Abstract
Relapsed or refractory acute myeloid leukemia (R/R AML) has a poor prognosis and is best treated with salvage chemotherapy as a bridge to allogeneic stem cell transplant (alloSCT). However, the optimal salvage therapy remains unknown. Here we compared two salvage regimens; mitoxantrone, etoposide, and cytarabine (MEC) and mitoxantrone and high-dose Ara-C (Ara-C couplets). We analyzed 155 patients treated at three academic institutions between 1998 and 2017; 87 patients received MEC and 68 received Ara-C couplets. The primary endpoint was overall response (OR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of hospitalization, hematologic and nonhematologic toxicities, and success in proceeding to alloSCT. Baseline characteristics of the cohorts were well matched, though patients receiving Ara-C couplets had more co-morbidities (48.5% vs 33%; P = .07). OR was achieved in 43.7% of MEC and 54.4% of Ara-C couplets patients (P = .10). Ara-C couplets patients also trended towards a longer OS and PFS, more frequently proceeded to alloSCT (31% vs 54.4%; P = .003), and experienced less febrile neutropenia (94% vs 72%; P < .001) and grade 3/4 gastrointestinal toxicities (17.2% vs 2.94%; P = .005). No significant differences in other toxicities or median duration of hospitalization were noted. This is the first multi-institutional study directly comparing these regimens in a racially diverse population of R/R AML patients. Although these regimens have equivalent efficacy in terms of achieving OR, Ara-C couplets use is associated with significant reductions in toxicities, suggesting it should be used more frequently in these patients.
1 |. INTRODUCTION
Despite approval of several novel agents in the de novo acute myeloid leukemia (AML) space within the past 2 years, treatment outcomes for patients with AML remain dismal, with 5-year survival rates of only 30%.1 Moreover, ~30% of AML patients present with primary refractory disease, whereas up to 50% of patients achieving complete remission (CR) eventually relapse.2 Thus, treatment of relapsed/refractory (R/R) AML represents a frequent therapeutic dilemma due to both low CR rates and short-lived responses.3 Currently no consensus exists on the optimal treatment regimen for R/R AML, and randomized, controlled trials comparing effective salvage regimens are lacking.2,3 Although the use of targeted agents is preferred when therapeutically exploitable mutations are present (eg, IDH1/2 or FLT3 mutations, described in 10%−20% and 20%−30% of R/R AML patients, respectively3,4), intensive chemotherapy remains an important treatment strategy that is frequently used as a bridge to allogeneic hematopoietic stem cell transplantation (alloSCT) in eligible patients. However with a lack of discrete national guidelines, the choice of salvage therapy used commonly depends on variables such as patient age, performance status, prior treatments, patient preference, disease burden, and individual clinician/institutional preferences.
Highlighting the therapeutic dilemma of R/R AML, several chemotherapeutic regimens—mostly containing a cytarabine backbone—have been developed, yet only show moderate activity in clinical trials.2 Re-induction rates with standard-dose cytarabine combined with an anthracycline (“7 + 3”) demonstrate CR rates ranging 30%−40%.5 In a pivotal small single-institutional study (n = 32) published by Amadori et al. the combined administration of mitoxantrone, etoposide, and intermediate-dose Ara-C (MEC), administered in the first-line salvage setting, produced a superior 66% CR rate (defined here as no evidence of leukemic blasts, recovery of neutrophil count to >1.5 × 109/L and platelet count to >100 × 109/L), with a low incidence of nonhematologic toxicity, leading to its frequent use as a R/R AML regimen. Yet, the median remission duration was only 16 weeks, and median overall survival (OS) was 36 weeks.6 Follow-up retrospective analyses of the use of MEC in R/R AML have revealed highly variable CR rates of 24%−68%, likely due to heterogeneous patient populations.7 In a more recent single-institution study (n = 78) by Larson et al. a high-dose cytarabine and mitoxantrone regimen (HiDAC/MITO; also referred to as Ara-C couplets) achieved comparable OR rates of 55% (defined in this study as CR/CRi) and was likewise well tolerated.8 Chemotherapy regimens frequently underperform in the real world setting, compared to their activity in clinical trials (due to the highly selected patient population enrolled in clinical trials, and the investigators’ experience with a particular regimen). Thus, we sought to directly compare, retrospectively, these two salvage regimens in R/R AML in a diverse population of 155 unselected patients, treated at three academic institutions.
