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N.J. Short and F. Ravandi et al.
Table 2. Ongoing measurable residual disease-based clinical trials in adults with acute myeloid leukemia.
Agent(s)
Autologous WT1-TCRc4 gene-transduced CD8+ T cells
Azacitidine + avelumab
BL-8040 (CXCR4 antagonist) + atezolizumab
DCP-001 (dendritic cell vaccine)
FLYSYN (anti-FLT3 monoclonal antibody)
Gemtuzumab ozogamicin
Guadecitabine (SGI-110)
+ donor lymphocyte infusion
Lenalidomide
Lenalidomide
Nivolumab
Nivolumab
(vs. observation)
Tagraxofusp (SL-401)
Study Phase
I/II
I/II Ib/II
II I
II II
II I II II
(randomized)
I/II
Timing of MRD positivity
First CR/CRi
Any time First CR/CRi
First CR/CRi Any time
Major inclusion/exclusion criteria
• Must have HLA-A*02:01 expression and elevated baseline WT1 expression
• Excludes patients with prior allogeneic HSCT
---
• Excludes patients with prior allogeneic HSCT
• Excludes patients with prior allogeneic HSCT
• Must have NPM1-mutated AML and FLT3 expression on leukemic cells
ClinicalTrials.gov identifier
NCT02770820
NCT03699384 NCT03154827
NCT03697707 NCT02789254
NCT03737955 NCT02684162
NCT02126553 NCT02370888 NCT02126553 NCT02275533
NCT02270463
• Any time •
Before or after allogeneic HSCT --- First or second CR/CRi ---
Excludes patients with prior allogeneic HSCT Must be CD33+
After allogeneic HSCT First or second CR/CRi First CR/CRi
First or second CR/CRi
• MRD detected by CD34+ chimerism assay ---
---
---
MRD: measurable residual disease; CR: complete remission; CRi: complete remission with incomplete hematologic recovery; HSCT: hematopoietic stem cell transplantation; AML: acute myeloid leukemia.
therapies is less clear in AML than in acute lymphoblastic leukemia. With the possible exceptions of allogeneic HSCT and hypomethylating agents, effective treatments for MRD-positive disease have not been established in AML. It has yet to be conclusively shown that eradication of MRD that persists or recurs after initial treatment is associated with improved outcomes in AML; however, given the available evidence (as discussed in detail below), we do frequently use HSCT or hypomethylating agents for patients with MRD-positive disease. Enrollment of these patients in MRD-directed clinical tri- als with novel agents and combinations is also imperative (Table 2).
Measurable residual disease-guided allogeneic hematopoietic stem cell transplantation
While it is common practice to refer patients who are MRD-positive to HSCT, robust data supporting this prac- tice are lacking. Nevertheless, while the outcomes of MRD-positive patients are relatively poor regardless of whether HSCT is or is not performed, several studies sug- gest that outcomes may be improved with HSCT.14,18,70,81 In a multicenter study of 116 patients with AML harbor- ing t(8;21), patients received either allogeneic HSCT or chemotherapy, with or without autologous HSCT, based on MRD response.70 High-risk patients were defined as those who did not achieve a major molecular response (i.e., a >3-log reduction in RUNX1/RUNX1T1 transcript levels in bone marrow, determined by PCR analysis) after the second consolidation, or who lost the major molecu- lar response within 6 months of achieving it. Among patients in the high-risk group, those who underwent allogeneic HSCT had a lower cumulative incidence of relapse compared to that of the patients who did not
undergo allogeneic HSCT (22.1% vs. 78.9%, respectively; P<0.001), which translated into an improvement in over- all survival (71.6% vs. 26.7%, respectively; P=0.007). Conversely, the overall survival rate was lower in low- risk patients who underwent allogeneic HSCT (75.7% vs. 100%; P=0.013). These data suggest that MRD could rea- sonably be used to assign patients with t(8;21) to post- remission therapies. Data for similar approaches in core- binding factor AML with inv(16) are lacking.
The role of allogeneic HSCT in patients with interme- diate-risk AML is controversial, and it is possible that MRD may be able to guide post-remission therapeutic decisions in this group.2,4 In a study of younger patients (age 18-60 years) with newly diagnosed NPM1-mutated AML, HSCT was associated with better disease-free sur- vival and overall survival in patients with non-favorable risk disease who had a <4-log reduction in mutant NPM1 in the peripheral blood at the time of remission (disease- free survival: HR, 0.25; 95% CI: 0.06-0.98; P=0.047; over- all survival: HR, 0.25; 95% CI: 0.06-0.98; P=0.047), whereas HSCT did not improve outcomes for patients with a >4-log reduction.14 Similarly in the National Cancer Research Institute AML17 study of standard-risk patients without NPM1 mutations, HSCT appeared to preferentially benefit those who remained MRD-positive by MFC after the second cycle of chemotherapy but not those who were MRD-negative, although the interaction between HSCT and MRD status did not reach statistical significance (P=0.16), possibly because of the small num- ber of patients in the cohort who underwent HSCT in first remission.18 Although definitive evidence is lacking, collectively these studies provide some support for the use of MRD to guide post-remission therapies in patients with intermediate-risk AML.
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haematologica | 2019; 104(8)