Activity Transcript

Geoffrey L. Uy, MD: Hello, my name is Geoffrey Uy from Washington University School of Medicine. Welcome to this program titled Expert Recommendations for Treating Newly Diagnosed High-Risk AML. Joining me today are Ashley Leak Bryant from the University of North Carolina Chapel Hill, and Amanda Seddon from Rush University. Welcome.

Over the last 10 years, next generation DNA sequencing has really advanced our understanding of the biology of acute myeloid leukemia (AML). One of the advances is in the identification of recurrently mutated genes in the disease that both have a prognostic impact and are potential therapeutic targets. Over the last two and a half years, there have been 8 new agents approved by the FDA for the treatment of AML and, with these changes, it has become much more complicated to identify appropriate therapy for patients with newly diagnosed disease.

In 2016, the World Health Organization updated their classification of hematologic neoplasms to incorporate the latest advances in our understanding of clinical, prognostic, and genetic factors to enable us to identify and assign patients to biologically and clinically relevant categories. In the case of high-risk AML, these include patients with therapy-related AML. This is AML that rises after treatment with either cytotoxic chemotherapy or ionizing radiation and is often associated with high-risk genetic features, such as mutations in tumor protein p53 (TP53) and mixed lineage leukemia (MLL), and a worse overall prognosis.

In addition, there is a category which is termed AML with myelodysplastic syndrome (MDS)-related changes. These include patients with multilineage dysplasia, which is defined as dysplasia in ≥50% of cells in ≥2 cell lineages, or patients who have an antecedent hematologic disorder, such as a myeloproliferative neoplasm or MDS. Ashley, what other factors can affect the treatment decision, and what is the role of the nurse in this assessment of a newly diagnosed patient with AML?

Ashley Leak Bryant, PhD, RN-BC, OCN: The role of the nurse in caring for newly diagnosed patients with AML includes identifying the type and number of comorbidities this patient may have, which will help determine the care that is provided to these patients. Our role is also important in determining the performance status -- is the patient able to engage in activities of daily living, or do they need assistance? What is their psychosocial status? Do they have several underlying medical diagnoses, including mental illnesses, that have not been diagnosed? Do they have family? What is their living situation? What referrals are needed to ensure that these patients continue to get the care they need, and are they suitable for transplant?

Dr Uy: Amanda, what role does the pharmacist play at this stage?

Amanda N. Seddon, PharmD, BCPS, BCOP: The pharmacist plays an important role in reviewing the diagnosis and confirming pathology, especially once a treatment plan has been identified. Additionally, we often note any current medications and any medications that need to be discontinued because of a potential drug interaction with the chemotherapy agents or targeted therapy that we are selecting.

Supportive care is also very important in these patients. We help manage adverse effects (AEs) of the treatment that we have selected, identifying those AEs as well as the role of fertility preservation if it is needed.

Dr Uy: Let's talk through some cases to discuss treatment options in high-risk AML. Amanda, would you like to present the first case?

Dr Seddon: Our first patient is a 49-year-old female with a history of dry eye syndrome with status post intraocular lens prosthesis, and her only medication is acetaminophen as needed. She owns an engineering firm, is married, and has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0. She presented to our hospital with fatigue, petechiae and right leg pain. She had leukocytosis with a white blood cell (WBC) count of 135K, pancytopenia in all lineages, 27% blasts, and an elevated lactate dehydrogenase (LDH). She underwent leukapheresis and then also received hydroxyurea. The bone marrow (BM) biopsy came back consistent with AML with monocytic differentiation, and so we decided to start therapy with 7+3 while awaiting the genetic test results.

Dr Uy: For the last 45 years, standard induction chemotherapy with 7 days of cytarabine infusion and 3 days of anthracycline has been established as the standard of care in younger patients with AML. This produces complete remission (CR) in approximately 65 to 70% of patients. There have been numerous attempts to improve therapy such as escalating the dose of cytarabine or adding a third agent, but for the most part, except for a few selected cases, 7+3 as upfront induction therapy has remained the standard of care.

