The treatment of acute myeloid leukemia (AML) has evolved over the past few years with the advent of next-generation sequencing. Targeted therapies alone or in combination with low-dose or high-intensity chemotherapy have improved the outcome of patients with AML treated in the frontline and relapsed/refractory settings. Despite these advances, allogeneic stem cell transplantation (allo-HCT) remains essential as consolidation therapy following frontline treatment in intermediate-and adverse-risk and relapsed/refractory disease. However, many patients relapse, with limited treatment options, hence the need for post-transplant strategies to mitigate relapse risk. Maintenance therapy following allo-HCT was developed for this specific purpose and can exploit either a direct anti-leukemia effect and/or enhance the bona fide graft-versus-leukemia effect without increasing the risk of graft-versus-host disease. In this paper, we summarize novel therapies for AML before, during, and after allo-HCT and review ongoing studies.
The past decade marked a revolution in the treatment of acute myeloid leukemia (AML) with the advent of next-generation sequencing, leading to the discovery of new mutations and a better understanding of the biology of AML. Following these innovations, the landscape of AML therapy has evolved rapidly; since 2017, several novel therapies have received regulatory approval, including CPX-351,1 midostaurin,2 gilteritinib,3 ivosidenib,4 enasidenib,5 venetoclax,6,7 and glasdegib,8 and gemtuzumab ozogamicin (GO) has re-emerged.9 Following these approvals, numerous doublet and triplet combinations have been tested in which targeted therapy was added to intensive or low-intensity chemotherapy and/or to other targeted agents. In patients lacking targetable mutations, the standard of care remains intensive chemotherapy in fit patients or low-intensity treatment in unfit patients. Several groups of patients, particularly those carrying high-risk mutations, namely TP53 mutations, and complex karyo-type, still have a dismal prognosis. Minor changes in the treatment of this category of patients have occurred, with only few drugs being studied for TP53-mutated disease, including APR-246 (eprenetapopt) and anti-CD47 monoclonal antibodies.10,11 Other novel drugs being tested in MLL-rearranged and NPM1-mutated relapsed AML, are menin inhibitors, which led to an overall response rate of 44% in that population.12 Following induction therapy, consolidation options include chemotherapy in favorable-risk disease or allogeneic hematopoietic cell transplant (allo-HCT) in intermediate- and adverse-risk AML. The optimal strategy depends on donor availability, patient- and disease-related characteristics, and the benefits of treatment weighed against treatment-related mortality. In this review, we summarize novel therapeutic approaches for AML before transplant. In addition, we discuss new combinations for conditioning regimens prior to allo-HCT, and we elaborate on post-allo-HCT maintenance strategies to diminish relapse.
Therapies available for use prior to allogeneic hematopoietic cell transplantation
Since the 1970s, the mainstay of first-line treatment in young, fit patients with AML has been the “7 + 3” regimen, serving as backbone therapy.13
This is usually followed by consolidation therapy to achieve lasting remission. This regimen consists of 7 days of continuous, standard-dose cytarabine (100-200 mg/m2 daily), along with anthracycline during the first 3 days and is usually reserved for younger, fit patients. Higher doses of cytarabine have been associated with a small added survival benefit relative to the increased toxicities.14,15 This benefit is more pronounced in young patients <46 years of age, as shown in the EORTC-GIMEMA AML12 trial. In this study, patients aged between 15-60 years were administered standard-dose cytarabine (100 mg/m2 continuous infusion over 10 days) or high-dose cytarabine (3,000 mg/m2 every 12 hours on days 1, 3, 5, and 7). Overall survival (OS) was significantly improved for patients receiving high-dose cytarabine compared to patients receiving standard-dose cytarabine (51.9% vs. 43.3%, respectively; P=0.009).16 On the other hand, 60 or 90 mg/m2 of daunorubicin and 12 mg/m2 of idarubicin have yielded similar survival and complete remission (CR) rates.14,17,18 The combination of fludarabine, cytarabine, granulocyte colony-stimulating factor (G-CSF), and idarubicin (FLAG-IDA), previously reserved for relapsed disease, is an alternative induction regimen yielding similar results, especially in favorable-risk disease.19 Moreover, the use of FLAG has been demonstrated to provide superior relapse-free survival, compared to idarubicin and cytarabine (P=0.046), in treating core-binding factor-AML.20 The UK MRC AML 15 trial showed a superior log-reduction reduction in minimal residual disease (MRD) with FLAG-IDA compared to the “7+3” regimen with or without etoposide, but this did not translate into a difference in OS.21 These conventional regimens offer high rates of remission and prolong OS in patients aged <60 years with newly diagnosed AML, but not in older patients, since up to 70% of patients >65 years die within 1 year of diagnosis.22
Newer laboratory techniques, namely next-generation sequencing, identified mutations critical in the pathogenesis of AML leading to the development of targeted therapies. This novel arsenal of targeted drug therapies used as monotherapy or in combination with conventional treatments has revolutionized the treatment landscape of AML. GO is an anti-CD33 monoclonal antibody that was initially approved by the Food and Drug Administration (FDA) for the treatment of CD33-positive AML in first relapse in older patients before being withdrawn because of reports of increased mortality in the SWOG trial in the group treated with “7+3” and GO.23 A meta-analysis of five trials involving more than 3,000 AML patients treated with GO in addition to standard therapy reported a reduction in relapse (P=0.0001) and improved survival (P=0.01) without increasing mortality in patients with favorable- and intermediate-risk cytogenetics.24 Currently, GO is approved by the FDA and European Medicines Agency (EMA) for treating adult patients with newly diagnosed CD33-positive AML at a dose of 3 mg/m2 on days 1, 4, and 7 with the “7+3” regimen. The addition of GO to the FLAG regimen has also demonstrated superiority over the long-used FLAG-IDA regimen in core-binding factor AML, achieving higher remission rates.25 A head-to-head comparison of “7+3”+GO and FLAG-IDA+GO regimens is needed in patients with core-binding factor AML.
In patients >65 years, treatment choices become more challenging given increased cytogenetic abnormalities and somatic mutations, and thus higher-risk disease, unpredictable response to chemotherapy, and increased chance of treatment-related mortality. Although prognosis is poor in this group compared to that in younger, fitter patients, induction chemotherapy remains standard, whenever possible, offering better outcomes than palliation.26 In this patient population, hypomethylating agents (HMA), alone or in combination, have been shown to play a significant role, such that azacitidine or decitabine alone demonstrated superiority over low-dose cytarabine (LDAC) or supportive care in two cornerstone trials.27,28 Novel therapies in AML prior to allo-HCT are described below. Trials for which results have been published are summarized in Table 1.
CPX-351 is a novel liposomal carrier containing cytarabine and daunorubicin in a fixed 5:1 molar ratio. It was first studied in a phase I dose-escalation study in 2011, in which the maximum dose tolerated was 100 units/m2, and adverse events were consistent with those of cytarabine and daunorubicin individually.29 A phase II trial randomizing 126 older patients with untreated AML in a 2:1 fashion to receive CPX-351 or the “7+3” regimen documented higher response rates in the CPX-351 arm (66.7% vs. 51.2%; P=0.07).1 A subgroup analysis of cases with secondary AML demonstrated notably improved response rates (57.6% vs. 31.6%, P=0.06), event-free survival (EFS) (hazard ratio [HR]=0.59; P=0.08), and OS (HR=0.46; P=0.01) with CPX-351.1 This compound was later approved by the FDA for the treatment of newly-diagnosed, therapy-related AML, and AML with myelodysplastic syndrome (MDS)-related changes based on results of a phase III trial comparing CPX-351 with the “7+3” regimen in which OS was improved with the liposomal formulation (HR=0.69; P=0.005) with an improved CR rate of 38% compared to 26% (P=0.035).30 More patients in the CPX-351 arm (56%) received allo-HCT than in the “7+3” arm (46%).31 At a median follow-up of 60 months, the median OS was not reached in the CPX-351 arm while it was 10.3 months in the “7+3” arm (HR=0.51). This study showed the impact of induction therapy on transplant outcomes, offering older patients with AML high CR rates and prolonged survival after CPX-351 induction therapy followed by allo-HCT. An Italian group reported similar results with CR rates of 70.4%.32 Patients in this study who had undergone allo-HCT had improved outcomes, thus highlighting the potential impact of CPX-351 on post-HCT outcomes.32 Its use was also investigated in the frontline setting to treat AML patients at high risk of mortality from standard induction in a phase II open-label trial.33 Fifty-six patients were enrolled to receive 50, 75, or 100 units/m2 on days 1, 3, and 5.33 The composite CR was lowest in the 50 units/m2 arm, although the difference was not statistically significant (19% vs. 38% vs. 44%; P=0.35).33 The median OS was 4.3 months in the 50 units/m2 arm compared to 8.6 and 6.2 months in the 75 and 100 units/m2 arms, respectively, thus underscoring the efficacy, safety, and tolerability at the substandard dose of 75 units/m2 in some patients at high risk of treatment-related mortality.33 Currently, CPX-351 is being investigated in the relapsed/refractory (R/R) setting in combination with FLT3 tyrosine kinase inhibitors (TKI), gilteritinib (NCT05024552) and quizartinib (NCT04128748), and GO, an anti-CD33 antibody drug conjugate (NCT03904251); in the frontline setting combined with fludarabine (NCT04425655), venetoclax (NCT04038437), quizartinib (NCT04128748) and palbociclib (NCT03844997); in therapy-related AML/MDS with glasdegib (NCT04231851); and in older patients with GO (NCT03878927).
B-cell lymphoma 2 (BCL-2) protects cells against apoptosis, and its expression in AML is associated with decreased sensitivity to cytotoxic therapy and, therefore, a higher probability of relapse. Venetoclax is an orally bioavailable inhibitor of BCL-2. Before its introduction for AML, it was FDA-approved for treating 17p-deletion-positive chronic lymphocytic leukemia. Early studies showed only modest efficacy of venetoclax monotherapy in treating R/R AML.34 However, the promising results of two large phase Ib/II trials combining an HMA or LDAC with venetoclax led to the FDA approval of venetoclax combined with azacitidine, decitabine, or LDAC for older (>75 years) patients, unfit for intensive chemotherapy, with the HMA-venetoclax combination being the most commonly used.35,36 The two phase III trials, VIALE-A and VIALE-C, demonstrated a significant survival benefit from combining venetoclax with a HMA.6,7 The VIALE-A trial included patients >75 years, unfit for intensive chemotherapy without prior exposure to HMA.6 Patients were randomized to receive either venetoclax-azacitidine or azacitidine alone: the CR rate was 36.7%, the clinical CR rate was 66.4%, and the median OS was 14.7 months in the group treated with the combination.6 In contrast, 20% of patients in the VIALE-C trial had been previously exposed to HMA treatment. Patients in this trial were randomized to receive either venetoclax-LDAC or LDAC alone: the median OS improved from 4.1 to 7.2 months with the addition of venetoclax, with a 25% reduction of the risk of death.7 These two trials established the combination of venetoclax-HMA as a standard of care for AML patients unfit for intensive therapy. It is essential to highlight that CR rates were significantly improved with this combination in all disease subgroups regardless of positive or negative prognostic mutations such as NPM1, IDH-1/2, or FLT3-ITD. This creates room for debate regarding patients with specific targetable mutations who responded to venetoclax-HMA. Do we combine novel drugs targeting mutations with venetoclax, HMA, or all three? The answer will depend on the safety profile of the triple drug combination and large randomized trials should be conducted to compare various doublet combinations to triplet combinations.