2 |. METHODS
2.1 |. Participants
We conducted a retrospective analysis of all 155 R/R AML patients treated with either MEC or Ara-C couplets between 1998 and 2017 at the University of Illinois at Chicago (UIC), Indiana University (IU), and the University of Chicago (UC). A total of 87 patients were treated with MEC, 15 from UIC and 72 from IU, whereas 68 patients were treated with Ara-C couplets, 36 at UIC and 32 at UC. The primary endpoint was to compare overall response rates (OR). Secondary endpoints included progression-free survival (PFS), OS, duration of hospitalization, hematologic and nonhematologic toxicities, and success in proceeding to alloSCT.
Additional data gathered included age, sex, race, cytogenetics, dates of treatment, comorbidities (to determine the Charlson Comorbidity Index [CCI]),9 and time from initial diagnosis to relapsed/refractory disease. Each patient’s disease was risk-stratified using the European LeukemiaNet 2010 classification.10 As validated molecular studies were not readily available for patients treated at earlier time points (specifically, only 10 patients receiving MEC and zero patients receiving Ara-C couplets had molecular data available), this data was not included in the analyses. The Institutional Review Board at each participating institution approved the protocol.
2.2 |. Treatment and monitoring
Dosing for MEC consisted of mitoxantrone 8 mg/m2 IV, etoposide 100 mg/m2 IV, and Ara-C 1 g/m2 IV on days 1–5.11 The regimen for Ara-C couplets was Ara-C 3 g/m2 once or 2 g/m2 (dose reduced for age > 60), and mitoxantrone 30 mg/m2 both given IV on day 1 and day 5.8 Following induction, additional therapy was dependent on remission status, clinical condition, and availability of an allogeneic transplant donor. Induction therapy required hospitalization, and complete blood counts were closely monitored until recovery of normal hematopoiesis. Antimicrobial prophylaxis and management of neutropenic fever were guided by the resistance patterns seen at the individual institutions.
2.3 |. Response criteria
Treatment success was defined as a complete remission (CR) per the modified 2003 International Working Group (IWG) criteria for AML, CRi (all CR criteria present except for residual neutropenia or thrombocytopenia [<1.0 × 109/L or < 100 × 109/L, respectively]), or MLFS (morphologic leukemia free state: no evidence of leukemic blasts in the bone marrow, with neither platelets nor neutrophils recovered to the above thresholds). We also identified patients who had a complete remission with residual thrombocytopenia as CRp and categorized them as a subset of CRi.10 Note that as validated molecular studies were only available for 10/155 patients, minimal residual disease assessment data was not utilized in this analysis.
Adverse events were graded by the Common Terminology Criteria for Adverse Events Version 4.0. The OS was measured from day 1 of induction to the date of death from any cause. The PFS was measured from day 1 of induction to the date of treatment failure, relapse, or death from any cause. Patients who were lost to follow-up were censored on the date they were last known to be alive.
2.4 |. Statistics
Patients treated either with MEC or Ara-C couplets were compared using descriptive statistics. The chi-square and Wilcoxon rank-sum tests, respectively, were used to compare categorical variables and medians, including efficacy, toxicity rates, and time-to-transplant. Time-to-event outcomes were described using the Kaplan-Meier method and equality of survivor functions was evaluated using weighted log-rank tests.
Two multivariable analyses were performed using time-dependent Cox proportional hazards models for OS, where time-varying exposure to hematopoietic stem cell transplantation was accounted for in (a) a landmark analysis and (b) a time-varying covariate adjustment. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated with adjustment for age, CCI, race, and cytogenetic risk, stratifying by institution.
