Teaching Old Drugs New Tricks?

Harry Erba, MD, PhD
Harry Erba, MD, PhD
Director of the UAB Hematologic Malignancy Program at the University of Alabama at Birmingham
Richard M. Stone, MD
Richard M. Stone, MD
Clinical director of the Adult Acute Leukemia Program at the Dana-Farber Cancer Institute in Boston

When the U.S. Food and Drug Administration (FDA) approved CPX-351 (a fixed combination of daunorubicin and cytarabine), it appeared that everything old was new again. The drug, which is a combination of two existing generic drugs encased in a liposome, received breakthrough-therapy designation in August 2017 for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes (MRC). Its safety and efficacy were demonstrated in a phase III trial comparing CPX-351 with the standard 7+3 regimen of cytarabine and daunorubicin in patients aged 60 to 75 years.

In this edition of Drawing First Blood, ASH Clinical News invited Harry Erba, MD, PhD, and Richard Stone, MD, to debate the question, “Can CPX-351 be used with other therapies, or outside of the approval study group, in AML?” Dr. Erba, director of the UAB Hematologic Malignancy Program at the University of Alabama at Birmingham, will argue on the “pro” side, and Dr. Stone, clinical director of the Adult Leukemia Program at Dana-Farber Cancer Institute in Boston, will argue on the “con” side.

Harry Erba, MD, PhD: In AML, the trouble is that while we’ve been giving 7+3 for the last 40 years, the schedule by which we give this regimen does not ensure a constant molar ratio of these two agents. We also know that the molar ratios of cytotoxic agents given in combination are important to achieve optimal cytotoxicity.

CPX-351 was developed based on preclinical and murine model observations that a 1:5 molar ratio of daunorubicin to cytarabine appeared to provide the most synergistic cytotoxic combination.1 The only way to do that would be to encapsulate these agents in a fixed–molar ratio in a liposome. In the preclinical murine AML studies, these liposomes appeared to be more preferentially taken up by leukemic blasts, as opposed to normal stem cells.2

Next, a subset analysis of a randomized, phase II study comparing CPX-351 and 7+3 in adults with previously untreated AML found a safety and efficacy signal in older patients with secondary AML, either following myelodysplastic syndromes (MDS) or treatment-related AML. This came in the form of a higher complete response rate and improved event-free and overall survival (OS), but with a lower induction mortality.3

However, these comparisons were underpowered and not statistically significant. That’s what launched the pivotal, phase III study in patients aged 60 to 75 years with secondary AML who were fit for chemotherapy.4 This trial met its primary endpoint for OS, which was statistically significantly improved with CPX-351 (9.6 vs. 6 months; p=0.005). This is not necessarily a less toxic way of giving 7+3, but it does appear to be a more efficacious way of giving it in this patient population.3

Richard Stone, MD: That’s an excellent summary of CPX-351’s history, and I have a couple of points to add: First, in terms of its mechanism of action, models of CPX-351 suggest that it delivers the compounds in a prolonged fashion in the bone marrow (BM), which may be good for patients with intrinsically resistant disease. Second, unfortunately, the trial sponsor did not prospectively collect biologic data on the type of AML being treated or the patients’ genetic profile.

We don’t know if, for example, patients with p53 mutations will benefit from CPX-351. We also don’t know much about the different patient subgroups enrolled in the trial. For example, did participants who had MDS that was treated with a hypomethylating agent (HMA) before receiving CPX-351 benefit from the new formulation or from 7+3? Although I agree with everything Dr. Erba said about CPX-351 being more efficacious than the 7+3 in the 60- to 75-year-old subgroup, there are still some important unanswered questions about the trial itself.

“[CPX-351] is not necessarily a less toxic way of giving 7+3, but it does appear to be a more efficacious way of giving it in this … population.”

—Harry Erba, MD, PhD

Dr. Erba: That’s true, and I’m concerned because we have seen data for the subset of patients with treatment-related AML, but we have not seen CPX-351 showing a benefit over 7+3 in patients with poor-risk cytogenetics or molecular profiles.

Dr. Stone: Understanding the role of hematopoietic cell transplantation (HCT) in CPX-351–treated patients may be the key to getting answers to questions about who can and should receive this treatment. One analysis looked at preliminary data from the phase III trial of people in first remission who had an HCT; compared with those receiving 7+3, patients receiving CPX-351 had a longer OS after HCT.5

There are also questions about consolidation therapy following CPX-351 induction. The trial findings suggest one of two things: Transplant patients treated with CPX-351 were less sick and didn’t die as often from HCT-related complications, or – more likely – the patients who underwent HCT after receiving CPX-351 had a lower disease burden. That’s kind of exciting, especially for the population we want to transplant – 60- to 75-year-old patients with secondary AML and one or another of its variants. The drug appeared to cause a better outcome and better disease control, without undue toxicity. So, how do we capitalize on those gains?

Dr. Erba: Right, the only potentially curative option for most of the patients in the trial is allogeneic HCT (alloHCT). In the randomized trial, more patients were able to go on to alloHCT after receiving CPX-351 than after 7+3, and it appears that, not only do patients do better after receiving CPX-351 followed by allogeneic transplant, but more patients may be eligible for that transplant.

“The main patients … who should receive CPX-351 are those with a history of MDS who were never treated with HMAs.”

—Richard Stone, MD

Dr. Stone: Our other major question is who should receive this drug now? The indication is for people who are fit to receive induction chemotherapy and who have either a history of MDS, a history of treatment for a prior cancer, or have MRC in their BM. The indication is a bit broader than the actual clinical trial would support, and I think we need to be careful about using the drug too broadly, for a few reasons.

