From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
associated with a poor prognosis, it is important to try to explain the potential reasons for the very short OS in this scenario. Such a short OS is not seen in other poor-risk CLL conditions such as RS (median OS of 8-30 months) and in fludarabine-refractory patients (median OS of 10 months).5,6 Clonal selection of aggressive CLL/RS clones already present at the time of therapy initiation could be postulated. Losses of TP53 and CDKN2A with MYC activation, as well as trisomy 12 in association with NOTCH1 mutations, were the most common alterations previously described in RS after CLL. These abnormalities were associated with a proliferative RS and an OS of ,6 months.7 Intrinsic resistance to ibrutinib in CLL could also play a role by the development of mutations in the C481S position of the Bruton tyrosine kinase gene and in PLCg2, as has been recently reported, especially in patients with progressive CLL but no RS.8,9 These events may be the reason for ibrutinib discontinuation not only in patients with progressive CLL but also in patients who stopped the drug for other reasons. Although these assumptions are purely hypothetical and speculative, they are suggested by the increased rate of ibrutinib discontinuation seen with longer follow-up (14% and 36% discontinuation rate at a median follow-up of 9.5 and 21 months, respectively), which could represent the acquisition of new mutations over time that could lead to resistance and/or development or expansion of aggressive CLL/RS clones. Many of these questions might be answered in the near future with next-generation sequencing studies at ibrutinib therapy initiation and on discontinuation, which could add more value to the present report. Definitely, ibrutinib has dramatically changed the landscape of relapsed/refractory CLL treatment and constitutes an important paradigm in the molecularly targeted approach of this disease, with excellent efficacy and tolerability. However, patients who discontinue treatment represent a challenge to the practicing oncologist, and treatment options are very limited. In the near future, early identification of very high-risk patients treated with ibrutinib should be the target of new combinatorial therapies that can improve the outcomes in this population. This report highlights that the road toward a cure (or effective disease
2014
control) of CLL has not ended and that, instead, we might be facing a new unmet need in this disease. Conflict-of-interest disclosure: J.P.-I. is a consultant for and received honoraria from Janssen; J.C.C. declares no competing financial interests. n
5. Parikh SA, Rabe KG, Call TG, et al. Diffuse large B-cell lymphoma (Richter syndrome) in patients with chronic lymphocytic leukaemia (CLL): a cohort study of newly diagnosed patients. Br J Haematol. 2013;162(6): 774-782.
REFERENCES
7. Chigrinova E, Rinaldi A, Kwee I, et al. Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia to Richter syndrome. Blood. 2013; 122(15):2673-2682.
1. Jain P, Keating M, Wierda W, et al. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood. 2015;125(13):2062-2067. 2. Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood. 2012;120(6):1175-1184.
6. Keating MJ, O’Brien S, Kontoyiannis D, et al. Results of first salvage therapy for patients refractory to a fludarabine regimen in chronic lymphocytic leukemia. Leuk Lymphoma. 2002;43(9):1755-1762.
8. Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370(24):2286-2294. 9. Woyach J, Ruppert A, Lozanski G, et al. Association of disease progression on ibrutinib therapy with the acquisition of resistance mutations: a single-center experience of 267 patients [abstract]. J Clin Oncol. 2014; 32:5s. Abstract 7010.
3. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32-42. 4. Byrd JC, Brown JR, O’Brien S, et al; RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014; 371(3):213-223.
© 2015 by The American Society of Hematology
l l l CLINICAL TRIALS AND OBSERVATIONS
Comment on Palumbo et al, page 2068
New prognostic tools for myeloma ----------------------------------------------------------------------------------------------------Ulf-Henrik Mellqvist
GOTHENBURG UNIVERSITY
In this issue of Blood, Palumbo et al show, in a study performed with the cooperation of the International Myeloma Working Group (IMWG), that detailed systematic geriatric assessment of elderly myeloma patients might be a useful tool for identifying fit and frail individuals.1 Like most malignancies, multiple myeloma mainly affects elderly patients. Even so, in daily clinical practice, we usually only consider chronological age (ie, is the patient under or above 65 years of age?). However, it is quite obvious that there is a huge difference between a 70-year-old fit patient and a frail patient above the age of 80.
