Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome

Charles Peters, Michael Balthazor, Elsa G. Shapiro, Roberta J. King, Craig Kollman, Janet D. Hegland, Jean Henslee-Downey, Michael E. Trigg, Morton J. Cowan, Jean Sanders, Nancy Bunin, Howard Weinstein, Carl Lenarsky, Peter Falk, Richard Harris, Tom Bowen, Thomas E. Williams, Guy H. Grayson, Phyllis Irene Warkentin, Leonard Sender & 9 others Valerie A. Cool, Mary Grillenden, Seymour Packman, Paige Kaplan, Lawrence A. Lockman, James Anderson, William Krivit, Kathryn Dusenbery, John Wagner

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Abstract

Long-term survival and improved neuropsychological function have occurred in selected children with Hurler syndrome (MPS I H) after successful engraftment with genotypically matched sibling bone marrow transplantation (BMT). However, because few children have HLA-identical siblings, the feasibility of unrelated donor (URD) BMT as a vehicle for adoptive enzyme therapy was evaluated in this retrospective study. Forty consecutive children (median, 1.7 years; range, 0.9 to 3.2 years) with MPS I H received high-dose chemotherapy with or without radiation followed by BMT between January 27, 1989 and May 13, 1994. Twenty-five of the 40 patients initially engrafted. An estimated 49% of patients are alive at 2 years, 63% alloengrafted and 37% autoengrafted. The probability of grade II to IV acute graft-versus-host disease (GVHD) was 30%, and the probability of extensive chronic GVHD was 18%. Eleven patients received a second URD BMT because of graft rejection or failure. Of the 20 survivors, 13 children have complete donor engraftment, two children have mixed chimeric grafts, and five children have autologous marrow recovery. The BM cell dose was correlated with both donor engraftment and survival. Thirteen of 27 evaluable patients were engrafted at 1 year following URD BMT. Neither T-lymphocyte depletion (TLD) of the bone marrow nor irradiation appeared to influence the likelihood of engraftment. Ten of 16 patients alive at 1 year who received a BM cell dose greater than or equal to 3.5 x 108 cells/kg engrafted, and 62% are estimated to be alive at 3 years. In contrast, only 3 of 11 patients receiving less than 3.5 x 108 cells/kg engrafted, and 24% are estimated to be alive at 3 years (P = .05). The mental developmental index (MDI) was assessed before BMT. Both baseline and post-BMT neuropsychological data were available for 11 engrafted survivors. Eight children with a baseline MDI greater than 70 have undergone URD BMT (median age, 1.5 years; range, 1.0 to 2.4 years). Of these, two children have had BMT too recently for developmental follow-up. Of the remaining six, none has shown any decline in age equivalent scores. Four children are acquiring skills at a pace equal to or slightly below their same age peers; two children have shown a plateau in learning or extreme slowing in their learning process. For children with a baseline MDI less than 70 (median age, 2.5 years; range, 0.9 to 2.9 years), post-BMT follow-up indicated that two children have shown deterioration in their developmental skills. The remaining three children are maintaining their skills and are adding to them at a highly variable rate. We conclude that MPS I H patients with a baseline MDI greater than 70 who are engrafted survivors following URD BMT can achieve a favorable long-term outcome and improved cognitive function. Future protocols must address the high risk of graft rejection or failure and the impact of GVHD in this patient population.

Original languageEnglish (US)
Pages (from-to)4894-4902
Number of pages9
JournalBlood
Volume87
Issue number11
StatePublished - Jun 1 1996

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Mucopolysaccharidosis I
Unrelated Donors
Bone Marrow Transplantation
Bone
Grafts
Graft vs Host Disease
Survivors
Graft Rejection
Siblings
Bone Marrow
Tissue Donors
Learning
Lymphocyte Depletion
Enzyme Therapy
Chemotherapy
T-cells
Survival
Dosimetry
Deterioration
Cognition

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Peters, C., Balthazor, M., Shapiro, E. G., King, R. J., Kollman, C., Hegland, J. D., ... Wagner, J. (1996). Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome. Blood, 87(11), 4894-4902.

Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome. / Peters, Charles; Balthazor, Michael; Shapiro, Elsa G.; King, Roberta J.; Kollman, Craig; Hegland, Janet D.; Henslee-Downey, Jean; Trigg, Michael E.; Cowan, Morton J.; Sanders, Jean; Bunin, Nancy; Weinstein, Howard; Lenarsky, Carl; Falk, Peter; Harris, Richard; Bowen, Tom; Williams, Thomas E.; Grayson, Guy H.; Warkentin, Phyllis Irene; Sender, Leonard; Cool, Valerie A.; Grillenden, Mary; Packman, Seymour; Kaplan, Paige; Lockman, Lawrence A.; Anderson, James; Krivit, William; Dusenbery, Kathryn; Wagner, John.

In: Blood, Vol. 87, No. 11, 01.06.1996, p. 4894-4902.

Research output: Contribution to journalArticle

Peters, C, Balthazor, M, Shapiro, EG, King, RJ, Kollman, C, Hegland, JD, Henslee-Downey, J, Trigg, ME, Cowan, MJ, Sanders, J, Bunin, N, Weinstein, H, Lenarsky, C, Falk, P, Harris, R, Bowen, T, Williams, TE, Grayson, GH, Warkentin, PI, Sender, L, Cool, VA, Grillenden, M, Packman, S, Kaplan, P, Lockman, LA, Anderson, J, Krivit, W, Dusenbery, K & Wagner, J 1996, 'Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome', Blood, vol. 87, no. 11, pp. 4894-4902.
Peters C, Balthazor M, Shapiro EG, King RJ, Kollman C, Hegland JD et al. Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome. Blood. 1996 Jun 1;87(11):4894-4902.
Peters, Charles ; Balthazor, Michael ; Shapiro, Elsa G. ; King, Roberta J. ; Kollman, Craig ; Hegland, Janet D. ; Henslee-Downey, Jean ; Trigg, Michael E. ; Cowan, Morton J. ; Sanders, Jean ; Bunin, Nancy ; Weinstein, Howard ; Lenarsky, Carl ; Falk, Peter ; Harris, Richard ; Bowen, Tom ; Williams, Thomas E. ; Grayson, Guy H. ; Warkentin, Phyllis Irene ; Sender, Leonard ; Cool, Valerie A. ; Grillenden, Mary ; Packman, Seymour ; Kaplan, Paige ; Lockman, Lawrence A. ; Anderson, James ; Krivit, William ; Dusenbery, Kathryn ; Wagner, John. / Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome. In: Blood. 1996 ; Vol. 87, No. 11. pp. 4894-4902.
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abstract = "Long-term survival and improved neuropsychological function have occurred in selected children with Hurler syndrome (MPS I H) after successful engraftment with genotypically matched sibling bone marrow transplantation (BMT). However, because few children have HLA-identical siblings, the feasibility of unrelated donor (URD) BMT as a vehicle for adoptive enzyme therapy was evaluated in this retrospective study. Forty consecutive children (median, 1.7 years; range, 0.9 to 3.2 years) with MPS I H received high-dose chemotherapy with or without radiation followed by BMT between January 27, 1989 and May 13, 1994. Twenty-five of the 40 patients initially engrafted. An estimated 49{\%} of patients are alive at 2 years, 63{\%} alloengrafted and 37{\%} autoengrafted. The probability of grade II to IV acute graft-versus-host disease (GVHD) was 30{\%}, and the probability of extensive chronic GVHD was 18{\%}. Eleven patients received a second URD BMT because of graft rejection or failure. Of the 20 survivors, 13 children have complete donor engraftment, two children have mixed chimeric grafts, and five children have autologous marrow recovery. The BM cell dose was correlated with both donor engraftment and survival. Thirteen of 27 evaluable patients were engrafted at 1 year following URD BMT. Neither T-lymphocyte depletion (TLD) of the bone marrow nor irradiation appeared to influence the likelihood of engraftment. Ten of 16 patients alive at 1 year who received a BM cell dose greater than or equal to 3.5 x 108 cells/kg engrafted, and 62{\%} are estimated to be alive at 3 years. In contrast, only 3 of 11 patients receiving less than 3.5 x 108 cells/kg engrafted, and 24{\%} are estimated to be alive at 3 years (P = .05). The mental developmental index (MDI) was assessed before BMT. Both baseline and post-BMT neuropsychological data were available for 11 engrafted survivors. Eight children with a baseline MDI greater than 70 have undergone URD BMT (median age, 1.5 years; range, 1.0 to 2.4 years). Of these, two children have had BMT too recently for developmental follow-up. Of the remaining six, none has shown any decline in age equivalent scores. Four children are acquiring skills at a pace equal to or slightly below their same age peers; two children have shown a plateau in learning or extreme slowing in their learning process. For children with a baseline MDI less than 70 (median age, 2.5 years; range, 0.9 to 2.9 years), post-BMT follow-up indicated that two children have shown deterioration in their developmental skills. The remaining three children are maintaining their skills and are adding to them at a highly variable rate. We conclude that MPS I H patients with a baseline MDI greater than 70 who are engrafted survivors following URD BMT can achieve a favorable long-term outcome and improved cognitive function. Future protocols must address the high risk of graft rejection or failure and the impact of GVHD in this patient population.",
author = "Charles Peters and Michael Balthazor and Shapiro, {Elsa G.} and King, {Roberta J.} and Craig Kollman and Hegland, {Janet D.} and Jean Henslee-Downey and Trigg, {Michael E.} and Cowan, {Morton J.} and Jean Sanders and Nancy Bunin and Howard Weinstein and Carl Lenarsky and Peter Falk and Richard Harris and Tom Bowen and Williams, {Thomas E.} and Grayson, {Guy H.} and Warkentin, {Phyllis Irene} and Leonard Sender and Cool, {Valerie A.} and Mary Grillenden and Seymour Packman and Paige Kaplan and Lockman, {Lawrence A.} and James Anderson and William Krivit and Kathryn Dusenbery and John Wagner",
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T1 - Outcome of unrelated donor bone marrow transplantation in 40 children with Hurler syndrome