3 |. RESULTS
3.1 |. Patient characteristics
A total of 155 R/R AML patients treated over a period of 20 years (1998–2017) with MEC or Ara-C couplets were included in this analysis. Baseline characteristics are summarized in Table 1. Of the 155 patients, 87 (56%) were treated with MEC and 68 (44%) with Ara-C couplets. Median age was similar between regimens: 52 years (range 20–75 years) for MEC and 54 years (range 22–75 years) for Ara-C couplets (P = .47). Significantly more non-Hispanic whites were treated with MEC, 63/87 (72.4%), compared with 36/68 (52.9%) in the Ara-C couplets cohort (P = .01). The incidence of unfavorable cytogenetics was similar between cohorts—32 patients in the MEC group (36.8%) and 22 in the Ara-C couplets group (32.4%)—and the median time from initial diagnosis to relapse or refractory disease was also similar at 303 and 285 days, respectively (P = .13). The Ara-C couplets cohort had a non-significant trend toward a higher CCI (defined as ≥4): 48.5% vs 33.3% (P = .07). Although significantly more patients receiving MEC had an ECOG score of zero than those receiving Ara-C couplets (P < .01), there was insufficient ECOG score data for most patients receiving Ara-C couplets.
TABLE 1.
Summary of patient demographics and baseline characteristics
| MEC (N = 87) |
Ara-C Couplets (N = 68) |
P | |
|---|---|---|---|
| n (%) | n (%) | ||
| Age at relapse | |||
| Mean (SD) (y) | 48 (14.2) | 52.6 (14.0) | .05 |
| < 50 y | 43 (49.4) | 24 (35.3) | .08 |
| ≥ 50 y | 44 (50.6) | 44 (64.7) | |
| Sex | |||
| Male | 43 (49.4) | 44 (64.7) | .06 |
| Female | 44 (50.6) | 24 (35.3) | |
| Race/ethnicity | |||
| White | 63 (72.4) | 36 (52.9) | .09 |
| Black | 12 (13.8) | 15 (22.1) | |
| Hispanic | 7 (8.0) | 9 (13.2) | |
| Other | 5 (5.7) | 8 (11.8) | |
| Year of treatment | |||
| 1993–2002 | 0 (0.0) | 10 (14.7) | <.01 |
| 2003–2007 | 3 (3.4) | 19 (27.9) | |
| 2008–2012 | 32 (36.8) | 28 (41.2) | |
| 2013–2017 | 52 (59.8) | 11 (16.2) | |
| Charlson comorbidity index | |||
| High (≥4) | 29 (33.3) | 33 (48.5) | .06 |
| Low (<4) | 58 (66.7) | 35 (51.5) | |
| Performance status prior to initiation | |||
| 0 | 28 (32.2) | 14 (20.6) | <.01 |
| 1 | 39 (44.8) | 16 (23.5) | |
| 2 | 10 (11.5) | 1 (1.5) | |
| 3 | 2 (2.3) | 0 (0.0) | |
| 4 | 1 (1.1) | 0 (0.0) | |
| Unknown | 7 (8.0) | 37 (54.4) | |
| Cytogenetics | |||
| Favorable | 13 (14.9) | 8 (11.8) | .60 |
| Intermediate | 41 (47.1) | 38 (55.9) | |
| Unfavorable | 32 (36.8) | 22 (32.4) | |
| Unknown | 1 (1.1) | 0 (0.0) | |
| Prior exposure to IDAC/HiDAC | |||
| Yes | 59 (67.8) | 43 (63.2) | .55 |
| No | 28 (32.2) | 25 (36.8) | |
| Initial induction therapy | |||
| 7 + 3 | 79 (90.8) | 35 (51.5) | <.01 |
| Other | 8 (9.2) | 33 (48.5) | |
| Number of salvage therapies | |||
| 0 | 70 (80.5) | 38 (55.9) | <.01 |
| 1 | 14 (16.1) | 24 (35.3) | |
| 2+ | 3 (3.4) | 6 (8.8) | |
| Time from initial diagnosis | |||
| Median days (interquartile range) | 303 (180–445) | 285 (188–505) | .93 |
| ≤ 6 months | 22 (25.3) | 15 (22.1) | .86 |
| 6–12 months | 31 (35.6) | 26 (38.2) | |
| > 12 months | 32 (36.8) | 27 (39.7) |
Of note, there was a significant difference as to when patients were treated with either regimen, with the MEC cohort treated relatively more recently (P < .01; see Table 1). Additionally, while most patients received either MEC or Ara-C couplets as their first salvage regimen, significantly more Ara-C couplets patients had received ≥1 prior salvage lines of therapy (30/68 [44%] vs 17/87 [19.5%], P < .01).