This patient presented acutely ill with a very high WBC count -- in this case, you really don't have the time to wait for either cytogenetic or molecular testing to obtain more information before you have to start therapy. It is certainly appropriate to stabilize the patient with either leukapheresis or hydroxyurea, but then they should probably start standard induction chemotherapy as soon as the diagnosis of AML is made.

Dr Seddon: Three days later, we received some testing results and found that the patient had normal cytogenetics and fms-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD)-positive AML with an allelic ratio of 0.6. The RATIFY trial established midostaurin as a FLT3 inhibitor that can be used in patients with a FLT3 positive mutation (either an internal tandem duplication or a tyrosine kinase domain mutation). It can be used for both mutations as both were included in the trial. The RATIFY trial randomized patients to receive the standard of care, 7+3, with either the addition of midostaurin or placebo. Midostaurin was added in the induction setting as well as in the consolidation setting, and patients also received maintenance therapy. We found that the addition of midostaurin to 7+3 therapy improved overall survival (OS) and event-free survival (EFS) in the induction and consolidation setting compared with patients who did not receive midostaurin.

Dr Uy: In patients with high-risk AML who are younger, a discussion of allogeneic hematopoietic stem cell transplant (HSCT) always comes up. Ashley, what is the role of nursing in the referral process and in considering whether patients are potentially candidates for HSCT?

Dr Bryant: The oncology nurse plays a huge role in this. I would say one of the primary roles in referring someone for transplantation would be in educating both the patient and the caregiver. There are 3 things that I think about -- education, preconditioning, and donor identification.

During the preconditioning phase -- initial screening, workup, and ensuring the patient understands the informed consent process as well as the logistics related to the time they will spend in the inpatient setting and the number of hospital visits they will have in the outpatient setting. Donor identification --determining if there is a family member that could potentially be a donor and, if not, identifying whether the patient needs to be placed on the transplant list. I would say ongoing education, before and even during the transplant.

Dr Uy: In terms of pharmacy considerations for the use of midostaurin, Amanda, are there specific things that practitioners should be aware of in terms of drug interactions or AEs?

Dr Seddon: You usually need to consider mold coverage with patients that are getting intensive induction chemotherapy, and most generally require more than fluconazole. Patients are often taking something like voriconazole or posaconazole; all of the azoles, as a class, have drug-drug interactions with midostaurin. The RATIFY trial was actually amended so that patients couldn't receive concomitant azole therapy.

The pharmacist plays a role in helping determine which antifungal agent the institution wants to use in patients taking midostaurin therapy. Additionally, patients often have nausea with this particular therapy, so keeping this in mind and providing supportive care for patients that are experiencing nausea or preventing nausea is much easier than having to treat vomiting.

Dr Uy: One important thing to note is that the adverse prognostic impact of FLT3-ITD seems to be eliminated by allogeneic HSCT in patients who receive a transplant in first complete remission (CR1). Some of the best results from the RATIFY trial occurred in patients who were randomized to the midostaurin arm and had received an allotransplant in CR1.

So, early transplant referral and involvement by nursing to help coordinate both the donor search and the patient pretesting are vitally important. It is also important to integrate the pharmacist to discuss the appropriate selection of antifungal agents and to help manage AEs.

When choosing your initial therapy, how might a potential transplant for the patient influence your choice of induction chemotherapy?

Dr Seddon: If the patient is a transplant candidate, we often like to start HLA typing early in the process to identify if they have family members that can be donors. When selecting an induction regimen, you want to make sure the patient has appropriate cardiac and renal function, and that you are not giving any medications that could potentially compromise those organs.

The patient will receive high-dose cytarabine (HiDAC) therapy with their induction treatment and potentially with any consolidation therapy they receive before their transplant. So, it is important to make sure we optimize their therapy with hydration and avoid nephrotoxic agents to ensure patients remain in good condition for an allogeneic HSCT.

Dr Uy: What are your thoughts on the use of gemtuzumab ozogamicin in the peritransplant period?

Dr Seddon: Gemtuzumab ozogamicin carries a risk of occlusive disease, otherwise known as sinusoidal obstruction syndrome (SOS). You may want to consider avoiding this agent in a transplant candidate since there is also a risk of SOS post-transplant.