A recent prospective trial assessed the use of a venetoclax-azacitidine combination as a bridge to allo-HCT using historical patients who had received intensive chemotherapy prior to allo-HCT as the comparison group.37 Patients who received venetoclax-azacitidine were older and had more secondary AML and adverse cytogenetics. They received mainly reduced intensity conditioning (RIC). The 12-month non-relapse mortality, relapse-free survival (RFS), and OS were 19.1%, 58%, and 63% in the venetoclax-azacitidine group compared to 11.8%, 54%, and 70% in the historical intensive chemotherapy group.37 Another retrospective single-center study compared outcomes of patients >60 years of age who received induction venetoclax-azacitidine followed by allo-HCT to the same population of patients eligible for transplant but who chose to defer it.38 The median OS was not reached for patients who underwent allo-HCT compared to 518 days for patients who did not (P=0.01), reinforcing the role of allo-HCT even in older patients. Those results are also valid for patients who receive triplet induction. In a phase II trial, FLT3 inhibitors in combination with venetoclax and decitabine (for 10 days) were studied in patients with newly diagnosed and R/R FLT3-mutated AML ≥60 years old.39 Four patients in the newly diagnosed cohort received consolidation with allo-HCT, followed by maintenance in two patients. At 2 years, all four patients were still alive. Hence, the use of triplet induction followed by allo-HCT followed by maintenance could improve long-term survival of newly diagnosed older patients with AML.39 More data are needed to confirm these findings. Venetoclax has since been studied in various combinations including with intensive chemotherapy. The MD Anderson Cancer Center group conducted a phase Ib/II trial of medically fit R/R or newly diagnosed AML patients treated with FLAG-IDA combined with up to 14 days of venetoclax. After an initial high rate of grades 3-4 febrile neutropenia in the first phase of the trial, chemotherapy doses were adjusted and the duration of venetoclax treatment reduced from 21 to 14 days, with a good safety profile. Results demonstrated robust efficacy, with 90% of newly diagnosed AML patients achieving CR and 96% achieving MRD negativity.40 The group also investigated the addition of venetoclax to cladribine, idarubicin, and cytarabine (CLIA), which proved safe in newly diagnosed patients without increased mortality and with durable MRD negativity.41 Another venetoclax and intensive chemotherapy combination is the addition of venetoclax to “5+2” induction in older patients, which resulted in high remission rates and had an acceptable safety profile.42 In a propensity-score analysis of trials combining venetoclax with intensive chemotherapy including anthracycline, purine analogues, and cytarabine, the addition of venetoclax led to high rates of MRD negativity compared to chemotherapy alone (86% vs. 61%; P=0.0028). A higher number of patients underwent allo-HCT in first remission in the venetoclax arms. Furthermore, the addition of venetoclax prolonged EFS (HR=0.57; 95% CI: 1.11-2.08; P=0.012).43 The results of this post-hoc analysis are encouraging and should be confirmed by large prospective trials.
It is worth noting that relapse remains common with these regimens secondary to emerging resistance to venetoclax due to overexpression of MCL-1, gain of function of FLT3-ITD, or loss of function of TP53.44 Combinations of a HMA with an IDH-1/2 inhibitor, which are discussed below, have also been studied to investigate possible synergistic effects of these two types of drugs.
Hedgehog pathway inhibitor: glasdegib
The role of the Hedgehog signaling pathway in hematopoiesis is not clear. The pathway plays an essential role in cellular development and is fundamental in some carcinogenic pathways. Glasdegib is the only Hedgehog pathway inhibitor approved for use in AML, based on the results of the BRIGHT 1003 AML phase II trial evaluating the addition of glasdegib to LDAC in patients with AML/MDS unsuitable for intensive chemotherapy.8 Eighty-eight and 44 patients were randomized to glasdegib-LDAC and LDAC, respectively. The median OS was 8.8 months in the combination group compared to 4.9 months in the LDAC group (HR=0.51, 80% CI: 0.39-0.67; P=0.0004). The CR rate was 17% vs. 2.3% (P<0.05) in the glasdegib-LDAC and LDAC arms, respectively. It is worth mentioning that this trial was criticized given that the results in the control arm (LDAC) were lower than those reported in previous studies. Nevertheless, this treatment provides an option for patients who are not eligible for intensive chemotherapy. Investigations of the combination of glasdegib with intensive chemotherapy (NCT03416179) with other novel treatments such as CPX-351 (NCT04231851) are underway.
Gene mutations are important in risk-stratification of AML. According to the European LeukemiaNet (ELN) 2017, the presence of a mutated FLT3-ITD or TP53 is associated with worse outcomes.45,46 On the other hand, mutations in NPM1 without an FLT3-ITD mutation confer a survival advantage.45,47 IDH1/2 mutations were not described in the ELN 2017 risk stratification of AML and their prognostic significance is controversial, largely depending on co-occurring mutations.48 As such, novel treatment has aimed at targeting detectable mutations.
The utility of TKI has been established in both solid and hematologic malignancies. Given the negative prognostic influence of FLT3-ITD mutations, the therapeutic potential of TKI has been investigated in this context. Early or first-generation TKI, including midostaurin and sorafenib, are non-specific, targeting an array of TKI other than FLT3-ITD. Next-generation TKI include quizartinib, crenolanib, and gilteritinib, which are more specific and potent. Nevertheless, the relation of specificity to TKI and toxicity profile is not well understood. For example, quizartinib, a fairly specific, second-generation TKI is associated with high rates of toxicity, namely immunosuppression and QTc prolongation.49
Several TKI targeting FLT3 have been evaluated in combination with intensive chemotherapy during induction treatment of AML. Sorafenib has been investigated for more than a decade. Ravandi et al. studied the outcome of patients with previously untreated AML who received a combination of sorafenib, cytarabine, and idarubicin, demonstrating a CR of 95% with an OS of 29 months.50 In contrast, sorafenib combined with the standard “7+3” regimen did not improve OS or EFS in patients >60 years.51 In patients aged <60 years, frontline sorafenib in combination with standard induction significantly prolonged EFS (21 vs. 9 months) and RFS (63 vs. 22 months) when compared to placebo combined with standard induction.52 Recently, a phase II trial documented an improved OS but not EFS with sorafenib combined with intensive frontline chemotherapy, especially in patients with an allelic ratio >0.7.53
The RATIFY trial, central to the FDA approval of midostaurin for treating newly diagnosed FLT3-mutated (FLT3-ITD or FLT3-TKD) AML, highlighted improved survival in more than 700 patients aged <60 years, randomized to receive either placebo or midostaurin 50 mg orally twice daily on days 8-21 of each “7+3” cycle and high-dose cytarabine (HiDAC) consolidation.2 Those in remission were also treated with daily midostaurin maintenance therapy for up to 1 year. EFS and 4-year OS were significantly improved in the midostaurin group (8.2 vs. 3 months and 51.4% vs. 44.2%, respectively).2 Importantly, the group that received midostaurin had improved outcomes regardless of the subtype of FLT3 mutation (TKD, ITD low allelic ratio or ITD high allelic ratio).2
The addition of crenolanib to the “7+3” regimen in patients <60 years has demonstrated tolerability and produced promising outcomes in a phase II study.54 Importantly, its use in patients with mutations other than FLT3 has demonstrated that the addition of crenolanib can overcome the poor prognosis implied by other concurrent mutations.55 Quizartinib, even as monotherapy, has produced significant remissions in R/R, FLT3-mutated AML.56 A phase III trial, QuANTUM-R, evaluated quizartinib monotherapy versus investigator choice of treatment in R/R FLT3-ITD AML. The OS associated with quizartinib monotherapy was 6.2 months compared to 4.7 months for the other patients (HR=0.76; P=0.02).49 Long-term follow-up of the trial confirmed the results (HR for OS=0.776; P=0.324).57 Although positive, QuANTUM-R results were strongly criticized by the FDA, thus leading to the drug not being approved. This was due to the reported improved OS, which correlated with a median survival extended by only 6 weeks without a significant improvement in EFS. Furthermore, the dropout rate from the chemotherapy arm was much higher (23% vs. 11%) and more patients treated with quizartinib underwent HCT (32% vs. 11%), further confounding the results.58 The phase III trial, ADMIRAL, evaluated monotherapy with gilteritinib versus investigator choice of treatment in the same population: treatment with gilteritinib improved OS from 5.6 to 9.3 months (P<0.001), which led to its approval in the USA and Europe for treatment of this patient population.59
Currently, midostaurin remains the only approved TKI for treating previously untreated FLT3-mutated AML. Midostaurin versus gilteritinib in combination with induction and consolidation in newly diagnosed FLT3-mutated AML is being explored in the HOVON 156 AML trial (NCT04027309). The frontline use of quizartinib in combination with the “7+3” regimen is being investigated in the phase III, double-blind, placebo-controlled QuANTUM-First trial (NCT02668653). Another phase III study is currently comparing crenolanib versus midostaurin when added to the “7+3” regimen in newly diagnosed FLT3-mutated AML (NCT03258931).60 The results of these two trials could change treatment guidelines for this challenging patient population. Quizartinib is also being evaluated in combination with CPX-351 (NCT04209725) and with CLIA (NCT04047641) in untreated and R/R FLT3-mutated AML. The addition of FLT3-TKI to low-intensity treatment was also studied in patients not eligible for chemotherapy. Sorafenib was added to azacitidine in a phase II trial, showing efficacy in patients with relapsed FLT3-ITD-positive AML.61 Sorafenib was studied in the frontline setting in another phase II trial in combination with azacitidine. Most of the patients were 60 years or older. The combination was both well tolerated and effective.62 Another FLT3 inhibitor, gilteritinib, was added to azacitidine and the combination compared to azacitidine monotherapy (NCT02752035) in the LACEWING phase III trial in the first-line setting.3 Midostaurin was assessed in combination with azacitidine in newly diagnosed and R/R AML in a phase I/II trial.63 Quizartanib was combined with azacitidine or LDAC in untreated and R/R AML in a phase I/II trial.64 Except for the last trial which showed acceptable CR and OS rates, FLT3-TKI alone or in combination with HMA or LDAC did not markedly change the outcomes of patients with FLT3-mutated AML not eligible for intensive chemotherapy. This could be largely due to an escape mechanism through which leukemic cells develop resistance to treatment. One of the mechanisms of resistance is the upregulation of BCL-2 receptors.65 Based on this finding, several ongoing studies are assessing the use of doublet or triplet combinations of FLT3-TKI and venetoclax. In a phase I/II trial presented at the American Society of Hematology annual meeting in 2021, gilteritinib was combined with venetclax and azacitidine for the treatment of newly diagnosed or R/R FLT3-mutated AML. Two doses were studied and 80 mg was chosen for a phase II trial based on dose-limiting toxicities observed with the 120 mg dose. Even at the 80 mg dose, the triplet combination was associated with marked myelosuppression requiring dose adjustments of azacitidine and venetoclax.66 Nevertheless the efficacy of this triplet combination is promising, with a high CR rate of 100% and 67% in the frontline and R/R AML setting, respectively.
IDH-1 and IDH-2 are critical for the oxidative carboxylation of isocitrate. Mutations in these enzymes result in the accumulation of 2-hydroxyglutyrate, causing DNA and histone hypermethylation, cellular differentiation arrest, and tumorigenesis. Such mutations account for 15% of newly diagnosed AML.67 Oral inhibitors of mutant IDH-1 (ivosidenib) and IDH-2 (enasidenib) have been explored in the frontline and R/R settings. In the R/R setting, the FDA approved the two drugs as monotherapy for the corresponding mutation, given promising results of ivosidenib and enasidenib with overall response rates of 41.6% and 40.3%, and median OS of 8.8 and 9.3 months, respectively.4,68 In the frontline setting, both inhibitors were also approved by the FDA for the treatment of older patients ineligible for intensive chemotherapy.69,70 Stein et al. studied the addition of either IDH inhibitor to the “7+3” regimen in patients with de novo IDH-mutated AML. Sixty had mutant IDH-1 and received ivosidenib, among whom the response rate was 93% and 1-year OS 79%. Ninety-one had mutated IDH-2 and received enasidenib, among whom the overall response rate was 73% and OS 75%.71
Combinations of IDH inhibitors with the previously discussed HMA have been explored. Ivosidenib combined with azacitidine was studied as frontline therapy in 23 patients with IDH-mutated AML: the overall response rate was 78% and the CR rate was 70%, with a median time to response of 1.8 months. IDH-mutation clearance was seen in 63% of the patients achieving a CR. Outcomes surpassed those expected with azacitidine alone.72,73 The recently published phase III AGILE trial (NCT03173248) compared azacitidine-ivosidenib and azacitidine-placebo in patients with untreated IDH1-mutated AML, ineligible for intensive chemotherapy.74 At a median follow-up of 12.4 months, EFS was significantly better in the combination group (HR=0.33; P=0.002).74 The median OS was 24 months versus 7.9 months in the azacitidine-ivosidenib and azacitidine-placebo groups, respectively (HR=0.44; P=0.001).74 These results led to FDA approval of the azacitidine-ivosidenib combination in patients >75 years or unfit for intensive chemotherapy in May 2022. Similarly, enasidenib combined with azacitidine has been studied in a phase Ib/II study with recently published results. One hundred and one patients (median age of 75 years) were randomized 2:1 to receive azacitidine-enasidenib or azacitidine alone. The overall response rate improved significantly from 36% to 74% in the combination group (OR=4.9; P=0.0003), but the study failed to show any survival difference with the combination.5 This finding could have been confounded by the subsequent use of salvage enasidenib in the azacitidine-only arm. A large, phase III trial is underway to investigate the impact of adding ivosidenib or enasidenib versus placebo to induction and maintenance therapy in IDH-mutated AML patients eligible for intensive chemotherapy (NCT03839771).
