a new more intense hypomethylator, guadecitabine, or SGI 110, that is being studied in elderly or unfit patients with AML. There are targeted agents out there such as IDH1 and IDH2 inhibitors for the 5 10% of patients with high risk MDS who have IDH inhibitors. We are just about to start a targeted agent trial that is focused on splicing. Splicing is the most common category mutation in MDS, and so the results of this are awaited. And vosaroxin, a DNA damaging agent has been studied in both HMA failures and acute leukemia patients. If you do not have a trial option for a patient, most patients will be treated with supportive care. If the blast proportion is increasing progressively, some investigators find low dose cytarabine or clofarabine helpful, but they do not tend to work very long. A small subset of patients may be candidates for induction therapy followed by transplant, but that is a very limited group of patients. 25

26 What about transplant? Really you should be thinking about transplant in the potentially eligible population as soon as a diagnosis of higher risk MDS is made because eventually the HMA will fail the patient. Currently as mentioned, only about 6% of patients undergo transplant even though it is the only potentially curative therapy, but many patients worry about risk and about the changes in lifestyle that are necessary for a transplant. It is unclear how we should be using hypomethylating agents around the time of transplant. Perhaps by using them appropriately, we could augment the graft versus leukemia effect without increasing graft versus host effect. 26

27 Thank you for your attention today, and I hope that this has been helpful for caring for your patients with higher risk myelodysplastic syndromes, a really difficult set of diseases, and I thank my colleagues with whom I am able to collaborate here in Boston on care of these patients. I would like to thank you for viewing this activity, and for additional resources, please view some of the other educational activities on ManagingMDS.com. 27