Steph’s Note: This week, we’re leaning into our tl;dr love of journal club with a discussion about a pretty groundbreaking oncology trial published in NEJM in December 2020. And here to teach us is Nate Ramsbacher, the volunteer who enthusiastically brought this topic to our attention. (His excitement got us excited because we always get excited when someone is excited about journal club. #alltheexcitement)

Nate is a current P4 student at the University of Montana - Skaggs School of Pharmacy. He’s passionate about oncology pharmacy, medical communications, and clinical research for oncology and immune-related disorders. Next year, he hopes to start a residency or fellowship in an oncology-related direction, and after that, he would like to pursue a career in clinical pharmacy, medical/drug information, and/or clinical research.

Oncology pharmacotherapy doesn’t HAVE to be your Mount Everest….you just need the right sherpa to guide you! (Image)

Whether you’re a student, tech, or pharmacist (or any other healthcare hero for that matter), there’s no doubt that you know at least one patient in your practice with cancer. For most of us in the non-oncology world, cancer treatment seems overwhelmingly complex - and it is! But who said it had to be an insurmountable knowledge wall? (Not tl;dr - check out this post for a useful overview of cancer therapy). Also, who said it had to be boring?

Luckily, azacitidine (Onureg), our star of the evening and the center of the QUAZAR-AML-001 trial, will largely be handled by our specialty pharmacist colleagues. Even so, healthcare providers in more fields than just oncology should really know more about this game changing medication. Plus, the increasing rate of approval for new oral cancer medications continues to grow exponentially every year.

For illustrative purposes, according to the National Community Oncology Dispensing Association (NCODA), oral chemo meds were only 7% of all total cancer medications in 2000, compared to a whopping 39% in 2018. (Also, FYI, NCODA is an AWESOME resource for all things oncology pharmacy!)

So why not start expanding your horizons into the specialty and oncology pharmacy realms right now? And what better place to learn about a new oral chemotherapy and its clinical trial than your tl;dr Pharmacy Journal Club?? Let’s get right into it!

The Basics of Acute Myeloid Leukemia (AML)

If you read tl;dr’s previous post on pediatric ALL, consider this a semi-related refresher (and if you haven’t, you should, if only to compare and contrast some pathophysiology).

So let’s start with the basics: leukemia. You’ve probably heard of it. You may have even helped care for patients that have it. But do you know where it comes from?

Here’s a ridiculously good (and relatively quick 10 minute) video to help simplify the differences between the 3 main types of blood cancers: lymphoma, myeloma, and leukemia.

Acute myeloid leukemia (AML) develops from dysregulation and uninhibited proliferation of myeloid stem cells, or myeloid blasts. Myeloid blasts are usually the precursors to red blood cells, platelets, eosinophils, neutrophils, and macrophages. AML mostly affects older people over age 60, of which many do not achieve complete remission and/or they have relapses.

There a number of genetic abnormalities associated with AML with one of the most prominent being Down Syndrome. Genetic abnormalities may play a large part in deciding which treatment might be most important for each patient since different mutations confer either favorable, intermediate, or poor risk categories according to the NCCN guideline on AML.

Treatment for AML mostly consists of chemotherapy and stem cell transplantation, with chemotherapy having two main phases - induction and consolidation. The induction phase provides the big guns of AML treatment with the goal of producing complete remission for the patient. Induction therapy is based on how favorable a person’s genetics are, which determines how intense the therapy may be.

The next phase is consolidation, during which a patient receives chemotherapy to kill any remaining cancer cells left after the induction phase.

The third phase of treatment is the maintenance phase, which is used to prevent recurrence. Maintenance therapy can last for years and is used to improve Overall Survival (OS) after achieving complete response - which brings us to azacitidine (Onureg).

What is Onureg (azacitidine)?

Onureg is the oral formulation of azacitidine, an analog of the DNA nucleoside cytosine. Azacitidine is a hypomethylating agent (HMA). It works by incorporating itself into DNA/RNA during the S phase of cell division and blocking the activity of DNA methyltransferase (DNMT). Blocking this enzyme prevents DNA/RNA synthesis, which leads to cell death.

Taking you back to high school biology for a hot minute… Remember the cell cycle? Note that the S phase is when cells are replicating their DNA in preparation for G2 and mitosis, when the cell actually divides. Once incorporated into DNA (or RNA) strands, azacitidine forms a covalent bond with the DNA methyltransferase enzyme, forming bulky structures and preventing the enzyme from executing its normal methylating actions. The bulky structures can physically inhibit DNA replication, and with time, the consequent overall hypomethylation of the genome can be directly cytotoxic. (Image)

Because azacitidine works through DNMT inhibition during the cell replication process, cells that are undergoing more rapid division are more susceptible to the effects of azacitidine.

