Abstract
Background: Whereas the molecular events underlying acute myeloid leukemia (AML) are increasingly identified, dynamics of hematologic suppression and recovery following induction chemotherapy remain enigmatic. In addition, thrombocytopenia at diagnosis is related to deregulated cytokine expression in specific leukemia subtypes rather than on the degree of bone marrow infiltration per se. Similarly, recovery of platelets after the first induction cycle among individual patients can vary from incomplete to excess recovery even if morphologic remission is achieved. In particular, excess platelet rebound (EPR) with values exceeding 500 G/L can be observed in some patients. However, this clinical observation of EPR is poorly understood so far, and its prognostic relevance is unknown. Methods: We analyzed platelet recovery after the first induction cycle in 291 consecutive AML patients receiving at least one cycle of intensive "3+7" based induction treatment. We defined excess platelet rebound (EPR) as a platelet increase above 500 G/L during hematologic recovery after the first induction cycle. Results: We observed EPR in 120 (41.2%) patients. EPR+ patients had lower platelets at diagnosis, higher marrow infiltration, more frequently NPM1 mutations, and were associated with ELN favorable risk. Absence of EPR correlated with complex karyotypes, ELN intermediate-I and adverse risk, and therapy-related AML. Overall survival was better in EPR+ patients than EPR- (median 125 versus 41 months; P=0.04), as was disease-free survival (Figure 1). By multivariate analysis, achievement of EPR+ was an independent parameter associated with favorable survival. Plasma thrombopoietin (TPO) levels at diagnosis indicated EPR+ (p<0.0001), while GATA-1, GATA-2 and MPL mRNA expression did not differ between EPR+ and EPR- patients. Finally, transcription factors blocking early megakaryopoiesis were upregulated in EPR- patients, while NFE2 involved in late megakaryocyte differentiation was increased in EPR+ patients. Conclusion: This study suggests that excess platelet rebound (EPR+) defined as platelets exceeding 500 G/L is a common event identified in AML patients after the first induction cycle. EPR+ was predominantly observed in ELN favorable risk AML, and it was associated with significantly better overall and disease-free survival as compared to EPR- patients. In addition, achievement of EPR+ represented an independent prognostic parameter for improved survival in a multivariate analysis, and may contribute to prognostic assessment in AML patients undergoing intensive treatment with intention to cure. Disclosures No relevant conflicts of interest to declare.
Highlights
We found that 120 patients (41.2%) had maximum platelet values exceeding 500 G/ L at least once and fulfilled the criteria for excess platelet rebound (EPR) (EPR+), while maximum platelet levels did not reach 500 G/L in 171 patients (58.8%; EPRÀ)
We investigated the dynamics of platelet recovery after the first standard chemotherapy induction cycle in 291 newly diagnosed acute myeloid leukemia (AML) patients treated at a single academic center
We found that excess platelet rebound (EPR+) defined as exceeding 500 G/L is a common event identified in 120 patients (41.2%)
Summary
Risk stratification in acute myeloid leukemia (AML) patients undergoing intensive chemotherapy is predominantly relying on disease characteristics obtained pre-treatment.[1,2,3] Among them, current classification systems acknowledge disease-specific molecular and cytogenetic abnormalities as the major determinants.[4,5,6] In contrast, clinical parameters at diagnosis of AML such as the degree of blast infiltration in the bone marrow and peripheral blood, presence and degree of cytopenias or leukocytosis, chemical parameters such as LDH, presence of extramedullary disease, or deregulated expression of cell surface markers hardly affect therapeutic decisions nowadays if at all.[2,3,4,5,6,7] Whereas combined molecular and cytogenetic parameters allow risk stratification in the routine and in the clinical trial setting, they represent a wide range as far as the outcome of individual patients is concerned. Data gathered after the start of AML treatment can potentially be useful as pre-treatment characteristics. Keating et al suggested that the number of courses needed to achieve CR was inversely related to remission duration, and achievement of early remission (after the first induction cycle) is increasingly recognized as an important favorable prognostic determinant.[8] the depth of response to induction treatment assessed by quantitative determination of molecular and/or immunophenotypic leukemia-specific marker profiles is of important prognostic relevance.[9,10,11,12,13,14,15] In addition, generation sequencing (NGS) has allowed for the identification of persisting molecular mutations in remission samples, with some of them predicting higher risk of relapse.[16] Other parameters obtained during treatment with favorable impact on relapse risk may include the decrease of the stem cell mobilization potential, delayed hematologic recovery after consolidation treatment, and low levels of transfusion-dependent iron load.[17,18,19]
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