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Blood First Edition Paper, prepublished online May 26, 2015; DOI 10.1182/blood-2015-01-625541
HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR INFANTILE OSTEOPETROSIS Category: Transplantation Running Title: HCT for Osteopetrosis Paul J. Orchard1, Anders L. Fasth2, Jennifer Le Rademacher3-4, Wensheng He3, Jaap Jan Boelens5, Edwin M. Horwitz6, Amal Al-Seraihy7, Mouhab Ayas7, Carmem M. Bonfim8, Farid Boulad9, Troy Lund1, David K. Buchbinder10, Neena Kapoor11, Tracey A. O’Brien12, Miguel A. Diaz Perez13, Paul A. Veys14 and Mary Eapen3 1
Division of Blood and Marrow Transplantation, Department of Pediatrics, University of
Minnesota, Minneapolis, MN;
2
Department of Pediatrics, Sahlgrenska University
Hospital, Gothenburg, Sweden; 3Center for International Blood and Marrow Transplant Research (CIBMTR®), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI; 4Division of Biostatistics, Institute for Health and Society, Medical College of Wisconsin, Milwaukee, WI; 5Pediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, Netherlands;
6
Nationwide
Children’s Hospital and The Ohio State University College of Medicine, Columbus, OH; 7
Department of Pediatric Hematology Oncology, King Fasial Specialist Hospital &
Research Center, Riyadh, Saudi Arabia; 8Hospital de Clinicas – UFPR, Curitiba, Brazil; 9
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY;
10
Children’s Hospital of Orange County, Orange, CA;
11
Department of Research
Immunology/Bone Marrow Transplant, Children’s Hospital of Los Angeles, Los Angeles, CA;
12
Cord & Marrow Transplant Program, Sydney Children’s Hospital, Sydney,
Australia;
13
Servicio de Oncohematologia, Hospital Infantil Universitario Nino Jesus,
Madrid, Spain;
14
Great Ormond Street Hospital for Children NHS Trust, London, United
Kingdom
1 Copyright © 2015 American Society of Hematology
From www.bloodjournal.org by guest on June 15, 2015. For personal use only.
Corresponding author: Paul Orchard, MD, Professor, Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota: Address: Mayo Mail Code 366, 420 Delaware Street S.E., Minneapolis, MN, 55455; Telephone: 612626-2961; Fax: 612-626-4074; E-mail Address: [email protected]
Key points 1. HCT results in long-term survival 2. Primary graft failure is very high and the predominant cause of death
2
From www.bloodjournal.org by guest on June 15, 2015. For personal use only.
Abstract We report the international experience in outcomes following related and unrelated hematopoietic transplantation for infantile osteopetrosis in 193 patients.
Thirty-four
percent of transplants used grafts from HLA-matched siblings, 13% from HLAmismatched relatives, 12% from HLA-matched and 41% from HLA-mismatched unrelated donors. The median age at transplantation was 12 months. Busulfan and cyclophosphamide was the most common conditioning regimen. Long-term survival was higher after HLA-matched sibling compared to alternative donor transplantation. There were no differences in survival after HLA-mismatched related, HLA-matched unrelated or mismatched unrelated donor transplantation.
The 5- and 10-year
probabilities of survival were 62% and 62% after HLA-matched sibling and 42% and 39% after alternative donor transplantation (p=0.01 and p=0.002 respectively). Graft failure was the most common cause of death accounting for 50% of deaths after HLAmatched sibling and 43% of deaths after alternative donor transplantation. The day-28 incidence of neutrophil recovery was 66% after HLA-matched sibling and 61% after alternative donor transplantation (p=0.49). The median age of surviving patients is 7 years. Seventy percent of evaluable surviving patients are visually impaired and 10% have impaired hearing and gross motor delay. Nevertheless, 65% reported performance scores of 90 or 100, and in 17%, a score of 80 at last contact. Most survivors older than 5 years are attending mainstream or specialized schools. Rates of veno-occlusive disease and interstitial pneumonitis were high at 20%.
