The pathogenesis of acute promyelocytic leukaemia: evaluation of the role of molecular diagnosis and monitoring in the management of the disease

Abstract

Fig 1.Chimaeric fusion products arising from alternative APL associated translocations. Each of the chromosomal rearrangements disrupts RARa within the second intron, leading to retention of the hormone receptor DNA-, RXR-, ligand-, co-activator-and co-repressor-binding domains within the fusion protein.

Assessing minimal residual disease (MRD) in leukemia: a changing definition and concept?

“…That the PCR status of the stem cell collection does not necessarily correlate with outcome has been shown in certain subtypes of AML, 37,57 while this conclusion is not supported by data in ALL. 58 Always remembering that relevant evidence is contributed by disease subtypes traceable by molecular markers, which in AML constitute half of the patient population, such discrepant information may be explained by a differential sensitivity of myelo-vs lymphoblasts to destruction in the freeze-thaw cycle prior to infusion, or by disparate benefits from a graftversus-leukemia response in AML vs ALL.…”

“…33 Of great clinical interest are patients who present with cryptic molecular markers, detected by PCR, which derive from chromosomal translocations with well-defined, prognostic significance, such as AML1/ETO (in patients lacking t [8;21]), 34 CBF␤/MYH11 (in patients lacking inv [16]) 35 or MLL-AF4 (in patients lacking t [4;11]), 36 as data on their clinical implication in comparison to that of the standard cytogenetic translocations are scarce and controversial. 34,37 Reports suggesting that FLT3 gene internal tandem duplications (ITDs) or other FTL3 gene mutations may be found in 25-30% of patients with AML and with high frequency in patients with a normal karyotype [38][39][40] may add a novel molecular tool to the repertoire of MRD detection. 41 Changes in the pattern of FLT3 mutations between diagnosis and relapse recently reported by Kottaridis et al 42 seem, however, to profoundly curtail this prospect.…”

“…The implications of postinduction residual disease remain a moving target also because they depend on the projected efficacy of treatment strategies. With the improvement of treatment modalities, expectations for disease reduction will be higher, such as after addition of ATRA to chemotherapy in APL, 37 or the introduction of the tyrosine kinase inhibitor STI571 in the management of CML. 50 Residual disease following therapy that is considered optimal by current standards implies a higher level of resistance of the malignant cells than if suboptimal therapies had been implied.…”

“…In APL, evidence suggests that outcome may be improved if patients are treated at the time of solely molecular evidence of disease. 37 Is it, however, justified to speak about molecular relapse if extremely low levels of BCR/ABL are found in every single CML patient after allogeneic transplant 54,55 and to suggest basing treatment decisions on molecular criteria, particularly in studies performed over long periods of times during which quantitative parameters for molecular monitoring were modified within the study group? 56 Consideration of molecular relapse may require the reappearance of disease following a period of molecular negativity, the reversal of a negative slope of test results or a rise in the level of disease above that determined to be compatible with remission in a particular disease, if applicable.…”

“…59 Benefits from in vivo purging during a preparative regimen for SCT or intensive maintenance chemotherapy and the significance of pre-in vivo purging minimal disease status for overall outcome appear to differ with disease subtype. 37,47 This may merely reflect differences available in treatment options or have its basis in pathogenetic mechanisms. The literature offers a plethora of possibilities of how PCR results may predict for long-term outcome.…”