Thread by @Berninini

PART 2: Enter Vyxeos (CPX-351), a liposomal encapsulation of “7+3” in a 1:5 molar ratio. This ratio is “most” synergistic in vitro (PMID18676016). Liposomal form ensures high tissue distribution (esp. bone marrow). Fun Fact: It’s purple b/c dauno is red + copper gluconate blue!

CPX-351 (n=153) was compared to 7+3 (dauno 60 mg/m2, n=156) in patients 60-75 with untreated sAML (note, did not include AML-MRC by morphology). PMID: 30024784

CPX-351 had a higher CR/CRi rate (47.7% vs. 33.3%, p=0.016), median EFS (2.53 vs. 1.31 mo., p=0.021), and median OS (9.56 vs. 5.95 mo., p=0.003). So, ~48% CR/Cri, EFS benefit of ~1 month, OS benefit of ~3.5 months. Is that a #gamechanger? What are some flaws with this study?

1a. Suboptimal control group. Patients in the 7+3 arm received 5+2 consolidation. Yes, it is technically listed in NCCN as an option, but in a fit 62-year-old, are you really not going to use HiDAC consolidation? If 5+2 is NOT your standard, this is a suboptimal control arm.

1b. To that end, pts in the 7+3 arm performed worse than nearly all other published studies of intensive chemo in similar elderly sAML populations (CR/CRi 33.3%). Response rates to 7+3 in sAML pts are consistently 45-60% in other studies (Löwenberg NEJM 2009, Vulaj Leuk Res 2018)

2. Approximately 1/3 of pts in both arms required 2 inductions for CR/CRi, the CR/CRi after cycle 1 of CPX is only 37.9%. In the 7+3 arm, 5+2 was the required reinduction. If you wanted to use another reinduction, those patients were induction failures.

3. What about the toxicity profile? Significantly more hemorrhage and prolonged cytopenias with CPX-351. It looks like bacteremia rates higher with CPX-351 (~10% vs. ~3%) in JCO manuscript, but the PI and manuscript are not concordant on AE rates.

4. Median time to neutrophil and platelet recovery were 35 and 36.5 days with CPX-351 after 1 induction cycle! Remember, 1/3 of patients required 2 inductions to attain remission, so you’re looking at months of low counts for many patients. What does the paper say about AEs?

“the proportion of patients who experienced adverse events in the CPX-351 cohort was comparable with that of those in the 7+3 cohort, which culminated in a lower rate of AEs per patient-year and suggests that CPX-351 may have a more favorable overall toxicity profile than 7+3.”

🙄That’s an oddly positive spin to describe the toxicity profile and duration of cytopenias with CPX-351, I wonder why that could be?...

5. “Medical writing and editorial assistance for the preparation of this article were provided by #medicalwriters under the direction of the authors; this assistance was financially supported by Jazz Pharmaceuticals.” 💰

The FDA approved CPX-351 for adults (any age) with newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML-MRC. Remember, patients with AML-MRC due to multilineage dysplasia and younger pts were NOT studied. #lowbarforFDAapproval

To that end, outcomes may be poor in younger pts treated with CPX-351 for sAML. This small (n=30) study of pts<60 demonstrated a CR/CRi of only 26.7%, 30-d mortality of 13.3%, and a median OS of 7 months ascopubs.org/doi/abs/10.120…

If anthracycline-based approaches are not the answer, what do outcomes look like for other “intensive” regimens in sAML? Purine analogue-cytarabine combos (FLAG, CLAG, etc.) produce CR/CRi rates of ~50-70% in similar populations with less toxicity. Examples:

1⃣FOSSIL Study (Vulaj, et al. Leuk Res, 2018) – 70% ORR in all sAML patients, 58.3% CR/CRi in pts >60, median OS 8.52 mo, 3% 30-d mortality, median 16 day duration of neutropenia; ncbi.nlm.nih.gov/pubmed/29908418

2⃣CLAG +/- M (Talati, et al. ASH 2018) – CLAG +/- M 53% CR/CRi (vs. 41.2% CPX-351). In pts w/>4 cycles of prior HMA: CLAG +/- M ↑ CR/CRi (50% vs. 25%, p=0.0068). doi.org/10.1182/blood-…

3⃣Finally, look for our ASH poster of a multi-center comparison of CPX-351 to purine analogue/Ara-C combinations in sAML patients (Benitez, et al. #2639. 12/8/19, 6-8 pm). I won’t spoil the outcomes but you should check it out! /END PART 2. See PART 3 for HMA, 💰🔥 , conclusions!