Optimizing patient selection for myeloablative allogeneic hematopoietic cell transplantation in chronic myeloid leukemia in chronic phase

Abstract

Outstanding results have been obtained in the treatment of chronic myeloid leukemia (CML) with first-line imatinib therapy. However, approximately 35% of patients will not obtain long-term benefit with this approach. Allogeneic hematopoietic stem cell transplantation (HCT) is a valuable second-and third-line therapy for appropriately selected patients. To identify useful prognostic indicators of transplantation outcome in postimatinib therapeutic interventions, we investigated the role of the HCT comorbidity index (HCT-CI) together with levels of C-reactive protein (CRP) before HCT in 271 patients who underwent myeloablative HCT for CML in first chronic phase. Multivariate analysis showed both an HCT-CI score higher than 0 and CRP levels higher than 9 mg/L independently predict inferior survival and increased nonrelapse mortality at 100 days after HCT. CML patients without comorbidities (HCT-CI score 0) with normal CRP levels (0-9 mg/L) may therefore be candidates for early allogeneic HCT after failing imatinib. IntroductionThe past decade has witnessed a dramatic change in the management of chronic myeloid leukemia (CML) such that the majority of patients initially receive therapy with imatinib rather than being offered allogeneic hematopoietic cell transplantation (HCT). 1 However, approximately 35% of these patients will fail to respond and/or develop intolerance. The treatment choices then include second-generation tyrosine kinase inhibitors and HCT, and the current challenge is to optimize the relative timings of these alternatives.The results of HCT in CML can be predicted using a prognostic score devised by the European Group for Blood and Marrow Transplantation (EBMT) based on 5 variables: donor type, disease phase, recipient age, donor/recipient sex combination, and interval from diagnosis to transplantation. 2 As the variable of disease phase resulted in higher relative risks than other variables in the model, 2 Passweg et al attempted to modify the score for patients in chronic phase for whom the decision of whether to undergo transplantation is most difficult. They found only one parameter with additional prognostic value, the Karnofsky performance score, and after inclusion the improvement over the original EBMT score was minimal. 3 The hematopoietic cell transplantation comorbidity index (HCT-CI) was developed to analyze the impact of comorbidities on outcome of HCT. 4 In several studies, the HCT-CI predicted for nonrelapse mortality (NRM) and overall survival (OS), 5-8 but it has never been studied specifically in patients with CML. C-reactive protein (CRP) is a sensitive marker of inflammation and persons with elevated levels of this acute phase protein are known to have an increased risk of cardiovascular diseases and malignancies. [9][10] We and others have previously shown the value of CRP levels shortly before HCT in predicting its outcomes. 11-12 However, it was unclear whether the elevated CRP was a reflection of an underlying comorbidity. In this study, we investigated the prognostic valu...

Comorbidities and Hematopoietic Cell Transplantation Outcomes

“…45 Further, the HCT-CI and C-reactive protein (CRP) were recently used together to rationalize the indications of allo-HCT for patients with chronic myelocytic leukemia (CML) who failed imatinib therapy. 46 …”

“…Patients with adverse comorbidities or high CRP levels might benefit from second-line tyrosine-kinase inhibitors. 46 …”

“…90,95 One study found CRP levels to add additional prognostic information to the HCT-CI. 46 Further studies are needed to clarify whether CRP levels are measurements of aggressive disease status, ongoing inflammatory/ infectious process, or impaired host immunity. Whether biomarkers add additional prognostic information to comorbidities and performance status is unknown.…”

Advanced Phase Chronic Myeloid Leukemia Treatment and Transplantation

“…Treatment with imatinib before allogeneic SCT had a positive impact on the probability of survival and second generation tyrosine kinase inhibitors before allogeneic SCT do not adversely affect allogeneic SCT. 4,5,6,8,9 …”

“…[1][2][3] Patients refractory to IM treatment compose 35% of CML patients and half of these patients are also refractory second generation TKIs. [3][4][5][6] The mortality risk of the allogeneic transplant has decreased continuous-ly during the last 20 years. The reasons for the dramatic improvements include better human leukocyte antigen typing, more careful patient selection and improved supportive care.…”