Post-remission treatment with allogeneic stem cell transplantation in patients aged 60 years and older with acute myeloid leukaemia: a time-dependent analysis

doi:10.1016/S2352-3026(15)00148-9

The Lancet Haematology

Volume 2, Issue 10, October 2015, Pages e427-e436

https://doi.org/10.1016/S2352-3026(15)00148-9 Get rights and content

Summary

Background

Acute myeloid leukaemia mainly affects elderly people, with a median age at diagnosis of around 70 years. Although about 50–60% of patients enter first complete remission upon intensive induction chemotherapy, relapse remains high and overall outcomes are disappointing. Therefore, effective post-remission therapy is urgently needed. Although often no post-remission therapy is given to elderly patients, it might include chemotherapy or allogeneic haemopoietic stem cell transplantation (HSCT) following reduced-intensity conditioning. We aimed to assess the comparative value of allogeneic HSCT with other approaches, including no post-remission therapy, in patients with acute myeloid leukaemia aged 60 years and older.

Methods

For this time-dependent analysis, we used the results from four successive prospective HOVON-SAKK acute myeloid leukaemia trials. Between May 3, 2001, and Feb 5, 2010, a total of 1155 patients aged 60 years and older were entered into these trials, of whom 640 obtained a first complete remission after induction chemotherapy and were included in the analysis. Post-remission therapy consisted of allogeneic HSCT following reduced-intensity conditioning (n=97), gemtuzumab ozogamicin (n=110), chemotherapy (n=44), autologous HSCT (n=23), or no further treatment (n=366). Reduced-intensity conditioning regimens consisted of fludarabine combined with 2 Gy of total body irradiation (n=71), fludarabine with busulfan (n=10), or other regimens (n=16). A time-dependent analysis was done, in which allogeneic HSCT was compared with other types of post-remission therapy. The primary endpoint of the study was 5-year overall survival for all treatment groups, analysed by a time-dependent analysis.

Findings

5-year overall survival was 35% (95% CI 25–44) for patients who received an allogeneic HSCT, 21% (17–26) for those who received no additional post-remission therapy, and 26% (19–33) for patients who received either additional chemotherapy or autologous HSCT. Overall survival at 5 years was strongly affected by the European LeukemiaNET acute myeloid leukaemia risk score, with patients in the favourable risk group (n=65) having better 5-year overall survival (56% [95% CI 43–67]) than those with intermediate-risk (n=131; 23% [19–27]) or adverse-risk (n=444; 13% [8–20]) acute myeloid leukaemia. Multivariable analysis with allogeneic HSCT as a time-dependent variable showed that allogeneic HSCT was associated with better 5-year overall survival (HR 0·71 [95% CI 0·53–0·95], p=0·017) compared with non-allogeneic HSCT post-remission therapies or no post-remission therapy, especially in patients with intermediate-risk (0·82 [0·58–1·15]) or adverse-risk (0.39 [0·21–0·73]) acute myeloid leukaemia.

Interpretation

Collectively, the results from these four trials suggest that allogeneic HSCT might be the preferred treatment approach in patients 60 years of age and older with intermediate-risk and adverse-risk acute myeloid leukaemia in first complete remission, but the comparative value should ideally be shown in a prospective randomised study.

Funding

None.

Introduction

Acute myeloid leukaemia mainly affects older adults, with a median age at diagnosis of between 67 and 71 years.¹ Intensive remission induction chemotherapy can be initiated in patients with a favourable performance status and without substantial comorbidities. A first complete remission is obtained in around 50–60% of patients.2, 3 Poor outcome of elderly patients can be explained by an increased incidence of relapse caused by a composite of poor-risk acute myeloid leukaemia characteristics. Thus, outcome is still disappointing in these patients, with 5-year overall survival of 15–30% after intensive induction chemotherapy.2, 3 Therefore, effective post-remission therapy in elderly patients is urgently needed. Post-remission therapy can include continued chemotherapy, autologous haemopoietic stem cell transplantation (HSCT), or allogeneic HSCT, although maintenance treatment has never been proven to be effective. The issue of post-remission chemotherapy in older patients with acute myeloid leukaemia has not been resolved, with equivalent outcomes reported for one cycle of chemotherapy compared with more than one cycle of post-remission chemotherapy.⁴ An earlier study by the HOVON-SAKK consortia⁵ did not show improved outcome following post-remission therapy with the monoclonal antibody gemtuzumab ozogamicin, but the efficacy of this treatment has been the subject of ongoing debate.5, 6, 7, 8 Allogeneic HSCT is the most effective post-remission therapy for the prevention of relapse in young patients with acute myeloid leukaemia in first complete remission.9, 10, 11, 12 However, non-relapse mortality can compromise these favourable effects on overall survival, especially in patients with advanced age, comorbidities, or both. Reduced-intensity conditioning regimens have been developed to reduce non-relapse mortality, while maintaining graft-versus-leukaemia effects.¹³ Allogeneic HSCT following reduced-intensity conditioning has been shown to be feasible and is increasingly used in older patients with newly diagnosed acute myeloid leukaemia.14, 15 Two comparative retrospective trials showed improved outcome by allogeneic HSCT following reduced-intensity conditioning as compared with chemotherapy in elderly patients.16, 17 In the present study, we aimed to compare allogeneic HSCT following reduced-intensity conditioning with other post-remission therapy approaches, including no further post-remission therapy, in patients with acute myeloid leukaemia aged 60 years or older, who were entered into four successive, prospective HOVON-SAKK acute myeloid leukaemia trials.

