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Key Points

Question听 What is the optimal postremission therapy in patients with intermediate-risk acute myeloid leukemia (AML)?

Findings听 In this randomized clinical trial of 143 adults 60 years or younger with intermediate-risk AML and an available donor, allogeneic hematopoietic cell transplantation (allo-HCT) performed during the first complete remission was associated with a significantly higher disease-free survival (69% vs 40%) but similar overall survival compared with consolidation chemotherapy and allo-HCT only in case of relapse.

Meaning听 In intermediate-risk AML in first complete remission, allo-HCT may be delayed to first relapse, and patients may be counseled accordingly.

Importance听 The ideal postremission strategy in intermediate-risk acute myeloid leukemia (AML) in first complete remission (CR) has been a matter of debate.

Objective听 To explore the optimal therapy for patients with intermediate-risk AML after first complete remission.

Design, Settings, and Participants听 This investigator-initiated, open-label, 2-armed, phase 3 randomized clinical trial assessed patients at 16 hospitals in Germany from February 2, 2011, until July 1, 2018. Key eligibility criteria included cytogenetically defined intermediate-risk AML according to Medical Research Council classification, first CR or CR with incomplete blood cell count recovery after conventional induction therapy, age of 18 to 60 years, and availability of a human leukocyte antigen (HLA)鈥搈atched sibling or unrelated donor. A detailed statistical analysis plan was written and finalized on July 7, 2020. Data were exported for analysis on April 13, 2021.

Interventions听 Patients were randomized 1:1 to receive allogeneic hematopoietic cell transplantation (HCT) or high-dose cytarabine for consolidation and salvage HCT only in case of relapse. Strata for randomization included age (18-40 vs 41-60 years), NPM1 and CEBPA variation status, and donor type (unrelated vs related).

Main Outcomes and Measures听 End points included overall-survival as the primary outcome and disease-free survival, cumulative incidence of relapse, treatment-related mortality, and quality of life measured according to the Medical Outcomes Study 36-Item Short-Form Health Survey as secondary outcomes.

Results听 A total of 143 patients (mean [SD] age, 48.2 [9.8] years; 81 [57%] male) with AML who fulfilled the eligibility criteria were randomized. In the intention-to-treat analysis, the probability of survival at 2 years was 74% (95% CI, 62%-83%) after primary allogeneic HCT and 84% (95% CI, 73%-92%) after consolidation chemotherapy (P鈥�=鈥�.22). Disease-free survival after HCT at 2 years was 69% (95% CI, 57%-80%) compared with 40% (95% CI, 28%-53%) after consolidation chemotherapy (P鈥�=鈥�.001). Allogeneic HCT during the first CR was associated with a cumulative incidence of relapse at 2 years of 20% (95% CI, 13%-31%) compared with 58% (95% CI, 47%-71%; P鈥�&濒迟;鈥�.001). Nonrelapse mortality at 2 years after primary allogeneic HCT was 9% (95% CI, 5%-19%) and 2% (95% CI, 0%-11%) after consolidation chemotherapy (P鈥�=鈥�.005). Similar outcomes were observed when analyses were confined to the 96 patients at intermediate risk according to the European Leukemia Network classification. Most importantly, all 41 patients relapsing after consolidation chemotherapy (36 hematologic, 4 molecular, and 1 extramedullary) proceeded to allogeneic HCT. No significant differences in health-related quality of life measures were observed between groups.

Conclusions and Relevance听 Primary allogeneic HCT during first CR was not associated with superior overall survival compared with consolidation chemotherapy in patients 60 years or younger with intermediate-risk AML during the first CR and an available donor.