U
sing data from almost 900 patients participating in 3 different clinical trials, IMWG has managed to identify a group of patients with highly significant but worse progression-free and overall survival. This inferior survival is most probably due to a larger frequency of treatment discontinuations and nonhematologic adverse events. The group of frail patients was defined by using geriatric assessment tools considering comorbidities and cognitive and physical status and by adding extra age intervals (65 to 74, 75 to 79, and $ 80), and the evaluation was performed at diagnosis, which avoided interference with treatmentrelated events. It is well known that myeloma is a disease in which prognosis varies widely.2 There have been several systems to classify myeloma,
from the study by Durie and Salmon3 to the International Staging System (ISS).4 They have all had their benefits, but so far they have not been able to provide information for adjusting the treatment of the individual patient. In this former study, the authors show that their new system could produce information not possible to obtain by using standard performance status, ISS, or even biological data from chromosomal analyses, which we normally regard as very important prognostic tools. The present study is also important, apart from giving prognostic information, as the assessment system has the potential to give guidance for individual treatment regimens. By identifying frail patients, it could help the clinician choose well-tolerated, low-toxicity
BLOOD, 26 MARCH 2015 x VOLUME 125, NUMBER 13
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
combinations, and thereby avoid harmful treatment regimens. Another potential important issue for a new robust frailty scoring system could be that elderly patients found fit could benefit from more intense treatment. In a study using population-based data, it was shown that regions in Sweden using more intense regimens for elderly patients with acute myeloid leukemia (AML) showed better survival results5 and these findings led to a change in treatment routines for elderly AML patients. A limitation with this study is that data are based on patients participating in clinical trials, where the frailest patients are excluded. Therefore, it would be valuable if this system could be supported by so-called “real world” data from large population-based registries. However, currently, these evaluations would be useful if they were included in upcoming clinical trials, making future comparisons between studies more adequate. Indeed, in a meta-analysis of one of the approved first-line therapies in Europe (melphalan, prednisone, and thalidomide), the results from the 6 trials differed widely, and it has been speculated that the different performance status of participating patients, even though apart from 1 study they were all .65 years of age, was the main cause.6 Also, as mentioned in this IMWG study, there are studies showing no difference between doublet and triplet treatment regimens, which accordingly might be due to less tolerability for the more intensive combinations among the frail patients.7,8 In conclusion, this report from the IMWG provides an evaluation system that enables the clinician to make a more detailed treatment decision. In the future, with a rapidly growing aging population, it will become increasingly important to tailor the treatment to the individual patient, thus avoiding harm and gaining maximal efficacy. Conflict-of-interest disclosure: The author is on advisory boards for Amgen and Celgene and has received lecture honoraria from Janssen, Mundipharma, Novartis, Amgen, and Celgene. n REFERENCES 1. Palumbo A, Bringhen S, Mateos M-V, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015;125(13):2068-2074. 2. Rajkumar SV, Kyle RA. Multiple myeloma: diagnosis and treatment. Mayo Clin Proc. 2005;80(10):1371-1382.
3. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975;36(3):842-854. 4. Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;20;23(15):3412-3420. 5. Juliusson G, Antunovic P, Derolf A, et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood. 2009;113(18):4179-4187. 6. Fayers PM, Palumbo A, Hulin C, et al; Nordic Myeloma Study Group; Italian Multiple Myeloma Network; Turkish Myeloma Study Group; Hemato-Oncologie voor Volwassenen Nederland; Intergroupe Francophone du My´elome; European Myeloma Network. Thalidomide for previously untreated
elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials. Blood. 2011;118(5):1239-1247. 7. Benboubker L, Dimopoulos MA, Dispenzieri A, et al; FIRST Trial Team. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;371(10):906-917. 8. Niesvizky R, Flinn I, Rifkin RM, et al. Efficacy and safety of three bortezomib-based induction and maintenance regimens in previously untreated, transplantineligible multiple myeloma (MM) patients (Pts): final results from the Randomized, Phase 3b, US CommunityBased UPFRONT Study (NCT00507416) [abstract]. Blood. 2013;122(21). Abstract 1966. © 2015 by The American Society of Hematology
l l l THROMBOSIS AND HEMOSTASIS
Comment on Tian et al, page 2151
When the brain tells the blood how to clot ----------------------------------------------------------------------------------------------------Eric Boilard
CENTRE DE RECHERCHE DU CENTRE HOSPITALIER UNIVERSITAIRE DE QU´EBEC