Dr Uy: Why don't we go onto another case, and I'll go ahead and introduce this. This is a 68-year-old man with a history of diffuse large B-cell lymphoma (DLBCL). He was treated with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) × 6 cycles ~5 years ago. The patient has been complaining of fatigue and dyspnea on exertion for the past 3 months, and when he went to see his primary care physician, he was noted to be pancytopenic with an absolute neutrophil count (ANC) of 800, hemoglobin (Hgb) level of 9.8 g/dL, and platelet count of 23K. He was referred to an oncologist who performed a BM biopsy, which revealed AML with multilineage dysplasia with ~25% myeloblasts.

The case of an older adult with AML is one of the most challenging for oncologists. It is the area where there is the most controversy between oncologists, as to the most appropriate course of treatment, and is also the setting where we have the most treatment options. In contrast to the first patient who was acutely ill, had a very high WBC count, and needed immediate treatment, this patient presented with a more indolent course, which is very typical of patients with therapy-related AML.

In this situation, you actually have time to do the BM biopsy and potentially wait 1-2 weeks to receive both the molecular and cytogenetic testing results to help better guide your treatment decisions. That is exactly what happened in this case. Treatment was delayed until both cytogenetic and molecular testing was back. The testing results showed that the patient had a normal karyotype (46, XY) and had mutations in DNMT3A, which is common in older adults and also in patients with MDS-related changes. The FLT3 mutational analysis did not show any mutations; the patient was FLT3 wild type.

There are multiple treatment options available for this patient that are FDA approved. They include intensive chemotherapy (IC) options such as CPX-351, which is a liposomal formulation of cytarabine and daunorubicin in a 5:1 ratio. It also includes the addition of gemtuzumab ozogamicin to standard 7+3 therapy, which was shown in a French randomized study to have improved EFS in the subcategory of patients aged 50 to 70 years.

For lower intensity treatments, venetoclax plus hypomethylating agents (HMAs) or low-dose cytarabine (LDAC) plus glasdegib is approved for older adults not fit for IC or >75 years. Ashley, do you want to discuss what role the nurse can play and how shared treatment decisions between the patient, their family, and the physician come into play when we talk about the choice of intensive vs non-intensive treatment options?

Dr Bryant: Shared decision-making is really important. It means making sure the patient fully understands their treatment and any potential AEs they may experience and assuring them that they are receiving the best care possible. It also means managing symptoms from the time they are diagnosed throughout their hospitalization and illness trajectory. Management of their symptoms such as nausea and vomiting, addressing their psychosocial needs, and ensuring we are asking them these questions, not just once during the shift, but in an ongoing manner, are all essential.

Dr Uy: In this case, after discussion with the patient and his family, they decided that they wanted to be very aggressive with his therapy, so they were offered induction chemotherapy with CPX-351. As I mentioned, this is a liposomal formulation of cytarabine and daunorubicin. In a randomized phase III study, CPX-351 was compared to standard 7+3 (cytarabine plus daunorubicin), and CPX-351 demonstrated superior OS.

Very similar to the RATIFY study, the patients who seemed to do the best were those who underwent allogeneic HSCT in CR1 after receiving CPX-351 induction chemotherapy. Amanda, what are some of the AEs and pharmacy considerations when administering either CPX-351 or standard 7+3?

Dr Seddon: Patients tend to have a little bit longer count recovery with CPX-351 vs 7+3; they tend to be pancytopenic for a bit longer. It is important to consider appropriate antifungal and antibacterial coverage for that time period. Patients receiving either CPX-351 or 7+3 are at risk for neutropenic fevers, so we closely monitor for this and have a key role in terms of helping select appropriate antimicrobial therapy.

Mucositis can be a problem for these patients with either CPX-351 or 7+3, although it seems to be a little worse with 7+3. The randomized trial did show higher rates of bleeding with CPX-351, though I do not particularly see this in my clinical practice. These are a few of the side effects that we are always monitoring for in patients receiving these therapies.

Dr Uy: What is the relevance of the patient's prior history of lymphoma and prior treatment with R-CHOP?