The QUAZAR AML-001 Trial

Why was this study conducted?

QUAZAR - what an (inter) stellar name for a trial, eh? (Image)

The QUAZAR AML-001 clinical trial was a phase III, international, randomized, double-blind, placebo-controlled study funded by Bristol Myers Squibb. Researchers hypothesized that the novel formulation of oral azacitidine (Onureg) would lead to better overall survival for older adults with AML post-remission therapy.

Because the maintenance phase of therapy for AML is not as well established as the first two phases - in fact, there has been no maintenance AML therapy shown to increase overall survival for these patients yet - it was hoped that this trial could potentially pave the way for other similar therapies and better, longer outcomes for AML patients.

Spoiler alert: this trial did in fact eventually lead to the approval of Onureg for maintenance therapy of adults with AML in first remission on September 1st, 2020.

But details, we need details!!

Which patients were studied?

Patients were included if they met the following criteria:

Greater than 55 years of age,
Newly diagnosed AML,
Had undergone intensive induction therapy with or without consolidation therapy,
Achieve first complete remission (CR) or CR with incomplete blood count recovery (with specific blood parameters),
Adequate liver, kidney, and bone marrow function, and
ECOG score 0-3.

On the other hand, patients were excluded if they had any of the following characteristics:

AML diagnosis with a favorable genetic profile,
Prior stem cell transplant or were a candidate for one,
Had achieved CR with a hypomethylating agent (like azacitidine) before,
Diagnosis of cancer within the previous 12 months,
Any medical condition (cardiac, infectious, psychiatric, gastrointestinal, etc) that could “confound the ability to interpret the data” or place the patient at “unacceptable risk,” or
CNS involvement of the leukemia.

So let’s take a moment and try to visualize who these patients were in the QUAZAR trial. We have a set of older adults who recently found out about their AML diagnosis but who had also undergone at least their first round of intensive chemotherapy. With ECOGs of 0-3, they could range from fully functional to relatively disabled, so it’s good to know that the investigators didn’t set out to cherry pick for the healthier subset of patients to try out their new azacitidine formulation. Additionally, to the investigators’ credit, they also didn’t cherry pick for patients with favorable genetic profiles who may at baseline simply have had a better chance of responding to therapies.

These things being said, they also wanted fairly uncomplicated, treatment naive patients, aka those who hadn’t undergone previous therapies like azacitidine or stem cell transplant and also those who didn’t have concurrent cancers or extensive (harder to treat) CNS involvement.

Makes sense though, right?

If you were designing this study, you wouldn’t want to include patients who previously responded to azacitidine in a trial to test response to…azacitidine. That wouldn’t exactly be a fair fight, now would it…

What were the outcomes of interest?

The primary endpoint was the cancer study gold standard: Overall Survival (OS). Per FDA definitions, this is the time from randomization until death from any cause. Couple key points here…

First, OS is a measurement of time, not a number of patients measurement. This means the study has to be conducted for a long enough period to adequately assess whether the treatment actually impacted death rates.

To illustrate, let’s say the mean survival time for cancer type A is 5 years. If a clinical trial of a new treatment for cancer type A only follows patients for 2 years, it’s probably missing the boat on capturing any changes in OS. Not very useful. So it’s important to put this endpoint in the context of the specific disease state being studied. For context, when it comes to AML, the 5 year survival rate for adults over age 20 is 26% (ouch), meaning 26% of adult patients with AML will still be alive 5 years after diagnosis. The median duration of follow up in the QUAZAR trial was 41.2 months, so about 3.5 years. Given a majority of folks with AML don’t make it the full 5 years, 3.5 years was likely a reasonable amount of time to follow patients to detect a difference in survival.

Another important note about OS is that it includes time to death from any cause, meaning cancer or non-cancer deaths. So it’s pretty unbiased in the sense that the only thing that really matters is what (arguably) most patients care most about - how long will they live? However, this also means it’s up to the remainder of the trial methods to control for other factors that could impact survival times (e.g., supportive care, toxicity management, etc.)

Secondary endpoints of the QUAZAR trial were the following:

Relapse Free Survival (RFS): the time from randomization until relapse or death (whichever occurred first),
Time to Relapse: pretty self-explanatory,
Time to Discontinuation from Treatment: also pretty self-explanatory,
Treatment Emergent Adverse Events (TEAEs): yep, you got it,
Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale, and
Several other quality of life measures.

How was the QUAZAR study conducted?