Trial Registration听 ClinicalTrials.gov Identifier:

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, less than 30% of adults with AML can be expected to survive and be cured.^1,2 The most important prognostic indicators for therapy response and outcome are cytogenetic and molecular genetic abnormalities in the leukemic cells. These abnormalities have been integrated into the most recent European Leukemia Network (ELN) classification to divide a given patient鈥檚 prognosis into favorable risk, intermediate risk, and adverse risk.³ In addition to biological risk factors, patient-specific characteristics, 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% to 70% of patients undergoing intensive induction chemotherapy are subsequently referred to postremission therapy.^5,6 Whereas patients at favorable risk clearly benefit from consolidation chemotherapy based on high-dose cytarabine, high-risk patients with an adequate performance status are candidates for allogeneic hematopoietic cell transplant (allo-HCT), if a suitable donor can be identified.⁷ In contrast, controversy exists about the optimal treatment algorithm in the intermediate-risk group. Although the risk of relapse is lowest with allo-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 allo-HCT after relapse of AML.^6,8

Retrospective studies^9,10 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 allo-HCT compared with chemotherapy, most pronounced in high-risk patients defined by cytogenetic assessment. One intergroup analysis also found an advantage for younger intermediate-risk patients with matched sibling donors.¹¹ With most patients with AML being older than 50 years, the improved outcomes after allo-HCT with reduced-intensity conditioning and the availability of matched unrelated donors for 70% to 80% of White patients, the relative role of allo-HCT should ideally be studied within a prospective randomized trial.^12,13 Hence, the multicenter ETAL-1 trial (Randomized Trial on Allogeneic Haematopoietic Stem Cell Transplantation in Patients Under the Age of 60 Years With Acute Myeloid Leukemia of Intermediate Risk in First Complete Remission and a Matched Sibling or Unrelated Donor) was initiated for adult patients with AML in first CR or CR with incomplete blood cell count recovery (CRi) for whom a suitable donor had been identified. Patients were randomized to receive allo-HCT (group A) or conventional consolidation chemotherapy with the option of salvage HCT in case of relapse (group B). This article presents the outcome of the randomized patients analyzed after premature closure of the study due to slow accrual.

The role of allo-HCT in patients with cytogenetically defined intermediate-risk AML in first CR was addressed by a prospective, intention-to-treat randomized clinical trial performed in 16 centers in Germany from February 2, 2011, until July 1, 2018. Key inclusion criteria were cytogenetically defined intermediate-risk AML according to Medical Research Council classification,¹⁴ first CR or CRi after conventional consolidation chemotherapy, age of 18 to 60 years, and availability of a human leukocyte antigen (HLA)鈥搈atched sibling or unrelated donor. For unrelated donors, a 9/10 HLA allelic match was acceptable except for patients with an NPM1 (OMIM ) variation, for whom full 10/10 allele matching was required. Blocked 1:1 randomization with variable block size was stratified according to age (18-40 vs 41-60 years), NPM1 and CEBPA (OMIM ) variant status as well as donor type (unrelated vs related). Data on race and ethnicity of participants are not reported because the proportion of patients of races other than White in the accrual area were expected to be minimal. Moreover, clinical trial standards and health records did not allow collecting this information during the study period. End points included overall survival (OS) as the primary outcome and disease-free survival (DFS), cumulative incidence of relapse, treatment-related mortality, and quality of life measured according to the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) as the secondary outcomes.¹⁵ The protocol and analyses were approved by the ethical commission of the Technical University Dresden. All patients provided written informed consent before study inclusion. Reporting of trial results followed the Consolidated Standards of Reporting Trials () reporting guideline.

The study was planned as a superiority trial with the binary primary end point of OS at 4 years. The assumptions for sample size calculation were a 60% OS proportion in the allo-HCT arm and a 45% in the consolidation chemotherapy arm. The type 1 error was set at 5% 2-sided, and the power of the trial to detect an effect of the assumed size should be 80%. The required sample size was calculated to be 346 in total.

Patients randomized to allo-HCT or consolidation chemotherapy were scheduled to start the envisioned next therapeutic intervention within 4 to 6 weeks after randomization. Intensive or reduced-intensity conditioning protocols proposed in the allo-HCT group, the respective immunosuppressive regimens, and the details of dosing and schedules in the consolidation chemotherapy group are provided in the trial protocol in Supplement 1.