TP53 mutations occur in up to 20% of patients, are usually associated with complex/monosomal karyotype, and are more common in older patients with therapy-related AML.75 They invariably confer resistance to conventional therapeutic approaches in most patients harboring such mutations.76 Eprenetapopt (APR-246) is a novel agent that could restore activity to mutant p53, thus inducing apoptosis of cancer cells.77 A phase Ib/II study (NCT03072043) investigated the safety and efficacy of adding eprenetapopt to azacitidine in 55 patients with TP53-mutated AML/MDS, in whom the overall response rate and CR in AML patients were 64% and 36%, respectively.10 OS in responding patients improved significantly (14.6 vs. 7.5 months; P=0.0005), and adverse events were those expected with azacitidine or eprenetapopt alone (febrile neutropenia, leukopenia).10 This combination was explored independently by the Groupe Francophone des Myelodysplasies in a phase II study (NCT03588078) of 52 TP53-mutated patients, of whom 18 had AML; the overall response rate and CR rates were 33% and 17%, respectively.78 These two studies highlighted the potential safety and benefit of combining eprenetapopt with azacitidine compared to azacitidine alone. The outcomes of patients with TP53-mutated AML remain poor, and no regimen has improved OS in those patients, including decitabine (10 days)/venetoclax.79
Immunotherapy Magrolimab (Hu5F9-G4)
CD47 has been studied as another potential target for treating AML, specifically in patients who are unfit for high-intensity therapy. The up-regulation of CD47 in AML allows tumor cells to evade destruction by macrophages, an effect independently associated with a poor prognosis.80 Hu5F9-G4 (magrolimab) is a monoclonal antibody that binds to CD47, leading to phagocytic elimination of tumor cells. The combination of magrolimab and azacitidine was evaluated in 34 patients with AML or intermediate-high risk MDS, in whom the overall response rate was 65% (CR, 40%).81 Interestingly, among patients with abnormal cytogenetics, 47% achieved a complete cytogenetic response. Among those with concurrently mutated TP53, the overall response rate was 71% (CR, 48%); these patients had a median OS of 12.9 months compared to 18.9 months in patients with TP53 wild-type AML.81 Thus, targeting CD47 without targeting mutated TP53 in this group resulted in favorable outcomes, paving the way for future trials involving the novel monoclonal antibody. There are currently two trials investigating the three-drug combination of magrolimab with venetoclax and azacitidine (NCT05079230 and NCT04435691). In addition, magrolimab-azacitidine is being compared to venetoclax-azacitidine versus intensive chemotherapy alone in previously untreated TP53-mutated AML in a phase III trial (NCT04778397).
Impact of minimal residual disease on the outcomes of allogeneic hematopoietic cell transplantation
Evaluation of MRD before and after allo-HCT is of clinical interest with the aim of tailoring patients’ treatment prior to allo-HCT based on their individual risks and identifying and treating patients who are MRD-positive after transplantation before any clinical relapse. Patients who are MRD-positive by multiparametric flow cytometry at the time of allo-HCT were shown to have an increased risk of relapse and decreased leukemia-free survival and OS.82 In an analysis of EBMT registry data, the presence of detectable IDH1-2 mutations prior to transplantation significantly increased the risk of relapse.83 In the HOVON-SAKK-132 phase III trial, patients with AML received consolidation with allo-HCT based on an MRD-adapted approach. Patients received induction chemotherapy with or without lenalidomide.84 After two cycles of induction, patients were randomized, based on baseline risk and MRD status, to a third cycle of induction (favorable-risk cases), autologous stem cell transplantation (intermediate-risk and MRD-negative cases), or allo-HCT (intermediate-risk and MRD-positive or unknown, or high-risk cases). The outcome of patients with intermediate-risk disease was similar for patients with MRD-negative or positive disease (4 -year RFS: 50% in MRD-positive cases vs. 52% in MRD-negative cases, HR=1.18, P=059; 4-year OS: 64% in MRD-positive cases vs. 69% in MRD-negative cases, HR=1.31, P=0.46).84 These results indicate that MRD-directed therapy could help to avoid allo-HCT in patients with intermediate-risk AML who are MRD negative prior to transplantation. However, patients stratified into the intermediate-risk group harbor diverse mutations and assessment of the role of MRD on the decision to perform allo-HCT should be studied in those different subgroups. A particular question that should be addressed is the impact of addition of targeted agents to induction treatment and the impact of MRD on the decision to perform allo-HCT, specifically in the era of maintenance therapy. In the post-allo-HCT setting, Shah et al. found that detection of MRD by multiparametric flow cytometry early after allo-HCT predicted relapse (within 2 months) and led to better risk-stratification of patients with AML after transplantation.85 This highlights the need for preventive measures to avoid relapses, discussed later in this review. In summary, MRD-directed therapy could be potentially used for treatment guidance for patients with AML; however, its impact on transplant decisions has not yet been established, especially in patients with intermediate-risk AML who become MRD-negative after transplantation. Similarly, post-allo-HCT MRD should be used to direct maintenance therapy.
Novel approaches in allogeneic hematopoietic cell transplantation for acute myeloid leukemia
While numerous novel therapies are emerging, allo-HCT remains the standard of care for patients with ELN 2017 intermediate- and adverse-risk disease in first CR.46 Based on the results of the BMT CTN 0901 randomized phase III trial, there is clear evidence that myeloablative conditioning (MAC) improves OS in patients with AML or MDS undergoing allo-HCT compared to RIC (HR=1.54; 95% CI: 1.07-2.2; P=0.03).86 Although RIC increases the risk of relapse, it is associated with reduced toxicity, leading to lower treatment-related mortality compared to MAC (9.9% vs. 25.1%; P<0.01), broadening the use of allo-HCT in the older population.86,87 However, the optimal conditioning therapy would be a regimen that carries lower risk of toxicity and treatment-related mortality but retains cytoreductive properties and, ideally, does not affect outcomes, a regimen that was recently described as “reduced toxicity conditioning”.88
Another unmet need is transplantation for refractory leukemia. Sequential approaches are conditioning platforms developed for patients with refractory or active AML. These regimens have two phases of therapy; induction chemotherapy that targets refractory leukemia followed by RIC, relying mainly on the graft-versus-leukemia (GvL) effect. FLAMSA (fludarabine, cytarabine, and amsacrine, followed by 4 Gy of total body irradiation, cyclophosphamide, and an anti-thymocyte globulin) was the first “sequential regimen” developed. More recently FLAMSA-like combinations have emerged.89 Other conditioning regimens recently developed for allo-HCT of active or refractory AML include targeted radiation therapy using anti-CD45 monoclonal antibody (Table 2 and Table 3).90 Novel therapies for use in AML during and after allo-HCT are secribed below. Those for which results have been published are summarized in Table 2. Table 3 lists ongoing trials involving novel therapies for AML before, during and after allo-HCT.
Treosulfan-based conditioning regimens
Busulfan is an alkylating agent with an erratic gastrointestinal absorption needing multiple daily oral or targeted intravenous dosing.91 It is associated with toxicity, mainly veno-occlusive disease and idiopathic pulmonary syndrome.92 Treosulfan is a bifunctional alkylating prodrug with myeloablative properties and a reduced non-hematologic toxicity profile. It is administered intravenously, but drug levels do not need to be monitored because it does not have dose-limiting organ toxicity.93 In a dose-finding study, treosulfan was evaluated in combination with fludarabine in patients with hematologic malignancies undergoing allo-HCT. There was no dose-limiting toxicity, and the final dose chosen for further studies was 14 g/m2 x3.93 Another phase II open-label, non-randomized trial (AlloTreo) evaluated the safety and efficacy of treosulfan (42 g/m2) with fludarabine in patients with hematologic malignancies undergoing first allo-HCT. Anti-thymocyte globulin was added to the conditioning regimen in patients undergoing unrelated donor transplants. After 12 years of follow-up, OS and PFS were 41.7% and 31.7%, respectively. The cumulative incidence of relapse was high at 44.5%. This could be explained by the higher disease risk of patients included in the study.94 To confirm these findings, a phase III, open-label, non-inferiority trial (MC-FludT.14/L) was conducted comparing treosulfan/fludarabine (FT10) to RIC fludarabine/busulfan in patients ≥50 years or with comorbidities. Treosulfan was given at a dose of 10 mg/m2 for 3 days. The study included 476 patients with AML or MDS. The median follow-up was 15.4 and 17.4 months for treosulfan- and busulfan-based conditioning, respectively. The 2-year EFS was higher in the treosulfan arm (64%) than in the busulfan arm (50.4%) (P<0.0001). Both drugs had similar hematologic toxicity rates (15%); however, treosulfan was associated with a lower risk of gastrointestinal toxicity (11% vs. 16%). This trial has shown that treosulfan is non-inferior to busulfan in older patients or those with comorbidities.
Based on this study, treosulfan was approved by the EMA at a dose of 30 mg/m2 for malignant diseases.95 A subgroup analysis of patients with AML was presented at the Tandem ASTCT and CIBMTR meetings in 2022: EFS, OS, and graft-versus-host disease (GvHD)-free, relapse/progression-free survival were significantly higher in the treosulfan group (64.7% vs. 53.3%, P=0.01; 72.8% vs. 64.7% P=0.03; and 52.9% vs. 39.6%, P=0.02, respectively).96 These results support the use of treosulfan rather than busulfan in patients not eligible for standard MAC.
Addition of targeted therapy to standard conditioning regimens
As mentioned earlier, the use of venetoclax has improved the outcomes of patients with AML in the frontline and R/R settings.6 A phase I dose-escalation study assessed the addition of venetoclax to RIC fludarabine/busulfan in adult patients with AML or MDS undergoing allo-HCT.97 Patients received venetoclax at a dose of 200-400 mg starting on day -8 for 6-7 days. A total of 22 patients were included. Acute GvHD was observed in 12/22 patients, with one patient having grade III acute GvHD. The median time to neutrophil engraftment was 15 days, similar to that observed with RIC fludarabine/busulfan. No dose-limiting toxicity was reported; hence, the dose of 400 mg was chosen for the phase II trial.97 A phase II trial assessed the addition of venetoclax to myeloablative fractionated busulfan, fludarabine, and cladribine conditioning in patients with AML or MDS. The authors hypothesized that adding venetoclax might be synergistic with chemotherapy. The study included 33 patients (AML, n=21; MDS, n=10) up to 70 years of age. Venetoclax was administered at a daily dose of 400 mg from day -22 to -3 without azoles. The 1-year OS, PFS, relapse, and NRM rates were 84%, 77%, 13%, and 10%, respectively. The median time to neutrophil and platelet engraftment was 15 and 23 days, respectively. The most common grade ≥3 adverse events were febrile neutropenia (58%), mucositis (18%), and pulmonary toxicity (21%). The day 100 grade II-IV acute GvHD rate was low at 3%.98 These results showed that adding venetoclax to the conditioning regimen was safe, did not affect engraftment, and had promising early outcome results.
