CPX-351 plus gemtuzumab ozogamicin in relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome

Key Points

• •The combination of CPX-351 and GO led to an overall response rate of 30% in patients with R/R AML and high-risk MDS after HMA.
• •Among patients with R/R AML who achieved a cCR, the 1-year OS rate was 56%, and no events of hepatic SOS were observed.

Visual Abstract

Abstract

Outcomes of patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) and those with myelodysplastic syndrome (MDS) with increased blasts (IB) who progress after therapy with hypomethylating agents (HMA) are dismal, especially when without targetable genetic aberrations. In this phase 2 pilot trial, we treated 50 patients (48 with R/R AML and 2 with post-HMA MDS-IB) with a combination of CPX-351 and gemtuzumab ozogamicin (GO). The median age of patients was 68.7 years (range, 21.5-76.8). Among patients with AML, 87% had received prior HMA, 83% prior venetoclax, 65% prior chemotherapy, and 15% had undergone hematopoietic stem cell transplantation (HSCT). Both patients with MDS had received HMA and venetoclax previously. A composite complete remission (CR; CRc; CR + CR with incomplete count recovery) was achieved in 9 patients (19%) with AML, 2 of whom were consolidated with HSCT, and 1 of the 2 patients with MDS achieved marrow CR with incomplete platelet recovery. The median event-free survival and overall survival (OS) for the entire group were 1.7 and 5.7 months, respectively, whereas in responders they were 6.1 and 9.3 months, respectively. Among patients with AML who achieved a CRc, the 1-year OS rate was 56%. Overall, 45 patients (90%) had a grade ≥3 adverse event (AE), with infections being the most common AE, and there were no AEs of hepatic sinusoidal obstruction syndrome. The combination of CPX-351 + GO is feasible and led to a CRc rate of 19% in patients with R/R AML but with limited duration of responses and low rates of subsequent HSCT. This trial was registered at www.clinicaltrials.gov as NCT03672539.

Introduction

Treatment outcomes of patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after therapy with a hypomethylating agent (HMA) are dismal, especially in the absence of targetable genetic aberrations.¹ The development of genomically agnostic salvage treatment options that are efficacious and tolerable is thus important, with the potential to salvage some of these patients with an allogeneic hematopoietic stem cell transplantation (HSCT).² Several such agents are in active development, but mature results are pending. CPX-351, a liposomal formulation of fixed-dose (1:5 ratio) daunorubicin and cytarabine (DA), is approved for induction therapy in pediatric and adult patients with therapy-related AML (T-AML) or AML with myelodysplasia-related changes (MRC). In the registrational trial, CPX-351 led to a statistically significant improvement in median overall survival (OS), 9.56 vs 5.95 months, compared with the standard-of-care 7+3 regimen, in older adults aged between 60 and 75 years with T-AML/AML and MRC (secondary AML).³ The drug was associated with more protracted neutropenia, although there was no difference in early mortality. Gemtuzumab ozogamicin (GO) is a CD33-targeting antibody-drug conjugate (conjugated with calicheamicin toxin) and is approved for the treatment of R/R AML in pediatric and adult patients with CD33⁺ AML and in combination with chemotherapy for the treatment of newly diagnosed AML. In randomized studies and meta-analyses, GO showed efficacy, particularly in patients with core-binding factor (CBF) AML and in those with intermediate-risk genomics.4, 5, 6, 7 In a recent trial by the UK National Cancer Research Institute (NCRI), a combination of GO with standard 7+3 DA chemotherapy was superior to CPX-351 monotherapy with respect to response rates and survival in older newly diagnosed patients with non–adverse-risk AML.⁸ Combination of CPX-351 with GO has not been previously evaluated in AML.

In patients with R/R AML, new agents have been approved for patients with targetable genomic aberrations, such as FLT3-ITD, IDH1/2 mutations, NPM1 mutation, or KMT2A rearrangement.9, 10, 11, 12, 13 However, treatment options remain limited in the large proportion of patients with R/R AML who do not harbor these aberrations. Although GO monotherapy is approved in older patients with R/R AML, its single-agent efficacy is limited.¹⁴ Outcomes of patients with high-risk (HR) MDS with increased blasts (IB) or chronic myelomonocytic leukemia (CMML) who progress after prior HMA therapy and/or HSCT are also dismal.¹⁵ Therefore, we present a pilot study of CPX-351 in combination with GO in adult patients with R/R AML and post-HMA HR-MDS.