3.2 |. Response/survival
Patient outcomes are summarized in Table 2. There was a trend towards greater OR rate in patients receiving Ara-C couplets (MEC: 38 [43.7%] vs Ara-C couplets: 37 [54.4%], P = .10). Median PFS was 66 days in the MEC cohort and 107.5 days in the Ara-C couplets cohort (P = .71; Figure 1). OS was 5.3 months (159 days) in the MEC cohort and 6.5 months (195 days) in the Ara-C couplets cohort (P = .35; Figure 2A). And, OS post-allo SCT was 13.9 months (417 days) in patients receiving MEC and 10.4 months (311 days) in patients receiving Ara-C couplets (P = .09; Figure 2B).
TABLE 2.
Outcomes after MEC or Ara-C Couplets salvage therapy
| MEC (N = 87) |
Ara-C Couplets (N = 68) |
P | |
|---|---|---|---|
| n (%) | n (%) | ||
| Treatment response | |||
| CR | 33 (37.9) | 26 (38.2) | .10 |
| CRi (CRp) | 2 (2.3) | 6 (6) (8.8) | |
| MLFS | 3 (3.4) | 6 (8.8) | |
| Refractory | 49 (56.3) | 30 (44.1) | |
| PFS (d) | 66 | 107.5 | .71 |
| OS (d) | 159 | 195 | .35 |
| OS post SCT (d) | 417 | 311 | .09 |
| Hospital stay (median d) | 29 | 30.5 | .08 |
| Time to count recovery (d) | |||
| ANC recovery | 30 | 40 | .01 |
| Platelet recovery | 30.5 | 52.5 | <.01 |
| Mortality | |||
| 30-day mortality | 9 (10.3) | 3 (4.4) | |
| 60-day mortality | 20 (23.0) | 8 (11.8) | |
| Time to relapse after salvage | |||
| Primary refractory | 49 (56.3) | 30 (44.1) | .47 |
| < 6 months | 16 (18.4) | 17 (25.0) | |
| 6–12 months | 9 (10.3) | 6 (8.8) | |
| > 12 months | 6 (6.9) | 5 (7.4) | |
| Still alive/in remission | 7 (8.0) | 10 (14.7) | |
| SCT | 27 (31) | 37 (54.4) | .003 |
| Donor type | |||
| MUD | 11 (12.6) | 18 (26.5) | .40 |
| MRD | 10 (11.5) | 10 (14.7) | |
| Haplo | 4 (4.6) | 2 (2.9) | |
| Cord | 2 (2.3) | 3 (4.4) | |
| Auto | 0 (0.0) | 3 (4.4) | |
| Syngeneic | 0 (0.0) | 1 (1.5) | |
| Time to transplant | |||
| Median days (interquartile range) | 83 (63.5–108.5) | 61 (48–89) | .055 |
FIGURE 1.
Kaplan–Meier curve of progression-free survival. Median progression-free survival was not significantly different between cohorts: 2.2 months (66 days) for MEC patients, and 3.6 months (107.5 days) for the Ara-C couplets cohort (P = .71) [Color figure can be viewed at wileyonlinelibrary.com]
FIGURE 2.