Research in context

Evidence before this study

We searched PubMed before submission (final search on March 8, 2015) for original research articles published since 2001 about reduced-intensity conditioning allogeneic haemopoietic stem cell transplantation (HSCT) versus chemotherapy in patients aged 60 years and older with acute myeloid leukaemia in first complete remission, using the search terms “acute myeloid leukaemia”, “allogeneic”, “reduced intensity”, and “elderly” or “60 years”. Although several studies showed the feasibility of allogeneic HSCT following reduced-intensity conditioning in elderly patients with acute myeloid leukaemia in first complete remission, no prospective randomised trials comparing allogeneic HSCT versus chemotherapy have been reported in these elderly patients with acute myeloid leukaemia. We identified two comparative retrospective trials that included patients with acute myeloid leukaemia aged 60 years and older and compared allogeneic HSCT with chemotherapeutic post-remission therapy. Both studies suggested improved outcome by allogeneic HSCT compared with other post-remission treatments, which was mostly present in intermediate-risk and adverse-risk subgroups of acute myeloid leukaemia. Similarly, in patients younger than 60 years of age with acute myeloid leukaemia in first complete remission, we and others have reported improved survival with allogeneic HSCT compared with chemotherapeutic post-remission therapy, especially in patients with intermediate-risk and adverse-risk acute myeloid leukaemias.

Added value of this study

Our study included a large number of patients with long follow-up who all received induction treatment for acute myeloid leukaemia in prospective phase 2 and 3 trials. Our results of a time-dependent analysis show that, in patients 60 years of age or older with acute myeloid leukaemia in first complete remission, allogeneic HSCT might provide improved outcome compared with a non-allogeneic HSCT post-remission therapy approach, especially in patients with intermediate-risk and adverse-risk acute myeloid leukaemias.

Implications of all the available evidence

As outlined recently, tailoring of post-remission therapy in elderly patients depends not only on disease-related risk factors, such as the underlying cytogenetic or molecular risk of the acute myeloid leukaemia, but also on patient risk factors, including comorbidity status and performance status. Outcome of post-remission therapy in patients with acute myeloid leukaemia, especially those aged 60 years and older, might benefit from a personalised treatment approach that takes into account both patient and disease factors, with the assessment of acute myeloid leukaemia risk status, comorbidities, and performance status. Although allogeneic HSCT might improve outcome in subgroups of elderly patients with acute myeloid leukaemia, these results need to be confirmed in a prospective trial, which is currently ongoing (NCT00766779).

Section snippets

Study design and participants

Patients aged 60 years and older with newly diagnosed acute myeloid leukaemia were included, who participated in consecutive, prospective HOVON-SAKK phase 3 trials (AML42/42A, AML43, AML81, and AML92) and who obtained first complete remission after one or two induction cycles of chemotherapy and were alive at day 30 after the second cycle of treatment.3, 5, 18 Detailed descriptions of the inclusion and exclusion criteria of these studies are available in appendix pp 9–17. Patients were

Results

Between May 3, 2001, and Feb 5, 2010, induction chemotherapy was started in 1155 patients aged 60 years and older with acute myeloid leukaemia in the four successive prospective HOVON-SAKK trials (figure 1). 515 (45%) of 1155 patients were excluded from the analyses, because of refractory disease or death without achieving first complete remission (427 [37%] of 1155 patients), death during cycle 2 of chemotherapy after an early complete remission (50 [4%] patients), or because they did not