Although allogeneic
transplantation results in long-term survival with acceptable social function, strategies to lower graft failure and hepatic and pulmonary toxicity are urgently needed.
3
From www.bloodjournal.org by guest on June 15, 2015. For personal use only.
Introduction Osteopetrosis refers to a heterogeneous group of inherited conditions characterized by dysfunctional osteoclasts, the multi-nucleated cells that resorb bone.1 The absence of functional osteoclasts in autosomal recessive osteopetrosis results in a bone marrow cavity
insufficient
to
support to
hematopoiesis.2
massive
The
hepatosplenomegaly,
ensuing frontal
extramedullary
hematopoiesis
leads
bossing
and
macrocephaly.
Bony overgrowth is often associated with encroachment of nerve
foramina in the skull, resulting in cranial nerve dysfunction.2 Infants with recessive osteopetrosis often have their vision severely affected very early in life, and may present with nystagmus and/or an inability to follow people and objects.2 Other clinical manifestations of bony overgrowth include nasal obstruction and obstructive sleep apnea, abnormal dentition and gross motor delays.2 Untreated, autosomal recessive osteopetrosis has a mortality rate of approximately 70% by 6 years of age, primarily due to complications from bone marrow failure due to insufficient hematopoiesis.
As
osteoclasts are hematopoietically derived, intrinsic osteoclast defects can be treated through the establishment of an allogeneic graft.3-5 Differentiation of functional osteoclasts following transplantation can lead to bony remodeling and reversal of pancytopenia and extramedullary hematopoiesis. In this report, we report long-term survival after related and unrelated donor transplantation for infantile osteopetrosis. Patients and Methods Data collection The Center for International Blood and Marrow Transplant Research (CIBMTR) is a working group of over 400 transplant centers worldwide that voluntarily contribute data
4
From www.bloodjournal.org by guest on June 15, 2015. For personal use only.
on their autologous and allogeneic transplants. consecutive
transplants,
and
detailed
Participating centers register
demographic,
disease
and
transplant
characteristics and outcomes are collected on a subset of registered patients using a weighted randomization scheme.
All patients are followed longitudinally and
compliance monitored with on-site audits.
The Institutional Review Boards of the
Medical College of Wisconsin and the National Marrow Donor Program approved the study. Inclusion criteria Included are patients with infantile osteopetrosis transplanted between 1990 and 2011 at 65 transplant centers and reported to the CIBMTR. The diagnosis was established by treating physicians; data on genotype is not collected on CIBMTR’s standardized reporting forms. As the study population covers over two decades, genotypic data are not available in the current analysis. However, based on the ages at transplantation virtually all of the included patients would be expected to have a severe recessive genotype. End points The primary endpoint was survival. Death from any cause was considered an event and surviving patients were censored at last follow-up. Hematopoietic recovery was defined as achieving an absolute neutrophil count 0.5 x 109/L or greater for three consecutive days, and platelet counts, 20 x 109/L or greater, unsupported for 7 days. The diagnosis of acute and chronic graft versus host disease (GVHD) was assigned using standard criteria.7-9
5
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Statistical analysis The probability of overall survival was calculated using the Kaplan-Meier estimator.10 The probabilities of neutrophil and platelet recovery and acute and chronic GVHD were calculated using the cumulative incidence estimator; death without an event was considered the competing risk.11 Confidence intervals were calculated using log transformation. Preliminary analysis of survival rates among recipients of alternative donor transplantation failed to show differences between the groups.
