Allogeneic hematopoietic cell transplantation in acute myeloid leukemia with intermediate-risk - results of the randomized ETAL-1 trial

doi:10.21203/rs.3.rs-1820408/v1

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Allogeneic hematopoietic cell transplantation in acute myeloid leukemia with intermediate-risk - results of the randomized ETAL-1 trial

https://doi.org/10.21203/rs.3.rs-1820408/v1

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The ideal post-remission strategy in patients with intermediate-risk (IR) acute myeloid leukemia (AML) in first complete remission (CR) has been a matter of debate. To address this question, one hundred and forty-three patients with AML, IR cytogenetics in first CR or CRi, aged ≤ 60 years with an available HLA-matched sibling or unrelated donor were randomized 1:1 to either receive allogeneic HCT or high-dose cytarabine for consolidation and salvage HCT only in case of relapse.

According to the intent-to-treat analysis, the probability of survival at 2 years was 71% (95%-CI 60-81%) and 84% (95%.CI 73-92%) in Arm A (Primary allogeneic HCT) and Arm B (Chemo-consolidation), respectively (p=.120). Disease-free survival after HCT in CR1 at 2 years was 69% (95%-CI 57-80%) compared to 41% (95%-CI 29-54%; p=.001). The cumulative incidence of relapse was 20% (95% CI 13-31%) and 57% (95%-CI 46-71%; p<.001), respectively. Non-relapse mortality at 2 years after primary allogeneic HCT was below 10% in both arms. No significant differences in health-related quality of life measures were observed. In summary, delayed allogeneic HCT in case of relapse may be a reasonable approach to patients ≤ 60 years of age with intermediate-risk AML in CR1 with an available donor.

acute myeloid leukemia

first remission

allogeneic hematopoietic cell transplantation

consolidation therapy

cytogenetic intermediate risk

Acute Myeloid Leukemia (AML) is a heterogeneous clonal, malignant disorder that originates from hematopoietic stem and progenitor cells. Despite improvements in stratified and targeted therapy and supportive care, fewer than 30% of adults with AML can be expected to survive and be cured.^1,2

The most important prognostic indicators with regard to therapy response and outcome are cytogenetic and molecular genetic abnormalities in the leukemic cells. These abnormalities have been integrated in the most recent ELN classification to divide a given patient’s prognosis into favorable-risk, intermediate-risk, and adverse-risk.³ Beside biologic risk factors, patient specific parameters such as age and performance status are also linked to outcome. ⁴

Although the likelihood of achieving a first complete remission (CR) largely depends on molecular risk factors, 50–70% of patients undergoing intensive induction chemotherapy are subsequently referred to post-remission therapy.^5,6 Whereas favorable risk patients clearly do benefit from consolidation therapy based on high-dose cytarabine, high-risk patients with an adequate performance status are candidates for allogeneic hematopoietic cell transplantation, if a suitable donor can be identified⁷. In contrast, there is controversy about the optimal treatment algorithm in the intermediate-risk group. While the risk of relapse is lowest with allogeneic HCT, this advantage can be offset by the higher risk of transplant-related mortality. Furthermore, a relevant proportion of intermediate-risk patients may still be rescued by allogeneic HCT after relapse of AML.^8,6

Retrospective studies comparing patients with and without a matched-sibling donor including time-dependent models, matched-pair analyses and meta-analyses have suggested a survival advantage for allogeneic HCT compared to chemotherapy, most pronounced in high-risk patients defined by cytogenetic assessment.^9–10 One intergroup analysis also found an advantage for younger intermediate-risk patients with matched sibling donors.¹¹ With the majority of AML patients being > 50 years, the improved outcomes after allogeneic HCT with reduced-intensity conditioning (RIC) and the availability of matched unrelated donors for 70–80% of Caucasian patients, the relative role of allogeneic HCT should ideally be studied within a prospective randomized trial.^12,13

Hence, the multicenter ETAL-1 trial was initiated for adult patients with AML in first CR/CRi (CR1) for whom a suitable donor had been identified. Patients were allocated to receive either allogeneic HCT (Experimental Arm A) or conventional consolidation therapy with the option of salvage HCT in case of relapse (control arm B). The current report presents the first efficacy data after 143 randomized patients analyzed with a minimum follow-up of two years and premature closure of the study due to slow accrual.