In the consolidation chemotherapy group, in the event of hematologic or molecular relapse, allo-HCT with the already identified donor was performed (salvage regimens applied were not prespecified). By the time of randomization and at every 3 months during the first 2 years and every 6 months during the third and fourth years after inclusion, the patients were asked to complete the SF-36 as a standardized quality of life questionnaire. Quality of life as a secondary end point was analyzed descriptively. In both treatment groups, adverse events and severe adverse events were monitored and documented as part of the safety assessment required by the German federal authorities.

Overall 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 time was calculated from date of randomization until relapse or death, whichever occurred first. Disease-free survival was censored on the date of last follow-up if none of the events occurred. Nonrelapse mortality was defined as any death not preceded by relapse. Relapse and CR 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 95% CIs are provided using Greenwood鈥檚 formula for the SE estimation. P values and 95% CIs 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 consolidation chemotherapy group as being alive at 2 years and being deceased in the transplant group. This approach was used only for the primary hypothesis test of the 2-year OS end point. A sensitivity analysis applying an opposing best-case scenario with missing data as being 鈥渄ead鈥� was performed and is presented in the eMethods in Supplement 2. Point estimates and 2-sided 95% Clopper-Pearson CIs are presented for this end point. The comparison was performed with the likelihood ratio test. In addition, 95% CIs for the differences in 2-year and 4-year survival were calculated. Comparisons of DFS were performed with a binomial variable indicating DFS at 2 years and the likelihood ratio test. Complete cases without imputation were used. Two-sided 95% CIs are presented. In addition, Kaplan-Meier estimates are presented.

Incidence of nonrelapse mortality and relapse were estimated using Gray鈥檚 method for competing events. The Gray test was used for comparison of cumulative incidences.

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

The subscales of the SF-36 were calculated according to the scoring manual. For descriptive analysis, means (SDs) were calculated for each visit and treatment group. Completion rates were calculated. The duration of hospitalization in both treatment groups was compared by applying a Mann-Whitney U test.

A detailed statistical analysis plan was written and finalized on July 7, 2020. The database was locked and data exported for analysis on April 13, 2021. All statistical analyses were performed with R software, version 4.0.3.¹⁸

A total of 143 patients (mean [SD] age, 48.2 [9.8] years; 81 [57%] male) with AML who fulfilled the eligibility criteria were randomized, 76 to the allo-HCT group and 67 to the conventional consolidation chemotherapy group. The trial was subsequently closed due to slow accrual. After discussion with the data safety monitoring board, we amended the statistical analysis plan as follows. To avoid imputation of 4-year OS or exclusion of a large number of patients from the analysis, we redefined 2-year OS as the primary end point in the detailed statistical analysis plan before the study database was locked and data were exported for analyses. Patient flow and reasons for protocol deviations are shown in Figure 1.

Major patient characteristics, including stratification variables (age, CEBPA, FLT3 [OMIM ], and NPM1 variant status, and donor type) and demographic characteristics are provided in the Table. As recommended in the protocol, 12 of 76 patients in the allo-HCT group received 1 consolidation course of high-dose cytarabine after having achieved CR to bridge until allo-HCT. All other patients received allo-HCT directly after induction therapy. Although most patients received fludarabine combined with 8-Gy total-body irradiation (n鈥�=鈥�34), treosulfan (n鈥�=鈥�2), or melphalan (n鈥�=鈥�9), 16 patients (26%) in the allo-HCT arm group were still conditioned with fludarabine plus 2 days of busulfan. In the consolidation chemotherapy group, all but 1 patient (n鈥�=鈥�66) received between 1 and 3 cycles of high-dose cytarabine consolidation (median, 3; range, 2-3). The median follow-up for surviving patients was 50 (IQR, 48-66) months.