Starting in May 2013, 472 patients from 148 sites in 23 countries were randomized 1:1 to receive either oral azacitidine 300mg or placebo once daily on days 1-14 of a repeating 28-day cycle. Patients who had relapses of AML as defined by 5-15% blasts in the blood or marrow could have their regimens increased to 21 days per cycle (instead of 14 days) if a physician determined that this was necessary. Treatment continued indefinitely or until blasts exceeded 15% (or unacceptable toxicities occurred).

Follow up visits occurred at standardized intervals throughout the study - with bone marrow biopsies completed every 3 months, and supportive care procedures were performed according to the local study site’s practice.

So pause. Is there anything that you would have done differently with the design of this study?

Well, it’s a multi-center, international study, which could help to increase the external validity - or generalizability - of the results. According to the Supplementary Appendix, sites were included from Australia, Europe, South America, Scandinavia, the Middle East, and Asia. Pretty diverse array, check.

While patients could have had differences in their supportive care regimens according to practice site protocols, proscribing these pieces for all included patients could (on the other hand) have deprived patients of optimal care. For example, if anti-emetic regimens were specified according to protocol, it’s possible that a patient who clinically needed more than what the study protocol allowed for could have been deprived of necessary medications (or had to drop out of the study due to protocol deviation). It’s also possible that some patients then would have been overtreated with medications that they may or may not have needed. So allowing for clinical discretion in supportive care and allowing for variance was likely the most patient-friendly way of managing these people.

The frequent, every 3 month bone marrow biopsies were useful for early detection of changes in blood counts, but it may not be the standard of practice at all sites. We should consider…could the outcomes have been different if patients weren’t monitored quite so frequently?

Next, do you agree with this study being placebo-controlled? Is that ethical?

In this case, we noted earlier that there has been no established maintenance therapy for AML to date that increases OS, so it’s not like having a placebo group is depriving patients of some widely accepted standard of care. So it’s reasonable for this trial to be placebo-controlled.

By and large, you won’t hear any major arguments with the study design from this corner.

What were the results of the QUAZAR trial?

Of 472 total patients, 238 received active study drug, and 234 received placebo. Patient characteristics were very similar in both groups: median ages of 68 years, roughly equal male to female ratios, largely white race, and mostly ECOG scores of 0 or 1. (So it turns out most of the included patients were higher functioning at the time of enrollment despite inclusion criteria of ECOG 0-3, and most of them ended up being white even though so many sites across the world were included).

After a median follow-up of 41.2 months, oral azacitidine demonstrated significant improved OS compared to placebo (24.7 months vs 14.8 months, p<0.001). The OS benefit with oral azacitidine was observed regardless of prior use of consolidation chemotherapy or attainment of complete remission after induction! In fact, those patients who had some minimum residual disease (MRD) at randomization may even have derived more benefit from the oral azacitidine. (This certainly widens the breadth of patients who could potentially benefit from this maintenance therapy.)

Now let’s spend a moment with their Kaplan-Meier survival curve here:

CC-486 = oral azacitidine (active drug)This curve is a little confusing to interpret in the context of the study publication’s text because at the time point of 41 months, the 2 groups’ survival curves certainly don’t look very divergent. That’s because the survival benefit was more apparent earlier within the 41.2 month follow up window. Look at the curve in this light: the point at which patients reached a 50:50 probability of survival was at just 14.8 months for those on placebo versus almost 10 months later at 24.7 months for those in the active arm. Pretty groundbreaking! — CC-486 = oral azacitidine (active drug)
This curve is a little confusing to interpret in the context of the study publication’s text because at the time point of 41 months, the 2 groups’ survival curves certainly don’t look very divergent. That’s because the survival benefit was more apparent earlier within the 41.2 month follow up window. Look at the curve in this light: the point at which patients reached a 50:50 probability of survival was at just 14.8 months for those on placebo versus almost *10 months later* at 24.7 months for those in the active arm. Pretty groundbreaking!

RFS was also significantly extended with oral azacitidine vs placebo: 10.2 months vs 4.8 months (p<0.001). Patients received a median number of 12 cycles of oral azacitidine compared to only 6 cycles of placebo, and only 51/238 (21%) of the active drug group received the escalated dosing of 21 day cycles. There were no clinically significant differences in the secondary endpoints related to the FACIT-Fatigue score or other quality of life measures between the two comparator groups.