Study design and Patients

The role of allogeneic HCT in cytogenetically defined intermediate-risk (IR) AML patients in CR1 was addressed by a prospective randomized trial performed in 16 centers in Germany. This study is registered with ClinicalTrials.gov, NCT 01246752 (completed).

Key inclusion criteria were: AML with IR-cytogenetics according to MRC classification¹⁴, first CR or CRi after conventional induction therapy, age of 18–60 years, and availability of an HLA-matched sibling or unrelated donor. For unrelated donors, a 9 out of 10 HLA allelic match was acceptable except for patients with an NPM1 mutation, for whom full 10/10 allele matching was required. Randomization 1:1 was stratified according to age (18–40 years vs. 41–60 years), NPM1 and CEBPA mutational status as well as donor type (unrelated vs. related). Endpoints included overall-survival (OS) as primary outcome and disease-free survival (DFS), cumulative incidence of relapse (CIR), treatment-related mortality (TRM), and quality of life (QoL) measured according to the short form (SF36) health status¹⁵.

Treatment

Patients allocated to the investigational arm A (allo HCT) were scheduled to start conditioning therapy within 4–6 weeks after randomization. Intensive conditioning regimens for patients ≤ 40 years included total-body irradiation (TBI) at 1200 cGy combined with 60 mg/kg cyclophosphamide per day over 2 days (days − 3 and − 2) or intravenous busulfan at a total dose of 12.8 mg/kg applied over 4 days followed by 60 mg/kg cyclophosphamide over 2 days (days − 3 and − 2). Patients > 40 years could receive either of the following reduced-intensity protocols: i) 800 cGy TBI with 30 mg/m² fludarabine over 4 days, ii) intravenous busulfan at 6.4 mg/kg with 30 mg/m² fludarabine over 5 days, iii) treosulfan 42 mg/m² with 30 mg/m² fludarabine over 5 days or iv) melphalan 140 mg/m² with 30 mg/m² fludarabine over 5 days. Antityhmocyte globulin ATG was administered at a dose of 3 × 10–20 mg/kg on days − 3 to − 1 (cumulative dose, 30–60 mg/kg) as prophylaxis for acute and chronic GvHD in patients receiving grafts from unrelated donors.

All patients undergoing allogeneic HCT received cyclosporine A (CsA) starting one day before transplantation, with target trough concentrations of 200 ng/mL or greater in combination with 15 mg/m² methotrexate on day 1 after transplantation and 10 mg/m² on days 3, 6, and 11 after transplantation. Mycophenolate mofetil was allowed in patients not tolerating methotrexate. CsA was tapered, if possible, after day 100 in case of a matched sibling donor and after day 180 when a graft from an unrelated donor had been transplanted. Both peripheral blood stem cells (PBSC) mobilized with granulocyte-colony stimulating factor (G-CSF) and bone marrow (BM) were accepted as hematopoietic cell grafts. Target cells doses were 4 × 10⁶/kg CD34 + cells for PBSC and > 2 × 10⁸/kg nuclear cells for bone marrow grafts. Donor eligibility was tested according to international standards. No post-grafting G-CSF was routinely administered.

In the control arm B, consolidation was scheduled to start 4–6 weeks after randomization. According to the ELN guidelines, three cycles of high dose cytarabine (AraC) on days 1-3-5 with 3000 mg/m² /BID each were planned. In the event of relapse in arm B, allogeneic HCT with the already identified donor was to be performed (salvage regimens applied were not pre-specified). In case of imminent detection of disease recurrence (e.g. molecular relapse (e.g. measurable residual disease), allogeneic salvage HCT could also be performed without prior re-induction therapy. Post-remission therapies and the indications for allogeneic HCT in the control arm B were documented and evaluated within the study.

By the time of randomization and every three months during the first two years and every six months during the third and fourth year after inclusion, the patients were asked to fill in the SF-36 health survey as a standardized quality of life (QOL) questionnaire. QoL as a secondary end-point was analyzed descriptively.

In both treatment arms, adverse events (AEs) and severe adverse events (SAEs) were monitored and documented as part of the safety assessment required for the investigational compound which had been the hematopoietic graft from the regulatory perspective. The protocol and analyses were approved by the ethical commission of the Technical University Dresden (EK 143052010). All patients provided written informed consent before study inclusion.