According to the intention-to-treat analysis, the probability of survival at 2 years was 74% (95% CI, 62%-83% [56 of 76 patients, 2 patients with missing values imputed as 鈥渄ead鈥漖) in the allo-HCT group and 84% (95% CI, 73%-92% [56 of 67 patients, 1 patient with missing value imputed as 鈥渁live鈥漖) in the conventional consolidation chemotherapy group (P鈥�=鈥�.22) (estimates with missing values censored were 76% [95% CI, 67%-86%] in the allo-HCT group and 83% [95% CI, 75%-93%] in the consolidation chemotherapy group) (Figure 2A). The difference between the proportional OS was 6.7% (95% CI, 鈭�10% to 25%) after 2 years in the allo-HCT arm and 7.1% (95% CI, 鈭�14% to 25% after 4 years) in the consolidation chemotherapy group. Two-year DFS after allo-HCT was 69% (95% CI, 57%-80%) compared with 40% (95% CI, 28%-53%) after conventional consolidation chemotherapy (P鈥�=鈥�.001) (estimates with missing values censored were 71% [95% CI, 61%-82%] in the allo-HCT group and 41% (95% CI, 30%-55%] in the consolidation chemotherapy group) (Figure 2B). Hazard ratios (95% CIs) for predefined subgroups on OS and DFS are provided in Figure 3. A post hoc analysis in patients with intermediate-risk AML according to the 2017 ELN classifications revealed roughly the same advantage in DFS after 2 years (70% after HCT and 39% after consolidation chemotherapy; P鈥�=鈥�.02) and no superiority with regard to OS (76% after allogeneic HCT vs 83% after consolidation chemotherapy (eFigure 1 in Supplement 2).

Nonrelapse mortality at 2 years was 9% (95% CI, 5%-19%) after allo-HCT compared with 2% (95% CI, 0%-11%) after conventional consolidation chemotherapy (P鈥�=鈥�.005). Primary allo-HCT was associated with a significantly lower cumulative incidence of relapse at 2 years of 20% (95% CI, 13%-31%) compared with 58% (95% CI, 47%-71%) after conventional consolidation chemotherapy (P鈥�<鈥�.001) (Figure 4A and B). Quantitative NPM1 polymerase chain reaction values could be attributed to 45 patients (80% of NPM1 variant cases). Eleven of 15 patients (73%) had detectable minimal residual disease (MRD) by the time of randomization in the allo-HCT group vs 10 of 16 (62%) in the control group. The numbers of patients with detectable NPM1 levels were 2 of 10 after 6 months and 2 of 8 after 10 months in the allo-HCT group. The corresponding numbers were 8 of 12 and 6 of 11 after cytarabine consolidation chemotherapy. One patient in the consolidation chemotherapy group died after salvage HCT due to early posttransplant complications. Most importantly, all 41 patients relapsing in the consolidation chemotherapy group (36 hematologic, 4 molecular, and 1 extramedullary) proceeded to undergo allo-HCT directly (n鈥�=鈥�20) or after salvage therapy (n鈥�=鈥�21). The regimens applied to treat relapse before salvage allo-HCT are summarized in the eTable in Supplement 2.

The number of patients for whom any serious adverse event was reported was not different between the allo-HCT group (55 of 74 [74%]) and the consolidation chemotherapy group (49 of 66 [74%]).

None of the SF-36 scales differed significantly between the treatment groups. The dimensions of all SF-36 variables during the follow-up in both groups are depicted in eFigures 1 and 2 in Supplement 2. The median duration of in-hospital stay was significantly shorter in the allo-HCT group (median [IQR], 42.5 [31.0-62.0] days) compared with conventional consolidation chemotherapy group (median [IQR], 106.0 [72.0-143.0] days; P鈥�&濒迟;鈥�.001).

The results of this randomized clinical trial indicate that the probability of survival after allo-HCT is not superior to that of conventional consolidation chemotherapy in case of relapse in patients 60 years or younger with cytogenetically defined intermediate-risk AML. The availability of a suitable donor in the consolidation chemotherapy group allowed allo-HCT to be performed in most patients with reoccurring disease, which led to comparable overall survival with both strategies. This optimized salvage procedure allowed for the compensation of the higher incidence of relapse in the control group, which meant that patients relapsing after consolidation chemotherapy 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 2017 ELN classification and were therefore likely to respond to salvage chemotherapy.

