Clinical Implications of Minimal Residual Disease Monitoring for Stem Cell Transplantation after Reduced Intensity and Nonmyeloablative Conditioning

Abstract

Allogeneic stem cell transplantation (SCT) is a potentially curative therapy for a variety of hematological malignancies; however, relapse and treatment-related toxicities are major obstacles to cure. Nonmyeloablative and reduced-intensity conditioning regimens were designed not to eradicate the malignancy completely, but rather to be immunosuppressive enough to allow engraftment, and to serve as a platform for additional cellular immunotherapy. Minimal residual disease (MRD) typically persists after SCT, and is gradually eliminated with different kinetics typical of each disease. Significant progress has been achieved with technologies for MRD assessment. Quantitative PCR tests are very sensitive in detecting tumor-associated transcripts, allowing serial monitoring. Threshold levels have been established for some malignancies, above which relapse is imminent. Persistent negative tests, a low level or a decreasing MRD level are consistent with continuous remission, whereas high-level MRD or increasing levels predict an incipient relapse. Patients at high risk of relapse are candidates for additional cellular or targeted therapy. Immunotherapy is more effective for MRD than at frank relapse. Timing and dosing of therapy are not yet well established and depend on aggressiveness of the disease, type of conditioning, level and kinetics of MRD.

Minimal residual disease diagnostics in myeloid malignancies in the post transplant period

“…94 Thus, some have suggested including the FLT3-LM in post transplantation follow-up strategies, 95 whereas others doubt its validity for this purpose. 50 Quantitative follow-up of the FLT3-LM and the FLT3-TKD in four mutated patients in the post transplant period by real-time quantitative PCR showed a significant association of relapse with PCR positivity whereas disease-free survival was associated with the achievement of PCR negativity. 52 This small series indicates that the FLT3-mutations warrant further evaluation as MRD parameters after SCT.…”

“…The sensitivity provided by nested PCR is in the same range. 50 These techniques gain increasing importance also in the post transplant period. Molecular analysis before SCT is not only essential for risk stratification, 51 but is also useful for exact definition of the mutational subtypes and of the breakpoints for later follow-up diagnostics.…”

“…50,103 Quantitative monitoring by reverse transcription-PCR in 50 patients with AML after SCT allowed determination of thresholds above which relapse within 40 days was predictable for all patients. There was a 100% relapse probability at an expression level of 1.0-5.0 Â 10 À2 , whereas in patients with an expression level of o4.0 Â 10 À4 the relapse risk was 0.8% only.…”

Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose intensity

“…Patients with minimal residual disease (MRD) after SCT had earlier tapering of immune suppression with both regimens and were eligible for donor lymphocyte infusions (DLI) if MRD was not cleared. 7 G-CSF was administered routinely from day þ 7 until engraftment.…”

Interactive diagnostics in the indication to allogeneic SCT in AML

“…30,31,127 The combination of immunophenotyping and molecular genetics for MRD detection might be a further step to more safety in the post-treatment period. Measurement of gene expression, for example, of WT1 119,123 or BAALC, 64,120 represents another promising approach for MRD measurement in myeloid malignancies. Novel methods, such as gene expression profiling by microarrays that allows the simultaneous measurement of the expression of tens of thousands of genes, might contribute to a more detailed risk stratification for allo-SCT.…”