Methods

This was an open-label, phase 2, single-arm pilot clinical trial that was conducted at the University of Texas MD Anderson Cancer Center (NCT03672539). This study was approved by the institutional review board, all patients signed an informed consent form, and the study was conducted according to the Declaration of Helsinki.

Patients and eligibility

Adult patients (aged ≥18 years) with CD33⁺ (>3% expression) R/R AML, treated secondary (TS) AML (ie, patients with prior MDS/CMML treated with HMA who progressed to AML, even if they had not received any therapy after AML diagnosis), or post-HMA failure HR MDS with >10% blasts were eligible. The eligible patients had Eastern Cooperative Oncology Group performance status ≤2, with acceptable hepatic (total serum bilirubin was ≤2 upper limit of normal [ULN] and ≤3 ULN, if the patient had known Gilbert syndrome; alanine/aspartate aminotransferase ≤3 ULN or ≤5 ULN, if the patient had suspected leukemia involvement of the liver) and renal function (serum creatinine ≤2 mg/dL). Patients with active central nervous system leukemia or any significant cardiovascular comorbidity (active unstable angina, myocardial infarction within 6 months of imminent therapy initiation, congestive cardiac failure of New York Heart Association (NYHA) class III/IV, or left ventricular ejection fraction <50%) were not eligible. Patients with cumulative anthracycline exposure of >200 mg/m² of daunorubicin equivalent were also not eligible. Patients who had received an allogeneic HSCT within 6 months of imminent study therapy, patients with active graft-versus-host disease requiring therapeutic systemic immunosuppression, and patients with active fungal, bacterial, or viral infections were also not eligible. Prior therapy with CPX-351 and/or GO was precluded. Further eligibility criteria are detailed in supplemental Protocol.

Treatment regimen

Study therapy consisted of a combination of CPX-351 and GO and was divided into induction, consolidation, and maintenance phases (supplemental Figure 1).

Induction

In the induction cycle, patients received CPX-351 (44 mg/m² daunorubicin and 100 mg/m² cytarabine) administered on days 1, 3, and 5. GO was administered at a starting dose of 3 mg/m² (up to 4.5 mg) on day 1. A cycle was defined as ∼28 days; however, the start of cycle 2 could be delayed if the patient achieved a complete remission (CR) or CR with incomplete count recovery (CRi) to allow for toxicity recovery. For patients who did not attain a clinical response, defined by the International Working Group (IWG) criteria, after 1 induction cycle, a second induction cycle of CPX-351 (same dose but given only on days 1 and 3) with GO (same dose/schedule) may have been administered, if there was no unacceptable toxicity.

Consolidation

Patients who achieved an IWG-defined clinical response (CR, CRi, or composite CR [CRc]) could receive the first consolidation cycle after a minimum of 4 weeks from the start of the last induction. The consolidation cycle could have been delayed as needed to allow for toxicity recovery after induction cycles. The recommended dose for consolidation was CPX-351 (29 mg/m² daunorubicin and 65 mg/m² cytarabine) on days 1 and 3, and for the first consolidation cycle, the recommended dose of GO was 3 mg/m² (up to 4.5 mg) on day 1. A second consolidation cycle could be administered after a minimum of 4 weeks from the start of the first consolidation cycle in patients who did not show disease progression or unacceptable toxicity and after blood count recovery (absolute neutrophil count ≥1 × 10⁹/L and platelet count ≥60 × 10⁹/L). GO was administered during the second consolidation cycle (same dose/schedule as the first consolidation), only if there was evidence of positive measurable residual disease (MRD), detected by multiparameter flow cytometry (MFC) at a sensitivity of 1 in 10⁴ in the bone marrow (BM).

Maintenance

GO could be administered as a single agent for maintenance at a dose of 3 mg/m² (up to 4.5 mg) on day 1 every 6 weeks, only in case of persistent detection of MRD in the BM. Patients who experienced a clinical benefit with acceptable toxicity could receive up to 6 GO maintenance cycles in total.