In this issue of Blood, Tian et al report that during traumatic brain injury, small membrane vesicles, called microparticles, disseminate procoagulant factors from the brain into the systemic circulation. The delivery appears to occur through the disrupted blood-brain barrier.1
D
efects in the coagulation process are common in patients with trauma, mostly due to major blood loss, consumption of coagulation factors, thrombocytopenia, fluid resuscitation, and hypothermia.2 As coagulopathy in trauma is associated with poor outcome, defining the factors that impair blood coagulation in this context is extremely important. Intrigued by the coagulopathy that accompanies traumatic brain injury, a category of trauma generally not
accompanied by heavy blood loss and fluid resuscitation,3 the authors hypothesized that factors generated by the injured brain could disseminate into the blood circulation and impact coagulation. Microparticles are extracellular vesicles measuring ;0.1 to 1 mm in diameter. They are produced from activated and apoptotic cells by membrane blebbing and fission and can support coagulation through exposure of phosphatidylserine and tissue factor, which is the trigger of the extrinsic pathway of
Trauma brain injury in mice and coagulation triggered by brain-derived microparticles. (A) Cerebral injury is visible in the left parietal lobe of a mouse 3 hours after induction of trauma using fluid percussion injury (FPI) compared with the brain from a mouse subjected to sham surgery (Sham). (B) The clotting time measured in platelet-poor plasma (PPP) collected from mice subjected to trauma brain injury (FPI) or sham surgery (Sham) was measured in a phosphatidylserine-dependent assay. (C) Clotting time was compared between PPP and homologous plasma depleted of any microparticles by centrifugation collected from mice subjected to trauma brain injury (FPI) and sham surgery (Sham). Adapted from Figure 1 in the article by Tian et al that begins on page 2151.
BLOOD, 26 MARCH 2015 x VOLUME 125, NUMBER 13
2015
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2015 125: 2014-2015 doi:10.1182/blood-2015-02-626408
New prognostic tools for myeloma Ulf-Henrik Mellqvist
Updated information and services can be found at: http://www.bloodjournal.org/content/125/13/2014.full.html Articles on similar topics can be found in the following Blood collections Free Research Articles (4041 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.
associated with a poor prognosis, it is important to try to explain the potential reasons for the very short OS in this scenario. Such a short OS is not seen in other poor-risk CLL conditions such as RS (median OS of 8-30 months) and in fludarabine-refractory patients (median OS of 10 months).5,6 Clonal selection of aggressive CLL/RS clones already present at the time of therapy initiation could be postulated. Losses of TP53 and CDKN2A with MYC activation, as well as trisomy 12 in association with NOTCH1 mutations, were the most common alterations previously described in RS after CLL. These abnormalities were associated with a proliferative RS and an OS of ,6 months.7 Intrinsic resistance to ibrutinib in CLL could also play a role by the development of mutations in the C481S position of the Bruton tyrosine kinase gene and in PLCg2, as has been recently reported, especially in patients with progressive CLL but no RS.8,9 These events may be the reason for ibrutinib discontinuation not only in patients with progressive CLL but also in patients who stopped the drug for other reasons. Although these assumptions are purely hypothetical and speculative, they are suggested by the increased rate of ibrutinib discontinuation seen with longer follow-up (14% and 36% discontinuation rate at a median follow-up of 9.5 and 21 months, respectively), which could represent the acquisition of new mutations over time that could lead to resistance and/or development or expansion of aggressive CLL/RS clones. Many of these questions might be answered in the near future with next-generation sequencing studies at ibrutinib therapy initiation and on discontinuation, which could add more value to the present report. Definitely, ibrutinib has dramatically changed the landscape of relapsed/refractory CLL treatment and constitutes an important paradigm in the molecularly targeted approach of this disease, with excellent efficacy and tolerability. However, patients who discontinue treatment represent a challenge to the practicing oncologist, and treatment options are very limited. In the near future, early identification of very high-risk patients treated with ibrutinib should be the target of new combinatorial therapies that can improve the outcomes in this population. This report highlights that the road toward a cure (or effective disease
2014
control) of CLL has not ended and that, instead, we might be facing a new unmet need in this disease. Conflict-of-interest disclosure: J.P.-I. is a consultant for and received honoraria from Janssen; J.C.C. declares no competing financial interests. n
5. Parikh SA, Rabe KG, Call TG, et al. Diffuse large B-cell lymphoma (Richter syndrome) in patients with chronic lymphocytic leukaemia (CLL): a cohort study of newly diagnosed patients. Br J Haematol. 2013;162(6): 774-782.