Within the cohort
receiving unrelated donor grafts, an analysis on HLA-matching was not considered as the majority were HLA-mismatched. The 5-year probabilities of overall survival after mismatched related, adult unrelated donor and umbilical cord blood transplants were 51% (95% CI 31-70), 43% (95% CI 30-56) and 38% (95% CI 25-53), respectively, p=0.75. All umbilical cord blood units were from unrelated donors except one from a HLA-mismatched sibling. Therefore, subsequent analysis considered donor type as two categories, HLA-matched sibling and alternative donors. Cox regression model was built to identify risk factors associated with mortality.12 Logistic regression model was built to identify risk factors associated with neutrophil recovery.13 Factors considered in model building included the following: age at transplantation (12 months), donor type (HLA-matched sibling vs. alternative donor) and transplant period (1990 – 2004 vs. 2005 – 2011). A p-value of 0.05 or less was considered statistically significant and all p-values are two-sided. All analyses were performed using the statistical package SAS version 9.2 (SAS Institute, Cary, NC).
6
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Results Patient, disease and transplant characteristics Patient, disease and transplant characteristics are shown in Table 1. Although about 70% of patients were transplanted within the first year of life regardless of whether an HLA-matched sibling or an alternative donor was available, HLA-matched sibling transplants were more common for those transplanted less than 6 months of age. There were no differences in the proportion of those transplanted older than 12 months by donor source. At time of transplantation, 45% of patients were reported to have a Lansky score of 90 or 100 and 27% reported scores of 80 or 70. Thirty-four percent of transplants utilized grafts from HLA-matched siblings (n=65), 13% from HLAmismatched relatives (n=25), 12% from HLA-matched (n=24) and 41% from HLAmismatched (n=79) unrelated donors. All but 10 patients received myeloablative transplant conditioning and busulfan with cyclophosphamide was the predominant regimen. Total body irradiation was included in only 15% of transplantation regimens. Transplant conditioning regimens for alternative donor transplantation were more likely to include in vivo T-cell depletion approaches (anti-thymocyte globulin or alemtuzumab). Bone marrow was the predominant graft source accounting for 66% of transplants; cord blood grafts were used in 25% of transplants. Unrelated donor transplants accounted for over half of transplants (102 or 193; 53%) and of these, 77% were HLA-mismatched. Most cord blood transplants occurred after 1999.
Almost all patients received
calcineurin inhibitor containing GVHD prophylaxis and 10% received bone marrow grafts that were T-cell depleted (ex vivo methods).
7
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Overall survival With a median follow up of 6 years, 94 of 193 patients (48.7%) are alive at last follow up. Of these 24 (25%) have been followed for 10 years or longer. The median age at last follow up was 7 years (range 0.5 – 18). There were no differences in day-100 survival after HLA-matched sibling compared to alternative donor transplantation. The day-100 probability of overall survival after HLA-matched sibling transplantation was 72% (95% CI 61-82) compared to 67% (95% CI 59-75) for alternative donor transplantation, p=0.46. However, survival differed thereafter, with higher survival rates observed after HLA-matched sibling compared to alternative donor transplantation. The 1-year and 5-year probabilities of survival were 65% (95% 53-77) and 62% (95% CI 49 75) after HLA-matched sibling transplants.
The corresponding 1-year and 5-year
probabilities of survival after alternative donor transplants were 50% (95% CI 41-58) and 42% (95% CI 34–51), p=0.04 and p=0.01, respectively. The 10-year probabilities of overall survival after HLA-matched sibling and alternative donor transplantation were 62% (95% CI 49–73) and 39% (95% CI 30–48), respectively p=0.002 (Figure 1). In multivariate analysis, donor type was the only factor associated with mortality; mortality risks were higher after alternative donor compared to HLA-matched sibling donor transplantation (HR 1.65, 95% CI 1.04-2.62, p=0.03). We also explored the effect of age (≤6 versus >6 months) at transplantation and found none (HR 1.05, 95% CI 0.691.58, p=0.83). Among recipients of HLA-matched sibling transplantation, the 5-year probabilities of survival for those transplanted aged less than 6 months versus older than 6 months was 50% (95% CI 31-68) and 71% (95% CI 56-85), p=0.08.
