Abstract
Outcomes for adults with relapsed/refractory (R/R) high-grade myeloid neoplasms remain poor, with allogeneic hematopoietic cell transplant (HCT) the only therapy likely to result in cure. Therefore, we conducted a study to determine the feasibility of early HCT – within 60 days of beginning reinduction chemotherapy – to see if getting patients to HCT in an expeditious manner would facilitate a larger number of patients being offered this curative option. In this proof-of-principle feasibility study, we included adults 18–75 with R/R myeloid malignancies with ≥10% blood/marrow blasts at diagnosis, who were eligible for a reduced-intensity HCT. Subjects received reinduction chemotherapy with cladribine, cytarabine, mitoxantrone, and filgrastim (CLAG-M) and proceeded to HCT with reduced-intensity conditioning (fludarabine/melphalan). We enrolled 30 patients: all received CLAG-M reinduction, although only 9 received HCT within 60 days (< 15, the predetermined threshold for feasibility “success”), with a median time to HCT of 48 days (range 42–60). Eleven additional subjects received HCT beyond the target 60 days (off-study), with a median time to transplant of 83 days (range 53–367). Barriers to early HCT included infection, physician preference, lack of an HLA-matched donor, logistical delays, and disease progression, all of which may limit real-world uptake of such early-to-transplant protocols.
Keywords: Hematopoietic cell transplantation, high-grade myeloid neoplasms
Introduction:
Despite recent advances in systemic therapy, most patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and other high-grade myeloid neoplasms continue to have poor outcomes, with allogeneic hematopoietic cell transplantation (HCT) remaining the only curative option.1 Since few adults transplanted with active disease survive long-term, salvage chemotherapy is typically given first to induce a complete remission (CR; < 5% morphologic blasts in bone marrow) before HCT.2,3 Poor pre-HCT disease control – measured by blast count and measurable residual disease (MRD)4–7 –portend higher post-HCT relapse rates, leading to aggressive attempts to induce MRD-negative CR. This approach exposes patients to risks of cumulative toxicity and complications, which can ultimately imperil their ability to undergo subsequent HCT with potentially little benefit since the likelihood of inducing an MRD-negative CR with chemotherapy alone is low (< 30%).
Historically, very few patients have received HCT as part of initial treatment for R/R disease (i.e., in lieu of antecedent salvage chemotherapy, followed by recovery and then HCT). In a series from the MD Anderson Cancer Center, only 10% (n = 28) of patients received HCT as initial salvage therapy for primary refractory disease between 1995–2009.8 However, retrospective data from Fred Hutch, MD Anderson, and HOVON indicate improved long-term outcomes for patients receiving this approach as compared to chemotherapy as initial salvage.3,9,10
One study11 that examined the early HCT approach used FLAMSA chemotherapy (fludarabine, amsacrine, and cytarabine) from days -12 to -9 followed by immediate reduced intensity conditioning (RIC) with 4 Gy total body irradiation (TBI): the overall CR rate was 91% with 32% 4-year OS. A separate study12 investigated a similar early approach in which patients in chemotherapy-induced aplasia received early HCT (the median time from diagnosis to HCT was 36 days), with a CR rate of 86%. Interestingly, in the latter study, pre-HCT blast count was not significantly associated with worse outcomes on multivariate analysis.
A subsequent trial from the US examined outcomes of patients with high-risk disease features who underwent HCT within 4 weeks of beginning reinduction chemotherapy while in chemotherapy-induced aplasia, and compared these patients to standard-risk patients who only proceeded to transplant ≥ 4 weeks after reinduction and after achieving adequate hematologic recovery post-reinduction.13 The OS and event free-survival (EFS) were similar between these groups, suggesting that the early HCT approach was feasible and as effective as a standard transplant approach.
To better evaluate the feasibility of early HCT for treatment of R/R high-grade myeloid malignancies, we conducted a prospective study to assess how often we could perform human leukocyte antigen (HLA)-matched HCT within 60 days of beginning re-induction chemotherapy.