A, Kaplan-Meier curve of overall survival. Overall survival was not significantly different between cohorts. Median OS was 5.3 months (159 days) for MEC patients and 6.5 months (195 days) for the Ara-C couplets cohort (P = .35). B, Kaplan-Meier curve of overall survival for patients receiving stem cell transplantation. The OS post-alloSCT was not significantly different between cohorts: 13.9 months (417 days) in the MEC cohort (n = 27), and 10.4 months in the Ara-C cohort of transplanted patients (n = 37), (P = .09) [Color figure can be viewed at wileyonlinelibrary.com]
Count recovery in the MEC cohort was significantly faster than in the Ara-C couplets cohort, with a median ANC and platelet recovery of 30 and 30.5 days, vs 40 and 52.5 days (P = .01 and P < .01), respectively. Despite the observed difference in count recovery, hospital stays were similar for both cohorts (median duration 29 and 30.5 days, respectively). Notably, only 27 (31%) of patients treated with MEC proceeded to transplant compared to 37 (54.5%) patients who received Ara-C couplets (P = .003). However, at UIC, the only institute where both regimens were used, equivalent numbers of these patients went on to transplant (MEC: 7/15 [46.7%], Ara-C couplets: 17/36 [47.2%], P = .97). Patients who received Ara-C couplets trended towards a shorter median time to transplant, 61 vs 83 days for patients receiving MEC (P = .055).
There were no significant differences in 30-day or 60-day mortalities, time to relapse after salvage, or donor type for those who received stem cell transplantation. Additionally, in multivariable analyses controlling for age, CCI, race, and cytogenetic risk, as well as accounting for clustering with stratification by institution, no difference in risk of overall mortality was observed between these regimens (HR 1.00; 95% CI 0.48–2.09; P = .99). Results from time-dependent models accounting for transplant in landmark analyses (HR 1.31; 95% CI 0.25–6.83; P = .75), as well as a time-varying covariate (HR 0.90, 95% CI 0.48–1.71; P = .75), were also consistent with the finding of no significant difference in all-cause mortality risk.
3.3 |. Toxicity
The most common adverse event was febrile neutropenia, occurring in 82 (94%) of MEC and 49 (72%) of the Ara-C couplets patients (P < .001). Grade 3 and 4 GI toxicity also occurred significantly more frequently in MEC patients (n = 15 [17.2%] vs n = 2 [2.94%], P= .005). There were no significant differences between cohorts in terms of pulmonary, liver, renal, cardiac, neurologic, or endocrine Grade 3/4 toxicities (Table S2).
4 |. DISCUSSION
R/R AML occurs frequently and remains a therapeutic challenge because of its poor prognosis and the lack of a clear-cut benefit for any particular second-line therapy. Allogeneic SCT is recognized as providing an opportunity for long-term survival for those in CR at the time of transplant.12 Thus, identification of the optimal salvage regimen for these patients is crucial. However, age, comorbidities, and prior cancer therapies often limit treatment options. One path towards improving CR rates, while minimizing toxicity profiles, has been to identify targetable mutations such as FLT3-ITD or IDH1/IDH2,5 but these mutations are present in only a fraction of patients with R/R AML. Additionally, regimens containing venetoclax, a BCL-2 inhibitor that induces leukemia cell apoptosis, are being increasingly used as an option (though not FDA-approved) in the R/R setting.13,14 Nonetheless, intensive chemotherapy regimens continue to play a valuable role for a substantial proportion of R/R AML cases, and understanding the efficacy and toxicity profile of regimens being used in this vulnerable population remains important.
Both MEC and, to a lesser extent, Ara-C couplets are chemotherapeutic regimens commonly used for patients who can tolerate aggressive therapy. Our multi-institutional study directly compared these two therapies in a large group of racially diverse patients treated at three academic institutions. In this retrospective analysis, in general, cohorts were well balanced with regards to age, sex, cytogenetics, and time to relapse. The cohort receiving Ara-C couplets contained a non-significant greater incidence of patients with a high CCI. Additionally, the number of non-Hispanic white patients was significantly higher in the MEC cohort; of importance as non-Hispanic whites tend to have superior 5-year outcomes in AML.15 Patients receiving MEC were also treated more recently and received fewer prior lines of salvage therapy. Despite this, the OR rate and median OS were comparable, with 43.7% of patients treated with MEC achieving a complete response, compared with 54.4% of patients treated with Ara-C couplets. Multivariate analyses confirmed the comparable risk of overall mortality of these two regimens. Our response rates were also similar to rates observed in previous studies of chemotherapy regimens for R/R AML.7
Notably, in the entire study population, the Ara-C couplets regimen appeared to be significantly more effective as a bridge to transplant, as all 37 responders went on to receive alloSCT, whereas only 27 of 38 patients responding to MEC received alloSCT. This may be related to the significantly higher rates of grade 3 or 4 GI toxicity and/or the higher incidence of febrile neutropenia observed in those receiving MEC (perhaps due to the well-established GI and hematologic toxicities observed in etoposide-containing regimens).16 This reduced toxicity of the Ara-C couplets regimen suggests its potential use as a chemotherapy backbone. Targeted agents can be added to improve treatment responses in R/R AML without conferring significant toxicity.