Dr Seddon: Before even selecting an initial therapy, this would definitely be a consideration. It is important to identify the dose that the patient received and their cumulative lifetime dose of anthracycline exposure, especially given the plan to use those agents. The liposomal formulation of daunorubicin within CPX-351 will suggest that there may be less cardiotoxicity compared with the non-liposomal daunorubicin formulation. However, identifying cumulative lifetime dose is important considering that your next line of therapy will likely contain that anthracycline.

Dr Uy: Are there any specific issues that nurses should be aware of and should know to discuss with the patient about CPX-351?

Dr Bryant: With the longer count recovery period that Amanda mentioned, I think about falls and safety. With decreased platelet count, lower WBC count, ANC, patients are at a greater risk for falls with injuries. Nurses should ensure that patients are fully aware that they need to use the call bell when in the hospital for assistance to get back and forth to the bathroom. There is also a risk of becoming very deconditioned. Working with physical therapists and occupational therapists to ensure that the patient maintains their mobility, particularly in older adults, is important.

Oftentimes, we think of chronological age, but biological age is also important to consider. As you know, we have seen some older adults who do fairly well compared to someone who may be chronologically younger. In general, though, those are the additional considerations that we must be mindful of to ensure that the patient remains safe and that we can get them out of the hospital and back to their home environment.

Dr Uy: What if this patient, instead of having normal karyotype and an isolated DNMT3A mutation, instead has a complex karyotype with TP53 mutations, abnormalities of chromosomes 5 and 7, and the patient is not interested in being in the hospital for 4-5 weeks to receive induction chemotherapy. Amanda, do you want to discuss some of the potential treatment options for this patient?

Dr Seddon: Yes. If they are not interested in being admitted, which is something I can imagine, they could easily receive outpatient therapy. This is where some of our HMAs plus venetoclax can come into play. Either decitabine or 5-azacitidine are given in the outpatient clinic and can be combined with venetoclax, which is an oral drug, which is great for our patients. The other option would be LDAC. The only problem with LDAC is that it requires a subcutaneous injection. Although this sounds really great for patients, it is given twice a day, which may not necessarily be ideal. In particular, older patients who do not have a family member or caregiver to help may find administration of a subcutaneous injection very difficult.

Dr Uy: Ashley, have you encountered any challenges in administering LDAC to your patients? Is that something that's routinely done at your institution?

Dr Bryant: Transportation back and forth is something that we have to be mindful of. Also, we should ensure they have spoken with a financial counselor or case manager to see if there is someone who could help them with these outpatient visits. Geoff, let's say this patient's results came back as complex karyotype with a TP53 mutation. What would be some of the treatment options now?

Dr Uy: Management of older adults with TP53 mutations is one of the most difficult challenges in AML. We know that with standard intensive approaches, such as 7+3 and maybe even CPX351, these patients tend to be resistant to conventional cytotoxic chemotherapy. Any remissions that are attained tend to be of relatively limited duration, and relapses and resistant disease are usually the norm. Even with allogeneic transplant, patients with TP53 mutations often still do very poorly and have relapses of their disease. For these patients, I often consider low-intensity approaches. For many years, these have revolved around either the use of HMAs (azacitidine or decitabine) or LDAC. More recently, these agents have been combined with the BCL-2 inhibitor venetoclax.

A phase 1/2 study looked at the combination of venetoclax with either azacitidine or decitabine in older patients with AML or those judged to be not fit for IC. In this study, the combination of a hypoomethylating agent plus venetoclax showed response rates in the ~60% range, with median OS approaching 18 months. These outcomes are ~6 months longer and 20 percentage points higher than what we typically see with HMAs alone.

In many parts of the United States, this approach has really taken over as the de facto standard of care for older adults with AML. In Europe and in other parts of the world where HMAs are not used as commonly for the upfront treatment of AML, they commonly use LDAC. In a similar phase 1/2 study, venetoclax was combined with LDAC and did show very promising remission rates, duration of remission, and OS that appeared to be much better than historical controls with LDAC alone.