AU - Peters, Charles

AU - Balthazor, Michael

AU - Shapiro, Elsa G.

AU - King, Roberta J.

AU - Kollman, Craig

AU - Hegland, Janet D.

AU - Henslee-Downey, Jean

AU - Trigg, Michael E.

AU - Cowan, Morton J.

AU - Sanders, Jean

AU - Bunin, Nancy

AU - Weinstein, Howard

AU - Lenarsky, Carl

AU - Falk, Peter

AU - Harris, Richard

AU - Bowen, Tom

AU - Williams, Thomas E.

AU - Grayson, Guy H.

AU - Warkentin, Phyllis Irene

AU - Sender, Leonard

AU - Cool, Valerie A.

AU - Grillenden, Mary

AU - Packman, Seymour

AU - Kaplan, Paige

AU - Lockman, Lawrence A.

AU - Anderson, James

AU - Krivit, William

AU - Dusenbery, Kathryn

AU - Wagner, John

PY - 1996/6/1

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N2 - Long-term survival and improved neuropsychological function have occurred in selected children with Hurler syndrome (MPS I H) after successful engraftment with genotypically matched sibling bone marrow transplantation (BMT). However, because few children have HLA-identical siblings, the feasibility of unrelated donor (URD) BMT as a vehicle for adoptive enzyme therapy was evaluated in this retrospective study. Forty consecutive children (median, 1.7 years; range, 0.9 to 3.2 years) with MPS I H received high-dose chemotherapy with or without radiation followed by BMT between January 27, 1989 and May 13, 1994. Twenty-five of the 40 patients initially engrafted. An estimated 49% of patients are alive at 2 years, 63% alloengrafted and 37% autoengrafted. The probability of grade II to IV acute graft-versus-host disease (GVHD) was 30%, and the probability of extensive chronic GVHD was 18%. Eleven patients received a second URD BMT because of graft rejection or failure. Of the 20 survivors, 13 children have complete donor engraftment, two children have mixed chimeric grafts, and five children have autologous marrow recovery. The BM cell dose was correlated with both donor engraftment and survival. Thirteen of 27 evaluable patients were engrafted at 1 year following URD BMT. Neither T-lymphocyte depletion (TLD) of the bone marrow nor irradiation appeared to influence the likelihood of engraftment. Ten of 16 patients alive at 1 year who received a BM cell dose greater than or equal to 3.5 x 108 cells/kg engrafted, and 62% are estimated to be alive at 3 years. In contrast, only 3 of 11 patients receiving less than 3.5 x 108 cells/kg engrafted, and 24% are estimated to be alive at 3 years (P = .05). The mental developmental index (MDI) was assessed before BMT. Both baseline and post-BMT neuropsychological data were available for 11 engrafted survivors. Eight children with a baseline MDI greater than 70 have undergone URD BMT (median age, 1.5 years; range, 1.0 to 2.4 years). Of these, two children have had BMT too recently for developmental follow-up. Of the remaining six, none has shown any decline in age equivalent scores. Four children are acquiring skills at a pace equal to or slightly below their same age peers; two children have shown a plateau in learning or extreme slowing in their learning process. For children with a baseline MDI less than 70 (median age, 2.5 years; range, 0.9 to 2.9 years), post-BMT follow-up indicated that two children have shown deterioration in their developmental skills. The remaining three children are maintaining their skills and are adding to them at a highly variable rate. We conclude that MPS I H patients with a baseline MDI greater than 70 who are engrafted survivors following URD BMT can achieve a favorable long-term outcome and improved cognitive function. Future protocols must address the high risk of graft rejection or failure and the impact of GVHD in this patient population.