Methods:
The principal objective of this study was to evaluate the feasibility of “early” HCT, defined as donor graft infusion within 60 days of starting intensive reinduction therapy with cladribine, high-dose cytarabine, mitoxantrone, and filgrastim (CLAG-M; the principal high-intensity salvage approach used at our center)14. CLAG-M consists of intravenous (IV) cladribine 5 mg/m2/day on days 1–5, cytarabine 2 g/m2/day on days 1–5, subcutaneous filgrastim given on days 0–5 at either 300 μg/day for adults <76kg or 480 μg/day for adults ≥76kg), and mitoxantrone at 16 mg/m2/day on days 1–3. The minimum time between the start of CLAG-M and the initiation of conditioning chemotherapy would be 14 days.
The feasibility study would be considered a success if (1) we were able to enroll 30 patients per year (which equates to 1/3 of the roughly 90 patients with R/R myeloid malignancies who present to our center each year); (2) at least 50% (n = 15) of study subjects are transplanted on-study within 60 days of the start of reinduction therapy; and (3) we observe a 6-month relapse-free survival (RFS) ≥ 40% after HCT. Unpublished data from our center from a series of 105 patients in second CR (CR2) indicate that only 20% received HCT within 60 days of reinduction.
Secondary objectives included estimates of OS, CR rate, the composite CR rate (inclusive of CR plus CR with incomplete hematologic recovery [CRi]; CR/CRi), and treatment-related mortality (TRM), with and without early HCT. Acute GVHD was reported for patients undergoing HCT. Other objectives include assessment of factors that distinguish those who proceeded to early HCT versus those who did not, and description of outcomes for those who went on to receive HCT more than 60 days after reinduction.
Eligible patients included adults age 18–75 years with R/R high-grade myeloid neoplasms, defined as ≥ 10% blood or marrow blasts at the time of initial diagnosis (examples include AML, myelodysplastic syndrome (MDS) with excess-blasts-2 (EB2), and chronic myelomonocytic leukemia-2 (CMML-2)), who received at least 1 cycle, but no more than 2 cycles of intensive induction chemotherapy (or no more than 3 cycles of hypomethylating agents) for their disease, and then had either relapsed or refractory disease with ≥ 5% blasts in the marrow or blood. Other key eligibility criteria included ability to undergo a reduced-intensity HCT, including adequate organ function and availability of a caregiver to provide post-HCT care. Key exclusionary criteria included prior HCT, > 2 induction courses, relapse within 3 months of MRD-negative CR after initial induction with CLAG-M, and low likelihood of being eligible for reduced intensity conditioning (RIC) HCT based upon known organ dysfunction at the time of screening (such as cardiac ejection fraction <40%, EGFR < 40 ml/m, liver disease, impaired DLCO and/or reduced FEV1), known HIV positivity, pregnant or nursing, invasive malignant tumor (other than non-melanoma skin cancer) within the last 5 years, serious uncontrolled infection, and ECOG PS > 2.
All patients received reinduction with CLAG-M and were supposed to proceed to HCT, irrespective of response to reinduction therapy, as determined by day 28 bone marrow evaluation. Subjects with appropriate organ function and performance status and adequate caregiver support received conditioning with fludarabine, melphalan +/− TBI (RIC) followed by HCT from a human leukocyte antigen (HLA)-matched related or unrelated donor or a single class I mismatched unrelated donor. Alternative donor sources (i.e., haploidentical or cord blood) were not allowed. Cyclosporine, mycophenolate mofetil (MMF) +/− sirolimus were used for graft-versus-host-disease (GVHD) prophylaxis, per our institutional standard. Full details on conditioning regimens and GVHD prophylaxis are included in the Supplmental Materials, tables 1–4. Myeloablative conditioning (MAC) was not allowed due to concerns of toxicity and complications if high-intensity reinduction and MAC were given in close sequence; fludarabine-melphalan was chosen as the RIC backbone as observational data has indicated that this confers a lower relapse risk as opposed to fludarabine-busulfan RIC.15 The study was approved by the Institutional Review Board and all subjects provided written informed consent. This was registered at clinicaltrials.gov (NCT02756572).
Having an HLA-matched donor prior to study enrollment was not an eligibility criterion for study enrollment. Subjects who did not have an HLA-matched donor available around the time of study enrollment had rapid HLA-typing performed (if HLA-typing not already done) followed by a rapid donor search: as soon as a patient was identified as a potential candidate for this protocol, the treating physician and study staff would work to expedite HLA-typing and/or donor search by using this rapid HLA-typing approach, for those subjects in need. Also, pre-HCT evaluations such as organ function assessment and clinical assessments (e.g. pulmonary/cardiac assessments, dental exams) would be expedited to the extent possible for all study subjects by working with the treating clinicians, the study team, and the HCT coordination department at our center.