Discussion

At present, outcome in older patients with acute myeloid leukaemia remains poor compared with that in younger patients because of an increased frequency of adverse cytogenetics,²⁴ more concurrent comorbidities,²⁵ and fewer potentially curative treatment options.²⁶ In our analysis, we recorded improved relapse-free survival by allogeneic HSCT compared with no further treatment and non-allogeneic HSCT post-remission therapy in intermediate-risk and adverse-risk patients, and the latter subgroup

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Acute myeloid leukemia (AML) treatment is challenging in older patients. There is a lack of evidence-based recommendations for older patients ≥70, a group largely underrepresented in clinical trials. With new treatment options being available in recent years, recommendations are needed for these patients. As such the International Society of Geriatric Oncology (SIOG) assembled a task force to review the evidence specific to treatment and outcomes in this population of patients ≥70 years. Six questions were selected by the expert panel in domains of (1) baseline assessment, (2) frontline therapy, (3) post-remission therapy, (4) treatment for relapse, (5) targeted therapies, and (6) patient reported outcome/function and enhancing treatment tolerance. Information from current literature was extracted, combining evidence from systematic reviews/meta-analyses, decision models, individual trials targeting these patients, and subgroup data. Accordingly, recommendations were generated using a GRADE approach upon reviewing current evidence by consensus of the whole panel. It is our firm recommendation and hope that direct evidence should be generated for patients aged ≥70 as a distinct group in high need of improvement of their survival outcomes. Such studies should integrate information from a geriatric assessment to optimize external validity and outcomes.
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Hematopoietic stem cell transplantation (HCT) is indicated for patients with higher-risk (HR) myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Age, performance status, patient frailty, comorbidities, and nonclinical factors (eg, cost, distance to site) are all recognized as important clinical factors that can influence HCT referral patterns and patient outcomes; however, the proportion of eligible patients referred for HCT in routine clinical practice is largely unknown. This study aimed to assess patterns of consideration for HCT among patients with HR-MDS and AML enrolled in the Connect® Myeloid Disease Registry at community/government (CO/GOV)- or academic (AC)-based sites, as well as to identify factors associated with rates of transplantation referral. We assessed patterns of consideration for and completion of HCT in patients with HR-MDS and AML enrolled between December 12, 2013, and March 6, 2020, in the Connect Myeloid Disease Registry at 164 CO/GOV and AC sites. Registry sites recorded whether patients were considered for transplantation at baseline and at each follow-up visit. The following answers were possible: “considered potentially eligible,” “not considered potentially eligible,” or “not assessed.” Sites also recorded whether patients subsequently underwent HCT at each follow-up visit. Rates of consideration for HCT between CO/GOV and AC sites were compared using multivariable logistic regression analysis with covariates for age and comorbidity. Among the 778 patients with HR-MDS or AML enrolled in the Connect Myeloid Disease Registry, patients at CO/GOV sites were less likely to be considered potentially eligible for HCT than patients at AC sites (27.9% versus 43.9%; P < .0001). Multivariable logistic regression analysis with factors for age (<65 versus ≥65 years) and ACE-27 comorbidity grade (<2 versus ≥2) showed that patients at CO/GOV sites were significantly less likely than those at AC sites to be considered potentially eligible for HCT (odds ratio, 1.6, 95% confidence interval, 1.1 to 2.4; P = .0155). Among patients considered eligible for HCT, 45.1% (65 of 144) of those at CO/GOV sites and 35.7% (41 of 115) of those at AC sites underwent transplantation (P = .12). Approximately one-half of all patients at CO/GOV (50.1%) and AC (45.4%) sites were not considered potentially eligible for HCT; the most common reasons were age at CO/GOV sites (71.5%) and comorbidities at AC sites (52.1%). Across all sites, 17.4% of patients were reported as not assessed (and thus not considered) for HCT by their treating physician (20.7% at CO/GOV sites and 10.7% at AC sites; P = .0005). These findings suggest that many patients with HR-MDS and AML who may be candidates for HCT are not receiving assessment or consideration for transplantation in clinical practice. In addition, treatment at CO/GOV sites and age remain significant barriers to ensuring that all potentially eligible patients are assessed for HCT.