AB - Long-term survival and improved neuropsychological function have occurred in selected children with Hurler syndrome (MPS I H) after successful engraftment with genotypically matched sibling bone marrow transplantation (BMT). However, because few children have HLA-identical siblings, the feasibility of unrelated donor (URD) BMT as a vehicle for adoptive enzyme therapy was evaluated in this retrospective study. Forty consecutive children (median, 1.7 years; range, 0.9 to 3.2 years) with MPS I H received high-dose chemotherapy with or without radiation followed by BMT between January 27, 1989 and May 13, 1994. Twenty-five of the 40 patients initially engrafted. An estimated 49% of patients are alive at 2 years, 63% alloengrafted and 37% autoengrafted. The probability of grade II to IV acute graft-versus-host disease (GVHD) was 30%, and the probability of extensive chronic GVHD was 18%. Eleven patients received a second URD BMT because of graft rejection or failure. Of the 20 survivors, 13 children have complete donor engraftment, two children have mixed chimeric grafts, and five children have autologous marrow recovery. The BM cell dose was correlated with both donor engraftment and survival. Thirteen of 27 evaluable patients were engrafted at 1 year following URD BMT. Neither T-lymphocyte depletion (TLD) of the bone marrow nor irradiation appeared to influence the likelihood of engraftment. Ten of 16 patients alive at 1 year who received a BM cell dose greater than or equal to 3.5 x 108 cells/kg engrafted, and 62% are estimated to be alive at 3 years. In contrast, only 3 of 11 patients receiving less than 3.5 x 108 cells/kg engrafted, and 24% are estimated to be alive at 3 years (P = .05). The mental developmental index (MDI) was assessed before BMT. Both baseline and post-BMT neuropsychological data were available for 11 engrafted survivors. Eight children with a baseline MDI greater than 70 have undergone URD BMT (median age, 1.5 years; range, 1.0 to 2.4 years). Of these, two children have had BMT too recently for developmental follow-up. Of the remaining six, none has shown any decline in age equivalent scores. Four children are acquiring skills at a pace equal to or slightly below their same age peers; two children have shown a plateau in learning or extreme slowing in their learning process. For children with a baseline MDI less than 70 (median age, 2.5 years; range, 0.9 to 2.9 years), post-BMT follow-up indicated that two children have shown deterioration in their developmental skills. The remaining three children are maintaining their skills and are adding to them at a highly variable rate. We conclude that MPS I H patients with a baseline MDI greater than 70 who are engrafted survivors following URD BMT can achieve a favorable long-term outcome and improved cognitive function. Future protocols must address the high risk of graft rejection or failure and the impact of GVHD in this patient population.

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