Maintaining Long-Term Efficacy in the Elderly MDS Patient with Poor Performance Status

Transcription

1 Hi, my name is Dr. Hetty Carraway. I am a staff physician at the Taussig Cancer Institute at the Cleveland Clinic. Welcome to Managing MDS. 1

2 As you all are aware, many of our patients with MDS are in an older age bracket. Here we see age-related incidence of MDS with median age in the area between 70 and 75 years of age. 2

3 In our patients that are diagnosed with MDS, we often try to establish treatment goals. For those patients with low risk or intermediate-1 IPSS scoring systems, the treatment goals can be distinct from those patients that have high-risk MDS. In those patients that are high-risk MDS, we typically try to stabilize marrow function, lower the risk of transformation to AML, and move to definitive therapy. For many of those patients, we hope that we can move to transplant, but in the patients that are over the age of 75, we have limited ability to offer that such therapy. 3

4 There are FDA-approved medications for patients with MDS, and those include hypomethylating therapies (HMT) including azacytidine and deoxyazacytidine, agents that are immunomodulatory agents such as lenalidomide and iron chelators that are used for patients with low-risk MDS. There are other medications that are also approved for other indications such as growth factors including G-CSF, Nplate, Promacta, and even EPO. Immunosuppressive therapy, thalidomide and high-dose chemotherapy as well as transplant can often be offered to our patients with MDS but are of limited utility in our patients that are elderly. 4

5 Here we see the age-specific SEER incidence rates for all races, both sexes from the years 2000 to We can appreciate that over 70% of our patients that are diagnosed with MDS are over the age of 70, and for that reason, the majority of our patients are looking towards using agents such as hypomethylating therapies. 5

6 Epigenetic therapies include both azacitidine and decitabine. Today, we will talk a little bit more about how to administer these agents and how to get our patients through these therapies with limited toxicities. 6

7 As you all are aware, azacitidine is used and indicated for patients with high-risk MDS, and the FDA-approved recommended dose is 75 mg/m 2 per day subcutaneous or IV for 7 days. There are number of alternative schedules that are examined, including the same dose for 5 days with 2 days off and then the remaining 2 days, or 50 mg/m 2 for 5 days for 2 weeks in a row skipping the weekend, or 75 mg/m 2 each day for 5 days alone. Three regimens were compared, and their overall hematologic improvement was similar to that of 7 days of therapy and was similar amongst those regimens, but this study was not designed for statistical significance and should be used with caution, although it is not infrequent that these regimens are used. 7

8 Similarly, decitabine was also FDA approved for patients with MDS of all subtypes based on phase 3 data comparing decitabine to best supportive care. The initial dosing that was used for these patients was 15 mg/m 2 IV every 8 hours for 3 days, and 30% of decitabine-treated patients had CR, PR, and hematologic improvement. Other alternative dosing regimens include 20 mg/m 2 per day IV for 5 days based upon phase 2 data, and it demonstrates overall response rates that are comparable to other dosing regimens to the tune of 46-73%. Interestingly, and as we will talk about in the next number of slides, the data for patients that received this therapy failed to demonstrate a survival benefit but used 15 mg/m 2 every 8 hours for 3 days. Current practice guidelines used decitabine relatively interchangeably with 5-azacytidine. 8

9 In general, what to expect with both of these agents is that we give them every 28 days or once a month, azacitidine typically over 7 days and decitabine over 5 days. In general, we plan to administer at least 4 to 6 cycles for our patients, and the typical side effects that we often will see in our patients are nausea, vomiting hematologic toxicities such as a decrease in the white count, anemia, and thrombocytopenia, as well as fatigue and onset of occasional fevers and infections. Side effects are manageable and often some of our patients require antibiotics, antiemetics, as well as transfusion support. 9