The
8
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corresponding probabilities of survival after alternative donor transplantation were 48% (95% CI 33-63) and 40% (95% CI 29-51), p=0.37. The overall rate of veno-occlusive disease was 19% and interstitial pneumonitis, 21%. Veno-occulsive disease was most frequent after mismatched related donor transplant, occurring in 11 of 25 recipients (44%) compared to 3 of 24 (12.5%) recipients of HLAmatched unrelated donor grafts, 12 of 79 (15%) recipients of HLA-mismatched unrelated donor transplants and 10 of 65 (16%) recipients of HLA-matched sibling donor transplants (p=0.05).
Rates of interstitial pneumonitis was higher after alternative
donor (34 of 128; 27%) compared to HLA-matched sibling donor transplantation (7 of 65; 11%), p=0.01. Neither veno-occlusive disease nor interstitial pneumonitis was associated with transplant period. Among the 94 patients alive at last contact, 77 patients (82%) reported performance scores of 80 (n=16), 90 (n=21) or 100 (n=39). The remaining patients reported scores of 60 or 70 (n=10) or lower (n=5). A performance score was not reported for 2 patients, although 1 is attending school and the other patient was aged 2 years at last contact. Among the 55 patients who are now aged 6 – 17 years, 45 are attending school (mainstream or special education). Three patients are now 18 years or older and all attended school. The reporting forms do not distinguish between school types. For 73 of the 94 (78%) patients who are alive, data on extramedullary hematopoiesis, cranial nerve dysfunction and motor function were available. Complete resolution of hepatosplenomegaly was reported, and serum calcium was within the normal range for these patients within 1-2 years after transplantation. Visual impairment was common
9
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occurring in 51 of 73 patients (70%). Fifteen patients reported normal visual acuity preand post-transplant and in 7 patients, visual acuity improved post-transplantation. For the remaining patients there was persistent visual impairment despite sustained engraftment. In contrast, hearing was reported as normal for most patients (57 of 73; 78%). Hearing was impaired in 16 patients pre-transplant with improvement in only 8 patients post-transplant. Pre- and post-transplant gross motor milestones were in keeping with chronologic age for most patients (48 of 68; 70%).
Gross motor milestones were
delayed in 20 patients pre-transplant but 14 of these patients demonstrated improvement post-transplant. Dentition was reported as normal in 62 patients (85%) pre- and post-transplant. Of the 11 patients with abnormal dentition pre-transplant, there was improvement for 6 patients. Chimerism data were available for 64 of 94 patients. Chimerism testing was more frequent after alternative donor transplant (46 of 53 patients) compared to HLA-matched sibling donor transplant (18 of 41).
Among the 46 recipients of alternative donor
transplant, 29 (63%) were reported to be 96% - 100% donor, 6 (13%) were reported 1090% donor and 11 (24%), 5% or lower donor chimerism.
Among the 18 recipients of
HLA-matched sibling donor transplant, 7 (39%) reported 96% - 100% donor, 7 (39%) were reportedly 10-90% donor and 4 (22%), 5% or lower donor chimerism. All patients with mixed chimerism are alive with sustained hematopoietic recovery; their median follow up was 6 years (range 2 – 12).
