The Dinakara equation for adjusting DLCO for hemoglobin in the HCT-CI is superior to the Cotes equation for predicting high-risk patients in allogeneic hematopoietic stem cell transplantation
Authors: Yasuhiko Shibasaki, Takayuki Katagiri, Hironori Kobayashi, Takashi Ushiki, Miwako Narita, Hirohito Sone, Tatsuo Furukawa, Masayoshi Masuko
Journal: American Journal of Hematology (2016)

The Dinakara equation for adjusting DLCO for hemoglobin in the HCT-CI is superior to the Cotes equation for predicting high-risk patients in allogeneic hematopoietic stem cell transplantationTo the Editor: The Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) and recently updated Comorbidity-age index are useful tools for pre-transplant risk assessments [1,2].In the HCT-CI and Comorbidity-age index, pulmonary disease is the most prevalent comorbidity captured [1].It is frequently demonstrated by a decreased diffusion capacity of carbon monoxide (DLCO).While the equation for DLCO adjusting for hemoglobin (Hb) used in the HCT-CI is based on the work by Dinakara et al. [3], many facilities in Japan use the equation reported by Cotes et al. [4].Moreover, the American Thoracic Society (ATS) and European Respiratory Society (ERS) guidelines also recommend that the Cotes equation be applied when adjusting DLCO for Hb [5].Therefore, HCT-CI scores in registrations in Japan, the United States, and Europe may contain data obtained using different equations.Coffey et al. reported that the HCT-CI score significantly differed following a comparison of the Cotes equation and Dinakara equation for adjusting DLCO for Hb [6].Although their findings suggest that the Cotes equation may overestimate non-relapse mortality (NRM) predicted by the HCT-CI, they failed to show differences in NRM and overall survival (OS) between low-or intermediate-risk patients and high-risk patients regardless of the equation applied.It currently remains unknown whether the equation method for adjusting DLCO affects risk stratification in the Comorbidity-age index.We herein analyzed the impact of each equation used to adjust DLCO for Hb in order to predict NRM and OS in allogeneic hematopoietic stem cell transplantation (allo-HSCT) using the HCI-CI and Comorbidity-age index.We retrospectively examined pre-transplant pulmonary function test results in 101 patients who underwent allo-HSCT in our hospital between 2005 and 2014.Median age of patients was 46 years (range: 16-67).Fifty-six patients received bone marrow transplantation, 19 received peripheral blood stem cell transplantation, and 30 received cord blood transplantation.The median Hb level was 9.2 (5.6-14.4)g/dL.Adjustments to DLCO (mL/ mmHg/min) for Hb (g/dL) were validated using the Dinakara equation [3] and Cotes equation [4].Since our hospital is nearly at sea level, DLCO was not adjusted for altitude.The mean %DLCO adjusted for Hb was 66.5% using the Cotes equation and 82.7% using the Dinakara equation (P < 0.001).All patients showed a higher %DLCO when adjusted with the Cotes equation than with the Dinakara equation.In the HCT-CI, 34 out of 54 patients (63.0%) that were scored 3 with the Cotes equation were scored 0-2 with the Dinakara equation.In the Comorbidity-age index, 22 out of 58 patients (45.5%) that were scored 3-4 with the Cotes equation were scored 1-2 with the Dinakara equation, while 5 out of 58 patients (8.6%) were scored 0. Furthermore, 2 out of 8 patients (25.0%) that were scored 5 with the Cotes equation were scored 3-4 with the Dinakara equation.Since risk stratification is important for deciding the adaptation of allo-HSCT, a uniform equation method for adjusting DLCO in the registry is needed in order to adapt the HCT-CI or Comorbidity-age index in clinical trial design and outcome analyses.Because the HCT-CI and Comorbidity-age index are tools to predict outcomes, we evaluated how each equation method for adjusting DLCO affected the positive predictive value (PPV) of NRM or OS with each index.In terms of NRM, the PPV of score 3 based on the HCT-CI adjusted with the Dinakara equation was higher than that with the Cotes equation (0.50 vs. 0.28).On the other hand, the negative predictive value (NPV) of score 0-2 based on the HCT-CI adjusted with the Dinakara equation was similar to that with the Cotes equation (0.89 vs. 0.91).Similar results were obtained with the Comorbidity-age index.In terms of OS, the PPV of score 3 based on the HCT-CI adjusted with the Dinakara equation was higher than that with the Cotes equation (0.70 vs. 0.54).The NPV of score 0-2 based on the HCT-CI adjusted with the Dinakara equation was similar to that with the Cotes equation (0.64 vs. 0.70).Similar results were obtained with the Comorbidity-age index (Table I).Our results indicate that the Dinakara equation is a superior equation for adjusting DLCO for Hb in order to predict high-risk patients in allo-HSCT.In a multivariate analysis, we determined whether score 3 in the HCT-CI or score 4 in the Comorbidity-age index was associated with outcomes.When we adapted the Dinakara equation, these scores were chosen as independent factors for NRM and OS.However, using the Cotes equation, we did not find a strong association between the indexes and outcomes (Supporting Information Table 1).Therefore, these results confirm the superiority of the Dinakara equation for adjusting DLCO for Hb in order to analyze outcomes in clinical trials.Although the ATS and ERS guidelines recommend the Cotes equation, the Dinakara equation is favored.The Cotes equation has a more robust ability than the Dinakara equation to account for the effects of anemia.Anemia is a common sign of primary hematological diseases, and is affected by pre-transplant therapy in patients undergoing allo-HSCT.Furthermore, anemia is improved by donor hematopoiesis after allo-HSCT regardless of the pre-HSCT Hb level.Therefore, the effects of anemia on DLCO may vary among therapeutic phases in patients with hematological diseases.C-statistic estimates for OS with the HCT-CI score and the Comorbidity-age index score based on the Dinakara equation vs. the Cotes equation were 0.650 vs. 0.648 and 0.672 vs. 0.684, respectively.These results were similar to previous findings regardless of the equation method [2].The superiority of the Dinakara equation to the Cotes equation was not proven in C-statistic estimates for OS.A new index that places other factors such as biomarkers into the HCT-CI or Comorbidity-age index may be needed for bedside decisions to adapt allo-HSCT.In conclusion, the equations for adjusting DLCO affect risk stratification by the HCT-CI and Comorbidity-age index prior to allo-HSCT.In order to predict outcomes in allo-HSCT, the Dinakara equation is superior to the Cotes equation for adjusting DLCO for Hb.