Once enrolled onto the study protocol, key inclusion criteria for receiving a HCT per protocol included having an identified matched-related or -unrelated donor: one allele mismatch in HLA-A, B, or C was permitted on this protocol. Key exclusion criteria for getting a HCT per-protocol included the presence of donor-specific antibodies to donor HLA-DQ or -DP, uncontrolled infection, or major organ toxicity. For subjects who enrolled without a donor and failed to identify a satisfactory donor), would be considered early HCT feasibility failures.
Results:
Between December 2016 and September 2019, we screened 33 and enrolled 30 subjects (Supplemental Figure 2: CONSORT diagram). Study participant characteristics are included in Table 1. Key among these include a median age of 56.5 years, 60% of whom were female; 29 (97%) had AML, 15 of these AML patients (52%) had adverse risk per ELN2017; patients had a median of 2 previous lines of therapy (range 1–3) and had a median prior CR1 duration of 2 months (range 0–31 months). All 30 subjects received reinduction CLAG-M. The most common serious adverse events (SAEs) after CLAG-M (Supplemental Table 5) were febrile neutropenia and infections (occurring in 77% of patients; total of 47 events), hypoxic respiratory failure (20%), and gastrointestinal toxicity (17%). The composite CR rate (inclusive of CR plus CR with incomplete hematologic recovery [CRi]; CR/CRi) after CLAG-M was 33% (n = 10) with 5 of these (50%) achieving MRD-negativity. (Table 2).
Table 1:
Baseline patient characteristics, reported as n (%) unless specified. The total cohort was 30 patients. A subset (n=11) of the feasibility failures (n=21) who underwent HCT off study are presented in the final column.
| Total study cohort | Feasibility successes | Feasibility failures | Transplanted off study | |
|---|---|---|---|---|
| Subjects groups, N (%) | 30 | 9 (30) | 21 (70) | 11 (37) |
| Age in years, median (range) | 56.5 (28–69) | 55 (36–67) | 57 (28–69) | 50 (28–69) |
| AML, N (%) | 29 (97) | 9 (100) | 20 (95) | 10 (91) |
| ELN 2017 risk | ||||
| Favorable | 5 (17) | 3 (33) | 2 (10) | 1 (9) |
| Intermediate | 10 (33) | 2 (22) | 8 (38) | 4 (36) |
| Adverse | 15 (50) | 4 (44) | 11 (50) | 6 (55) |
| Relapsed (vs. refractory) | 16 (53) | 6 (67) | 10 (48) | 5 (45) |
| TRM score, median (range) | 2.33 (0.57–8.2) | 2.15 (0.61–3.67) | 3.05 (0.57–8.2) | 2.26 (0.74–8.2) |
| Male | 12 (40) | 1 (11) | 11 (52) | 5 (45) |
| Prior lines of therapy, median | 2 | 1 | 2 | 2 |
| Duration of CR1 in months, median (range) | 2 (0–31) | 2 (0–31) | 2 (0–16) | 2 (0–16) |
Abbreviations: acute myeloid leukemia (AML); European LeukemiaNet (ELN); treatment-related mortality (TRM) score21; first complete remission (CR1)
Table 2:
morphological marrow response (baseline, pre-HCT, day +28 post-HCT, day +84 post-HCT). Day +28 and +84 marrow exams apply only to subjects who had early HCT per protocol and had these respective marrow exams.
| Post CLAG-M N=281 | Day +28 Post HCT N=83 | Day +84 Post HCT N=8 | |
|---|---|---|---|
| CR | 82 | 8 | 6 |
| MRD-pos | 3 | 0 | 0 |
| MRD-neg | 52 | 8 | 6 |
| CRi | 2 | 0 | 0 |
| MRD-pos | 2 | -- | -- |
| MRD-neg | 0 | -- | -- |
| MLFS | 8 | 0 | 0 |
| MRD-pos | 5 | ||
| MRD-neg | 3 | ||
| Persistent disease | 10 | -- | -- |
| Relapse | -- | -- | 2 |
Only 28 of the 30 patients had post-CLAG-M marrow exams: two patients did not have post CLAG-M bone marrow assessments due to their clinical status.