Dose modifications for CPX-351 and/or GO for hematologic and nonhematologic toxicities are detailed in supplemental study Protocol. Although subsequent cycle initiation was required to be delayed (preferably not >8 weeks) for adequate blood count recovery (in patients with CRc), the cycle could be started after 4 weeks without further delay in the presence of MRD⁺ disease. All patients received standard antimicrobial prophylaxis according to the institutional standards; however, no concurrent other investigational drugs were allowed.

Study evaluation

Disease assessment by BM evaluation (aspirate and/or biopsy), cytogenetics, an 81-gene myeloid mutational profile, and MFC-MRD assessment at a sensitivity of 1 in 10⁴ were performed at baseline screening before first consolidation and before first maintenance cycle. Further evaluation was required as clinically indicated.

Outcome measure

The primary outcome of the study was efficacy, evaluated as the best overall response rate (ORR), calculated as a combination of CRc, morphological leukemia-free state (MLFS), and partial response (PR) according to the revised recommendations of the IWG for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in AML and myelodysplasia.^16,17 For MDS, ORR included CR, PR, hematologic response (hemoglobin, platelet, and neutrophil response), and marrow CR (BM with <5% blasts, with hematologic response parameters but not reaching peripheral blood CR parameters). Safety was a coprimary end point.

Statistical analysis

Efficacy analysis was performed over 2 cycles of therapy to determine the best overall response. The target ORR was 30%. An ORR of <15% was considered a failure, whereas significant drug-related adverse events (AEs) of grade ≥3 of >30% were considered unacceptable. Interim monitoring rules were established using these futility and safety cutoffs.

Secondary end points included rates of MFC-MRD⁻ CRc, event-free survival (EFS), and OS. EFS events included disease progression, lack of response, initiation of new leukemia-directed therapy, or death, whichever occurred first. EFS was calculated from the start of study therapy. OS was calculated from study therapy initiation to death and censored at last follow-up. Neither EFS nor OS was censored for HSCT when HSCT was performed while the patient remained in continued response after the study. Duration of response (DOR) was evaluated from the time of best OR to relapse and censored for death in remission but not censored for HSCT in continued response after the study. Kaplan-Meier estimates were used for time-to-event analysis, and inverse Kaplan-Meier estimates were used for follow-up duration estimation.

Results

From November 2018 to June 2025, 63 patients were screened, and 50 adult patients at a median age of 68.7 years (range, 21.5-76.8) were treated in this study, including 36 patients (72%) who were aged ≥60 years (Table 1). Of these, 34 patients (68%) were male, and 41 patients (82%) were White. Overall, 48 patients (96%) had R/R AML (including 18 patients [38%] with TS-AML, 5 patients [10%] with T-AML, and 3 patients [6%] with postmyeloproliferative neoplasm AML), and 2 patients (4%) had HR post-HMA MDS-IB. Among the patients with AML, the median number of prior lines of therapy was 2 (range, 1-5), and 30 patients (62%) had received ≥ 2prior lines of therapy (including prior MDS-/CMML-directed treatment, if any). A total of 42 of the 48 patients with AML (87%) had received prior HMA, 40 of the 48 patients (83%) had received prior venetoclax, 31 of the 48 (65%) had received prior chemotherapy, and 7 of the 48 (15%) patients had undergone prior HSCT, with 1 patient having undergone 2 prior HSCTs. Among the 31 patients who had received chemotherapy, 12 patients (25%) had received intensive chemotherapy, and 11 patients (23%) had received an anthracycline. Both patients with MDS had received 2 prior lines of therapy, including HMA and venetoclax, and the BM blast percentage before the study therapy was 15% and 16%, respectively. Neither of the patients with MDS had undergone prior HSCT.

Table 1.