Another targeted agent added to a conditioning regimen was a first-generation FLT3-TKI, investigated in a phase I study presented at the Tandem meetings in 2022, in which sorafenib was added to MAC fractionated busulfan/fludarabine.99 Twenty-four patients with AML were included. Sorafenib was added from day -24 to -5 at different dose levels (200, 400, 600, and 800 mg). The dose of 800 mg was recommended for the phase II study. The 1-year OS and PFS rates for all patients were 86% and 89%, respectively. The grade II-IV and grade III-IV acute GvHD rates at day 100 were 54% and 5%, respectively. These results show that sorafenib can be safely added to the fractionated busulfan regimen, although longer follow-up and larger studies are needed for a more complete evaluation.
Anti-CD117 monoclonal antibody
An anti-CD117 (c-KIT) monoclonal antibody, JSP191 was added to non-MAC consisting of low-dose total body irradiation and fludarabine. JSP191 depletes both hematopoietic stem cells and leukemic cells and synergizes with total body irradiation and fludarabine facilitating engraftment.100 The phase I study reporting the outcomes of 17 patients was presented at the Tandem meetings in 2022. The combination was safe without any infusion or serious adverse effects observed. Neutrophil engraftment occurred between day 19 and day 26. Only one grade 2-4 side effect was observed. Donor chimerism was evaluated in 14 patients at day 90; all of them had full myeloid donor chimerism. High rates of MRD clearance were observed in 15/17 subjects who were MRD-positive at the time of transplantation. These results are promising especially with the use of non-myeloablative allo-HCT. The study is ongoing and final results are awaited (NCT04429191).
Sequential approach in relapsed/refractory patients and those transplanted in active disease
Given the low response rates and short survival of patients with refractory leukemia, allo-HCT remains the only option of cure. However, MAC is associated with a high treatment-related mortality of around 40% and RIC, although it decreases treatment-related mortality, is insufficient to control refractory leukemia alone through the GvL effect.89,101 A sequential approach was developed through the addition of a short course of intensive chemotherapy prior to RIC with the aim of reducing the disease burden and enhancing the GvL effect. The first sequential regimen developed was the FLAMSA regimen which was associated with high toxicity mainly related to amsacrine and total body irradiation. Another sequential regimen published by Duléry et al. was the TEC-RIC regimen (thiotepa, etoposide, cyclophosphamide followed by RIC of fludarabine, busulfan, and anti-thymocyte globulin). Sixty-one percent of the patients had AML. Results were promising, with 2-year OS and EFS rates of 54.7% and 49.3%, 49.2% and 43.8%, 37.9%, and 28%, in haploidentical, related, and unrelated donor transplants, respectively. Mucositis and gut toxicities were the most common toxicities observed.89 These results indicated the safety and efficacy of the TEC-RIC sequential approach in allo-HCT for active or refractory AML.
Targeted radiation therapy with an anti-CD45 monoclonal antibody (Iomab-B)
Many patients with active R/R AML are not fit for intensive chemotherapy or MAC, making them ineligible for sequential approaches. The SIERRA trial (Study for Iomab-B in Elderly Relapsed or Refractory AML) investigated using Iomab-B, a 131I-labeled anti-CD45 monoclonal antibody, as conditioning prior to allo-HCT.90,102 Patients were randomized to receive Iomab-B followed by fludarabine and low-dose total body irradiation, or conventional care. The median age of the participants was 65 years. The rate of allo-HCT was higher in the Iomab-B arm (90%) than in the conventional care arm (17%). Patients who did not achieve CR in the conventional care arm could cross over to the Iomab-B arm. Median times of neutrophil and platelet engraftment were 14 and 18 days, respectively. Patients enrolled in the Iomab-B arm had a significantly lower incidence of grade ≥3 side effects compared to those in the conventional care arm (5% vs. 30%; P<0.05), with these side effects being mainly sepsis and mucositis. These data show that the Iomab-B-based conditioning regimen is safe and associated with acceptable engraftment kinetics.90,102
Novel maintenance approaches to mitigate relapse after allogeneic hematopoietic cell transplantation
The outcomes of younger patients with R/R AML have improved over the years, likely due to advances in therapeutic regimens. In an EBMT registry analysis, Bazarbachi et al. showed a significant improvement in OS of younger patients with AML relapsing after allo-HCT in more recent years of transplant (2000-2004; HR=0.82; P<0.02 for 2010-2014 and HR=0.72; P=0.0002 for 2015-2018).103 Despite these advances in the treatment of AML and the potential curative approach with allo-HCT in intermediate- and adverse-risk disease, relapse is inevitable in many patients, and they have a dismal prognosis.104 Post-transplant salvage therapy in AML is an area of unmet need. In relapsed patients, treatments are limited and include palliative care, low-dose or high-intensity treatments, donor lymphocyte infusion, and a second allo-HCT in selected cases. Nevertheless, many patients do not tolerate high-dose therapies, hence the need for novel approaches to prevent or treat relapse. Maintenance strategies have been studied recently in many trials aiming to prevent relapse. The main purpose of post-transplant maintenance is not only to induce a direct anti-leukemic effect through the elimination of any residual leukemia not detected by current laboratory techniques but also to stimulate the GvL effect, ideally without increasing the risk of GvHD.105 Maintenance therapy can also act as a bridge to mount a GvL effect. Several drugs have been assessed in the post-transplant setting, including a HMA alone or in combination with a BCL-2 inhibitor or granulocyte colony-stimulating factor, FLT3 inhibitors, IDH1/2 inhibitors, and there are early data on histone deacetylase (HDAC) inhibitors; many of these have shown efficacy in the frontline or relapsed setting.
Hypomethylating agent therapy alone or in combination
The HMA azacitidine and decitabine are the most studied drugs in the post-transplant maintenance setting, mainly because of their acceptable safety profile. Data from pre-clinical animal models have shown that azacitidine, in addition to its direct anti-leukemic effect, can upregulate tumor antigens on leukemic cells, activate CD8+ tumor-specific T cells, and induce regulatory T-cell activity. This in turn increases the GvL effect without a concomitant increase in GvHD.106 Following these findings, several trials were conducted to investigate the role of these agents as maintenance therapy after allo-HCT.107 While many studies support the consideration of a maintenance strategy, some did not demonstrate any benefit.108
In a dose-finding phase I trial, the use of azacitidine mono-therapy for maintenance was assessed, starting on day +42 after transplantation. Different dose levels were used. The recommended dose for later studies was 32 mg/m2/day for 5 days in a 30-day cycle. Higher doses were associated with thrombocytopenia. After 12 months of follow-up, the median disease-free survival was 58%, and the 1-year OS was 77%.109 In another phase I/II trial, azacitidine was administered at a dose of 36 mg/m2/day for 5 days in a 28-day cycle leading to an increased GvL effect through induction of circulating regulatory T cells without an increase in GvHD.106 In a case series including 18 patients with AML or MDS who were FLT3-negative and in remission following allo-HCT, post-transplant azacitidine maintenance was assessed after starting at a median of 60 days after transplantation. Patients received low-dose azacitidine 32 mg/m2/day for 5 days in a 28-day cycle for up to 5 years.110 A phase III trial comparing azacitidine monotherapy maintenance after allo-HCT at a dose of 32 mg/m2/day for 5 days in a 28-day cycle to no intervention did not show benefit of azacitidine maintenance. Azacitidine was administered for up to 12 cycles (median, 4; range, 1-12). The study included 87 patients with AML, MDS, or chronic myelomonocytic leukemia. After a median follow-up of 4.6 years, azacitidine maintenance did not improve RFS. In a subgroup analysis, patients who received nine or more cycles had an increase in RFS, albeit not statistically significant.111 Despite the negative azacitidine maintenance phase III trial, the use of maintenance therapy should not be abandoned for several reasons. First, the trial involved patients with high-risk disease, including those with FLT3 mutations. Studies have shown that patients with FLT3-mutated AML benefit from the addition of FLT3 inhibitors as maintenance therapy, as discussed later in this review.112 The inclusion of this population could have affected the result of the trial. Second, the study had some selection bias as it excluded patients who received azacitidine for MRD-positive disease. This strategy is denoted as pre-emptive rather than maintenance; those patients might have needed higher doses of azacitidine in addition to other treatment approaches.
Oral azacitidine (CC-486) maintenance improved OS and RFS in older patients with AML in remission after induction therapy in the QUAZAR-AML-001 trial.113 Based on these results, CC-486 was studied as maintenance therapy in patients in CR after allo-HCT. In a phase I/II trial, CC-486 was given to seven patients at a dose of 200-300 mg for 7 days and to 23 patients at a dose of 150-200 mg for 14 days in up to 12 cycles of 28 days. The 1-year RFS was 54% and 72%, respectively. CC-486 was tolerated, with gastrointestinal and hematologic toxicities being the most common grade 3-4 adverse events. Only two patients developed chronic GvHD.114 The AMADEUS phase III trial (NCT04173533) is ongoing and will address concerns regarding dosing, treatment schedule, and therapy duration using maintenance oral azacitidine (CC-486) compared to placebo for AML and MDS in CR after allo-HCT.
Decitabine was also studied for maintenance therapy after allo-HCT. A small dose-finding study assessed the use of low-dose decitabine maintenance therapy after allo-HCT for patients with AML or MDS in CR. Decitabine was given at a dose of 5, 7.5, 10, or 15 mg/m2/day for 5 days in a 6-week cycle starting between day +50 and day +100. The maximum tolerated dose was not reached but 10 mg/m2 was chosen because of hematologic toxicities with the 15 mg/m2 dose.115 Results showed a high 2-year OS of 56% and a low cumulative incidence of relapse of 28%. This study indicated that decitabine is safe after allo-HCT and could potentially be used as maintenance therapy. A phase II, open-label, multicenter, randomized controlled trial explored the use of decitabine for maintenance in 204 patients with high-risk AML in CR who were MRD negative after allo-HCT. Patients were randomized, between days 60 and 100 after allo-HCT, to receive recombinant human G-CSF in combination for 6 days with low-dose decitabine for 5 days (G-DEC) or no intervention. The cumulative incidence of relapse was lower in the G-DEC group at 15% compared to 38% in the no-intervention group (HR=0.92; 95% CI: 0.18-0.57; P<0.1). There was no statistically significant difference in the incidence of chronic GvHD (G-DEC 23% vs. no-intervention 21.7%; P=0.81).116 Immune cell subtype monitoring revealed a significant increase in CD8+ and regulatory T cells and NK cells by the second or third cycle in the G-DEC group (P<0.5).
The latter results are encouraging and demonstrate a potential benefit of maintenance therapy. Nevertheless, more randomized trials are needed to identify the population of patients who would benefit from maintenance therapy, find the best combination, and standardize the dose and schedule of treatment.117
BCL-2 inhibitors, mainly venetoclax, showed promising results in the treatment of AML. Hence, venotoclax was studied in the post-transplant setting. In a cohort study, 23 patients with high-risk AML/MDS in remission after allo-HCT received venetoclax (400 mg daily) for 1 year.118 Venetoclax was withheld or its dose was reduced in 11 of the 23 patients. The most common adverse events were cytopenia (7/23) and diarrhea (7/23). Six-month OS and RFS rates were both 87%. This was a small cohort study showing the safety of venetoclax after transplantation. However, doses of venetoclax had to be withheld or reduced in many patients, perhaps because of the continuous daily dosing of the drug rather than administration on fixed days per cycle, allowing cell count recovery. An ongoing phase I trial is currently assessing adding venetoclax to fludarabine/busulfan conditioning and azacitidine maintenance after allo-HCT in patients with AML/MDS (NCT03613532).
The venetoclax and low-dose decitabine combination was assessed in a prospective study to prevent relapse in high-risk patients with AML or MDS.119 Decitabine was given at a dose of 15 mg/m2 for 3 days and venetoclax at a dose of 200 mg daily for 21 days starting day +100 after transplantation. Twenty patients were included. No grade ≥3 adverse events were observed. The 2-year OS and EFS were 85.2% and 84.7%, respectively. The 100-day acute and chronic GvHD rates were 55% and 20%, respectively. Furthermore, treatment of GvHD did not affect maintenance therapy.119 These studies show that the addition of venetoclax to an HMA to prevent relapse is feasible and safe. Randomized trials should be conducted to confirm these findings, establish the best treatment schedule, and identify patients who would benefit from a combination maintenance approach.