At our institution in St. Louis, we encounter difficulties with administering LDAC in that the most commonly used regimen is 10 mg administered twice daily for 10 days in a row. We have encountered regulatory hurdles that home health agencies do not want to deal with administering chemotherapy or do not have the proper certifications. As a result, for the most part, since we know that HMAs are not inferior to LDAC, this has really become the de facto standard of care.

The other treatment option that is also approved in this patient population is the hedgehog inhibitor, glasdegib. The addition of glasdegib to LDAC has shown an OS benefit over LDAC alone. The issue with glasdegib is that it has only been studied with LDAC and not with HMAs. Until we receive more data about that, the use and adoption of glasdegib in the treatment of AML is not likely to really take off.

Amanda, for patients treated with HMAs and venetoclax, are there any specific precautions or drug interactions that physicians, nurses, and patients need to be aware of?

Dr Seddon: We know from the chronic lymphocytic leukemia (CLL) data that venetoclax can cause tumor lysis syndrome (TLS). Since we were aware of this, in the AML study with venetoclax and HMAs, patients were already started on allopurinol and receiving hydration. Patients in that study were all admitted, so they were already in the hospital and were carefully monitored. I do not necessarily think that means all patients need to be admitted and monitored for TLS, but I think they should be aware of what types of things to look out for at home.

If they are going to receive HMAs with venetoclax as outpatients, they should certainly make sure they increase their fluid intake while at home. When they receive the HMA, they can get additional fluid boluses to try to be preemptive about preventing TLS. Making sure patients are taking allopurinol at home, if they are able to, is also important.

Dr Uy: Ashley, are there any things that nurses can look at to help patients decide whether they may be better suited to be treated as an inpatient vs as an outpatient?

Dr Bryant: I would go back to the performance status -- how fit are they? Do they have caregiver support at home? What is their preference, what do they desire? Do they want to be closely monitored within the hospital or be at home and have someone there with them? I think those are the considerations. You have the other factors too. I think it goes back to transportation. Are they going to have to travel in every day for this? How often are they going to come to clinic -- is it 2 days a week, 3 days a week? And you have to ensure that they understand they must keep their appointments for them to have their lab work closely monitored.

Dr Seddon: I think those are great points that you bring up, Ashley. Educating patients and their caregivers on the therapy that they are going to be receiving is very important so that they monitor and alert their providers of potential AEs that they see. That education can be done by the pharmacist, by nurses, as well as by the oncologists and hematology/oncology fellows. Education is key for our patients to successfully and safely get through their chemotherapy.

Dr Uy: In the first part of our discussion, we talked exclusively about induction chemotherapy and selecting the appropriate therapy. What do we do with the patient now that they have achieved a CR? How do we decide whether a patient should undergo an allogeneic HSCT, standard consolidation with cytarabine, or continue their HMA with venetoclax?

We know for younger patients that HiDAC has proven to be effective, particularly in patients with good risk cytogenetics -- the core binding factor leukemias, inv(16)s and t(8;21)s. HiDAC given at a dose between 1.5 and 3 g/m² twice a day for 6 doses has been established as the standard of care. For patients who are older or who do not have good risk cytogenetics, the dose of cytarabine is less clear. Amanda, what are some of the considerations when selecting the right dose of cytarabine for use in consolidation?

Dr Bryant: Kidney function plays a huge role in determining what dose you are going to use, in addition to age. We know that cerebellar toxicity is a notable toxicity of HiDAC and, in very old data, 3 risk factors were identified that put patients at a higher risk for developing this toxicity. Age, renal function and, interestingly, an alkaline phosphatase elevation.

Identifying these risk factors in patients will help us determine which dose we need. So, measuring their creatinine clearance and then determining the appropriate dose reduction, whether it be 1.5 g/m² or maybe 2 g/m² in someone with much better renal function.

Dr Uy: Ashley, what are the typical supportive care procedures or interventions that need be done in patients receiving cytarabine as consolidation?