10 When we talk about supportive care, there are some considerations that we should be thinking about, particularly in our patients that are older. Where some of our patients that have been neutropenic for some time because of their disease favor using antimicrobials in the context of treating them before they start or embark on chemotherapy. For example, we will give preventative antibiotics including acyclovir and ciprofloxacin on occasion, and for some of those patients that have had profound neutropenia for a long period of time we consider using antifungals like fluconazole or voriconazole. The side effects to these medications are not negligible, particularly in our patients that may have issues with antifungals. So, we have to be considerate when we think about the comorbidities in our patient population. Specifically for voriconazole, patients can have hallucinations and our older patients may not tolerate that very well. So, it is important for us to know what medications we might be adding and as a result what toxicities may also be encountered. In terms of antiemetics, we often want to use agents that are not sedating so that our older patients are not having issues with ambulation or decreased activity. This can already be an issue for them, so choosing antiemetics that are not sedating may be an important thing to consider. Furthermore, there are antiemetics that can prolong QTC in our older population, this may be an important thing to be mindful of. Many of our patients have issues with anorexia when they get chemotherapy, and for some of our patients that have profound issues with this and cannot drink enough on their own, for some period of time, it is important to consider IV hydration or even nutritional supplements given anorexia that occurs with chemotherapy. Transfusion support is very common for our patients that are getting this chemotherapy, and in our older population, it is important for us to consider the addition of furosemide in the posttransfusion setting if our patients have decreased cardiac function or issues with fluid overload. 10

11 When we think about the data that were generated by Lewis Silverman in the CALGB 9221 study, this was a very important and relevant study when we looked at patients that were diagnosed with MDS. 11

12 The patients were randomized to either supportive care or receiving azacitidine, and patients actually were monitored over the duration of the study for quality of life. Patients on the observation arm or the supportive care arm were able to cross over to receive azacitidine, and when we looked at the outcome of this randomized phase 3 study, we were able to appreciate that there was a delayed progression to leukemia in those patients that were receiving azacitidine. Those patients that had received azacitidine had a median time to progression to leukemia of 21 months compared to those patients that received supportive care, which was 12 months, and this was statistically significant. 12

13 It should be highlighted, particularly for our patients that are older is that patients did show, and this paper supported that there was an improvement in the quality of life. Specifically, there was an improvement in patients with regard to physical function, improvement in physical function, specifically a decrease in fatigue and a decrease in their dyspnea. These were so meaningful that this also added to the data to support the approval of azacitidine and move it forward for FDA approval. 13

14 To summarize, azacitidine did improve, fatigue, dyspnea, improved physical function, positive affect, as well as psychological distress. Importantly, 45% of the patients became transfusion independent, and 9% had a 50% reduction in transfusions. 14

15 Approval of azacitidine led to further investigations including this study that was done by Pierre Fenaux comparing patients that were diagnosed with high-risk MDS, and they would receive either azacitidine compared to patients that would be enrolled in conventional care regimen (CCR). The conventional care regimen was included as either best supportive care (BSC), low-dose Ara-C (LDAC), or standard chemotherapy. 15

16 Important piece to this study is that those patients that received azacitidine versus those patients that received conventional care regimen had an improvement in overall survival of 9.4 months. 16

17 A subset analysis or unplanned analysis that was performed looked at our older patients over the age of 75 that were also enrolled in the study. This evaluation by John Seymour shows us that those patients that were in this age range over the age of 75 actually also had an improvement in overall survival. I think this is an important piece of data that we should share with our patients that are in that age range in questioning whether or not they would truly benefit from azacitidine. 17

18 Additional work was done with the agent decitabine mimicking the study design that was done by Pierre Fenaux comparing decitabine versus best supportive care, and patients were randomized to one arm versus the other. 18

19 Unfortunately in this study, overall survival was not demonstrated when decitabine was compared with supportive care. However, there was a median time to AML or death was 12 months in the decitabine arm versus 7.8 months in the supportive care arm. 19

