EDITORIAL Leukapheresis: have we been looking at the right outcome?
T
he treatment of patients with leukemia with leukapheresis has always seemed so logical. Remove the bad cells and the patients will do better. The history of its continuing use demonstrates our persistent belief that this logic must be so despite evidence that it is not. If one examines the story of apheresis device development, it was collaboration between IBM and the National Cancer Institute (NCI) to treat patients with chronic myeloid leukemia, which led to the development of the 2997, the first continuous-flow centrifuge.1,2 When leukapheresis was used for patients with chronic leukemia, it was found that although the level of peripheral leukocytosis could be held in check, there was no improvement in the patient survival.3 Of interesting historic note, the collected products were often transfused to patients with cytopenia without apparent ill consequences. The use of leukapheresis to decrease the white blood cell (WBC) count in acute leukemia dates to the 1970s,4 the same time period as the use of hydroxyurea for the same purpose.5 Both continue to be used to decrease the number of circulating WBCs, with leukapheresis more likely to be used when there are symptoms of leukostasis. Studies have been performed specifically examining variables of decreasing theWBC count, short-term survival and long-term survival. The findings of these studies can be summarized thusly. The method is effective for decreasing the circulating WBCs. Short-term survival appears dependent on decreasing the WBC count but a preferential method of decreasing the WBC count has not been determined. And finally, decreasing the WBC count has been found to have little to no effect on long-term survival.6 One of the supporting comments often stated is that if enough WBCs could be removed, maybe there could be an effect on the development of tumor lysis syndrome. With fewer cells to release cytokines, perhaps there could be an appreciable difference in patient tolerance of initial chemotherapy and a reduction of side effects of myeloablative therapy. One area of great variability in the studies is the definition of short term. It can range from the period of induction chemotherapy to longer periods of time. In an article in this edition of TRANSFUSION, Kurnaz and colleagues7 have modified the leukapheresis procedure to be a combined leukapheresis and volume replacement (LR-VR) procedure, which by their report has the effect of increasing the number of WBCs removed while
TRANSFUSION 2013;53:2603-2604.
simultaneously performing a partial plasma exchange. In the standard WBC depletion the collected buffy coat is removed from the chamber at a stable rate with a final volume of buffy coat product of approximately 600 mL, which is less than 15% of the patient’s blood volume. When a larger volume is collected, patient blood volume has been maintained using normal saline. In the procedure described in this article more than 20% of the blood volume was collected as buffy coat with a median volume 1900 mL, which was replaced using thawed plasma. A comparison of patients at their institution with symptoms of leukostasis treated using the LR compared to LR-VR showed a sevenfold greater decrease in WBC count and improved short-term (100 day) survival for these patients (28.6% for LR vs. 86.2% for LR-VR). The authors hypothesize that the improved short-term survival may result from removal of the damaging cytokines released during leukostasis and WBC destruction by the volume replacement. Unfortunately, this short-term improvement was not carried forward to improved overall survival. Improvements in overall survival for these patients will be dependent on the identification the molecular changes initiating the disease and developing medications to reverse or mitigate their effects. This study, which uses a more prolonged definition of short term provides continuing fuel to the thought that apheresis in these patients can be beneficial, although the context is palliative rather than curative. Decreasing theWBC count has not been shown to alter the overall survival in these critically ill patients. We have always taken the approach that the depletion of leukemic cells is beneficial. It has been said that if we decrease the number of cells that can lyse, tumor lysis syndrome can be reduced. The current study suggests that clinical improvement comes from decreasing circulating cytokines. As data from acute sepsis and multiorgan failure have shown, there can be benefits from the “out with the bad, in with the good” that comes from plasma exchange. There continues to be a role for leukapheresis in the acute management of patients with hyperleukocytic leukemias. The symptoms of leukostasis improve with leukapheresis and patients being considered for research protocols may be precluded from using hydroxyurea. The article by Kurnaz and colleagues suggests that there are opportunities to improve its effectiveness. It seems worth the effort to find out if the increased WBC reduction using LR-VR reported by the authors can be reproduced. More importantly, did the exchange of plasma-containing cytokines lead to the benefit of improving survival to Day 100 and beyond? Volume 53, November 2013 TRANSFUSION
2603
EDITORIAL
CONFLICT OF INTEREST None.