Baseline characteristics of the study patients

Parameters	N (%) or median (range)
Age, y	68.7 (21.5-76.8)
≥60	36 (72)
≥70	21 (42)
Sex
Male	34 (68)
Race
White	41 (82)
Black	4 (8)
Hispanic	2 (4)
Asian	1 (2)
Other	2 (4)
Diagnosis
AML	48 (96)
MDS	2 (4)
Prior therapy lines
AML	2 (1-5)
≥2 prior lines	30 (62)
HMA	42 (87)
Venetoclax	40 (83)
Chemotherapy	31 (65)
Anthracycline	11 (23)
HSCT	7 (15)
MDS	2
HMA	2 (100)
Venetoclax	2 (100)
Cytogenetics
AML
CBF	1 (2)
Diploid	15 (31)
Adverse	23 (48)
Complex	11 (23)
MECOMr	4 (8)
KMT2Ar	3 (6)
5/del5q;-7/del7q	5 (10)
MDS
Diploid	1 (50)
Complex	1 (50)
Mutations∗
ASXL1	8 (16)
IDH1/IDH2	3 (6)
NPM1	4 (8)
RAS	12 (24)
RUNX1	15 (30)
TP53	8 (16)

r, rearrangement.

^∗The 2 patients with MDS had ASXL1, SRSF2, GATA2, STAG2 mutation and ASXL1, RUNX1, SF3B1 mutation, respectively (included in the list).

Among patients with AML, 15 of the 48 (31%) had a diploid karyotype, and 23 of the 48 (48%) had adverse cytogenetics according to the European LeukemiaNet 2017 criteria. Among the 2 patients with MDS, 1 had a complex karyotype and the other a diploid karyotype. Overall, 8 patients (16%) had a TP53 mutation (all AML), no patients had an FLT3-TKD/ITD mutation, 4 patients (8%) had an NPM1 mutation, 2 patients (4%) had an IDH1 mutation (both AML), and 1 patient (2%) with AML had an IDH2 mutation. Both patients with an IDH1 mutation had TS-AML, were previously exposed to HMA, but were venetoclax naive. The patient with an IDH2 mutation had received 5 prior lines of therapy, including prior HMA, venetoclax, enasidenib, and HSCT. Overall, according to the European LeukemiaNet 2017 risk stratification, 4 patients (8%) with AML had favorable-risk disease (1 CBF-AML; 3 with NPM1 mutation), 11 patients (23%) had intermediate-risk disease, and the remaining 33 patients (69%) had adverse-risk disease.

Response and survival outcomes

An overall response was achieved in 15 patients (30%), including CR in 6 patients (12%), CRi (all being CR with incomplete platelet recovery [CRp]) in 3 patients (6%), MLFS in 4 patients (8%), PR in 1 patient (2%), and BM CRp in 1 patient with MDS (Figure 1; supplemental Table 1). Outside the protocol-defined response, 1 patient with AML had BM blast reduction from 34% to 6% after 1 cycle. Thus, the CRc rate in patients with AML was 19% (9 of the 48 patients), 3 of whom also became MRD⁻ (6% of the full AML cohort and 33% of patients with CRc). The median time to response was after 1 cycle, with only 1 patient achieving an overall response after reinduction. Overall, 14 patients (28%) received >1 induction/consolidation cycle, and only 3 patients (6%) received GO maintenance.

Figure 1.

Swimmer plot depicting relevant events. Patients 1 and 2 had HR-MDS, and patients 3 to 50 had R/R AML.

Of the 15 patients who achieved a response, 7 patients (47%) had received only 1 prior line of therapy, 6 patients (40%) had received 2 prior lines of therapy, and 1 patient (7%) each had received 3 and 4 prior lines of therapy. Of these, 14 patients (93%) had received prior HMA, 10 patients (67%) had received prior venetoclax, 7 patients (47%) had received prior chemotherapy (only 1 patient [7%] had received prior anthracycline), and 2 patients (13%) had undergone a prior HSCT. Among the responders, cytogenetics at the time of clinical trial enrolment was diploid in 6 patients, nondiploid intermediate-risk in 3 patients, and 2 patients each had a complex karyotype, MECOMr, and KMT2Ar. Thus, overall, 9 of the 15 patients (60%) had non–adverse-risk cytogenetics. None of the patients with TP53 mutation achieved a response. Among the 4 patients with MECOMr, 1 patient each achieved a CRp and MLFS, whereas among the 3 patients with KMT2Ar, 1 patient each achieved a CR and PR. Only 2 of the 13 patients (15%) with a complex karyotype achieved a response (CR and CRp).