FLT3 inhibitors have improved the outcomes of patients with FLT3-mutated AML when added to frontline chemotherapy, as shown in the RATIFY trial, making them a reasonable option to consider for maintenance after allo-HCT.2 In 2015, Antar et al. reported the efficacy and safety of so-rafenib maintenance in five patients with FLT3-ITD-mutated AML in remission after allo-HCT.120 These results were reproduced in another multicenter retrospective study showing high 2-year PFS and OS rates (73% and 80%).121,122 In an analysis of the EBMT registry, sorafenib post-transplant maintenance was safe and OS was significantly improved compared to no-sorafenib in 28 patients with FLT3-mutated AML receiving allo-HCT with in vivo T-cell depletion (2-year OS: 82.8% vs. 61.5%; P=0.007).123 Two phase II trials assessed the use of FLT3-inhibitors as maintenance therapy for FLT3-mutated AML after allo-HCT. The SORMAIN phase II trial randomized patients with FLT3-ITD-mutated AML to receive sorafenib for 2 years versus placebo. A total of 84 patients were included.112 The 24-month probability of RFS was significantly higher in patients who received sorafenib (85%) than that in the placebo group (53.3%) with a 74% reduction in relapse or death (HR=0.256, 95% CI: 0.10-0.65; P=0.002). The estimated 24-month OS was higher in the sorafenib group (90.5%) than in the placebo arm (66.2%) (HR=0.241, 95% CI; 0.08-0.74; log-rank P=0.007). At a median follow-up of 55.1 months, median OS had not been reached in either arm (HR=0.52, 95% CI: 0.24-1.11; P=0.086). Results were seen across patients with or without FLT3-ITD mutations, suggesting an off-target effect of sorafenib in AML. The RADIUS phase II trial assessed the use of midostaurin compared to placebo in 60 patients. The study showed no difference in outcomes, but it was not powered to detect such differences.124 Most patients in both trials did not receive F LT 3 inhibitors prior to transplantation.
In a large, open-label, randomized, phase III trial, 202 patients with FLT3-ITD-mutated AML were randomized to receive sorafenib or placebo as maintenance therapy after allo-HCT.125 The median time to starting sorafenib was 30 days after allo-HCT. At a median follow-up of 22.3 months, the cumulative incidence of relapse was significantly better in the sorafenib arm than in the placebo arm (HR=0.25, 95% CI: 0.11-0.57; P=0.0010). The 2-year leukemia-free survival and OS rates were significantly higher in the sorafenib arm than in the placebo arm: 78.9% versus 56.6% (HR=0.37, 95% CI: 0.22-0.63; P<0.0001) and 82.1% versus 68% (HR=0.48, 95% CI: 0.27-0.86; P=0.012), respectively. These studies establish the utility of sorafenib as maintenance therapy for FLT3-ITD-mutated AML after allo-HCT. These findings led to the publication of a position statement of the EBMT including worldwide experts endorsing the use of sorafenib as post-allo-HCT maintenance.126
Other more selective FLT3 inhibitors are being evaluated in this setting. The BMT-CTN 1506 phase III trial is ongoing and will address the safety and efficacy of gilteritinib compared to placebo for FLT3-ITD-mutated AML as maintenance after allo-HCT (NCT02997202).127
As mentioned earlier, IDH1/2 inhibitors have proved efficacious as monotherapy or combined with HMA or induction chemotherapy in the frontline and relapsed setting.4,68 Patients with IDH-mutated AML undergoing allo-HCT with MRD-positive disease have a higher risk of relapse.83 Given the favorable safety profile of ivosidenib and enasidenib, these agents would be suitable for post-transplant maintenance. Several studies are currently evaluating the safety and efficacy of IDH1/2 inhibitors for IDH-mutated AML after allo-HCT (NCT03564821, NCT03515512, NCT03728335, NCT04522895).
Eprenetapopt for TP53-mutated acute myeloid leukemia
Allo-HCT is the only curative therapy for patients with TP53-mutated AML. However, despite allo-HCT, their outcomes remain very poor. Eprenetapopt, as described above, is a first-in-class clinical-stage molecule reactivating mutant p53.77
In a phase II, single-arm, open-label trial, presented at the Tandem meetings in 2022, eprenetapopt was given at a dose of 3.7 g/day for 4 days in combination with azacitidine at a dose of 36 mg/m2/day for 5 days.128 Thirty-three adult patients with TP53-mutated AML (n=14) or MDS (n=19) were included. Ten out of 14 patients with AML had detectable TP53 at the time of their transplant. Grade 3-4 adverse events were mainly hematologic. The 1-year RFS was 58%. With a median follow-up of 429 days, the median OS was 586 days, and the 1-year OS was 79%. No apparent treatment-related increase in GvHD was observed. Acute and chronic GvHD were documented in four and ten patients, respectively. These results show that eprenetapopt maintenance after allo-HCT is safe and certainly promising and its use should be studied further in a large, randomized, phase III trial.
Histone deacetylase inhibitors
HDAC inhibitors are epigenetic modifiers that have direct anti-leukemic and immunomodulatory activity. Additionally, they can modulate regulatory T-cell activity.129 Panobinostat is an oral pan-HDAC inhibitor that has a much higher affinity to class I than to class II HDAC. At a low dose, it saturates class I receptors leading to decreased regulatory T-cell inhibitory function. At higher doses, it saturates class I receptors and attaches to class II receptors which become dominant. This leads to increased regulatory T-cell activity. These properties make it a theoretically suitable drug for post-allo-HCT maintenance.129 The phase I/II PANOBEST trial assessed the feasibility of panobinostat in patients with high-risk AML or MDS in CR after allo-HCT. Patients were treated on a weekly or every other week schedule. Dose-limiting toxicities were reached at 20 mg and 30 mg in the weekly and every other week schedules, respectively. In the phase II part of the trial, patients were randomized to one or other of the schedules using the dose-limiting toxicity identified. The median time of starting panobinostat was 96 days. The main grade 3-4 adverse event was thrombocytopenia (weekly schedule: 28%, every other week: 19%). The cumulative incidence of chronic GvHD at 2 years was 29% and did not differ between the two schedules.130 The 2-year OS and RFS were 81% and 75%, respectively. The findings of this trial are promising, and results are being confirmed in the large phase III ETAL-4/HOVON-145 trial (NCT04326764).
Other agents are being investigated with the aim of preventing relapse after allo-HCT. Monalizumab, an IgG4 monoclonal antibody, is an NKG2A checkpoint inhibitor. It improves the NK cell-mediated GvL effect without increasing the risk of GvHD.131 In a phase I dose-finding study presented at the American Society of Hematology meeting in 2021, monalizumab was given at a median time of 83 days after allo-HCT to 15 patients with a hematologic malignancy, including nine with AML and three with MDS. No dose-limiting toxicities were observed, justifying the use of the 1 mg/kg dose. No disease recurrence was observed in patients with AML. Future studies should aim at assessing the efficacy of monalizumab in the clinical setting.132
Conclusions and perspective
Targeted therapy has revolutionized the treatment of AML and improved outcomes. However, in the frontline setting standard induction chemotherapy for fit patients and low-intensity treatment (HMA, LDAC) for unfit patients remain the backbone to which targeted therapies are added. Venetoclax is used in the frontline and in the relapsed setting in combination with chemotherapy or HMA owing to its synergistic effect, broadening treatment options, particularly for patients without identified targetable mutations. With the advent of next-generation sequencing, several mutations have been discovered; and future studies should aim at deciphering their role in the pathogenesis of AML. There is also an unmet need to develop novel approaches to target or bypass these mutations.
Up to now, allo-HCT has been the mainstay treatment for patients with intermediate- and adverse-risk AML in remission after frontline therapy. We believe that future work should focus on assessing the role of allo-HCT in the era of novel therapies, particularly in the intermediate risk group. With the introduction of next-generation sequencing, the prognostic value of MRD before and after allo-HCT needs to be evaluated. Early studies show worse outcomes after allo-HCT in patients with persistent MRD detectable by next-generation sequencing.83,133 Conditioning regimens have not changed markedly over the last few years despite the emergence of new conventional chemotherapies with anti-leukemia activity. Adding targeted therapies to conventional conditioning regimens (MAC or RIC), is being studied but long-term follow-up is still needed to better understand the effect of the combinations on engraftment as well as early and late post-transplant complications and GvHD. Allo-HCT alone has proven to provide long-lasting remissions, although relapses still occur in many patients. Prospective studies should aim to identify patients in need of therapies, whether as maintenance or post-transplant consolidation, to prevent relapse. As with FLT3-mutated AML, in which sorafenib is an established, effective maintenance strategy,126 studies should focus on assessing the role of post-allo-HCT maintenance in other groups of AML. Furthemore, the optimal duration of post-allo-HCT maintenance therapy is not well established, with most studies using an arbitrary duration of 1 to 2 years. However, in the real-life setting, the decision to discontinue maintenance in patients tolerating such therapies is certainly challenging. Accordingly, studies are needed to help to define the optimal maintenance regimen and identify patients who are most likely to benefit.
- Received May 28, 2022
- Accepted September 2, 2022
No conflicts of interest to disclose.
RM designed and wrote the manuscript. RAH wrote the manuscript. EB, AB, and MM supervised the work and helped to write the manuscript. All authors reviewed and agreed on the final version of the manuscript.