3. Buckner D, Graw RG, Eisel RJ, Henderson ES, Perry S. Leukapheresis by continuous flow centrifugation (CFC) in patients with chronic myelocytic leukemia (CML). Blood
Joanne L. Becker, MD Laboratory Medicine Roswell Park Cancer Institute Buffalo, NY e-mail: [email protected]
1969;33:353-69. 4. Eisenstaedt RS, Berkman EM. Rapid cytoreduction in acute leukemia management of cerebral leukostasis by cell pheresis. Transfusion 1979;18:113-5. 5. Grund FM, Armitage JO, Burns P. Hydroxyurea in the prevention of the effects of leukostasis in acute leukemia. Arch Int Med 1977;137:1246-7.
REFERENCES 1. Judson G, Jones A, Kellogg R, Buckner D, Eisel R, Perry S, Greenough W. Closed continuous-flow centrifuge. Nature 1968;217:816-8. 2. Buckner D, Eisel R, Perry S. Blood cell separation in the dog by continuous flow centrifugation. Blood 1968;31: 653-72.
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TRANSFUSION Volume 53, November 2013
6. Ganzel C, Becker J, Mintz PD, Lazarus HM, Rowe JM. Hyperleukocytosis, leukostasis, and leukapheresis: practice management. Blood Rev 2012;23:117-22. 7. Kurnaz F, Sivgin S, Pala C, Yildirim R, Baldane S, Kaynar L, Solmaz M, Ozturk A, Eser B, Cetin M, Unal A. The effect of volume replacement during therapeutic leukapheresis on white blood cell reduction in patients with extreme leukocytosis. Transfusion 2013;53:2629-34.
T
he treatment of patients with leukemia with leukapheresis has always seemed so logical. Remove the bad cells and the patients will do better. The history of its continuing use demonstrates our persistent belief that this logic must be so despite evidence that it is not. If one examines the story of apheresis device development, it was collaboration between IBM and the National Cancer Institute (NCI) to treat patients with chronic myeloid leukemia, which led to the development of the 2997, the first continuous-flow centrifuge.1,2 When leukapheresis was used for patients with chronic leukemia, it was found that although the level of peripheral leukocytosis could be held in check, there was no improvement in the patient survival.3 Of interesting historic note, the collected products were often transfused to patients with cytopenia without apparent ill consequences. The use of leukapheresis to decrease the white blood cell (WBC) count in acute leukemia dates to the 1970s,4 the same time period as the use of hydroxyurea for the same purpose.5 Both continue to be used to decrease the number of circulating WBCs, with leukapheresis more likely to be used when there are symptoms of leukostasis. Studies have been performed specifically examining variables of decreasing theWBC count, short-term survival and long-term survival. The findings of these studies can be summarized thusly. The method is effective for decreasing the circulating WBCs. Short-term survival appears dependent on decreasing the WBC count but a preferential method of decreasing the WBC count has not been determined. And finally, decreasing the WBC count has been found to have little to no effect on long-term survival.6 One of the supporting comments often stated is that if enough WBCs could be removed, maybe there could be an effect on the development of tumor lysis syndrome. With fewer cells to release cytokines, perhaps there could be an appreciable difference in patient tolerance of initial chemotherapy and a reduction of side effects of myeloablative therapy. One area of great variability in the studies is the definition of short term. It can range from the period of induction chemotherapy to longer periods of time. In an article in this edition of TRANSFUSION, Kurnaz and colleagues7 have modified the leukapheresis procedure to be a combined leukapheresis and volume replacement (LR-VR) procedure, which by their report has the effect of increasing the number of WBCs removed while
TRANSFUSION 2013;53:2603-2604.