With the advent of sensitive and specific techniques to monitor disease burden during treatment, most patients currently and in the future will have the option to be stratified according to on-therapy disease dynamics.^19,20 The routine incorporation of MRD monitoring in patients with NPM1-mutated AML was only established during the accrual of the ETAL-1 trial.²¹ Because of a limited number of patients with complete MRD data, a formal comparison between treatment groups and an analysis of the prognostic relevance of MRD positivity on outcomes was not feasible.

Furthermore, an improved safety and thereby efficacy of allo-HCT with reduced-intensity conditioning and lower treatment-related mortality has been observed even in older patients in previous analyses.^22,23 In parallel, donor availability has improved, with many suitable donors being enlisted, and the increasing use of posttransplant cyclophosphamide after mismatched or haploidentical HCT procedures enables transplantation in almost all patients.^24,25 All these findings contribute to an increased likelihood of detecting imminent relapse early and of performing HCT in most patients with AML relapse after conventional consolidation.

Prospective randomized clinical 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, such as 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 allo-HCT in patients with FLT3 internal tandem duplication/tyrosine kinase domain variants is an example of improving efficacy of HCT for relapsed patients by maintenance strategies.^28,29

An important and rewarding finding of this trial was the low nonrelapse mortality after both treatment strategies even in a multicenter setting in patients with a median age older than 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 quality of life remained below our expectations, other quality of life outcomes, except for temporal physical dysfunction, did not differ between the treatment groups. Such a finding is of practical relevance and can be incorporated into future patient counseling. As expected, the duration of hospitalization was significantly longer for patients who underwent 2 to 3 cycles of consolidation chemotherapy. This information needs to be factored in when shared decision-making is pursued with patients and their families. As mentioned previously, 21 of 41 patients in the consolidation chemotherapy group had to receive additional salvage regimens before allo-HCT. Therefore, the cumulative exposure to chemotherapy may be considerable and should be kept in mind when patients with a considerable risk of relapse are advised on whether to undergo allo-HCT at first CR. To accommodate the preferences with regard to conditioning regimen, 4 different reduced-intensity conditioning treatments were offered to patients older than 40 years and to younger patients with comorbidities. Because the fludarabine plus busulfan regimen is reportedly associated with an excess incidence of relapse,²⁷ the differential antileukemic activity of the chosen regimens has to be kept in mind when interpreting the outcome data in the primary allo-HCT arm.

We acknowledge certain limitations of this study, including incomplete accrual. Unsurprisingly, patients tend to refuse leaving a decision for an intensive and potentially life-threatening procedure such as allo-HCT to a computer-based randomization algorithm. In line with our experience, a similar UK Medical Research Council 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 led to the inclusion of favorable-risk patients for whom current guidelines would not recommend allo-HCT in first CR.³ Finally, the routine use of MRD studies before and after allo-HCT had been developed but not standardized in 2012 and were not a mandatory part of the trial protocol.

The results of this randomized clinical trial support the notion that patients 60 years or younger with intermediate-risk AML, as defined by Medical Research Council cytogenetic criteria, despite an improved DFS, do not benefit from allo-HCT during first CR with regard to OS. The early identification of a suitable donor allows timely rescuing of those patients with relapse after conventional consolidation chemotherapy. Future studies that apply longitudinal monitoring of residual disease dynamics will help to personalize the ideal time point for allo-HCT in most patients.

Accepted for Publication: November 18, 2022.

Published Online: February 9, 2023. doi:10.1001/jamaoncol.2022.7605

Corresponding Authors: Martin Bornh盲user, MD, Medical Clinic I, University Hospital Carl Gustav Carus, Technical University Dresden, Fetscherstrasse 74, 01307 Dresden, Germany (martin.bornhaeuser@uniklinikum-dresden.de); Matthias Stelljes, MD, Department of Medicine A, University Hospital M眉nster, Albert-Schweitzer-Campus 1, Geb盲ude A12, 48129 M眉nster, Germany (stelljes@uni-muenster.de).

Author Contributions: Dr Bornh盲user had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Ehninger, Berdel, and Stelljes share senior authorship.

