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A Risk Score for Mortality after Allogeneic Hematopoietic Cell Transplantation

Tanyalak Parimon, MD; David H. Au, MD, MS; Paul J. Martin, MD; and Jason W. Chien, MD, MS
[+] Article and Author Information

From the Fred Hutchinson Cancer Research Center and the Veterans Affairs Puget Sound Health Care System, Seattle, Washington.


Grant Support: By American Lung Association of Washington Research grant K23HL69860-01 and the Amy Strelzer Manasevit Research Award from the National Marrow Donor Program. Dr. Au is the recipient of a Veterans Administration Health Services Research and Development Career Development Award.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Jason W. Chien, MD, MS, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Suite D5-280, Seattle, WA 98109-1024; e-mail, jchien@fhcrc.org.

Current Author Addresses: Dr. Parimon: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Suite D3-245, Seattle, WA 98109-1024.

Dr. Au: Veterans Affairs Puget Sound Health Care System, Health Services Research and Development, 1100 Olive Way, Suite 1400, Seattle WA 98101.

Dr. Martin: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Suite D2-100, Seattle, WA 98109-1024.

Dr. Chien: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Suite D5-280, Seattle, WA 98109-1024.

Author Contributions: Conception and design: T. Parimon, D.H. Au, J.W. Chien.

Analysis and interpretation of the data: T. Parimon, D.H. Au, P.J. Martin, J.W. Chien.

Drafting of the article: T. Parimon, D.H. Au, P.J. Martin, J.W. Chien.

Critical revision of the article for important intellectual content: T. Parimon, D.H. Au, P.J. Martin, J.W. Chien.

Final approval of the article: T. Parimon, D.H. Au, P.J. Martin, J.W. Chien.

Provision of study materials or patients: T. Parimon, P.J. Martin, J.W. Chien.

Statistical expertise: T. Parimon, D.H. Au, J.W. Chien.

Obtaining of funding: J.W. Chien.

Administrative, technical, or logistic support: J.W. Chien.

Collection and assembly of data: T. Parimon, J.W. Chien.


Ann Intern Med. 2006;144(6):407-414. doi:10.7326/0003-4819-144-6-200603210-00007
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Patients who are candidates for allogeneic HCT represent a specialized population at high risk for death. Although several independent risk factors have been previously shown to be associated with increased mortality rates, their performance as clinical predictors of death has not been assessed in an integrated fashion. Some of the 8 variables that we identified as important were previously recognized as independent risk factors for death related to relapse or transplantation. Integration of these variables into a single model demonstrates the relative importance of these pretransplantation variables. When examined together, these variables probably provide a comprehensive preliminary assessment of risk for post-transplantation complications, such as graft-versus-host disease, opportunistic infections, and severe pulmonary syndromes, all of which are well-known causes of death after HCT.

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Figure.
Assessment of model fit.CMLAMLMDS

The actual Kaplan–Meier survival curves of the early and late validation cohorts and for the 3 most common disease categories (chronic myelogenous leukemia [ ], acute myelogenous leukemia [ ], and the myelodysplastic syndrome [ ]) were compared with the Pretransplantation Assessment of Mortality (PAM) score–predicted survival curves as calculated by the Cox proportional hazards model. The category 1 curves were excluded from the acute myelogenous leukemia and myelodysplastic syndrome graphs because there were no patients in those respective quartiles. Near superimposition of the actual and predicted survival curves indicates that the PAM model fits the 5 cohorts well.

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Risk score for mortality after allogeneic hematopoietic stem cell transplantation
Posted on April 7, 2006
Alois Gratwohl
Hematology, University Hospital Basel, Switzerland
Conflict of Interest: None Declared

Sir,

We read with interest the report by Parimon and coworkers on a novel risk score for mortality after hematopoietic stem cell transplantation (HSCT) (1). The authors are to be congratulated to address this important topic in order to improve predictability of outcome on an individual patient basis. Integration of pulmonary, renal and liver function tests into the traditional model (2-4) which is based on age of the patient, stage of the disease, donor type, donor recipient sex combination and time from diagnosis to transplants adds a new dimension. As the authors state, this score should be tested on a more broader basis. Still, before routine application, a few open questions should be considered and be answered. In their work, the authors looked at survival as primary endpoint. This is correct but survival is the composite result of transplant related mortality and death from the disease despite the transplant. Some of the factors, e.g. disease stage have concordant effects on both outcomes. Advanced disease stage increases both risk of transplant related mortality and risk of relapse death. Other factors e.g. donor type have discordant effects. Similarly, reduced intensity conditioning reduces the risk of transplant related mortality but at the expense of increased relapse. It can hardly be integrated as a general variable for survival in all conditions.