One patient had a marrow CR without MRD, but had extramedullary disease
One patient died day +45 post-HCT and never had these studies completed
Abbreviations: allogeneic hematopoietic cell transplant (HCT); complete remission (CR); measurable residual disease (MRD); complete remission with incomplete hematologic recovery (CRi); morphologic leukemia free state (MLFS); cladribine, cytarabine, mitoxantrone, and filgrastim (CLAG-M)
A total of 9 (30%) subjects proceeded to HCT within the study-stipulated 60-day timeframe and the specified conditioning regimen (“early HCT”). Another 11 patients proceeded to HCT more than 60-days after reinduction or received a different preparative regimen. The remaining 10 subjects did not undergo HCT. All transplanted patients received 10/10 HLA-matched allografts from unrelated donors. The median time to HCT in those who received early HCT per protocol (n=9) was 48 days (range 42–60). The day +28 and day +84 CR rate among those who received early HCT was 8/9 and 6/9, respectively, all MRD-negative (Table 2). The most common SAEs after HCT (Supplemental Table 6) were febrile neutropenia (89%), mucositis/esophagitis (89%), and nausea/vomiting (63%) as expected. There were no instances of grade III-IV acute GVHD by day +100. Among the 9 patients who received early HCT, 6 have died with causes including diffuse alveolar hemorrhage in 1; disease progression/relapse in 4; and suicide in 1. Three remain alive and in CR at last follow-up (median time from HCT to most recent follow-up, 4.7 years).
Eleven additional patients ultimately received HCT more than 60 days after reinduction or off-study with a different conditioning regimen, a median of 83 days (range 53–367) after reinduction; two received HCT within 60 days but with a different conditioning regimen than specified in the protocol. The median time to HCT among the total 20 study subjects who ultimately proceeded to HCT was 58 days (range 42–376). The most common reasons for not proceeding to HCT per protocol (n=21) included treating physician’s choice (transplant not clinically indicated; n=6); infections (n=5); and lack of appropriate donor (4). Among the 2 patients who received early HCT using different conditioning regimens, one patient elected to enroll on a different investigational HCT protocol (this patient is alive and in remission at last follow-up) and the other patient was taken off protocol due to treating physician choice to proceed to a myeloablative HCT (this patient is alive and in remission at last follow-up). Among the 11 subjects who received a HCT within 60 days, 4 were in CR at the time of HCT; the 1-year and 2-year OS for these 11 subjects (respectively) was 73% (95% CI: 51–100%) and 55% (95% CI: 32–94%).
The median OS for the entire study cohort (including those who did not receive a HCT), calculated from the time of enrollment, was 13.0 months (95% confidence interval [CI] 7.2–37.5 months; Supplemental Figure 1). The median RFS from enrollment was 8.6 m (95% CI 6.8–26.9 m). Among the 20 patients who underwent HCT, the median RFS from HCT was 11.4 m (95% CI 5.7-not reached) with a 6-month RFS of 65% (95% CI 47–90%). Among the 9 patients who had early HCT, the 6-month RFS was 78% (95% CI 44–100%). The two-year OS for the entire cohort was 33% with 95% CI of 20–55%.
Among patients alive at 6 months after study registration, there were seven who had not undergone HCT; zero of seven were alive at 2 years after study registration. Among subjects alive at the 6-month landmark, 16 had undergone HCT at 2 years (18 months after the 6-month landmark); the fractional OS estimate at 2 years was 63% (95% CI 43–91%); the 2.5-year OS estimate (2 years after the 6-month landmark) was 56% (95% CI 37–87%).
Conclusions
In this study, we tested the feasibility of early HCT within 60 days following high-intensity reinduction for adults with R/R high-grade myeloid neoplasms. With only 9 (30%) subjects transplanted per protocol within the study-stipulated 60-day window after initiation of CLAG-M reinduction chemotherapy, this study’s primary feasibility endpoint (> 50% of study participants transplanted in < 60 days on-protocol) was not met. However, the criteria for receipt of HCT per the study protocol were quite limited (including a RIC regimen and no alternative allograft sources), and 11 (37%) additional participants ultimately underwent HCT. The treatment approach was well-tolerated with acceptable toxicity, and yielded a 6-month RFS among transplant recipients was 65% (well above the protocol-specified primary efficacy endpoint of a 6-month RFS of 40%). Thus, the early HCT approach may be of benefit but requires optimization.