- Lancet JE, Cortes JE, Hogge DE. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood. 2014; 123(21):3239-3246. https://doi.org/10.1182/blood-2013-12-540971PubMedPubMed CentralGoogle Scholar
- Stone RM, Mandrekar SJ, Sanford BL. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017; 377(5):454-464. https://doi.org/10.1056/NEJMoa1614359PubMedPubMed CentralGoogle Scholar
- Wang ES, Montesinos P, Minden MD. Phase 3, open-label, randomized study of gilteritinib and azacitidine vs azacitidine for newly diagnosed FLT3-mutated acute myeloid leukemia in patients ineligible for intensive induction chemotherapy. Blood. 2021; 138(Suppl 1):700. https://doi.org/10.1182/blood-2021-145379Google Scholar
- DiNardo CD. Ivosidenib in IDH1-mutated acute myeloid leukemia. N Engl J Med. 2018; 379(12):1186. https://doi.org/10.1056/NEJMc1809507Google Scholar
- DiNardo CD, Schuh AC, Stein EM. Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial. Lancet Oncol. 2021; 22(11):1597-1608. https://doi.org/10.1016/S1470-2045(21)00494-0PubMedGoogle Scholar
- DiNardo CD, Jonas BA, Pullarkat V. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020; 383(7):617-629. https://doi.org/10.1056/NEJMoa2012971PubMedGoogle Scholar
- Wei AH, Montesinos P, Ivanov V. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020; 135(24):2137-2145. https://doi.org/10.1182/blood.2020004856PubMedPubMed CentralGoogle Scholar
- Cortes JE, Heidel FH, Hellmann A. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia. 2019; 33(2):379-389. https://doi.org/10.1038/s41375-018-0312-9PubMedPubMed CentralGoogle Scholar
- Lambert J, Pautas C, Terre C. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2019; 104(1):113-119. https://doi.org/10.3324/haematol.2018.188888PubMedPubMed CentralGoogle Scholar
- Sallman DA, DeZern AE, Garcia-Manero G. Eprenetapopt (APR-246) and azacitidine in TP53-mutant myelodysplastic syndromes. J Clin Oncol. 2021; 39(14):1584-1594. https://doi.org/10.1200/JCO.20.02341PubMedPubMed CentralGoogle Scholar
- Daver NG, Vyas P, Kambhampati S. Tolerability and efficacy of the first-in-class anti-CD47 antibody magrolimab combined with azacitidine in frontline TP53m AML patients: phase 1b results. J Clin Oncol. 2022; 40(16_suppl):7020. https://doi.org/10.1200/JCO.2022.40.16_suppl.7020Google Scholar
- Stein EM, Aldoss I, DiPersio JF. Safety and efficacy of menin inhibition in patients (Pts) with MLL-rearranged and NPM1 mutant acute leukemia: a phase (Ph) 1, first-in-human study of SNDX-5613 (AUGMENT 101). Blood. 2021; 138(Suppl 1):699. https://doi.org/10.1182/blood-2021-146944Google Scholar
- Rai KR, Holland JF, Glidewell OJ. Treatment of acute myelocytic leukemia: a study by Cancer and Leukemia Group B. Blood. 1981; 58(6):1203-1212. https://doi.org/10.1182/blood.V58.6.1203.bloodjournal5861203Google Scholar
- Estey EH. Acute myeloid leukemia: 2014 update on risk-stratification and management. Am J Hematol. 2014; 89(11):1063-1081. https://doi.org/10.1002/ajh.23834PubMedGoogle Scholar
- Lowenberg B. Sense and nonsense of high-dose cytarabine for acute myeloid leukemia. Blood. 2013; 121(1):26-28. https://doi.org/10.1182/blood-2012-07-444851PubMedGoogle Scholar
- Willemze R, Suciu S, Meloni G. High-dose cytarabine in induction treatment improves the outcome of adult patients younger than age 46 years with acute myeloid leukemia: results of the EORTC-GIMEMA AML-12 trial. J Clin Oncol. 2014; 32(3):219-228. https://doi.org/10.1200/JCO.2013.51.8571PubMedGoogle Scholar
- Gong Q, Zhou L, Xu S, Li X, Zou Y, Chen J.. High doses of daunorubicin during induction therapy of newly diagnosed acute myeloid leukemia: a systematic review and meta-analysis of prospective clinical trials. PLoS One. 2015; 10(5):e0125612. https://doi.org/10.1371/journal.pone.0125612PubMedPubMed CentralGoogle Scholar
- Li X, Xu S, Tan Y, Chen J.. The effects of idarubicin versus other anthracyclines for induction therapy of patients with newly diagnosed leukaemia. Cochrane Database Syst Rev. 2015; 6:CD010432. https://doi.org/10.1002/14651858.CD010432.pub2PubMedGoogle Scholar
- Burnett AK, Russell NH, Hills RK. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the medical research council AML15 trial. J Clin Oncol. 2013; 31(27):3360-3368. https://doi.org/10.1200/JCO.2012.47.4874PubMedGoogle Scholar
- Borthakur G, Kantarjian H, Wang X. Treatment of core-binding-factor in acute myelogenous leukemia with fludarabine, cytarabine, and granulocyte colony-stimulating factor results in improved event-free survival. Cancer. 2008; 113(11):3181-3185. https://doi.org/10.1002/cncr.23927PubMedPubMed CentralGoogle Scholar
- Yin JA, O'Brien MA, Hills RK, Daly SB, Wheatley K, Burnett AK. Minimal residual disease monitoring by quantitative RT-PCR in core binding factor AML allows risk stratification and predicts relapse: results of the United Kingdom MRC AML-15 trial. Blood. 2012; 120(14):2826-2835. https://doi.org/10.1182/blood-2012-06-435669PubMedGoogle Scholar
- Meyers J, Yu Y, Kaye JA, Davis KL. Medicare fee-for-service enrollees with primary acute myeloid leukemia: an analysis of treatment patterns, survival, and healthcare resource utilization and costs. Appl Health Econ Health Policy. 2013; 11(3):275-286. https://doi.org/10.1007/s40258-013-0032-2PubMedGoogle Scholar
- Petersdorf SH, Kopecky KJ, Slovak M. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 2013; 121(24):4854-4860. https://doi.org/10.1182/blood-2013-01-466706PubMedPubMed CentralGoogle Scholar
- Hills RK, Castaigne S, Appelbaum FR. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol. 2014; 15(9):986-996. https://doi.org/10.1016/S1470-2045(14)70281-5PubMedPubMed CentralGoogle Scholar
- Borthakur GM, Cortes JE, Ravandi F. Fludarabine, cytarabine, G-CSF and gemtuzumab ozogamicin (FLAG-GO) regimen results in better molecular response and relapse-free survival in core binding factor acute myeloid leukemia than FLAG and idarubicin (FLAG-Ida). Blood. 2019; 134(Suppl_1):290. https://doi.org/10.1182/blood-2019-126014Google Scholar
- Lowenberg B, Zittoun R, Kerkhofs H. On the value of intensive remission-induction chemotherapy in elderly patients of 65+ years with acute myeloid leukemia: a randomized phase III study of the European Organization for Research and Treatment of Cancer Leukemia Group. J Clin Oncol. 1989; 7(9):1268-1274. https://doi.org/10.1200/JCO.1922.214.171.1248PubMedGoogle Scholar
- Kantarjian HM, Thomas XG, Dmoszynska A. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012; 30(21):2670-2677. https://doi.org/10.1200/JCO.2011.38.9429PubMedPubMed CentralGoogle Scholar
- Dombret H, Seymour JF, Butrym A. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015; 126(3):291-299. https://doi.org/10.1182/blood-2015-01-621664PubMedPubMed CentralGoogle Scholar
- Feldman EJ, Lancet JE, Kolitz JE. First-in-man study of CPX-351: a liposomal carrier containing cytarabine and daunorubicin in a fixed 5:1 molar ratio for the treatment of relapsed and refractory acute myeloid leukemia. J Clin Oncol. 2011; 29(8):979-985. https://doi.org/10.1200/JCO.2010.30.5961PubMedPubMed CentralGoogle Scholar
- Lancet JE, Uy GL, Cortes JE. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018; 36(26):2684-2692. https://doi.org/10.1200/JCO.2017.77.6112PubMedPubMed CentralGoogle Scholar
- Uy GL, Newell LF, Lin TL. Transplant outcomes after CPX-351 vs 7+3 in older adults with newly diagnosed high-risk and/or secondary AML. Blood Adv. 2022; 6(17):4989-4993. https://doi.org/10.1182/bloodadvances.2021006468PubMedPubMed CentralGoogle Scholar
- Guolo F, Fianchi L, Minetto P. CPX-351 treatment in secondary acute myeloblastic leukemia is effective and improves the feasibility of allogeneic stem cell transplantation: results of the Italian compassionate use program. Blood Cancer J. 2020; 10(10):96. https://doi.org/10.1038/s41408-020-00361-8PubMedPubMed CentralGoogle Scholar
- Issa GC, Kantarjian HM, Xiao L. Phase II trial of CPX-351 in patients with acute myeloid leukemia at high risk for induction mortality. Leukemia. 2020; 34(11):2914-2924. https://doi.org/10.1038/s41375-020-0916-8PubMedGoogle Scholar
- Konopleva M, Pollyea DA, Potluri J. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016; 6(10):1106-1117. https://doi.org/10.1158/2159-8290.CD-16-0313PubMedPubMed CentralGoogle Scholar
- DiNardo CD, Pratz K, Pullarkat V. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019; 133(1):7-17. https://doi.org/10.1182/blood-2018-08-868752PubMedPubMed CentralGoogle Scholar
- Wei AH, Strickland SA, Hou JZ. Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study. J Clin Oncol. 2019; 37(15):1277-1284. https://doi.org/10.1200/JCO.18.01600PubMedPubMed CentralGoogle Scholar
- Pasvolsky O, Shimony S, Ram R. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first complete remission after 5-azacitidine and venetoclax: a multicenter retrospective study. Ann Hematol. 2022; 101(2):379-387. https://doi.org/10.1007/s00277-021-04693-8PubMedGoogle Scholar
- Pollyea DA, Winters A, McMahon C. Venetoclax and azacitidine followed by allogeneic transplant results in excellent outcomes and may improve outcomes versus maintenance therapy among newly diagnosed AML patients older than 60. Bone Marrow Transplant. 2022; 57(2):160-166. https://doi.org/10.1038/s41409-021-01476-7PubMedGoogle Scholar
- Maiti A, DiNardo CD, Daver NG. Triplet therapy with venetoclax, FLT3 inhibitor and decitabine for FLT3-mutated acute myeloid leukemia. Blood Cancer J. 2021; 11(2):25. https://doi.org/10.1038/s41408-021-00410-wPubMedPubMed CentralGoogle Scholar
- DiNardo CD, Lachowiez CA, Takahashi K. 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. https://doi.org/10.1200/JCO.20.03736PubMedPubMed CentralGoogle Scholar
- Reville PK, Kantarjian HM, Borthakur G. Cladribine, idarubicin, cytarabine (ara-C), and venetoclax in treating patients with acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood. 2020; 136(Suppl 1):7-9. https://doi.org/10.1182/blood-2020-141075Google Scholar
- Chua CC, Roberts AW, Reynolds J. Chemotherapy and Venetoclax in Elderly Acute Myeloid Leukemia Trial (CAVEAT): a phase Ib dose-escalation study of venetoclax combined with modified intensive chemotherapy. J Clin Oncol. 2020; 38(30):3506-3517. https://doi.org/10.1200/JCO.20.00572PubMedGoogle Scholar
- Lachowiez CA, Reville PK, Kantarjian H. Venetoclax combined with induction chemotherapy in patients with newly diagnosed acute myeloid leukaemia: a post-hoc, propensity score-matched, cohort study. Lancet Haematol. 2022; 9(5):e350-e360. https://doi.org/10.1016/S2352-3026(22)00076-XPubMedPubMed CentralGoogle Scholar
- DiNardo CD, Tiong IS, Quaglieri A. Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. Blood. 2020; 135(11):791-803. https://doi.org/10.1182/blood.2019003988PubMedPubMed CentralGoogle Scholar
- Al Hamed R, Labopin M, Daguindau E. Measurable residual disease, FLT3-ITD mutation, and disease status have independent prognostic influence on outcome of allogeneic stem cell transplantation in NPM1-mutated acute myeloid leukemia. Cancer Med. 2022; 11(4):1068-1080. https://doi.org/10.1002/cam4.4218PubMedPubMed CentralGoogle Scholar
- Dohner H, Estey E, Grimwade D. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017; 129(4):424-447. https://doi.org/10.1182/blood-2016-08-733196PubMedPubMed CentralGoogle Scholar
- Patel JP, Gonen M, Figueroa ME. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012; 366(12):1079-1089. https://doi.org/10.1056/NEJMoa1112304PubMedPubMed CentralGoogle Scholar
- Boddu P, Takahashi K, Pemmaraju N. Influence of IDH on FLT3-ITD status in newly diagnosed AML. Leukemia. 2017; 31(11):2526-2529. https://doi.org/10.1038/leu.2017.244PubMedGoogle Scholar