Statistical analysis

Primary endpoint was Overall survival. Survival time was calculated from date of randomization until date of death and was censored on date of last follow-up, if no death occurred. The observational period was limited to 4 years per patient.

Disease free survival (DFS) was calculated from date of randomization until relapse or death, whatever occurred first. DFS was censored on date of last follow-up, if none of the events occurred. NRM was defined as any death not preceded by relapse. CR and relapse were defined according to criteria published by Cheson et al.¹⁶ Median follow-up time was estimated by the reverse Kaplan-Meier method.

The Kaplan–Meier method was used to estimate OS and DFS probabilities. Point wise confidence intervals (CI) are provided using Greenwood’s formula for the standard error estimation. P-values and confidence intervals provided are 2-sided.

Due to the violation of the proportional hazards assumption the primary hypothesis test comparing overall survival at 2 years was conducted using a binomial variable indicating survival status at 2 years. Missing data were imputed using a worst case approach imputing missing data in the control arm as being alive at 2 years and being deceased in the transplant arm. This approach was only used for the primary hypothesis test of the 2 year overall survival endpoint. Point estimates and two-sided 95% Clopper-Pearson confidence intervals are presented for this endpoint. The comparison was performed with the likelihood ratio test. Because this conservative approach may result in estimates biased favoring the control arm Kaplan-Meier estimates are presented also. Comparisons of disease free survival were performed with a binomial variable indicating disease free survival at 2 years and the likelihood ratio test. Complete cases without imputation were used. Two-sided 95% confidence intervals are presented. In addition Kaplan-Meier estimates are also presented.

Incidence of NRM and relapse were estimated using Gray’s methodology for competing events. The Gray-Test was used for comparison of cumulative incidences.

Multivariable Cox regression models for time-to-event endpoints were applied. The proportional hazard (PH) assumption held for all covariates except treatment arm, as expected. We decided to report results of the Cox models to enable comparisons with historical data. The resulting hazard ratio for the treatment-effect allo-HCT vs chemo consolidation can be interpreted as weighted average of hazard ratios over the entire follow-up period.¹⁷

The subscales of the SF-36 questionnaire were calculated according to the scoring manual. For descriptive analysis mean and standard deviation were calculated for each visit and treatment arm. Completion rates were calculated. The duration of hospitalization in both treatment arms was compared by applying a Mann-Whitney-U Test. All statistical analyses were performed with R version 4.0.3.¹⁸

Accrual of patients and clinical characteristics

Until July 1st 2018, one-hundred and forty-three patients with AML in first CR1 were randomized into Arm A (n = 76, allo HCT) and Arm B (n = 67, conventional consolidation and allo HCT only in case of relapse). The trial was subsequently closed due to slow accrual. Patient flow and reasons for protocol deviations are summarized in the CONSORT statement in Fig. 1.

Major patient characteristics including stratification variables (age, CEBPA, FLT3 and NPM1 mutational status, donor type) and demographics are provided in Table 1. As expected, most baseline parameters and biologic risk factors are well balanced between both groups. With cytogenetic IR being the inclusion criteria chosen in 2012, a similar proportion of patients with normal karyotype are categorized to the ELN favorable risk category due to CEBPA bi-allelic mutations, NPM1 mutations and absence or low mutational burden of FLT3-ITD in both treatment arms. As recommended in the protocol, 12 out of 76 patients in arm A received one consolidation course of high-dose cytarabine after having achieved CR to bridge until allogeneic HCT. All other patients received allogeneic HCT directly after induction therapy. In arm B, all but one patients (n = 66) received between one and three cycles of high-dose cytarabine consolidation (median = 3, range 2–3). The median follow-up for surviving patients was 48 (IQR, 42–49) months.