In order to achieve a higher rate of early HCT, flexibility will be required. The use of alternative donor sources would have expanded options for study participants without a suitable matched related or unrelated donor (accounting for 19% of study participants who did not receive a HCT). Additionally, allowing higher intensity conditioning regimens should be tested. We only allowed one harmonized RIC approach to conditioning in this study due to concerns about cumulative toxicity from CLAG-M followed by transplant conditioning. As a result, some younger, fitter patients who could tolerate a MAC-based preparative regimen may have deferred enrollment on this study in order to receive a MAC approach off-protocol to try to reduce post-HCT relapse as compared to RIC.16
Lessons learned from this study are being applied to an ongoing study examining early HCT that is currently open at Fred Hutchinson Cancer Center; the study further shortens the time window from reinduction to HCT, with CLAG-M or FLAG-Ida given to study participants starting at day −9 pre-HCT, along with escalating doses of TBI. Additionally, this study also allows haploidentical donors and newer forms of GVHD prophylaxis (NCT04375631). An additional emerging approach to HCT conditioning in myeloid malignancies is radioimmunotherapy. This approach, in many patients, may be able to overcome the presence of residual or overt disease at the time of HCT and reduce the time to HCT. The randomized phase III SIERRA trial (NCT02665065)17 treated patients ≥55 years old with R/R AML and ineligible for conventional transplant conditioning with the CD45-directed radioimmunoconjugate 131I-apamistamab versus physicians’ choice of conventional care. Preliminary results from this trial support the regimen as safe and effective, which may expand the population of those patients considered eligible for HCT. Another investigational radioimmunotherapy approach of interest employes a different radioisotope – astatine-211 (211AT) – with an ongoing clinical trial at our center using an 211AT-CD45 antibody as part of HCT conditioning for the treatment of AML/high grade myeloid neoplasms (NCT03670966). Additional emerging conditioning paradigms that may allow rapid engraftment include the use of monoclonal antibodies to CD117 (c-KIT) and/or CD47. While these approaches have primarily been pre-clinical to-date,18 clinical trials using antibody-based therapy are now being conducted (NCT04429191).
The role that intensive reinduction chemotherapy should play in treating R/R myeloid malignancies is questioned by results from the recent phase III ASAP trial (Accelerated Second Transplantation in Relapsed/Refractory Acute Myeloid Leukemia)19. The ASAP trial randomized adults with R/R AML to receive conventional intensive salvage chemotherapy followed by HCT vs. “watchful waiting” (which included as-needed doses of mitoxantrone for disease control) before proceeding expeditiously to HCT. There was no difference in post-transplant CR rates (at day 56) or 1-year and 3-year OS between these two groups. These data suggest that patients do not derive extra benefit from receiving intensive induction chemotherapy before HCT, and that when HCT is available, proceeding as soon as possible may be the optimal approach.
How the recent data from the ASAP and SIERRA trials will be incorporated into standard practice remains to be seen. In our study, the majority of study participants did not enter into a morphologic CR with CLAG-M reinduction. Moreover, CLAG-M toxicity was the primary culprit in cases where HCT was either delayed or deferred altogether, either due to toxicity/complications, lack of efficacy, or a combination thereof. Our study was conducted before the widespread introduction of venetoclax into the AML treatment paradigm. Venetoclax-based salvage approaches could in theory mitigate suboptimal repsonses and decrease additional toxicity observed with CLAG-M, by for instance using hypomethylating agents plus venetoclax as a salvage in certain patient subsets. Similarly, in younger, fit patients, FLAG-IDA-VEN induces higher CR rates in the R/R setting compared to those observed in separate studies CLAG-M.14,20 In the future, reinduction may be tailored to each individual patient’s need depending on whether they require intervention with salvage CLAG-M (such as those with highly proliferative disease), or would be better served by a “watch-and-wait” minimalist chemotherapy approach.