At a median estimated follow-up of 43.3 months from study therapy initiation, no patient remained on the study therapy, and 3 patients were alive (supplemental Figure 2). The median EFS was 1.7 months (95% confidence interval [CI], 1.4-2.1), and the median OS was 5.7 months (95% CI, 3.4-7.3; Figure 2A). Among responders, the median EFS was 6.1 months (95% CI, 1.8-8.2), and the 1-year EFS rate was 17%, whereas the median OS was 9.3 months (95% CI, 4.1-19.1), and the 1-year OS rate was 44% (Figure 2B). The 1-year EFS and OS rates among the 9 patients with AML who achieved a CRc were 25% and 56%, respectively (Figure 2C). The median DOR in all responders was 6.2 months (95% CI, 1.0-10.3 months), and the 1-year DOR rate was 28%. Among patients with AML and CRc, the median DOR was 7.6 months (95% CI, 2.9-28.0), and the 1-year DOR rate was 29% (Figure 2D).

Figure 2.

Survival outcomes and DOR with study therapy. resp., responders.

In addition, 2 patients were able to proceed to HSCT after study therapy. The first patient, aged 47 years, with MECOMr AML, previously exposed to HMA, chemotherapy, and venetoclax but not anthracycline (total 3 prior lines of therapy), achieved an MRD⁺ CRp after 1 cycle of study therapy and underwent an HSCT. The patient relapsed after a DOR of 6.4 months and died from infections and progressive leukemia. The second patient, aged 66 years, had AML with a diploid karyotype and no TP53 mutation, previously exposed to both HMA and venetoclax (1 prior line of therapy) but no chemotherapy. The patient achieved MRD⁺ CR after 2 cycles of the study therapy and underwent an HSCT thereafter, with a continuous DOR of 42.0 months at last follow-up.

Safety

The most common cause for going off the study was disease progression/inadequate response in 38 patients (76%). A total of 45 patients (90%) had at least 1 grade ≥3 nonhematological AEs regardless of attribution, of which infection-related AEs were the most common, affecting 37 patients (74%). There were no events of hepatic sinusoidal obstruction syndrome (SOS) during or after the study therapy, including in patients who subsequently underwent an HSCT. All grade ≥3 AEs, irrespective of attribution, are mentioned in Table 2. All grade 5 events were unrelated to the study regimen. Possible drug-related AEs included grade 2 mucositis in 2 patients, grade 3 mucositis in 1 patient, grade 3 liver transaminase elevation in 1 patient, and grade 4 seizure in 1 patient. Among the patients who achieved a CRc (n = 5) and received >1 cycle of treatment, the time to the next cycle (consolidation) was 45 days (range, 42-46).

Table 2.