10
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Causes of Death Ninety-nine of 193 patients died (Table 2). Most deaths (86 of 99; 89%) occurred within the first year after transplantation. There were 10 deaths between 1 – 5 years after transplantation and 3 deaths beyond 5 years. In both donor groups, graft failure was the predominant cause of death, accounting for 50% of deaths (12 of 24) after HLA-matched sibling and 43% of deaths (32 of 75) after alternative donor transplants. There were another 12 deaths (infection n=3, interstitial pneumonitis/adult respiratory distress syndrome n=2, veno-occlusive disease n=5, GVHD n=1, not reported n=1) after HLA-matched sibling transplant and 42 deaths in patients transplanted with alternative donor sources (GVHD n=8, interstitial pneumonitis/adult respiratory distress syndrome n=3, infection n=10, veno-occlusive disease n=8 and organ failure n=11). Of the 3 late deaths (beyond 5 years), two had received alternative donor transplants and died from GVHD and organ failure and the remaining patient, who received an HLA-matched sibling transplant, died from GVHD. Hematopoietic recovery Neutrophil recovery was slow after both HLA-matched sibling and alternative donor transplantation but did not differ between donor groups. The median time to neutrophil recovery after HLA-matched sibling and alternative donor transplantation was 20 days. The day-28 probabilities of neutrophil recovery after HLA-matched sibling and alternative donor transplantation were 66% (95% CI 54-76) and 61% (95% CI 53-60), respectively (p=0.49), Figure 2. The corresponding day-60 probabilities of recovery were 83% (95% CI 73-91) and 73% (95% CI 65-80), p=0.10. Similarly, platelet recovery
11
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was less than optimal. The day-100 probability of platelet recovery was higher after HLA-matched sibling transplant compared to alternative donor transplant; 67% (95% CI 55-78) and 47% (95% CI 38-56), p=0.007, Figure 3. The median time to recovery after HLA-matched sibling transplant was 41 days compared to 50 days after alternative donor transplant. In multivariate analysis, age at transplantation (odds ratio [OR] 0.78, 95% CI 0.43-1.42, p=0.42, donor type (OR 1.18, 95% CI 0.64-2.21, p=0.59) and transplant period (OR 1.26, 95% CI 0.64-2.48, p=0.50) were not associated with neutrophil recovery. Forty-two patients had primary graft failure (defined as an inability to achieve an absolute neutrophil count ≥0.5 x 109/L) and 25 patients, secondary graft failure (defined as sustained loss of absolute neutrophil count
Blood First Edition Paper, prepublished online May 26, 2015; DOI 10.1182/blood-2015-01-625541
HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR INFANTILE OSTEOPETROSIS Category: Transplantation Running Title: HCT for Osteopetrosis Paul J. Orchard1, Anders L. Fasth2, Jennifer Le Rademacher3-4, Wensheng He3, Jaap Jan Boelens5, Edwin M. Horwitz6, Amal Al-Seraihy7, Mouhab Ayas7, Carmem M. Bonfim8, Farid Boulad9, Troy Lund1, David K. Buchbinder10, Neena Kapoor11, Tracey A. O’Brien12, Miguel A. Diaz Perez13, Paul A. Veys14 and Mary Eapen3 1
Division of Blood and Marrow Transplantation, Department of Pediatrics, University of
Minnesota, Minneapolis, MN;
2
Department of Pediatrics, Sahlgrenska University
Hospital, Gothenburg, Sweden; 3Center for International Blood and Marrow Transplant Research (CIBMTR®), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI; 4Division of Biostatistics, Institute for Health and Society, Medical College of Wisconsin, Milwaukee, WI; 5Pediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, Netherlands;
6
Nationwide
Children’s Hospital and The Ohio State University College of Medicine, Columbus, OH; 7
Department of Pediatric Hematology Oncology, King Fasial Specialist Hospital &
Research Center, Riyadh, Saudi Arabia; 8Hospital de Clinicas – UFPR, Curitiba, Brazil; 9
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY;
10
Children’s Hospital of Orange County, Orange, CA;
11
Department of Research
Immunology/Bone Marrow Transplant, Children’s Hospital of Los Angeles, Los Angeles, CA;
12
Cord & Marrow Transplant Program, Sydney Children’s Hospital, Sydney,
Australia;
13
Servicio de Oncohematologia, Hospital Infantil Universitario Nino Jesus,
Madrid, Spain;
14
Great Ormond Street Hospital for Children NHS Trust, London, United
Kingdom
1 Copyright © 2015 American Society of Hematology
From www.bloodjournal.org by guest on June 15, 2015. For personal use only.
Corresponding author: Paul Orchard, MD, Professor, Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota: Address: Mayo Mail Code 366, 420 Delaware Street S.E., Minneapolis, MN, 55455; Telephone: 612626-2961; Fax: 612-626-4074; E-mail Address: [email protected]
Key points 1. HCT results in long-term survival 2. Primary graft failure is very high and the predominant cause of death
2
From www.bloodjournal.org by guest on June 15, 2015. For personal use only.