20 When we think about delivering these agents, we also have to think about the comorbidities that our patients have. Age is not the best predictor of this, and we often look to things like performance status to help us determine how well a patient will do in the context of chemotherapy. Other comorbidities to be mindful of include cardiac history, such as hypertension, coronary artery disease, and it is not uncommon for our patients to have arrhythmias that are induced because of dehydration or because of supportive medications to help them through chemotherapy or even supportive transfusions. Being mindful of their cardiac function and their ejection fraction can also help in the management of getting them through these therapies. Their pulmonary function comes into play if they have a history of COPD or asthma or if they are actively smoking. These patients I worry more about and I am more liberal in giving them preventative antibiotics such as ciprofloxacin. Furthermore, patients that have issues with renal function, whether it is chronic renal insufficiency or acute renal failure, are patients that we tend to be careful about with regard fluid overload and transfusions. Data support that patients with issues with creatinine with a higher creatinine or decreased creatinine clearance can still tolerate these medications as long as we monitor them carefully. And some of us favor using decitabine in that context as compared to azacitidine. Rheumatologic or orthopedic issues are not unfamiliar to our patients given that they have often arthritic conditions and sometimes a need for prednisone, which further causes immunosuppression. When we talk about their infection history, this helps us to use preventative antibiotics in a way that may be meaningful to help manage or prevent any further infectious complications. For our patients that are over the age of 65, I typically will vaccinate my patients and make sure they have gotten the flu shot annually and keep their other vaccinations up-to-date, particularly their pneumonia vaccines, pneumococcal vaccines. 20

21 Dr. Santini actually evaluated the most common adverse events that were seen in the azacitidine study, the Lewis Silverman CALGB study in addition to the Pierre Fenaux AZA-001 study. In reviewing the adverse events for each of the cohorts, here she demonstrates that patients were able to experience or did experience toxicities in both the AZA-001 study and the CALGB Majority of the toxicities that were appreciated were hematologic toxicities such as anemia, neutropenia, and thrombocytopenia. In addition, other adverse events included diarrhea, constipation, nausea, vomiting, and fatigue. There were some patients that complained of injection site reactions or even fevers, and we can talk a little bit more about how those were managed. 21

22 Again, the most common toxicities that were appreciated in both of those studies included the hematologic cytopenias, injection site reactions, GI distress whether it is nausea, vomiting, constipation, or diarrhea, and greater than 83% of these adverse events were resolved during ongoing therapy. In general, the hematologic adverse events were most frequently observed during early treatment cycles and decreased during subsequent cycles and were usually managed with dosing delays, and this happened in about 25% of the patients. 22

23 What have we learned about hypomethylating therapy or DNA methyltransferase inhibitors? We have learned that responses are slow in our patients and the median number of cycles to any response is 2 cycles. In general, 91% of responses occur by cycle 6, and that responses may increase with continued therapy, and it is important to keep our patients on therapy as long as they are tolerating it. The responses are associated with improved survival. We see that in the decitabine study where responders to drug had improved survival, and the AZA-001 study showed that there was an interaction of hematologic improvement with overall survival. We know that elderly patients can tolerate this therapy. Eighty-seven patients that were treated on the AZA-001 study that were over the age of 75 did show that there was an improvement in their overall survival. Additionally, in the data that came out of the CALGB study, we know that there is an improvement in quality of life for those patients that are on azacitidine compared to best supportive care. 23

24 One of the things that I also wanted to step into was to talk a little bit about how can we improve the epigenetic therapy or the responses to this therapy, and sometimes we need to consider increasing the dose of the therapy if patients are not responding. This is also included in the package insert for azacitidine, and if patients are tolerating the therapy but not responding to the optimal way, it is reasonable to consider increasing the dose. More often though, we are worried about the cytopenias and the side effects for our older patients. So, it is also important for us to consider dose reduction in order to keep them on therapy rather than delay it too long. There has been lots of discussion about combination therapy, and logical combinations include the addition of vorinostat or other immunomodulatory agents such as lenalidomide or PDL-1 inhibitors. Furthermore, as we looked toward the future, we are trying to identify which patients may respond best to these therapies by looking at their molecular mutation profile, what specific mutations help us predict or identify who will more likely benefit from this therapy or who should be spared from this therapy as they will not benefit from it. So, we are beginning to better understand these populations and hopefully will be able to select the best therapy for our patients in the future. 24