In-depth time-dependent analysis of the benefit of allo-HSCT for elderly patients with CR1 AML: a FILO study
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The benefit of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with acute myeloid leukemia (AML) aged >60 years remains a matter of debate, notably when performed in first complete remission (CR1). To clarify this issue, the French Innovative Leukemia Organization (FILO) performed a 10-year real-world time-dependent analysis. The study enrolled patients between 60 and 70 years of age with AML in CR1 after intensive chemotherapy with intermediate (IR) or unfavorable (UR) risk according to the European LeukemiaNet (ELN) 2010 classification. The impact of allo-HSCT was analyzed through three models: (1) time-dependent Cox; (2) multistate for dynamic prediction; and (3) super landmark. The study enrolled 369 (73%) IR and 138 (27%) UR patients with AML, 203 of whom received an allo-HSCT. Classical multivariate analysis showed that allo-HSCT significantly improved relapse-free survival (RFS; hazard ratio [HR] [95% confidence interval (CI)], 0.47 [0.35-0.62]; P < .001) and overall survival (OS; HR [95% CI], 0.56 [0.42-0.76]; P < .001), independently of the ELN risk group. With the multistate model, the predicted 5-year probability for IR and UR patients to remain in CR1 without allo-HSCT was 8% and 1%, respectively. Dynamic predictions confirmed that patients without allo-HSCT continue to relapse over time. Finally, the super landmark model showed that allo-HSCT significantly improved RFS (HR [95% CI], 0.47 [0.36-0.62]; P < .001) and OS (HR [95% CI], 0.54 [0.40-0.72]; P < .001). allo-HSCT in CR1 is reported here as significantly improving the outcome of fit older patients with AML. Long-term RFS without allo-HSCT is very low (<10%), supporting allo-HSCT as being the best curative option for these patients.
Maintenance therapy with hypomethylating agents for patients with acute myeloid leukemia in first remission not eligible for allogeneic hematopoietic cell transplantation: A systematic review and meta-analysis
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Older patients encompass about 75 % of patients with acute myeloid leukemia (AML). Today therapeutic options to prevent relapse in older patients who managed to achieve complete remission (CR) after intensive chemotherapy are scarce. Recent randomized controlled trials (RCTs) have aimed to reduce the risk of relapse by means of post-CR maintenance therapy.
We performed a systematic review and meta-analysis of RCTs comparing the efficacy and safety of maintenance with hypomethylating agents (HMA) vs. observation, conventional care or placebo in older patients with AML who are not candidates for allogeneic hematopoietic transplantation (allo−HCT). We searched Cochrane Library, PubMed and conference proceedings up to August 2021.
Six trials were included. Treatment with hypomethylating agents significantly improved overall survival (HR 0.80, 95 % CI 0.70 to 0.91, I² = 30 %), and disease control (HR 0.80, 95 % CI 0.70 to 0.91, I² = 0). A significant decrease was seen in both one year mortality (Risk Ratio [RR] 0.61, 95 % CI 0.48 to 0.77, I² = 0) and mortality at the end of follow-up (RR 0.77, 95 % CI 0.67 to 0.88, I² = 0). The rate of relapse at 6 months and at one-two years was lower in the HMA arm vs. control (RR, 0.59; 95 % CI, 0.47−0.72; RR, 0.74, I² = 0; 95 % CI 0.69 – 0.91, I² = 41 %, respectively). HMA were associated with a statistically non-significant increase in the risk of serious adverse events (RR 3.44, 95 % CI 0.93–12.74, I² = 80 %).
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Hypomethylating Agents and FLT3 Inhibitors As Maintenance Treatment for Acute Myeloid Leukemia and Myelodysplastic Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation–A Systematic Review and Meta-Analysis
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Disease relapse remains the major cause of death among patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) who receive an allogeneic hematopoietic cell transplant (allo-HCT). Maintenance treatment with FLT3 inhibitors and hypomethylating agents (HMA) has been studied in various clinical trials with mixed results.
To synthesize the current evidence on the efficacy and safety of FLT3 inhibitors and HMA for maintenance therapy after allo-HCT in AML and MDS.