Abstract We report the international experience in outcomes following related and unrelated hematopoietic transplantation for infantile osteopetrosis in 193 patients.
Thirty-four
percent of transplants used grafts from HLA-matched siblings, 13% from HLAmismatched relatives, 12% from HLA-matched and 41% from HLA-mismatched unrelated donors. The median age at transplantation was 12 months. Busulfan and cyclophosphamide was the most common conditioning regimen. Long-term survival was higher after HLA-matched sibling compared to alternative donor transplantation. There were no differences in survival after HLA-mismatched related, HLA-matched unrelated or mismatched unrelated donor transplantation.
The 5- and 10-year
probabilities of survival were 62% and 62% after HLA-matched sibling and 42% and 39% after alternative donor transplantation (p=0.01 and p=0.002 respectively). Graft failure was the most common cause of death accounting for 50% of deaths after HLAmatched sibling and 43% of deaths after alternative donor transplantation. The day-28 incidence of neutrophil recovery was 66% after HLA-matched sibling and 61% after alternative donor transplantation (p=0.49). The median age of surviving patients is 7 years. Seventy percent of evaluable surviving patients are visually impaired and 10% have impaired hearing and gross motor delay. Nevertheless, 65% reported performance scores of 90 or 100, and in 17%, a score of 80 at last contact. Most survivors older than 5 years are attending mainstream or specialized schools. Rates of veno-occlusive disease and interstitial pneumonitis were high at 20%.
Although allogeneic
transplantation results in long-term survival with acceptable social function, strategies to lower graft failure and hepatic and pulmonary toxicity are urgently needed.
3
From www.bloodjournal.org by guest on June 15, 2015. For personal use only.
Introduction Osteopetrosis refers to a heterogeneous group of inherited conditions characterized by dysfunctional osteoclasts, the multi-nucleated cells that resorb bone.1 The absence of functional osteoclasts in autosomal recessive osteopetrosis results in a bone marrow cavity
insufficient
to
support to
hematopoiesis.2
massive
The
hepatosplenomegaly,
ensuing frontal
extramedullary
hematopoiesis
leads
bossing
and
macrocephaly.
Bony overgrowth is often associated with encroachment of nerve
foramina in the skull, resulting in cranial nerve dysfunction.2 Infants with recessive osteopetrosis often have their vision severely affected very early in life, and may present with nystagmus and/or an inability to follow people and objects.2 Other clinical manifestations of bony overgrowth include nasal obstruction and obstructive sleep apnea, abnormal dentition and gross motor delays.2 Untreated, autosomal recessive osteopetrosis has a mortality rate of approximately 70% by 6 years of age, primarily due to complications from bone marrow failure due to insufficient hematopoiesis.
As
osteoclasts are hematopoietically derived, intrinsic osteoclast defects can be treated through the establishment of an allogeneic graft.3-5 Differentiation of functional osteoclasts following transplantation can lead to bony remodeling and reversal of pancytopenia and extramedullary hematopoiesis. In this report, we report long-term survival after related and unrelated donor transplantation for infantile osteopetrosis. Patients and Methods Data collection The Center for International Blood and Marrow Transplant Research (CIBMTR) is a working group of over 400 transplant centers worldwide that voluntarily contribute data
4
From www.bloodjournal.org by guest on June 15, 2015. For personal use only.
on their autologous and allogeneic transplants. consecutive
transplants,
and
detailed
Participating centers register
demographic,
disease
and
transplant
characteristics and outcomes are collected on a subset of registered patients using a weighted randomization scheme.
All patients are followed longitudinally and
compliance monitored with on-site audits.