Supplementary Material
Table 3:
reasons for no HCT per protocol
| Reason | N=21 |
|---|---|
| No appropriate donor | 4 |
| Transplant clinically not appropriate | 6 |
| Infection | 5 |
| Poor functional status | 1 |
| Extramedullary disease | 2 |
| Pre-transplant evaluation delays | 1 |
| Death | 2 |
Abbreviations: allogeneic hematopoietic cell transplant (HCT)
Highlights:
Hematopoietic cell transplant (HCT) remains the only curative option for adults with relapsed/refractory (R/R) high-grade myeloid neoplasms.
Early HCT for R/R disease remains an area of interest in the field, and we conducted a proof-of-principle feasibility study to address this question.
While this feasibility study did not meet its primary endpoint, important lessons can be derived from this study and applied to future practice surrounding early HCT.
Acknowledgements:
the authors wish to acknowledge the late Dr. Eli Estey for his contribution to this work and for his massive contributions to the field of AML research.
Funding:
This study was supported by the Cancer Consortium Support Grant New Investigator Pilot Award (0000879105). NEK received research funding from the NHLBI T32 training grant (T32HL007093-47).
Conflict-of-interest disclosure:
M.B.P. reports research funding from Pfizer, Celgene/Bristol-Myers Squibb, GlycoMimetics, Biosight, Telios, Ascentage Pharma, and Astex Pharmaceuticals. MO reports consulting fees from Merck and Biosight and membership on Data Safety Monitoring Boards with BMS, Glycomimetics, and Grifols. BMS reports a consulting fee from Actinium pharmaceuticals. P.S.B. reports institutional research support from Glycomimetics, Pfizer, GPCR, Notable labs and rare disease medical advisor for Accordant Health Services. has received research funding from Amgen, Kite/Gilead, Incyte, Merck, Pfizer, Servier, and Vanda Pharmaceuticals; consultancy/honoraria from Amgen, Jazz, Kite/Gilead, and Pfizer; membership on a board or advisory committee for Autolus and PeproMene Bio; and spouse was employed by and owned stock in Seagen. A.B.H. has received research funding from Imago Biosciences/Merck, Merck, Bayer, Gilead, Jazz, Incyte, Karyopharm Therapeutics, and Disc Medicine; and consultancy from Abbvie and Notable Labs. V.G.O. has received research funding from Pfizer; and consultancy from Pfizer, Novartis, and Ascentage. R.B.W. received laboratory research grants and/or clinical trial support from Aptevo, Celgene/Bristol Myers Squibb, ImmunoGen, Janssen, Jazz, Kite, Kura, and Pfizer; has ownership interests in Amphivena; and is (or has been) a consultant to Abbvie, Adicet, Amphivena, BerGenBio, Celgene/Bristol Myers Squibb, GlaxoSmithKline, ImmunoGen, Kura, and Orum. All other authors declare no competing financial interests.
Footnotes
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References:
- 1.Appelbaum FR. Indications for allogeneic hematopoietic cell transplantation for acute myeloid leukemia in the genomic era. Am Soc Clin Oncol Educ Book. 2014:e327–333. [DOI] [PubMed] [Google Scholar]
- 2.Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022;140(12):1345–1377. [DOI] [PubMed] [Google Scholar]
- 3.Clift RA, Buckner CD, Appelbaum FR, et al. Allogeneic marrow transplantation during untreated first relapse of acute myeloid leukemia. J Clin Oncol. 1992;10(11):1723–1729. [DOI] [PubMed] [Google Scholar]
- 4.Jentzsch M, Bischof L, Backhaus D, et al. Impact of MRD status in patients with AML undergoing allogeneic stem cell transplantation in the first vs the second remission. Blood Adv. 2022;6(15):4570–4580. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Araki D, Wood BL, Othus M, et al. Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia: Time to Move Toward a Minimal Residual Disease-Based Definition of Complete Remission? J Clin Oncol. 2016;34(4):329–336. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Hoffmann AP, Besch AL, Othus M, et al. Early achievement of measurable residual disease (MRD)-negative complete remission as predictor of outcome after myeloablative allogeneic hematopoietic cell transplantation in acute myeloid leukemia. Bone Marrow Transplant. 2020;55(3):669–672. [DOI] [PubMed] [Google Scholar]