Table 1

Patient and treatment characteristics
	Arm A, HCT (n = 76)	Arm B, Chemo consol. (n = 67)
Age [years]
Median	50.5	51
Range	(19–60)	(24–60)
Age subgroup [No. (%)]
18–40 years	16 (21)	11 (16)
41–60 years	60 (79)	56 (84)
Gender [No. (%)]
Female	31 (41)	31 (46)
Male	45 (59)	36 (54)
Cytogenetics [No. (%)]
Normal karyotype Other intermediate abnormalities	54 (71) 16 (29)	55 (82) 12 (18)
CEBPA status
Biallellic Mutation	4 (5)	1 (1)
NPM1 Status/FLT3- ITD status [No. (%)]
Mutated/Mutated	12 (17)	13 (20)
Mutated/Wild-type	17 (25)	14 (22)
Wild-type/Mutated	5 (7)	3 (5)
Wild-type/Wild-type	35 (51)	34 (53)
Missing	7 (9)	3 (4)
FLT3-ITD ratio
Median (range)	0.57 (0.36-1)	0.54 (0.22–0.63)
ELN 2017 Category
Favorable	24 (32)	19 (28)
Intermediate	50 (66)	46 (69)
Adverse	2 (2)	2 (3)
Available Donor [No. (%)]
Matched sibling	18 (24)	23 (34)
Matched unrelated (10/10)	51 (67)	35 (52)
1 allele mismatched unrelated (9/10)	7 (9)	9 (13)
CMV serostatus* [patient, No. (%)]
Positive	41 (54)	36 (54)
Negative	35 (46)	31 (46)
Conditioning therapy
Intensive	9	-
Reduced-Intensity	61	-
SC, standard conditioning; RIC, reduced-intensity conditioning; CEBPA, CCAAT/enhancer-binding protein alpha gene; FLT3-ITD, fms-like tyrosine kinase 3 gene-internal tandem duplication; NPM1, nucleophosmin-1 gene; ELN, European Leukemia Network; CMV, cytomegalovirus

Overall and Disease-free survival

According to the intent-to-treat analysis, the probability of survival at 2 years was 71% (95% CI 60–81%) (54/76 patients, 4 patients with missing values imputed as ‘dead’) and 84% (95% CI 73–92%) (56/67 patients, 4 patients with missing values imputed as ‘alive’)) in Arm A (allo HCT) and Arm B (conventional consolidation), respectively (p = .120; estimates with missing values censored were 76% (95% CI 67–86%) and 83% (95% CI 74–93%) (Fig. 2A). Two-year DFS after allogeneic HCT was 69% (95% CI 57–80%) compared to 41% (95% CI 29–54%) after conventional consolidation (p = .001; estimates with missing values censored were 71% (95% CI 61–82%) and 41% (95% CI 31–55%)) (Fig. 2B). Hazard ratios and 95% confidence intervals for pre-defined subgroups on OS (A) and DFS (B) are provided in Fig. 3. A post-hoc analysis in patients with intermediate-risk AML according to ELN20017 revealed exactly the same advantage in disease-free survival after two years (69% after HCT and 40% after chemo-consolidation; p = 0.04) and no difference in overall survival (75% after allogeneic HCT vs. 82% after conventional postremnission therapy, Supplementary Figure S1).

Non-relapse mortality, safety and relapse incidence

Primary allogeneic HCT was associated with a significantly lower cumulative incidence of relapse at 2 years with 20% (95%-CI 13–31%) compared to 57% (95%- CI 46–71%) after conventional consolidation (p < .001). Non-relapse mortality at 2 years was 9% (95%-CI 5–19%) compared to 2% (95%-CI 0–11%) after conventional consolidation (p = .017). Most importantly, all 38 patients relapsing in arm B (33 hematologic, 4 molecular and 1 extramedullary) proceeded to allogeneic HCT either directly (n = 19) or after salvage therapy (n = 19). The regimens applied to treat relapse before salvage allogeneic HCT are summarized in supplementary table 1.

The percentage of patients for whom any SAE was reported, was not different between the HCT arm (74%, n = 55/74) and the control group (74%, n = 49/66).

Measurable residual disease

For patients with NPM1-mutated AML regular monitoring of measurable residual disease (MRD) out of bone marrow samples by PCR was recommended¹⁹. Overall, 309 serial samples and MRD results could be attributed to 31 patients (65% of NPM1 mutated cases). The percentage of patients with detectable MRD by the time of randomization was 73% (n = 11/15) in the HCT arm vs. 62% (n = 10/16) in the control arm. Six and twelve months after inclusion, only 2/10 and 2/8 remained NPM1 positive by PCR in the HCT arm. In contrast, 8/12 and 6/11 of patients receiving cytarabine consolidation were NPM1-positive by PCR assay at these landmarks, respectively. Due to limited number of patients with complete MRD data, an analysis of the prognostic relevance of MRD positivity on outcome parameters was not feasible.