For this systematic review and meta-analysis Cochrane Library, Google Scholar, Ovid Medline, Ovid Embase, PubMed, Scopus, and Web of Science Core Collection were searched from inception to March 2021 for studies on maintenance therapies after allo-HCT in AML and MDS. Studies were excluded if they were reviews, commentaries, case series with <5 patients, or basic research articles, not published in English, not on post-allo-HCT maintenance with FLT3 inhibitors or HMA in AML or MDS, or if they were clinical trials without published results or duplicate publications from the same patient cohort. Studies with insufficient reporting of the primary endpoint (2-year overall survival [OS]) and studies using FLT3 inhibitors or HMA for pre-emptive treatment of imminent relapse based on positive measurable residual disease testing were excluded. Random-effects models were used to pool response rates for the primary outcome of 2-year OS. Hazard ratios (HR) for death and relapse were calculated for studies that included a control group. Rates of relapse-free survival (RFS), non-relapse mortality, and acute and chronic graft-versus-host-disease (GVHD) were studied as secondary endpoints. Downs and Black checklist and risk of bias assessments were used to gauge the quality of individual studies. The study protocol has been registered on PROSPERO (CRD42020187298).
Our search strategy identified 5559 studies. Twenty-one studies with a total of 809 patients were included in the meta-analysis. The 2-year OS rates were 81.7% (95% confidence interval [CI], 73.8%-87.7%) and 65.7% (95% CI, 55.1%-74.9%) among patients treated with FLT3 inhibitors and HMA, respectively. In sensitivity analyses restricted to studies that included a control group, maintenance therapy with FLT3 inhibitors (HR for death = 0.41; 95% CI, 0.26-0.62) or HMA (HR = 0.45; 95% CI, 0.31-0.66) appeared superior to no maintenance therapy. The 2-year RFS rates were 79.8% (95% CI, 75.0%-83.9%) and 62.4% (95% CI, 50.6%-72.9%) among patients treated with FLT3 inhibitors and HMA, respectively. Rates of any grade acute and chronic GVHD were 33.1% (95% CI, 25.4%-41.8%; grade 3/4: 16.5%) and 42.5% (95% CI, 26.3%-60.4%) among FLT3 inhibitor and 42.7% (95% CI, 33.5%-52.4%; grade 3/4: 8.1%) and 41.5% (95% CI, 32.0%-51.6%) among HMA-treated patients, respectively.
Maintenance therapy with either FLT3 inhibitors or HMA after allo-HCT can lead to prolonged and improved OS and RFS with a favorable safety profile. Additional studies are needed to define the optimal duration of treatment, the role of measurable residual disease status, and transplant characteristics in patient selection.
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T cell based immunotherapies can be applicable to acute myeloid leukemia (AML). Therefore, the selection of optimal T cells, cell manufacturing, and therapeutic T cell engineering are essential for the development of effective adoptive T cell therapies for AML. Autologous tumor-infiltrating lymphocytes (TILs) have been in clinical trials to treat solid malignancies. Herein, we assessed whether TILs can be isolated from the bone marrow (BM) of AML patients, expanded ex vivo and utilized as a novel therapeutic strategy for AML. To this end, firstly we analyzed the immunophenotypes of a series of primary BM samples from AML patients (N = 10) by flow cytometry. We observed a variable amount of CD3+ TILs (range ∼2.3–∼32.6% of mononuclear cells) among BM samples. We then developed a novel protocol that produced a three-log ex vivo expansion of TILs isolated from AML patient BM (N = 10) and peripheral blood (PB) (N = 10), including from patients with a low number of CD3+ T cells, within 3, 4 weeks. Further, we identified previously described naïve T cells (CCR7+CD95-/or CD62L+CD45RA+) in AML BM and PB samples, which seemed to be required for a successful TILs ex vivo expansion. Finally, we showed that the expanded TILs could: (1) cause cytotoxicity to autologous AML blasts ex vivo (90.6% in control without T cell treatment vs. 1.89% in experimental groups with PB derived T cells and 1.77% in experimental groups with BM derived TILs, p < 0.01), (2) be genetically engineered to express CYP27B1 gene, and (3) infiltrate the BM and reside in close proximity to pre-injected autologous AML blasts of engrafted immunodeficiency mice. Altogether, these results provide a rationale for further studies of the therapeutic use of TILs in AML.

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^*: Contributed equally

^†: All participating HOVON-SAKK institutes and investigators are listed in the appendix

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ArticlesPost-remission treatment with allogeneic stem cell transplantation in patients aged 60 years and older with acute myeloid leukaemia: a time-dependent analysis

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Blood

Blood

Lancet Oncol

Lancet

Blood

Blood

Biol Blood Marrow Transplant

Blood

Lancet

Blood

Blood

Blood

SEER Cancer Statistics Review 1975–2008

The impact of dose escalation and resistance modulation in older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome: the results of the LRF AML14 trial

Br J Haematol

High-dose daunorubicin in older patients with acute myeloid leukemia

N Engl J Med

Articles
Post-remission treatment with allogeneic stem cell transplantation in patients aged 60 years and older with acute myeloid leukaemia: a time-dependent analysis