Grade ≥3 AEs irrespective of attribution

	Grade ≥3	Grade 3	Grade 4	Grade 5
AEs	n (%)	n (%)	n (%)	n (%)
Infections
Febrile neutropenia	22 (44)	22 (44)	0	0
Bacteremia	14 (28)	13 (26)	0	1 (2)
Lung infection	8 (16)	8 (16)	0	0
Sepsis	6 (12)	0	4 (8)	2 (4)
Skin infection	2 (4)	2 (4)	0	0
Typhlitis	1 (2)	1 (2)	0	0
Hepatic infection	1 (2)	1 (2)	0	0
URTI	1 (2)	1 (2)	0	0
Facial cellulitis	1 (2)	1 (2)	0	0
Inguinal cellulitis	1 (2)	1 (2)	0	0
COVID-19	1 (2)	1 (2)	0	0
Sinusitis	1 (2)	1 (2)	0	0
Pulmonary
ARDS	4 (8)	0	2 (4)	2 (4)
Diffuse alveolar hemorrhage	1 (2)	0	0	1 (2)
Pneumonitis	1 (2)	1 (2)	0	0
Pleural effusion	1 (2)	1 (2)	0	0
Gastrointestinal
Melena	3 (6)	3 (6)	0	0
ALT/AST elevation	2 (4)	2 (4)	0	0
Mucositis	2 (4)	2 (4)	0	0
LGI bleed	1 (2)	1 (2)	0	0
Anorexia	1 (2)	1 (2)	0	0
Abdominal pain	1 (2)	1 (2)	0	0
Diarrhea	1 (2)	1 (2)	0	0
Vomiting	1 (2)	1 (2)	0	0
Cardiovascular
Hypotension	3 (6)	3 (6)	0	0
Cardiac arrest	2 (4)	0	1 (2)	1 (2)
Syncope	2 (4)	2 (4)	0	0
Myocardial infarction	1 (2)	1 (2)	0	0
Noncardiac chest pain	1 (2)	1 (2)	0	0
Sinus bradycardia	1 (2)	1 (2)	0	0
Neurological
Seizure	2 (4)	1 (2)	1 (2)	0
Confusion	1 (2)	1 (2)	0	0
Headache	1 (2)	1 (2)	0	0
Renal and electrolyte abnormalities
Hypophosphatemia	2 (4)	2 (4)	0	0
Acute kidney injury	1 (2)	1 (2)	0	0
Hypokalemia	1 (2)	1 (2)	0	0
Miscellaneous
Multiorgan failure	3 (6)	0	0	3 (6)
Oncocytoma (renal)	1 (2)	0	0	1 (2)
Epistaxis	1 (2)	1 (2)	0	0
Rash	1 (2)	1 (2)	0	0
Facial pain	1 (2)	1 (2)	0	0
Neck pain	1 (2)	1 (2)	0	0

Each patient could have had ≥1 nonoverlapping event.

ALT, alanine aminotransferase; ARDS, acute respiratory distress syndrome; AST, aspartate aminotransferase; LGI, lower gastro-intestinal; URTI, upper respiratory tract infections.

Additionally, 4 patients (8%) died while receiving the study therapy: 3 patients with AML and 1 patient with MDS. Of these, 2 patients died before postinduction BM assessment, 1 patient after having no response to 1 cycle of induction therapy, and 1 patient after achieving delayed CRp after 1 induction cycle but with significant complications (renal failure, pleural effusion, infection, etc) precluding further cycles of therapy and died in remission 6.1 months after study therapy initiation and 2.0 months after achievement of response. Overall, 2 patients had nonrelapse mortality, including 1 patient who is described previously, and the other patient, aged 50 years, who achieved CR but had infection-related complications, declined further therapy, and died in remission 2.4 months after study therapy initiation. The 30-day and 60-day mortality rates were 8% and 20%, respectively. Among patients with a 30-day mortality, the causes of death were Pneumocystis jirovecii infection with diffuse alveolar hemorrhage in 1 patient, cerebrovascular bleed with Candida glabrata sepsis and multiorgan failure in 1 patient, and pneumonia with adult respiratory distress syndrome in 2 patients.

Discussion

Despite improvements in treatment options for R/R AML, most of the novel approved agents are genomically directed, whereas >50% of patients with relapsed AML lack a currently targetable aberration.² Improving genomically agnostic treatment options is thus important to improve outcomes in this challenging and large group of patients. In this pilot study, we demonstrated an ORR of 30% with the CPX-351 + GO combination, meeting the prespecified efficacy cutoff with reasonable safety, and the CRc rate (in AML) was 19%. Although DORs were short, meaningful survival was achieved in 9 patients (19%) with R/R AML who achieved a CRc, with a 1-year OS rate of 56%, especially considering that 8 of these patients were previously exposed to HMA and 5 to venetoclax-based therapies. Beyond expected toxicities in this setting, the regimen was not associated with any hepatic SOS, including in the 2 patients who proceeded to HSCT after the study. However, the absence of a central review of AE attribution is a limitation of this study and might account for lower reported rates of attributable toxicities compared with those in real-world experience or large multicenter studies.