simultaneously performing a partial plasma exchange. In the standard WBC depletion the collected buffy coat is removed from the chamber at a stable rate with a final volume of buffy coat product of approximately 600 mL, which is less than 15% of the patient’s blood volume. When a larger volume is collected, patient blood volume has been maintained using normal saline. In the procedure described in this article more than 20% of the blood volume was collected as buffy coat with a median volume 1900 mL, which was replaced using thawed plasma. A comparison of patients at their institution with symptoms of leukostasis treated using the LR compared to LR-VR showed a sevenfold greater decrease in WBC count and improved short-term (100 day) survival for these patients (28.6% for LR vs. 86.2% for LR-VR). The authors hypothesize that the improved short-term survival may result from removal of the damaging cytokines released during leukostasis and WBC destruction by the volume replacement. Unfortunately, this short-term improvement was not carried forward to improved overall survival. Improvements in overall survival for these patients will be dependent on the identification the molecular changes initiating the disease and developing medications to reverse or mitigate their effects. This study, which uses a more prolonged definition of short term provides continuing fuel to the thought that apheresis in these patients can be beneficial, although the context is palliative rather than curative. Decreasing theWBC count has not been shown to alter the overall survival in these critically ill patients. We have always taken the approach that the depletion of leukemic cells is beneficial. It has been said that if we decrease the number of cells that can lyse, tumor lysis syndrome can be reduced. The current study suggests that clinical improvement comes from decreasing circulating cytokines. As data from acute sepsis and multiorgan failure have shown, there can be benefits from the “out with the bad, in with the good” that comes from plasma exchange. There continues to be a role for leukapheresis in the acute management of patients with hyperleukocytic leukemias. The symptoms of leukostasis improve with leukapheresis and patients being considered for research protocols may be precluded from using hydroxyurea. The article by Kurnaz and colleagues suggests that there are opportunities to improve its effectiveness. It seems worth the effort to find out if the increased WBC reduction using LR-VR reported by the authors can be reproduced. More importantly, did the exchange of plasma-containing cytokines lead to the benefit of improving survival to Day 100 and beyond? Volume 53, November 2013 TRANSFUSION
2603
EDITORIAL
CONFLICT OF INTEREST None.
3. Buckner D, Graw RG, Eisel RJ, Henderson ES, Perry S. Leukapheresis by continuous flow centrifugation (CFC) in patients with chronic myelocytic leukemia (CML). Blood
Joanne L. Becker, MD Laboratory Medicine Roswell Park Cancer Institute Buffalo, NY e-mail: [email protected]
1969;33:353-69. 4. Eisenstaedt RS, Berkman EM. Rapid cytoreduction in acute leukemia management of cerebral leukostasis by cell pheresis. Transfusion 1979;18:113-5. 5. Grund FM, Armitage JO, Burns P. Hydroxyurea in the prevention of the effects of leukostasis in acute leukemia. Arch Int Med 1977;137:1246-7.
REFERENCES 1. Judson G, Jones A, Kellogg R, Buckner D, Eisel R, Perry S, Greenough W. Closed continuous-flow centrifuge. Nature 1968;217:816-8. 2. Buckner D, Eisel R, Perry S. Blood cell separation in the dog by continuous flow centrifugation. Blood 1968;31: 653-72.
2604
TRANSFUSION Volume 53, November 2013
6. Ganzel C, Becker J, Mintz PD, Lazarus HM, Rowe JM. Hyperleukocytosis, leukostasis, and leukapheresis: practice management. Blood Rev 2012;23:117-22. 7. Kurnaz F, Sivgin S, Pala C, Yildirim R, Baldane S, Kaynar L, Solmaz M, Ozturk A, Eser B, Cetin M, Unal A. The effect of volume replacement during therapeutic leukapheresis on white blood cell reduction in patients with extreme leukocytosis. Transfusion 2013;53:2629-34.