Quality of life and duration of hospitalization

None of the SF-36 scales differed significantly between treatment arms. The dimensions of all SF-36 variables over the follow-up in both groups are depicted in Fig. 1 of the supplement (Suppl. Figure 1). The median duration of in-hospital stay was significantly shorter in the HCT arm (median 42.5 days, IQR 31–62) compared to conventional consolidation (median 106 days, IQR 72–143), p < .0001.

The results of the current study indicate that allogeneic HCT can be delayed until 1st relapse in patients ≤ 60 years of age with cytogenetically defined intermediate-risk AML. The availability of a suitable donor in the control arm allowed to perform allogeneic HCT in all patients with reoccurring disease which lead to comparable overall survival with both strategies. This optimized salvage procedure allowed to compensate for the higher incidence of relapse in the control arm. However, this means that patients relapsing after chemotherapeutic consolidation had to undergo salvage therapies and conditioning and were subject to higher cumulative doses of cytotoxic treatment. Furthermore, a considerable proportion of patients had favorable risk according to the ELN2017 classification and were therefore likely to respond to salvage chemotherapy.

With the advent of sensitive and specific techniques to monitor disease burden during the course of treatment, the majority of patients currently and in the future will have the option to be stratified according to on-therapy disease dynamics. ^19,20 As the routine incorporation of MRD studies in patients was only established during the accrual of the ETAL1 trial²¹, quantitative NPM1-PCR values could be attributed to 45 patients (80% of NPM1 mutated cases). The percentage of patients with detectable MRD by the time of randomization was 73% (n = 11/15) in the HCT arm vs. 62% (n = 10/16) in the control arm. The number of patients with detectable NPM1 levels after six and twelve months, was 2 out of 10 and 2 out of 8 in the HCT arm. The corresponding numbers were 8 out of 12 and 6 out of 11 after cytarabine consolidation, respectively. Due to limited number of patients with complete MRD data, a formal comparison between treatment arms and an analysis of the prognostic relevance of MRD positivity on outcome parameters was not feasible.

Furthermore, an improved safety and thereby efficacy of allogeneic HCT with reduced-intensity conditioning and lower treatment-related mortality has been be observed even in older patients in recent analyes.^22,23 In parallel, donor availability has improved with many suitable donors being enlisted and the increasing use of post-transplant cyclophosphamide (PTCY) after mismatched or haploidentical HCT procedures enables transplantation in almost all patients.^24,25 All this contributes to an increased likelihood to detect imminent relapse early and to perform HCT in the majority of patients with AML relapse after conventional consolidation.

Prospective randomized trials as well as retrospective cohort studies have demonstrated that the choice of conditioning therapy affects the likelihood of relapse and that MRD status should be regarded as an important variable for allocating the intensity of conditioning therapy.^26,27 Whether more unspecific strategies like hypomethylating agents, targeted therapies or immunotherapeutic approaches are most effective in achieving and maintaining a second MRD negative state is an important question for future clinical research. The positive results of tyrosine-kinase inhibitors after allogeneic HCT in patients with FLT3-ITD/TKD mutations is an example to improve efficacy of HCT for relapsed patients by maintenance strategies.^28,29

The ETAL-1 study has several weaknesses. First, the trial had to be stopped prematurely, due to slow accrual. Reasons for slow recruitment are potentially multifactorial and not fully clear, but according to the screening log patients obviously tend to refuse leaving a decision for an intensive and potentially life-threatening procedure like allogeneic HCT to a computer-based randomization algorithm. In line with our experience, a similar UK Medical Research Council (MRC) trial which had intended to randomize patients with a matched sibling donor had to be terminated prematurely due to lack of accrual with only 40 patients being randomized.³⁰ Furthermore, the use of a cytogenetic classifier by the time, of trial initiation in 2012 lead to the inclusion of ELN favorable risk patients for whom current guidelines would not recommend allogeneic HCT in first CR³. Still, the analysis of intermediate-risk patients according to ELN revealed exactly the same results. Finally, the routine use of MRD studies before and after allogeneic HCT had been developed but not standardized in 2012 and were not a mandatory part of the trial protocol. As assumed, the available quantitative NPM1 data suggest a higher probability of MRD negativity after primary allogeneic HCT.