Reduced pulmonary, renal and liver function tests did add to the score; no details were given on whether each of these variables has indeed additive value. It would also be of interest to see on how much they correlate with the well documented predictive value of the simple Karnofsky score (4). Last but not least, it is intriguing to note that patient sex and the donor recipient combination were not considered in the final equation. Several studies have independently shown a higher transplant related mortality but a reduced relapse rate in male recipients of female transplants (2-4) and a higher rejection of male grafts from female recipients (5). It appears essential to have an explanation for these apparent discrepancies before wide application can be recommended.

References

1. Parimon T, Au DH, Martin PJ, Chien JW

A risk score for mortality after allogeneic hematopoietic cell transplantation.

Ann Intern Med 2006; 21: 407-414.

2. Gratwohl A, Hermans J, Goldman JM, Arcese W, Carreras E, Devergie A, Frassoni F, Gahrton G, Kolb HJ, Niederwieser D:

Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

Lancet 1998; 352: 1087-1092

3. De Souza CA, Vigorito AC, Ruiz MA, Nucci M, Dulley FL, Funcke V, Tabak D, Azevedo AM, Byington R, Macedo MC, Saboya R, Penteado Aranha FJ, Oliveira GB, Zulli R, Martins Miranda EC, Azevedo WM, Lodi FM, Voltarelli JC, Simoes BP, Colturato V, De Souza MP, Silla L, Bittencourt H, Piron- Ruiz L, Maiolino A, Gratwohl A, Pasquini R: Validation of the EBMT risk score in chronic myeloid leukemia in Brazil and allogeneic transplant outcome.

Haematologica 2005; 90: 232-237.

4. Passweg JR, Walker I, Sobocinski KA, Klein JP, Horowitz MM, Giralt SA:

Chronic Leukemia Study Writing Committee of the International Bone Marrow Transplant Registry.

Validation and extension of the EBMT Risk Score for patients with chronic myeloid leukaemia (CML) receiving allogeneic haematopoietic stem cell transplants.

Br J Haematol 2004; 125: 613-620

5. Vogt MH, Goulmy E, Kloosterboer FM, Blokland E, de Paus RA, Willemze R, Falkenburg JH:

UTY gene codes for an HLA-B60-restriced human male-specific minor histocompatibility antigen involved in stem cell graft rejection: characterization of the critical polymorphic amino acid residues for T- cell recognition.

Blood 2000; 96: 3126-3132

This report was supported by the European Leukemia Net LSHC-CT-2004- 503216 and the Swiss National Research Foundation 3200B0-106105

Conflict of Interest:

None declared

A Risk Score for Mortality after Allogeneic Hematopoietic Cell Transplantation
Posted on April 18, 2006
Eiji Kusumi
Division of Exploratory Research, Institute of Medical Science, University of TOKYO, Tokyo, Japan
Conflict of Interest: None Declared

Sir,

Parimon et al. reported a predictor model of death within the first 2 years after allogeneic hematopoietic stem cell transplantation (allo-HSCT) (1). We would like to comment on this article. Some prospective randomized trials have demonstrated that allo-HSCT improves the prognosis of some hematologic diseases compared with standard chemotherapies; however, such comparison has not been conducted in most hematologic malignancies including malignant lymphoma, multiple myeloma, and myelodysplastic syndrome. Since susceptibility to allogeneic immunity is different among various hematologic malignancies, and graft-versus-tumor (GVT) effects (2) are frequently cancelled by graft-versus-host diseases (GVHD), it remains unknown whether allo-HSCT actually improves the prognosis of most hematologic diseases. Management of GVHD might be different according to the types of underlying diseases. When patients with different backgrounds are analyzed together to identify the predicting factors of overall survival, it is difficult to interpret the results of this study. Enrollment into this study should be restricted to patients with acute leukemia and chronic myeloid leukemia, since evidence supporting the benefit of allo-HSCT is limited to these hematologic malignancies (3, 4).

References

1. Parimon T, Au DH, Martin PJ, Chien JW. A risk score for mortality after allogeneic hematopoietic cell transplantation. Ann Intern Med. 2006;144(6): 407-14.

2. Kolb HJ, Schattenberg A, Goldman JM, et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Blood. 1995;86(5):2041-50.

3. Zittoun RA, Mandelli F, Willemze R, et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups. N Engl J Med. 1995;332 (4):217-23.

4. Monitoring treatment and survival in chronic myeloid leukemia. Italian Cooperative Study Group on Chronic Myeloid Leukemia and Italian Group for Bone Marrow Transplantation. J Clin Oncol. 1999;17(6):1858-68.

Conflict of Interest:

None declared

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