25 When we look at combination therapy in our patients with MDS and AML, I highlighted two of the studies, one by Dr. Sekeres and another one by Dr. Silverman that added the addition of lenalidomide and vorinostat. You can see here that CR and overall response rates are higher compared to single agent or other added agents in comparison. The overall response rate is in the range of 70% for both these studies. Additionally, I highlighted another study that was led by Dr. Garcia-Manero looking at patients that were unfit for clinical trial, and those patients actually were able to tolerate combination therapy with the addition of vorinostat to azacitidine and still had a meaningful response rate in the range of 40%. 25

26 When we think about adding additional drugs to azacytidine or deoxyazacytidine, we worry about the added toxicities that you might incur with the combination therapy. This study led by Dr. Sekeres S1117 was actually presented at ASH last year as well as this year. In this study for higher-risk patients with MDS, patients received either 5-azacytidine alone, 5-azacytidine plus lenalidomide, or 5- azacytidine plus vorinostat. 26

27 In general, as we look at the patient characteristics, you can appreciate that the median age was about 70 or 71, depending on which arm, and the majority of patients had baseline white count that was similar in each of the arms as well as a low platelet count and a low baseline blast percentage under 10%. 27

28 When we look at the patients with regard to their IPSS scoring system, the majority of these patients were intermediate-2 or higher, and about 50% or higher were transfusion dependent 28

29 When we look at the responses in the S1117 study, we are able to appreciate that those patients that received azacitidine alone their overall response was similar to those patients that received azacitidine plus lenalidomide versus azacitidine plus vorinostat. There was no statistical difference between any of the arms with regard to overall response rate, CR, PR, HI, or relapse-free survival. When we looked at patients that were on therapy greater than 6 months, there was also no appreciable or statistical difference between those groups. 29

30 One of the reasons why I wanted to highlight this study is because I wanted to evaluate and review the grade greater than grade 3 toxicities in this patient population and point out that azacitidine was fairly well tolerated in this patient population. There were 10 cases of febrile neutropenia, four cases of GI toxicity greater than grade 3, and two greater than grade 3 issues with rash. Not surprisingly, those toxicities were higher in those patients with regard to rash in those patients that received lenalidomide, and there were a higher number of toxicities with GI toxicity specifically for those patients that had AZA plus vorinostat. Interestingly, there were patients that ended up coming off therapy due to these toxicities to the tune of almost 25% in the combination arms compared to 9% in those patients that were getting single-agent therapy. This is important because, as we have discussed, it is important for our patients to remain on therapy in order to obtain a benefit, and I think that is one of the more important take-home messages is to try to keep your patients on therapy and even if they have to incur a dose reduction. Combination therapies were added to non-protocol-defined dose modifications, and that was somewhat frustrating but telling that patients and physicians were uncomfortable in keeping patients on combination therapy. This began as one of the reasons why it is important for us to become better at managing the toxicities for our patients, and it may be that we can improve therapies if we can keep them on therapy, whether it is single agent or combination therapy, but we need to be able to better manage the toxicities with single agent as well as combination. Again here, I would like to point out that the non-protocol defined dose modifications happened in about 25% of patients, and this is similar to some of the reports that we reviewed with Dr. Santini in the prior slides. I think with improved management of toxicities for our patients we will ultimately be able to improve the response rates for our patients whether independent of their age, whether they are young or old. 30

31 Again, the response rates in this study I highlighted earlier are no different from single-agent to combination therapy. There is an interesting response in patients with CMML that I will not go into further here. 31

32 In general, recommendations for hypomethylating therapy is that early declaration of failure may be a mistake as responses can be seen after cycle 6. Continuous dosing is recommended as long as patients are responding and stable on therapy. Drug holidays in general are not recommended as patients who have progressed are less likely to respond when rechallenged with the drug, and dose reductions are favored for patients on long-term treatment who develop cytopenias versus prolonged dosing intervals. 32

33 In conclusion, I hope some of the lessons and take-home messages include that epigenetic agents are effective for some but do not cure MDS. That we need to optimize epigenetic therapy by keeping our patients on therapy even if they need a dose reduction. Preventative antibiotics may have a role for elderly patients especially if they have comorbid illnesses such as COPD and prior infections. Epigenetic agents have shown improvement in quality of life in all of the patients that were on the studies, specifically the CALGB study led by Lewis Silverman, and that toxicities in our patients receiving these agents are manageable. 33