- 7.Walter RB, Buckley SA, Pagel JM, et al. Significance of minimal residual disease before myeloablative allogeneic hematopoietic cell transplantation for AML in first and second complete remission. Blood. 2013;122(10):1813–1821. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Jabbour E, Daver N, Champlin R, et al. Allogeneic stem cell transplantation as initial salvage for patients with acute myeloid leukemia refractory to high-dose cytarabine-based induction chemotherapy. Am J Hematol. 2014;89(4):395–398. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Armistead PM, de Lima M, Pierce S, et al. Quantifying the survival benefit for allogeneic hematopoietic stem cell transplantation in relapsed acute myelogenous leukemia. Biol Blood Marrow Transplant. 2009;15(11):1431–1438. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Breems DA, Van Putten WL, Huijgens PC, et al. Prognostic index for adult patients with acute myeloid leukemia in first relapse. J Clin Oncol. 2005;23(9):1969–1978. [DOI] [PubMed] [Google Scholar]
- 11.Schmid C, Schleuning M, Schwerdtfeger R, et al. Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation. Blood. 2006;108(3):1092–1099. [DOI] [PubMed] [Google Scholar]
- 12.Stölzel F, Platzbecker U, Mohr B, et al. Early intervention with allogeneic hematopoietic cell transplantation during chemotherapy-induced aplasia in patients with high-risk acute myeloid leukemia. Leukemia. 2013;27(10):2068–2072. [DOI] [PubMed] [Google Scholar]
- 13.Chen GL, Liu H, Zhang Y, et al. Early versus late preemptive allogeneic hematopoietic cell transplantation for relapsed or refractory acute myeloid leukemia. Biol Blood Marrow Transplant. 2014;20(9):1369–1374. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Halpern AB, Othus M, Huebner EM, et al. Phase I/II trial of cladribine, high-dose cytarabine, mitoxantrone, and G-CSF with dose-escalated mitoxantrone for relapsed/refractory acute myeloid leukemia and other high-grade myeloid neoplasms. Haematologica. 2019;104(4):e143–e146. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Damlaj M, Alkhateeb HB, Hefazi M, et al. Fludarabine-Busulfan Reduced-Intensity Conditioning in Comparison with Fludarabine-Melphalan Is Associated with Increased Relapse Risk In Spite of Pharmacokinetic Dosing. Biol Blood Marrow Transplant. 2016;22(8):1431–1439. [DOI] [PubMed] [Google Scholar]
- 16.Scott BL, Pasquini MC, Logan BR, et al. Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes. J Clin Oncol. 2017;35(11):1154–1161. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Gyurkocza B, Nath R, Seropian S, et al. Clinical experience in the randomized phase 3 Sierra trial: anti-CD45 iodine (131I) apamistamab [Iomab-B] conditioning enables hematopoietic cell transplantation with successful engraftment and acceptable safety in patients with active, relapsed/refractory AML not responding to targeted therapies [abstract]. Blood 2021; 138 (Suppl 1):1791. In. [Google Scholar]
- 18.Persuad SP YA, Ritchey JK, DiPersio JF. Fully Myeloablative Antibody-Drug Conjugates Condition for Hematopoietic Stem Cell Transplantation and Provide Durable Antileukemia Benefit. Blood (2022) 140 (Suppl 1): 1570–1571. In.36173658 [Google Scholar]
- 19.Stelljes MMJ, Bug G, Wagner EM. In Patients with Relapsed/Refractory AML Sequential Conditioning and Immediate Allogeneic Stem Cell Transplantation (allo-HCT) Results in Similar Overall and Leukemia-Free Survival Compared to Intensive Remission Induction Chemotherapy Followed By Allo-HCT: Results from the Randomized Phase III ASAP Trial. Blood 2022; 140 (Supplement 1): 9–11. In. [Google Scholar]
- 20.DiNardo CD, Lachowiez CA, Takahashi K, et al. Venetoclax Combined With FLAG-IDA Induction and Consolidation in Newly Diagnosed and Relapsed or Refractory Acute Myeloid Leukemia. J Clin Oncol. 2021;39(25):2768–2778. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Walter RB, Othus M, Borthakur G, et al. Prediction of early death after induction therapy for newly diagnosed acute myeloid leukemia with pretreatment risk scores: a novel paradigm for treatment assignment. J Clin Oncol. 2011;29(33):4417–4423. [DOI] [PMC free article] [PubMed] [Google Scholar]
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