REFERENCES
7. Chigrinova E, Rinaldi A, Kwee I, et al. Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia to Richter syndrome. Blood. 2013; 122(15):2673-2682.
1. Jain P, Keating M, Wierda W, et al. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood. 2015;125(13):2062-2067. 2. Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood. 2012;120(6):1175-1184.
6. Keating MJ, O’Brien S, Kontoyiannis D, et al. Results of first salvage therapy for patients refractory to a fludarabine regimen in chronic lymphocytic leukemia. Leuk Lymphoma. 2002;43(9):1755-1762.
8. Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370(24):2286-2294. 9. Woyach J, Ruppert A, Lozanski G, et al. Association of disease progression on ibrutinib therapy with the acquisition of resistance mutations: a single-center experience of 267 patients [abstract]. J Clin Oncol. 2014; 32:5s. Abstract 7010.
3. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32-42. 4. Byrd JC, Brown JR, O’Brien S, et al; RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014; 371(3):213-223.
© 2015 by The American Society of Hematology
l l l CLINICAL TRIALS AND OBSERVATIONS
Comment on Palumbo et al, page 2068
New prognostic tools for myeloma ----------------------------------------------------------------------------------------------------Ulf-Henrik Mellqvist
GOTHENBURG UNIVERSITY
In this issue of Blood, Palumbo et al show, in a study performed with the cooperation of the International Myeloma Working Group (IMWG), that detailed systematic geriatric assessment of elderly myeloma patients might be a useful tool for identifying fit and frail individuals.1 Like most malignancies, multiple myeloma mainly affects elderly patients. Even so, in daily clinical practice, we usually only consider chronological age (ie, is the patient under or above 65 years of age?). However, it is quite obvious that there is a huge difference between a 70-year-old fit patient and a frail patient above the age of 80.
U
sing data from almost 900 patients participating in 3 different clinical trials, IMWG has managed to identify a group of patients with highly significant but worse progression-free and overall survival. This inferior survival is most probably due to a larger frequency of treatment discontinuations and nonhematologic adverse events. The group of frail patients was defined by using geriatric assessment tools considering comorbidities and cognitive and physical status and by adding extra age intervals (65 to 74, 75 to 79, and $ 80), and the evaluation was performed at diagnosis, which avoided interference with treatmentrelated events. It is well known that myeloma is a disease in which prognosis varies widely.2 There have been several systems to classify myeloma,
from the study by Durie and Salmon3 to the International Staging System (ISS).4 They have all had their benefits, but so far they have not been able to provide information for adjusting the treatment of the individual patient. In this former study, the authors show that their new system could produce information not possible to obtain by using standard performance status, ISS, or even biological data from chromosomal analyses, which we normally regard as very important prognostic tools. The present study is also important, apart from giving prognostic information, as the assessment system has the potential to give guidance for individual treatment regimens. By identifying frail patients, it could help the clinician choose well-tolerated, low-toxicity
BLOOD, 26 MARCH 2015 x VOLUME 125, NUMBER 13
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
combinations, and thereby avoid harmful treatment regimens. Another potential important issue for a new robust frailty scoring system could be that elderly patients found fit could benefit from more intense treatment. In a study using population-based data, it was shown that regions in Sweden using more intense regimens for elderly patients with acute myeloid leukemia (AML) showed better survival results5 and these findings led to a change in treatment routines for elderly AML patients. A limitation with this study is that data are based on patients participating in clinical trials, where the frailest patients are excluded. Therefore, it would be valuable if this system could be supported by so-called “real world” data from large population-based registries. However, currently, these evaluations would be useful if they were included in upcoming clinical trials, making future comparisons between studies more adequate. Indeed, in a meta-analysis of one of the approved first-line therapies in Europe (melphalan, prednisone, and thalidomide), the results from the 6 trials differed widely, and it has been speculated that the different performance status of participating patients, even though apart from 1 study they were all .65 years of age, was the main cause.6 Also, as mentioned in this IMWG study, there are studies showing no difference between doublet and triplet treatment regimens, which accordingly might be due to less tolerability for the more intensive combinations among the frail patients.7,8 In conclusion, this report from the IMWG provides an evaluation system that enables the clinician to make a more detailed treatment decision. In the future, with a rapidly growing aging population, it will become increasingly important to tailor the treatment to the individual patient, thus avoiding harm and gaining maximal efficacy. Conflict-of-interest disclosure: The author is on advisory boards for Amgen and Celgene and has received lecture honoraria from Janssen, Mundipharma, Novartis, Amgen, and Celgene. n REFERENCES 1. Palumbo A, Bringhen S, Mateos M-V, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015;125(13):2068-2074. 2. Rajkumar SV, Kyle RA. Multiple myeloma: diagnosis and treatment. Mayo Clin Proc. 2005;80(10):1371-1382.
3. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975;36(3):842-854. 4. Greipp PR, San Miguel J, Durie BG, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;20;23(15):3412-3420. 5. Juliusson G, Antunovic P, Derolf A, et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood. 2009;113(18):4179-4187. 6. Fayers PM, Palumbo A, Hulin C, et al; Nordic Myeloma Study Group; Italian Multiple Myeloma Network; Turkish Myeloma Study Group; Hemato-Oncologie voor Volwassenen Nederland; Intergroupe Francophone du My´elome; European Myeloma Network. Thalidomide for previously untreated
elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials. Blood. 2011;118(5):1239-1247. 7. Benboubker L, Dimopoulos MA, Dispenzieri A, et al; FIRST Trial Team. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;371(10):906-917. 8. Niesvizky R, Flinn I, Rifkin RM, et al. Efficacy and safety of three bortezomib-based induction and maintenance regimens in previously untreated, transplantineligible multiple myeloma (MM) patients (Pts): final results from the Randomized, Phase 3b, US CommunityBased UPFRONT Study (NCT00507416) [abstract]. Blood. 2013;122(21). Abstract 1966. © 2015 by The American Society of Hematology
l l l THROMBOSIS AND HEMOSTASIS
Comment on Tian et al, page 2151
When the brain tells the blood how to clot ----------------------------------------------------------------------------------------------------Eric Boilard
CENTRE DE RECHERCHE DU CENTRE HOSPITALIER UNIVERSITAIRE DE QU´EBEC
In this issue of Blood, Tian et al report that during traumatic brain injury, small membrane vesicles, called microparticles, disseminate procoagulant factors from the brain into the systemic circulation. The delivery appears to occur through the disrupted blood-brain barrier.1
D
efects in the coagulation process are common in patients with trauma, mostly due to major blood loss, consumption of coagulation factors, thrombocytopenia, fluid resuscitation, and hypothermia.2 As coagulopathy in trauma is associated with poor outcome, defining the factors that impair blood coagulation in this context is extremely important. Intrigued by the coagulopathy that accompanies traumatic brain injury, a category of trauma generally not
accompanied by heavy blood loss and fluid resuscitation,3 the authors hypothesized that factors generated by the injured brain could disseminate into the blood circulation and impact coagulation. Microparticles are extracellular vesicles measuring ;0.1 to 1 mm in diameter. They are produced from activated and apoptotic cells by membrane blebbing and fission and can support coagulation through exposure of phosphatidylserine and tissue factor, which is the trigger of the extrinsic pathway of
Trauma brain injury in mice and coagulation triggered by brain-derived microparticles. (A) Cerebral injury is visible in the left parietal lobe of a mouse 3 hours after induction of trauma using fluid percussion injury (FPI) compared with the brain from a mouse subjected to sham surgery (Sham). (B) The clotting time measured in platelet-poor plasma (PPP) collected from mice subjected to trauma brain injury (FPI) or sham surgery (Sham) was measured in a phosphatidylserine-dependent assay. (C) Clotting time was compared between PPP and homologous plasma depleted of any microparticles by centrifugation collected from mice subjected to trauma brain injury (FPI) and sham surgery (Sham). Adapted from Figure 1 in the article by Tian et al that begins on page 2151.
BLOOD, 26 MARCH 2015 x VOLUME 125, NUMBER 13
2015
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2015 125: 2014-2015 doi:10.1182/blood-2015-02-626408
New prognostic tools for myeloma Ulf-Henrik Mellqvist
Updated information and services can be found at: http://www.bloodjournal.org/content/125/13/2014.full.html Articles on similar topics can be found in the following Blood collections Free Research Articles (4041 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.