One significant confounding variable limiting the analysis of which regimen more successfully allows patients to proceed to alloSCT is the “center effect.” Specifically, whether institutional practice may guide who is chosen to proceed to transplant. One institution (UC) used exclusively Ara-C couplets and another (IU) used exclusively MEC. At the institution where both regimens were used (UIC), there was no difference between the two regimens in how frequently patients were able to proceed to alloSCT, though the small subgroup size (15 patients received MEC and 36 Ara-C couplets) limits the ability to draw meaningful conclusions. Differences in the rate of proceeding to alloSCT may be guided by patient or physician preferences, or both. We attempted to address the former in weighted, time-dependent Cox models stratified by institution (Table S1), which showed no significant differences in baseline patient characteristics that would benefit patients receiving Ara-C couplets in proceeding to transplant. However, our study is unable to fully elucidate physician practice differences between institutions.
In addition to this limitation, our study was a retrospective study that compared two nonrandomized treatment regimens to better understand their efficacy and toxicity profiles. Although we collected information on multiple clinical characteristics predictive of treatment response, bias from unmeasured confounding factors is possible. This, combined with the question of the aforementioned “center effect,” indicates that study of much larger cohorts of patients in a variety of academic and nonacademic institutions may be required to find small differences in patient outcomes, with the various regimens used for R/R AML.
Establishing a regimen with clearly superior CR rates for R/R AML has proven particularly difficult. A recent meta-analysis of 157 studies—the majority were retrospective analyses with only 24 of 157 randomized-controlled trials—evaluated regimens falling into six general categories (cytarabine monotherapy, anthracycline + cytarabine, anthracycline + cytarabine + a third agent, purine analogue + cytarabine, other intensive combinations, and less intensive approaches). Notably, no regimen was clearly superior, and the most effective regimens had CR/CRi rates in the 50%−55% range, similar to the OR rates observed here. Moreover, responses were of short duration (PFS 4.9–9.8 months; OS 6.2–8.7 months).7 More recent retrospective analyses have shown similar results. One retrospective study compared six regimens for R/R AML and found no significant difference in CR,17 as did another retrospective study comparing cladribine, Ara-C, and G-CSF (CLAG) and fludarabine, Ara-C, and G-CSF (FLAG).18 These data indicate that, while R/R AML is a heterogeneous disease, it is universally difficult to achieve sustained response rates, and that there appears to be little difference in the CR rates between regimens. Therefore, we suggest that, in addition to the CR rate, the primary factors determining the choice of regimen in this population should include the potential toxicities of the regimen and, perhaps most critically, whether it improves the probability of proceeding to alloSCT, the only potentially curative option for R/R AML.
In summary, our retrospective analysis of a large, racially diverse patient population at three different academic institutions suggests that Ara-C couplets, a less frequently used regimen, should be considered a safe and effective salvage for patients with R/R AML. There are a number of salvage chemotherapy regimens available in the relapsed/refractory setting, without a clearly superior regimen. Molecular studies and techniques appear to be a rational method to identify regimens that work best in targeted populations, including the use of patient-specific, genome-wide gene expression profiles and in vitro drug response curves. One recent study using these techniques identified SMARCA4 as a driver of sensitivity to mitoxantrone and etoposide.19 Additionally, BH3 profiling of patient samples may help identify their tumor sensitivity to specific anti-apoptotic agents.20,21
Supplementary Material
Footnotes
SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting Information section at the end of this article.
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