Dr Bryant: For nursing, one key element is continual and thorough assessment, particularly with cerebellar toxicity. We do these each shift to ensure that there is no nystagmus, unsteady gait, or anything else that seems to be concerning. Continuously check their lab work (once a day), particularly when they are in the hospital. See if they need any blood transfusions, which they usually do not and, if so, it is near the end of their therapy. Ensure that they have the support of their family. Encourage them to walk around -- oftentimes, they get their therapy on days 1, 3, and 6 so, when they have days off, we encourage them to get out of their room, connect with others, and become more active.

Dr Uy: After patients are discharged from the hospital, what sort of interventions are typically done for patients in terms of scheduled visits, lab draws, prophylactic medications, etc?

Dr Seddon: We expect patients to become myelosuppressed or have some degree of myelosuppression post consolidation. Patients should follow up with their oncologist in the clinic as well as get routine lab work done. Check CBC at least weekly but, in some cases, you may want to do twice a week or more frequently depending on the patient's age and some other risk factors, such as how well their bone marrow reserve may be.

Additionally, because we expect them to have some degree of neutropenia, identifying patients and making sure they have antiviral prophylaxis (eg, acyclovir), as well as antifungal prophylaxis, is important. In the case of consolidation chemotherapy, fluconazole is often what we use at our institution because the degree and duration of neutropenia is not as long as it is in induction. You can also consider bacterial prophylaxis during neutropenic episodes if your institution uses it.

Dr Uy: We know that for many high-risk patients cytarabine alone is not sufficient to keep them in remission and potentially cure them. So, patients that are considered fit for allogeneic transplant and are appropriate candidates are offered a transplant. What sort of considerations from a nursing standpoint are there during this period, and what happens when patients are being worked up for a transplant?

Dr Bryant: As I mentioned earlier, it is key to make sure that the patient understands why they are getting the transplant. We know that transplant is curative therapy, so ensure that they fully understand the informed consent process, the impact it is going to have on their family, and that they are going to be in the hospital for a long period of time. There are also outpatient transplants that are happening.

The other consideration is symptom management from the very beginning. Ensuring that patients are doing saline rinses 3-4 times per day to get their mucositis under control. Making sure they are moving as much as they can in their room, so they do not become deconditioned. And getting physical therapy (PT), occupational therapy (OT), and even recreational therapy involved to not only ensure they have movement but also for their mental health. Nursing takes a more holistic approach -- ensuring that we are taking care of the person's physical, emotional, and even spiritual needs while they are in the hospital for an extended length of time. Nursing is essential in the care of these patients.

Dr Uy: You mentioned other members of the care team, including PT and OT. How important are their roles, and what other ancillary care providers are usually involved in treating patients with leukemia? What do you think is their importance?

Dr Bryant: They all bring something very valuable to the team. Oftentimes, physical therapists and occupational therapists are underutilized. We call them after someone falls or when they are getting ready to be discharged and sent home. We really need to get them involved from the very beginning, when a patient is admitted, because we know they will decline OT.

When talking about spiritual care, getting the chaplain involved, and not just when the patient is admitted to the hospital but throughout their stay, to see if any changes have occurred in which they need some spiritual support. Consider the case worker, case manager, or social worker to ensure that the patient’s needs are being taken care of at home. Those are the key interdisciplinary team members who are often not included or included after the fact.

Dr Seddon: A dietician is also important because, as the length of the hospital admission increases and especially when patients are myelosuppressed, neutropenic, and anemic, they tend to eat less and stay in their room more because of their fatigue. The dietician can provide ways to manage some of the side effects of chemotherapy, such as the dull taste of food and food not tasting the same as it used to. They help encourage nutrition and provide nutritional support during these long and lengthy admissions.

Dr Uy: This was a very informative and useful discussion. There are a couple of key take home messages from our talk today. AML is a heterogeneous disease. Upfront recognition of both clinical and genetic risk factors is important in identifying the right patient for the right treatment. We have much more information today than we used to, in terms of which patients may benefit from which therapies. It takes a multidisciplinary team, involving physicians, nurses, and pharmacists that work in coordination with other providers such as physical therapists, occupational therapists, and dieticians, to choose the appropriate care after discussing with the patient and their family. I want to thank Ashley and Amanda for participating in this activity. And thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This transcript has been edited for style and clarity.