Concept and design: Bornh盲user, Schetelig, R枚llig, Beelen, Schmid, Berdel, Stelljes.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Bornh盲user, Schliemann, Schetelig, R枚llig, Kramer, M眉ller, Beelen, Tischer, Alakel, Ehninger, Berdel, Stelljes.

Critical revision of the manuscript for important intellectual content: Schliemann, Schetelig, R枚llig, Kramer, Glass, Platzbecker, Burchert, H盲nel, M眉ller, Klein, Bug, Beelen, R枚sler, Sch盲fer-Eckart, Schmid, Jost, Lenz, Spiekermann, Pfirrmann, Serve, St枚lzel, Alakel, Middeke, Thiede, Berdel, Stelljes.

Statistical analysis: Schetelig, R枚llig, Kramer.

Obtained funding: Bornh盲user, R枚llig, Alakel, Stelljes.

Administrative, technical, or material support: R枚llig, Platzbecker, Burchert, M眉ller, Bug, Beelen, Schmid, Jost, Lenz, Spiekermann, Serve, St枚lzel, Ehninger, Berdel.

Supervision: Bornh盲user, Platzbecker, H盲nel, M眉ller, Pfirrmann, Middeke, Berdel, Stelljes.

Coordination of the trial and patient care on trial: Berdel.

Conflict of Interest Disclosures: Dr Bornh盲user reported receiving personal fees from Jazz Pharmaceuticals and Gilead outside the submitted work. Dr Schetelig reported receiving grants from the German Ministry for Education and Research (Bundesministerium f眉r Bildung und Forschung) during the conduct of the study, personal fees from the AstraZeneca and BeiGene advisory boards, and lecture fees and personal fees from the Janssen, Bristol Myers Squibb (BMS), and AbbVie advisory boards outside the submitted work. Dr R枚llig reported receiving grants from AbbVie, Novartis, and Pfizer and personal fees from Amgen, BMS, Jazz Pharmaceuticals, and Servier outside the submitted work. Dr Burchert reported receiving personal fees from Gilead, AOP Health, Incyte, and from Pfizer outside the submitted work. Dr H盲nel reported receiving personal fees from Amgen, Bayer Vital, Celgene, Gilead, GlaxoSmithKline, Jazz Pharmaceuticals, Novartis, Roche, and Takeda outside the submitted work. Dr M眉ller reported receiving grants from Amgen Inc and personal fees from Celgene, Pfizer, and Neovii outside the submitted work. Dr Bug reported receiving personal fees from Novartis, Jazz Pharmaceuticals, Celgene/BMS, Pfizer, Gilead, and Novartis outside the submitted work. Dr Lenz reported receiving grants from Roche, Janssen, Agios, Aquinox, AstraZeneca, Gilead, Morphosys, and Bayer and personal fees from Roche, Janssen, AstraZeneca, BMS, Gilead, Sobi, ADC Therapeutics, AbbVie, Genmab, Morphosys, Incyte, Bayer, Karyopharm, Miltenyi, PentixaPharm, Novartis, Takeda, NanoString, and Constellation outside the submitted work. Dr Middeke reported receiving grants from Janssen, Novartis, and Jazz Pharmaceuticals and personal fees from AbbVie, AstraZeneca, Roche, Astellas, Jazz Pharmaceuticals, Janssen, and Novartis outside the submitted work. Dr Thiede reported part ownership in AgenDix GmbH during the conduct of the study and receiving personal fees from Novartis, Jazz Pharmaceuticals, Bayer, and Janssen outside the submitted work. No other disclosures were reported.

Funding/Support: This study was funded by grant DFG BO 2908/2-1 from the Deutsche Forschungsgemeinschaft (Drs Bornh盲user and Stelljes).

Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Meeting Presentation: This work was previously presented at the 63rd Annual Meeting of the American Society of Hematology; December 2, 2021; Atlanta, Georgia.

Data Sharing Statement: See Supplement 3.

Additional Contributions: Annett Haake, University Hospital Dresden, Dresden, Germany assisted with trial organization, monitoring, and source data verification and was not compensated for this work. 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. The SaxoCell Cluster4Future is acknowledged for supporting the clinical trial infrastructure.