- Cortes JE, Khaled S, Martinelli G. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2019; 20(7):984-997. https://doi.org/10.1016/S1470-2045(19)30150-0PubMedGoogle Scholar
- Ravandi F, Arana Yi C, Cortes JE. Final report of phase II study of sorafenib, cytarabine and idarubicin for initial therapy in younger patients with acute myeloid leukemia. Leukemia. 2014; 28(7):1543-1545. https://doi.org/10.1038/leu.2014.54PubMedPubMed CentralGoogle Scholar
- Serve H, Krug U, Wagner R. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol. 2013; 31(25):3110-3118. https://doi.org/10.1200/JCO.2012.46.4990PubMedGoogle Scholar
- Rollig C, Serve H, Huttmann A. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2015; 16(16):1691-1699. https://doi.org/10.1016/S1470-2045(15)00362-9PubMedGoogle Scholar
- Wei AH, Kennedy GA, Morris KL. Results of a phase 2, randomized, double-blind study of sorafenib versus placebo in combination with intensive chemotherapy in previously untreated patients with FLT3-ITD acute myeloid leukemia (ALLG AMLM16). Blood. 2020; 136(Suppl 1):36-38. https://doi.org/10.1182/blood-2020-141711Google Scholar
- Wang ES, Tallman MS, Stone RM. Low relapse rate in younger patients ≤ 60 years old with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) treated with crenolanib and cytarabine/anthracycline chemotherapy. Blood. 2017; 130(Suppl 1):566. Google Scholar
- Goldberg AD, Coombs CC, Wang ES. Younger patients with newly diagnosed FLT3-mutant AML treated with crenolanib plus chemotherapy achieve adequate free crenolanib levels and durable remissions. Blood. 2019; 134(Suppl_1):1326. https://doi.org/10.1182/blood-2019-130863Google Scholar
- Cortes J, Perl AE, Dohner H. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2018; 19(7):889-903. https://doi.org/10.1016/S1470-2045(18)30240-7PubMedPubMed CentralGoogle Scholar
- Erba H, Montesinos P, Vrhovac R. S100: quizartinib prolonged survival vs placebo plus intensive induction and consolidation therapy followed by single-agent continuation in patients aged 18-75 years with newly diagnosed FLT3-ITD+ AML. HemaSphere. 2022; 6(Suppl 3):1-2. https://doi.org/10.1097/01.HS9.0000843296.73803.85Google Scholar
- Fletcher L, Joshi SK, Traer E.. Profile of quizartinib for the treatment of adult patients with relapsed/refractory FLT3-ITD-positive acute myeloid leukemia: evidence to date. Cancer Manag Res. 2020; 12:151-163. https://doi.org/10.2147/CMAR.S196568PubMedPubMed CentralGoogle Scholar
- Perl AE, Martinelli G, Cortes JE. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019; 381(18):1728-1740. https://doi.org/10.1056/NEJMoa1902688PubMedGoogle Scholar
- Antar AI, Otrock ZK, Jabbour E, Mohty M, Bazarbachi A.. FLT3 inhibitors in acute myeloid leukemia: ten frequently asked questions. Leukemia. 2020; 34(3):682-696. https://doi.org/10.1038/s41375-019-0694-3PubMedGoogle Scholar
- Ravandi F, Alattar ML, Grunwald MR. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013; 121(23):4655-4662. https://doi.org/10.1182/blood-2013-01-480228PubMedPubMed CentralGoogle Scholar
- Ohanian M, Garcia-Manero G, Levis M. Sorafenib combined with 5-azacytidine in older patients with untreated FLT3-ITD mutated acute myeloid leukemia. Am J Hematol. 2018; 93(9):1136-1141. https://doi.org/10.1002/ajh.25198PubMedGoogle Scholar
- Strati P, Kantarjian H, Ravandi F. Phase I/II trial of the combination of midostaurin (PKC412) and 5-azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome. Am J Hematol. 2015; 90(4):276-281. https://doi.org/10.1002/ajh.23924PubMedPubMed CentralGoogle Scholar
- Swaminathan M, Kantarjian HM, Levis M. A phase I/II study of the combination of quizartinib with azacitidine or low-dose cytarabine for the treatment of patients with acute myeloid leukemia and myelodysplastic syndrome. Haematologica. 2021; 106(8):2121-2130. https://doi.org/10.3324/haematol.2020.263392PubMedPubMed CentralGoogle Scholar
- Daver N, Venugopal S, Ravandi F.. FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm. Blood Cancer J. 2021; 11(5):104. https://doi.org/10.1038/s41408-021-00495-3PubMedPubMed CentralGoogle Scholar
- Short NJ, DiNardo CD, Daver N. A triplet combination of azacitidine, venetoclax and gilteritinib for patients with FLT3-mutated acute myeloid leukemia: results from a phase I/II study. Blood. 2021; 138(Suppl 1):696. https://doi.org/10.1182/blood-2021-153571Google Scholar
- Short NJ, Konopleva M, Kadia TM. Advances in the treatment of acute myeloid leukemia: new drugs and new challenges. Cancer Discov. 2020; 10(4):506-525. https://doi.org/10.1158/2159-8290.CD-19-1011PubMedGoogle Scholar
- Stein EM, DiNardo CD, Pollyea DA. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017; 130(6):722-731. https://doi.org/10.1182/blood-2017-04-779405PubMedPubMed CentralGoogle Scholar
- Pollyea DA, Tallman MS, de Botton S. Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia. Leukemia. 2019; 33(11):2575-2584. https://doi.org/10.1038/s41375-019-0472-2PubMedPubMed CentralGoogle Scholar
- Roboz GJ, DiNardo CD, Stein EM. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood. 2020; 135(7):463-471. https://doi.org/10.1182/blood.2019002140PubMedPubMed CentralGoogle Scholar
- Stein EM, DiNardo CD, Fathi AT. Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study. Blood. 2021; 137(13):1792-1803. https://doi.org/10.1182/blood.2020007233PubMedPubMed CentralGoogle Scholar
- DiNardo CD, Stein AS, Stein EM. Mutant isocitrate dehydrogenase 1 inhibitor ivosidenib in combination with azacitidine for newly diagnosed acute myeloid leukemia. J Clin Oncol. 2021; 39(1):57-65. https://doi.org/10.1200/JCO.20.01632PubMedPubMed CentralGoogle Scholar
- Daigle SR, Choe S, Quek L. High rate of IDH1 mutation clearance and measurable residual disease negativity in patients with IDH1-mutant newly diagnosed acute myeloid leukemia treated with ivosidenib (AG-120) and azacitidine. Blood. 2019; 134(Suppl 1):2706. https://doi.org/10.1182/blood-2019-122590Google Scholar
- Montesinos P, Recher C, Vives S. Ivosidenib and azacitidine in IDH1-mutated acute myeloid leukemia. N Engl J Med. 2022; 386(16):1519-1531. https://doi.org/10.1056/NEJMoa2117344PubMedGoogle Scholar
- Sasaki K, Kanagal-Shamanna R, Montalban-Bravo G. Impact of the variant allele frequency of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 on the outcomes of patients with newly diagnosed acute myeloid leukemia. Cancer. 2020; 126(4):765-774. https://doi.org/10.1002/cncr.32566PubMedGoogle Scholar
- Welch JS, Petti AA, Miller CA. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med. 2016; 375(21):2023-2036. https://doi.org/10.1056/NEJMoa1605949PubMedPubMed CentralGoogle Scholar
- Lehmann S, Bykov VJ, Ali D. Targeting p53 in vivo: a firstin-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J Clin Oncol. 2012; 30(29):3633-3639. https://doi.org/10.1200/JCO.2011.40.7783PubMedGoogle Scholar
- Cluzeau T, Sebert M, Rahme R. Eprenetapopt plus azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia: a phase II study by the Groupe Francophone des Myelodysplasies (GFM). J Clin Oncol. 2021; 39(14):1575-1583. https://doi.org/10.1200/JCO.20.02342PubMedPubMed CentralGoogle Scholar
- Maiti A, DiNardo CD, Qiao W. Ten-day decitabine with venetoclax versus intensive chemotherapy in relapsed or refractory acute myeloid leukemia: a propensity score-matched analysis. Cancer. 2021; 127(22):4213-4220. https://doi.org/10.1002/cncr.33814PubMedPubMed CentralGoogle Scholar
- Jaiswal S, Jamieson CH, Pang WW. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell. 2009; 138(2):271-285. https://doi.org/10.1016/j.cell.2009.05.046PubMedPubMed CentralGoogle Scholar
- Sallman DA, McLemore AF, Aldrich AL. TP53 mutations in myelodysplastic syndromes and secondary AML confer an immunosuppressive phenotype. Blood. 2020; 136(24):2812-2823. https://doi.org/10.1182/blood.2020006158PubMedPubMed CentralGoogle Scholar
- Klyuchnikov E, Christopeit M, Badbaran A. Role of pre-transplant MRD level detected by flow cytometry in recipients of allogeneic stem cell transplantation with AML. Eur J Haematol. 2021; 106(5):606-615. https://doi.org/10.1111/ejh.13557PubMedGoogle Scholar
- Mohty R, Bazarbachi AH, Labopin M. Isocitrate dehydrogenase (IDH) 1 and 2 mutation is an independent predictor of better outcome in patients with acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation: a study of the ALWP of EBMT. Blood. 2021; 138(Suppl 1):2920. https://doi.org/10.1182/blood-2021-149794Google Scholar
- Lowenberg B, Pabst T, Maertens J. Addition of lenalidomide to intensive treatment in younger and middle-aged adults with newly diagnosed AML: the HOVON-SAKK-132 trial. Blood Adv. 2021; 5(4):1110-1121. https://doi.org/10.1182/bloodadvances.2020003855PubMedPubMed CentralGoogle Scholar
- Shah MV, Jorgensen JL, Saliba RM. Early post-transplant minimal residual disease assessment improves risk stratification in acute myeloid leukemia. Biol Blood Marrow Transplant. 2018; 24(7):1514-1520. https://doi.org/10.1016/j.bbmt.2018.02.003PubMedGoogle Scholar
- Scott BL, Pasquini MC, Fei M. Myeloablative versus reduced-intensity conditioning for hematopoietic cell transplantation in acute myelogenous leukemia and myelodysplastic syndromes - long-term follow-up of the BMT CTN 0901 clinical trial. Transplant Cell Ther. 2021; 27(6):483. https://doi.org/10.1016/j.jtct.2021.02.031PubMedPubMed CentralGoogle Scholar
- Sengsayadeth S, Savani BN, Blaise D, Malard F, Nagler A, Mohty M.. Reduced intensity conditioning allogeneic hematopoietic cell transplantation for adult acute myeloid leukemia in complete remission - a review from the Acute Leukemia Working Party of the EBMT. Haematologica. 2015; 100(7):859-869. https://doi.org/10.3324/haematol.2015.123331PubMedPubMed CentralGoogle Scholar
- Oudin C, Chevallier P, Furst S. Reduced-toxicity conditioning prior to allogeneic stem cell transplantation improves outcome in patients with myeloid malignancies. Haematologica. 2014; 99(11):1762-1768. https://doi.org/10.3324/haematol.2014.105981PubMedPubMed CentralGoogle Scholar
- Dulery R, Menard AL, Chantepie S. Sequential conditioning with thiotepa in T cell- replete hematopoietic stem cell transplantation for the treatment of refractory hematologic malignancies: comparison with matched related, haplo-mismatched, and unrelated donors. Biol Blood Marrow Transplant. 2018; 24(5):1013-1021. https://doi.org/10.1016/j.bbmt.2018.01.005PubMedGoogle Scholar
- Gyurkocza B, Nath R, Seropian SE. High rates of transplantation in the phase III Sierra trial utilizing anti-CD45 (iodine) 131I-apamistamab (Iomab-B) conditioning with successful engraftment and tolerability in relapsed refractory (R/R) acute myeloid leukemia (AML) patients after lack of response to conventional care and targeted therapies. Transplant Cell Ther. 2022; 28(3):S35-S36. https://doi.org/10.1016/S2666-6367(22)00201-9Google Scholar
- Palmer J, McCune JS, Perales MA. Personalizing busulfan-based conditioning: considerations from the American Society for Blood and Marrow Transplantation Practice Guidelines Committee. Biol Blood Marrow Transplant. 2016; 22(11):1915-1925. https://doi.org/10.1016/j.bbmt.2016.07.013PubMedGoogle Scholar
- Pidala J, Kim J, Anasetti C. Pharmacokinetic targeting of intravenous busulfan reduces conditioning regimen related toxicity following allogeneic hematopoietic cell transplantation for acute myelogenous leukemia. J Hematol Oncol. 2010; 3:36. https://doi.org/10.1186/1756-8722-3-36PubMedPubMed CentralGoogle Scholar