The most frequent grade 1 or 2 adverse events (AE) in the oral azacitidine group were gastrointestinal symptoms (nausea, vomiting, and diarrhea), which seemed to improve after the first 2 cycles and the incorporation of supportive care medications. The most frequent grade 3 or 4 AE were neutropenia, thrombocytopenia, and anemia, which, unlike the GI symptoms, persisted throughout the entirety of most patients’ ~12 cycle study periods. Dosing interruptions or modifications occurred more frequently in the azacitidine group (largely secondary to neutropenia), although only small percentages of patients discontinued active treatment due to AE (5% due to GI effects and 1% because of hematologic).

Serious infections were more common in the active drug group compared with placebo (17% vs 8%), and more patients died in the active drug group than in the placebo group (4% vs 2%) with sepsis being responsible for 3/9 deaths in the azacitidine group. On the note of what happened to patients after study’s end, 58% of oral azacitidine patients vs 73% of placebo patients moved on to at least one additional form of subsequent treatment, including intensive salvage chemotherapy or stem cell transplant.

So taking this all together, and doing what we pharmacists do… let’s weigh risk vs benefit. The data demonstrated a pretty clear survival and relapse benefit with the oral azacitidine, at least in these relatively functional, cytogenetically less favorable, newly diagnosed AML patients. This benefit was not necessarily accompanied by a clear improvement (or decrease) in quality of life, and patients certainly had some adverse effects to manage. Luckily, supportive care helped with some of the day to day GI issues, but hematologic issues and infectious complications were real issues requiring active monitoring and management.

What were the strengths and weaknesses of the QUAZAR study?

The QUAZAR AML-001 trial had many strengths, and it can be difficult to criticize a trial that was as rigorous as this. To start, it met the standard of clinical trials being international, randomized, double blind, and placebo controlled. (I feel like this long phrase we hear endlessly in school deserves a cool acronym nickname. I’m thinking I R D B P C = IRDuBPiC? Hmm, maybe not. Doesn’t quite have a catchy ring to it, does it.)

Patients were very well balanced between the oral azacitidine group and placebo group. The ratio of males to females and races was very similar. Other characteristics like ECOG scores, age, induction response, and disease status at baseline were all very similar, too. The fact that the trial included patients with poor genetic profiles really bolsters its credibility as well as potentially offering a more difficult-to-treat population some hope.

Now to crack down on the nitty gritty and talk about some tough love with the QUAZAR trial. First, it’s important to consider that stem cell transplant was not used in this trial (one of the inclusion criteria being that a patient couldn’t be a candidate). While we noted above that there is no standard of care maintenance therapy proven to increase OS in AML, stem cell transplant may be critically important for some patients after consolidation therapy!

Because this study didn’t take transplant into any consideration, whether as a comparator or as an adjacent therapy, we can’t conclude right now that oral azacitidine could ever replace transplants for post-consolidation therapy. We also don’t have much guidance for sequencing of these therapies or whether that could even be a useful possibility.

Next, let’s talk about performance status, or ECOG scores. The majority of patients enrolled in this study had an ECOG score of 0 or 1 (meaning they had normal or low-good levels of fitness), which could potentially not translate well to most AML patients that have an ECOG score of 1+.

Lastly, on to MRD. MRD, or minimal residual disease, is a term used in AML to describe patients that still have a small number of cancer cells left in the body after induction treatment. MRD positive patients may be more responsive to chemo and thus have better survival outcomes. The number of patients that were MRD positive before receiving treatment could have unequally favored oral azacitidine over placebo.

The tl;dr of the QUAZAR AML-001 trial

Overall, oral azacitidine (Onureg) has proven itself worthy of its recent fame. Overall Survival was a huge win for this trial - boasting almost a year more than its placebo counterpart; however, we still don’t have a good grasp on the best order of operations when it comes to pursuing this treatment versus proceeding straight to stem cell transplant. It certainly offers another option though - not to mention stem cell transplants aren’t exactly walks in the park. Maintenance therapies for AML seem to be becoming more and more popular, and we might just see them as a standard someday, especially if we can nail down an effective ORAL option!

Regardless of your area of practice, if you see this drug on a patient’s medication plan, remember that GI adverse effects will definitely require some supportive care. At least half of your patients will probably experience them, and they might not be tolerable. Patients will probably also experience some cytopenias and should be counseled and monitored regarding warning signs and infection prevention.

The best patient for this drug will probably be someone who is MRD+, is older than 65, and absolutely cannot undergo transplant. Onureg is one of many new oral chemotherapies coming to the market, and pharmacists in any area can help to ensure patients understand the importance of adherence with its unusual dosing regimen, checking for drug interactions, and managing adverse effects.

The tl;dr Pharmacy Journal Club: Oral Azacitidine for Acute Myeloid Leukemia (The QUAZAR Trial)