An important and rewarding finding of this trial was the low non-relapse mortality after both treatment strategies even in a multicenter setting in patients with a median age of > 50 years. This achievement is clearly due to the availability of less toxic but still effective conditioning therapies and modern antiviral and antifungal prophylaxis.¹² Although the returns of the QOL remained below our expectations, it was interesting to appreciate that except a temporal physical dysfunction, other QOL parameters did not differ between both treatment arms. Such a finding is of practical relevance and can be incorporated into future patient counseling. Expectedly, the duration of hospitalization was significantly longer for patients who underwent 2–3 cycles of consolidation chemotherapy. This information is of major relevance for the patient and their families and needs to be factored in when shared decision making is pursued. As mentioned previously, and additional 38 patients in the control had to be rescued by allogeneic HCT. These patients have been exposed to several cycles of high-dose chemotherapy plus additional salvage regimens before allogeneic HCT in 14 cases. Therefore, the cumulative exposure to chemotherapy may get considerable and should be kept in mind when patients with a considerable risk of relapse are advised pro or contra allogeneic HCT in first CR. In order to accommodate the preferences with regard to conditioning regimen, four different RIC were offered for patients > 40 or for younger patients with comorbidities. Although the majority of patients received Fludarabine combined with 8Gy TBI (n = 34), Treosulfan (n = 2) or Melphalan (n = 9), still 16 patients (26%) in arm A were conditioned with Fludarabine plus two days of Busulfan. As this regimen (FluBU2) has been shown to be associated with an excess incidence of relapse²⁷, the differential anti-leukemic activity of the chosen regimens has to be kept in mind when interpreting the outcome data in the experimental arm.

In conclusion, the results of this randomized prospective trial support the notion that patients ≤ 60 years intermediate-risk AML, as defined by MRC cytogenetic criteria, despite an improved disease-free survival, do not benefit from allogeneic HCT in first CR with regards to overall survival. The early identification of a suitable donor allows timely rescuing those patients with relapse after conventional consolidation therapy. Future studies, applying longitudinal monitoring of residual disease dynamics will help to personalize the ideal time-point for allogeneic HCT in the majority of patients.

Acknowledgments: We greatly acknowledge the contribution of Annett Haake in trial organization, monitoring, and source data verification. We thank all the nursing staff and physicians for the excellent patient care. We also acknowledge the local data managers for helping with data acquisition. This study was funded by the Deutsche Forschungsgemeinschaft (DFG BO 2908/2-1)

Clinical trial information: This study was registered with Clintrials.gov NCT 01246752.

Authorship: Contributions: MB, WEB, GE, MP and MStell designed the clinical trial. MB, MK, JS and MStell wrote the report. MB, CS, JS, CR, MK, BG, UP, AB, MH, LPM, SK, GB, DB, WR, KSE, CSCH, EJ, GL, JT, KS, GE, WEB, HS, JMM, CT, FS, NA and MStell recruited patients and gathered the data. MK and JS performed statistical analysis. MB, JS, MK, WEB and MStell interpreted the data. All authors reviewed and edited the report and have seen and approved the final draft.

Conflict-of interest: MB reports scientific advisory board memberships and speaker honoraria from Jazz Pharmaceuticals, MSD Sharp & Dome and Alexion. CS reports research grant support by ANTUREC Pharmaceuticals GmbH. JS reports research grant support by the German Bone Marrow Registry (DKMS). UP reports research grant support and speaker honoraria form Celgene. AB reports speaker honoraria and research grant support from Bayer. GL reports speaker honoraria from Incyte Biosciences. HS reports research grant support and speaker honoraria from Bayer. CT is CEO of Agendix, a company offering molecular diagnostics in hematology. GE is founder and CEO of the biotech companies Gemoab and Cellex. WEB is founder and CEO of ANTUREC Pharmaceuticals GmbH. MSt reports institutional research grant support and speaker honoraria from Pfizer. The other authors not declare any conflict-of interest.

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Allogeneic hematopoietic cell transplantation in acute myeloid leukemia with intermediate-risk - results of the randomized ETAL-1 trial

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Abstract

Figures

Introduction

Patients And Methods

Study design and Patients

Treatment

Statistical analysis

Results

Accrual of patients and clinical characteristics

Overall and Disease-free survival

Non-relapse mortality, safety and relapse incidence

Measurable residual disease

Quality of life and duration of hospitalization

Discussion

Declarations

References

Additional Declarations

Supplementary Files

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