First, the main patients – and maybe the only patients – who should receive CPX-351 are those with a history of MDS who were never treated with HMAs. Data have shown that HMA-treated patients may not have benefited as much as non–HMA-treated patients.

Second, do we really know the patients who have treatment-related AML without bad features? There are plenty of data showing that treatment-related AML is not one disease; some patients have cytogenic and/or genetic features that suggest a more de novo AML pathophysiology, and these patients may not benefit from CPX-351.

Third, patients who have only sudden MRC in their BM morphology represent a sticky situation. It’s been difficult to reproduce the trial data in the past.

Given these limitations, I believe we should restrict CPX-351 to the population of patients who were eligible for the phase III trial.

Dr. Erba: I agree with most of those assertions. The label is broader than the population that was studied in two main respects.

One is age – the trial enrolled patients aged 60 to 75 years and stratified them into two groups (60-65 years and 70-75 years). The other is the definition of AML with MRC. The FDA uses the 2016 World Health Organization (WHO) definition of MRC, which requires at least 20 percent blasts and any of the following three criteria: history of MDS or MDS/myeloproliferative neoplasm, MDS-related cytogenetic abnormalities, or multilineage dysplasia.6 In the study, though, we did not include the third category of MRC, multilineage dysplasia; however, some research has suggested that their prognosis does not differ from other subsets of patients with AML-MRC.urthermore, to make the diagnosis of MRC based on multilineage dysplasia per the WHO criteria, we would need to exclude the presence of NPM1 and biallelic CEBPA mutations. This molecular information often is not available when making the initial treatment choice.

However, I would argue that you should strongly consider using CPX-351 in a patient who has one of these high-risk features, because our goal with younger patients is to get them into a complete remission and then perform alloHCT, with the least toxicity possible. As was shown in the pivotal trial, more people went on to transplant (even in older participants who are more susceptible to toxicity) and experienced better outcomes post-transplant when receiving CPX-351 induction.

The reason for the pivotal study being done in the selected population was because this was the subset where we believed CPX-351 was going to perform better than 7+3, but in the broader randomized, phase II study, there wasn’t a subset where CPX-351 did worse.

Dr. Stone: I do think CPX-351 needs to be tested against 7+3 in a broader population because, as you pointed out, it wasn’t that it was bad in the non-secondary AML patients, but it just wasn’t better. Yet, if we performed a large trial of CPX-351 versus 7+3, CPX-351 might perform better, depending on the selected endpoint.

Dr. Erba: Of course, there are other clinical questions that also need to be resolved, such as how CPX-351 can be used in combination with other approved drugs. Should we add midostaurin? Should we add gemtuzumab ozogamicin?

Also, what do we do if a patient is not responding to CPX-351 induction? Typically, with 7+3 chemotherapy, if the patient has cytoreduction at day 14, he or she is supposed to get a reinduction, but what if a patient has no change in their BM after CPX-351? We don’t yet know what to do. Personally, I would switch them to a high-dose cytarabine-containing regimen.

Dr. Stone: Yes, that’s another thing that’s never been proven for 7+3 treatment failures. I feel like the next step is 5+2, but many people move to high-dose cytarabine.

Dr. Erba: In the pivotal trial, CPX-351 was administered in the inpatient setting for the vast majority of individuals (98%). As consolidation, it was administered via 90-minute infusion, which could potentially be given in the outpatient setting.

Patients presenting with AML are often ill with neutropenia, are getting transfusions, or are in disseminated intravascular coagulation and need to be admitted. In patients who are not ill, though, there is a debate about whether CPX-351 can be given in the outpatient setting during induction. This approach would require close monitoring, and I recommend it only be used in a patient who can reliably get back to the hospital quickly because it is a myelosuppressive drug with a similar toxicity profile to 7+3.

Dr. Stone: However, the issue there is an important one that we often overlook: cost. This is an expensive drug. In many health-care systems, it makes a difference where such an expensive drug is administered. That’s owing to the vagaries of our health-care system. Although there may be patients who can receive CPX-351 safely in the clinic, we always want to make the choice that’s best for the patient, and cost to the patient is something we need to think about.

Dr. Erba: It’s unfortunate that we occasionally need to make decisions about what drugs we use in the inpatient setting based on diagnosis-related group (DRG) payments and the cost of the intervention. If this drug was priced reasonably and did not eat up most of our DRG payments, I think the debate about which patients should receive it would be settled.

References

  1. Lim WS, Tardi PG, Xie X, et al. Schedule- and dose-dependency of CPX-351, a synergistic fixed ratio cytarabine:daunorubicin formulation, in consolidation treatment against human leukemia xenografts. Leuk Lymphoma. 2010;51:1536-42.
  2. Lim WS, Tardi PG, Dos Santos N, et al. Leukemia-selective uptake and cytotoxicity of CPX-351, a synergistic fixed-ratio cytarabine:daunorubicin formulation in bone marrow xenografts. Leuk Res. 2010;34:1214-23.
  3. Lancet JE, Cortes JE, Hogge DE, et al. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood. 2014;123:3239-46.
  4. Lancet JE, Uy GL, Cortes JE, et al. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. Abstract #7000. Presented at the 2016 ASCO Annual Meeting, June 4, 2016; Chicago, IL.
  5. Brunetti C, Anelli L, Zagaria A, et al. CPX-351 in acute myeloid leukemia: can a new formulation maximize the efficacy of old compounds? Exp Rev Hematol. 2017;10:853-62.
  6. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391-405.