- Casper J, Wolff D, Knauf W. Allogeneic hematopoietic stem-cell transplantation in patients with hematologic malignancies after dose-escalated treosulfan/fludarabine conditioning. J Clin Oncol. 2010; 28(20):3344-3351. https://doi.org/10.1200/JCO.2009.23.3429PubMedGoogle Scholar
- Lazzari L, Ruggeri A, Lupo Stanghellini MT. Treosulfan-based conditioning regimen prior to allogeneic stem cell transplantation: long-term results from a phase 2 clinical trial. Front Oncol. 2021; 11:731478. https://doi.org/10.3389/fonc.2021.731478PubMedPubMed CentralGoogle Scholar
- European Medicine Agency. Trecondi.Publisher Full TextGoogle Scholar
- Stölzel F, Stelljes M, Beelen DW. Favourable outcome after treosulfan based conditioning in patients undergoing an allogeneic hematopoietic cell transplantation (alloHCT) for the treatment of acute myleloid leukaemia (AML): a subgroup analysis of the randomized phase III MC-Fludt.14/L trial. Transplant Cell Ther. 2022; 28(3):S81-S82. https://doi.org/10.1016/S2666-6367(22)00255-XGoogle Scholar
- Garcia JS, Kim HT, Murdock HM. Adding venetoclax to fludarabine/busulfan RIC transplant for high-risk MDS and AML is feasible, safe, and active. Blood Adv. 2021; 5(24):5536-5545. https://doi.org/10.1182/bloodadvances.2021005566PubMedPubMed CentralGoogle Scholar
- Popat UR, Mehta RS, Bassett R. Myeloablative fractionated busulfan conditioning regimen with venetoclax in patients with AML/MDS: prospective phase II clinical trial. Blood. 2021; 138(Suppl 1):2879. https://doi.org/10.1182/blood-2021-146253Google Scholar
- Popat UR, Mehta RS, Thall P. Myeloablative fractionated busulfan conditioning regimen with sorafenib in patients with AML: results of phase I clinical trial. Transplant Cell Ther. 2022; 28(3):S78-S79. https://doi.org/10.1016/S2666-6367(22)00252-4Google Scholar
- Muffly L, Lee CJ, Gandhi A. Preliminary data from a phase 1 study of JSP191, an anti-CD117 monoclonal antibody, in combination with low dose irradiation and fludarabine conditioning is well-tolerated, facilitates chimerism and clearance of minimal residual disease in older adults with MDS/AML undergoing allogeneic HCT. Transplant Cell Ther. 2022; 28(3):S476-S478. https://doi.org/10.1016/S2666-6367(22)00784-9Google Scholar
- Blaise D, Vey N, Faucher C, Mohty M.. Current status of reduced-intensity-conditioning allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica. 2007; 92(4):533-541. https://doi.org/10.3324/haematol.10867PubMedGoogle Scholar
- Gyurkocza B, Nath R, Seropian S. 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. Blood. 2021; 138(Suppl 1):1791. https://doi.org/10.1182/blood-2021-148497Google Scholar
- Bazarbachi A, Schmid C, Labopin M. Evaluation of trends and prognosis over time in patients with AML relapsing after allogeneic hematopoietic cell transplant reveals improved survival for young patients in recent years. Clin Cancer Res. 2020; 26(24):6475-6482. https://doi.org/10.1158/1078-0432.CCR-20-3134PubMedGoogle Scholar
- Bejanyan N, Weisdorf DJ, Logan BR. Survival of patients with acute myeloid leukemia relapsing after allogeneic hematopoietic cell transplantation: a Center for International Blood and Marrow Transplant Research study. Biol Blood Marrow Transplant. 2015; 21(3):454-459. https://doi.org/10.1016/j.bbmt.2014.11.007PubMedPubMed CentralGoogle Scholar
- Schroeder T, Rautenberg C, Haas R, Germing U, Kobbe G.. Hypomethylating agents for treatment and prevention of relapse after allogeneic blood stem cell transplantation. Int J Hematol. 2018; 107(2):138-150. https://doi.org/10.1007/s12185-017-2364-4PubMedGoogle Scholar
- Goodyear OC, Dennis M, Jilani NY. Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML). Blood. 2012; 119(14):3361-3369. https://doi.org/10.1182/blood-2011-09-377044PubMedGoogle Scholar
- Assi R, Masri N, Abou Dalle I, El-Cheikh J, Bazarbachi A.. Post-transplant maintenance therapy for patients with acute myeloid leukemia: current approaches and the need for more trials. J Blood Med. 2021; 12:21-32. https://doi.org/10.2147/JBM.S270015PubMedPubMed CentralGoogle Scholar
- Kungwankiattichai S, Ponvilawan B, Roy C, Tunsing P, Kuchenbauer F, Owattanapanich W.. Maintenance with hypomethylating agents after allogeneic stem cell transplantation in acute myeloid leukemia and myelodysplastic syndrome: a systematic review and meta-analysis. Front Med (Lausanne). 2022; 9:801632. https://doi.org/10.3389/fmed.2022.801632PubMedPubMed CentralGoogle Scholar
- de Lima M, Giralt S, Thall PF. Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome: a dose and schedule finding study. Cancer. 2010; 116(23):5420-5431. https://doi.org/10.1002/cncr.25500PubMedPubMed CentralGoogle Scholar
- El-Cheikh J, Massoud R, Fares E. Low-dose 5-azacytidine as preventive therapy for relapse of AML and MDS following allogeneic HCT. Bone Marrow Transplant. 2017; 52(6):918-921. https://doi.org/10.1038/bmt.2017.31PubMedGoogle Scholar
- Oran B, de Lima M, Garcia-Manero G. Maintenance with 5-azacytidine for acute myeloid leukemia and myelodysplastic syndrome patients. Blood. 2018; 132(Suppl 1):971. https://doi.org/10.1182/blood-2018-99-111582Google Scholar
- Burchert A, Bug G, Fritz LV. Sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with FLT3–internal tandem duplication Mutation (SORMAIN). J Clin Oncol. 2020; 38(26):2993-3002. https://doi.org/10.1200/JCO.19.03345PubMedGoogle Scholar
- Wei AH, Dohner H, Pocock C. Oral azacitidine maintenance therapy for acute myeloid leukemia in first remission. N Engl J Med. 2020; 383(26):2526-2537. https://doi.org/10.1056/NEJMoa2004444PubMedGoogle Scholar
- de Lima M, Oran B, Champlin RE. CC-486 maintenance after stem cell transplantation in patients with acute myeloid leukemia or myelodysplastic syndromes. Biol Blood Marrow Transplant. 2018; 24(10):2017-2024. https://doi.org/10.1016/j.bbmt.2018.06.016PubMedPubMed CentralGoogle Scholar
- Pusic I, Choi J, Fiala MA. Maintenance therapy with decitabine after allogeneic stem cell transplantation for acute myelogenous leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant. 2015; 21(10):1761-1769. https://doi.org/10.1016/j.bbmt.2015.05.026PubMedPubMed CentralGoogle Scholar
- Gao L, Zhang Y, Wang S. Effect of rhG-CSF combined with decitabine prophylaxis on relapse of patients with high-risk MRD-negative AML after HSCT: an open-label, multicenter, randomized controlled trial. J Clin Oncol. 2020; 38(36):4249-4259. https://doi.org/10.1200/JCO.19.03277PubMedPubMed CentralGoogle Scholar
- El Chaer F, Borate U, Dulery R. Azacitidine maintenance after allogeneic hematopoietic cell transplantation for MDS and AML. Blood Adv. 2021; 5(6):1757-1759. https://doi.org/10.1182/bloodadvances.2020003839PubMedPubMed CentralGoogle Scholar
- Kent A, Pollyea DA, Winters A, Jordan CT, Smith C, Gutman JA. Venetoclax is safe and tolerable as post-transplant maintenance therapy for AML patients at high risk for relapse. Blood. 2020; 136(Suppl 1):11-12. https://doi.org/10.1182/blood-2020-138832Google Scholar
- Wei Y, Xiong X, Li X. Low-dose decitabine plus venetoclax is safe and effective as post-transplant maintenance therapy for high-risk acute myeloid leukemia and myelodysplastic syndrome. Cancer Sci. 2021; 112(9):3636-3644. https://doi.org/10.1111/cas.15048PubMedPubMed CentralGoogle Scholar
- Antar A, Kharfan-Dabaja MA, Mahfouz R, Bazarbachi A.. Sorafenib maintenance appears safe and improves clinical outcomes in FLT3-ITD acute myeloid leukemia after allogeneic hematopoietic cell transplantation. Clin Lymphoma Myeloma Leuk. 2015; 15(5):298-302. https://doi.org/10.1016/j.clml.2014.12.005PubMedGoogle Scholar
- Battipaglia G, Ruggeri A, Massoud R. Efficacy and feasibility of sorafenib as a maintenance agent after allogeneic hematopoietic stem cell transplantation for Fms-like tyrosine kinase 3-mutated acute myeloid leukemia. Cancer. 2017; 123(15):2867-2874. https://doi.org/10.1002/cncr.30680PubMedGoogle Scholar
- Battipaglia G, Massoud R, Ahmed SO. Efficacy and feasibility of sorafenib as a maintenance agent after allogeneic hematopoietic stem cell transplantation for Fms-like tyrosine kinase 3 mutated acute myeloid leukemia: an update. Clin Lymphoma Myeloma Leuk. 2019; 19(8):506-508. https://doi.org/10.1016/j.clml.2019.04.004PubMedGoogle Scholar
- Bazarbachi A, Labopin M, Battipaglia G. Allogeneic stem cell transplantation for FLT3-mutated acute myeloid leukemia: in vivo T-cell depletion and posttransplant sorafenib maintenance improve survival. A retrospective Acute Leukemia Working Party-European Society for Blood and Marrow Transplant study. Clin Hematol Int. 2019; 1(1):58-74. https://doi.org/10.2991/chi.d.190310.001PubMedPubMed CentralGoogle Scholar
- Maziarz RT, Levis M, Patnaik MM. Midostaurin after allogeneic stem cell transplant in patients with FLT3-internal tandem duplication-positive acute myeloid leukemia. Bone Marrow Transplant. 2021; 56(5):1180-1189. https://doi.org/10.1038/s41409-020-01153-1PubMedPubMed CentralGoogle Scholar
- Xuan L, Wang Y, Huang F. Sorafenib maintenance in patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised phase 3 trial. Lancet Oncol. 2020; 21(9):1201-1212. https://doi.org/10.1016/S1470-2045(20)30455-1PubMedGoogle Scholar
- Bazarbachi A, Bug G, Baron F. Clinical practice recommendation on hematopoietic stem cell transplantation for acute myeloid leukemia patients with FLT3-internal tandem duplication: a position statement from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica. 2020; 105(6):1507-1516. https://doi.org/10.3324/haematol.2019.243410PubMedPubMed CentralGoogle Scholar
- Levis MJ, Hamadani M, Logan BR. BMT CTN Protocol 1506: a phase 3 trial of gilteritinib as maintenance therapy after allogeneic hematopoietic stem cell transplantation in patients with FLT3-ITD+ AML. Blood. 2019; 134(Suppl_1):4602. https://doi.org/10.1182/blood-2019-124322Google Scholar
- Mishra A, Tamari R, DeZern AE. Phase II trial of eprenetapopt (APR-246) in combination with Azacitidine (AZA) as maintenance therapy for TP53 mutated acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) following allogeneic hematopoietic cell transplantation (HCT). Transplant Cell Ther. 2022; 28(3):S34-S35. https://doi.org/10.1016/S2666-6367(22)00200-7Google Scholar
- Shen L, Pili R.. Class I histone deacetylase inhibition is a novel mechanism to target regulatory T cells in immunotherapy. Oncoimmunology. 2012; 1(6):948-950. https://doi.org/10.4161/onci.20306PubMedPubMed CentralGoogle Scholar
- Bug G, Burchert A, Wagner EM. Phase I/II study of the deacetylase inhibitor panobinostat after allogeneic stem cell transplantation in patients with high-risk MDS or AML (PANOBEST trial). Leukemia. 2017; 31(11):2523-2525. https://doi.org/10.1038/leu.2017.242PubMedPubMed CentralGoogle Scholar
- Minetto P, Guolo F, Pesce S. Harnessing NK cells for cancer treatment. Front Immunol. 2019; 10:2836. https://doi.org/10.3389/fimmu.2019.02836PubMedPubMed CentralGoogle Scholar
- Devillier R, Furst S, boyer Chammard A. Safety of anti-NKG2A blocking antibody monalizumab as maintenance therapy after allogeneic hematopoietic stem cell transplantation: a phase I study. Blood. 2021; 138(Suppl 1):1817. https://doi.org/10.1182/blood-2021-150730Google Scholar
- Kim HJ, Kim Y, Kang D. Prognostic value of measurable residual disease monitoring by next-generation sequencing before and after allogeneic hematopoietic cell transplantation in acute myeloid leukemia. Blood Cancer J. 2021; 11(6):109. https://doi.org/10.1038/s41408-021-00500-9PubMedPubMed CentralGoogle Scholar
Figures & Tables
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.