Given the time profile of the trial, some of the study patients (NPM1 mutated = 4; KMT2Ar = 3) would now be eligible for menin inhibitors, whereas the 2 patients with R/R IDH1-mutated AML would be eligible for ivosidenib-/olutasidenib-based therapy. However, most of the patients in our study would not have been eligible for any approved novel agents. This highlights the need to evaluate other drugs and combinations that are genomically agnostic in combination for efficacy and safety as salvage therapy in HMA-exposed MDS-IB and R/R AML. Other genomically agnostic therapies in development include anti-CD123 targeted agents, CD70- and other myeloid antigen-targeted cellular therapies, and others, but mature clinical data remain limited.^18,19 Overall, as with several previously studied genomically agnostic salvage chemotherapies, the combination of CPX-351 and GO did not lead to very promising response durations or high rates of consolidation with HSCT.

Although CPX-351 monotherapy is approved for newly diagnosed AML with myelodysplasia-related biology, it has been studied in combination with other drugs in the salvage setting. In a phase 2 study, the CPX-351 and venetoclax combination in 33 adult patients with R/R AML led to an ORR of 46% and a CRc rate of 39% in the whole cohort, whereas the CRc rate was 70% in patients with TP53 wild-type mutations who were receiving their first salvage therapy.²⁰ The median EFS and OS were 3 months and 6 months, respectively, and the 2-year EFS and OS rates were 19% and 35%, respectively. However, in this study, 58% of the patients were previously exposed to venetoclax compared with 83% of the patients in our study, whereas patients with R/R TS-AML were 12% compared with 38% of the patients with AML in our study, a group intrinsically associated with inferior outcomes.²¹ In a multicenter phase 1b trial, among 13 patients with R/R AML treated with CPX-351 and GO, a CRc was achieved in 31%, and 2 patients were able to proceed to an HSCT.²² Other CPX-351–based combinations are also being evaluated in R/R AML, including with enasidenib in R/R IDH2-mutated AML and with palbociclib or tazemedostat in R/R AML irrespective of genomics, and clinical results are pending.^23,24

Although in the registrational trial the efficacy of CPX-351 was particularly better in T-AML and AML-MRC, those who had received previous HMA for MDS/CMML did not have any benefit with CPX-351 over the standard-of-care 7+3 therapy.^3,25,26 In a randomized comparison of CPX-351 with fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor in patients with newly diagnosed AML harboring adverse cytogenetics or HR-MDS, CPX-351 led to improved relapse-free survival but not OS, except in patients with AML harboring MDS-related mutations, but not MDS-related cytogenetics or clinically secondary AML.²⁷ With respect to GO, although the drug is approved as monotherapy in R/R CD33⁺ AML based on CR rates of 26% in the registrational Mylofrance 1 phase 2 trial (in the era before venetoclax), GO has been used more commonly as part of frontline therapy for CBF-AML, HR acute promyelocytic leukemia, and other favorable AML subtypes.28, 29, 30 With the limited monotherapy efficacy of GO in salvage, its combination with other agents warranted evaluation. Although concerns about hepatic SOS remain after GO (from its conjugated calicheamicin), no such events occurred in our study, and hepatic AEs were limited to grade 3 alanine aminotransferase/aspartate aminotransferase elevation. A recent randomized trial by the UK NCRI showed better response rates (CR rates, 60% vs 48%), 3-year EFS (34% vs 27%), and OS (52% vs 35%) rates with 7+3 DA + GO compared with CPX-351.⁸ Even among patients with MDS-related mutations, DA + GO fared better than CPX-351. These findings warrant evaluation of the combination of CPX-351 + GO in frontline settings to assess whether the addition of GO to CPX-351 improves upon historical outcomes with CPX-351 and recently reported outcomes with DA + GO. However, given the known risks of delayed neutrophil and platelet recovery with CPX-351 compared with DA, the additive myelotoxicity from GO needs closer evaluation. These effects were difficult to assess in our R/R patient cohort, especially with the low rates of CR in the salvage settings.

In summary, the CPX-351 + GO combination in a heavily treated population of patients with MDS/AML led to a CRc rate of 19% in AML, but DORs were short. It can be considered as a salvage option in a selected group of patients with R/R AML without adverse genomics or targetable aberrations or in those with progression after treatment with targeted agents. AEs observed with the regimen were within expectations for salvage therapy in R/R AML, with infection-related events being the most common.

Conflict-of-interest disclosure: The authors declare no competing financial interests.