The Institutional Review Boards of the
Medical College of Wisconsin and the National Marrow Donor Program approved the study. Inclusion criteria Included are patients with infantile osteopetrosis transplanted between 1990 and 2011 at 65 transplant centers and reported to the CIBMTR. The diagnosis was established by treating physicians; data on genotype is not collected on CIBMTR’s standardized reporting forms. As the study population covers over two decades, genotypic data are not available in the current analysis. However, based on the ages at transplantation virtually all of the included patients would be expected to have a severe recessive genotype. End points The primary endpoint was survival. Death from any cause was considered an event and surviving patients were censored at last follow-up. Hematopoietic recovery was defined as achieving an absolute neutrophil count 0.5 x 109/L or greater for three consecutive days, and platelet counts, 20 x 109/L or greater, unsupported for 7 days. The diagnosis of acute and chronic graft versus host disease (GVHD) was assigned using standard criteria.7-9
5
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Statistical analysis The probability of overall survival was calculated using the Kaplan-Meier estimator.10 The probabilities of neutrophil and platelet recovery and acute and chronic GVHD were calculated using the cumulative incidence estimator; death without an event was considered the competing risk.11 Confidence intervals were calculated using log transformation. Preliminary analysis of survival rates among recipients of alternative donor transplantation failed to show differences between the groups.
Within the cohort
receiving unrelated donor grafts, an analysis on HLA-matching was not considered as the majority were HLA-mismatched. The 5-year probabilities of overall survival after mismatched related, adult unrelated donor and umbilical cord blood transplants were 51% (95% CI 31-70), 43% (95% CI 30-56) and 38% (95% CI 25-53), respectively, p=0.75. All umbilical cord blood units were from unrelated donors except one from a HLA-mismatched sibling. Therefore, subsequent analysis considered donor type as two categories, HLA-matched sibling and alternative donors. Cox regression model was built to identify risk factors associated with mortality.12 Logistic regression model was built to identify risk factors associated with neutrophil recovery.13 Factors considered in model building included the following: age at transplantation (12 months), donor type (HLA-matched sibling vs. alternative donor) and transplant period (1990 – 2004 vs. 2005 – 2011). A p-value of 0.05 or less was considered statistically significant and all p-values are two-sided. All analyses were performed using the statistical package SAS version 9.2 (SAS Institute, Cary, NC).
6
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Results Patient, disease and transplant characteristics Patient, disease and transplant characteristics are shown in Table 1. Although about 70% of patients were transplanted within the first year of life regardless of whether an HLA-matched sibling or an alternative donor was available, HLA-matched sibling transplants were more common for those transplanted less than 6 months of age. There were no differences in the proportion of those transplanted older than 12 months by donor source. At time of transplantation, 45% of patients were reported to have a Lansky score of 90 or 100 and 27% reported scores of 80 or 70. Thirty-four percent of transplants utilized grafts from HLA-matched siblings (n=65), 13% from HLAmismatched relatives (n=25), 12% from HLA-matched (n=24) and 41% from HLAmismatched (n=79) unrelated donors. All but 10 patients received myeloablative transplant conditioning and busulfan with cyclophosphamide was the predominant regimen. Total body irradiation was included in only 15% of transplantation regimens. Transplant conditioning regimens for alternative donor transplantation were more likely to include in vivo T-cell depletion approaches (anti-thymocyte globulin or alemtuzumab). Bone marrow was the predominant graft source accounting for 66% of transplants; cord blood grafts were used in 25% of transplants. Unrelated donor transplants accounted for over half of transplants (102 or 193; 53%) and of these, 77% were HLA-mismatched. Most cord blood transplants occurred after 1999.
Almost all patients received
calcineurin inhibitor containing GVHD prophylaxis and 10% received bone marrow grafts that were T-cell depleted (ex vivo methods).
7
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Overall survival With a median follow up of 6 years, 94 of 193 patients (48.7%) are alive at last follow up. Of these 24 (25%) have been followed for 10 years or longer. The median age at last follow up was 7 years (range 0.5 – 18). There were no differences in day-100 survival after HLA-matched sibling compared to alternative donor transplantation. The day-100 probability of overall survival after HLA-matched sibling transplantation was 72% (95% CI 61-82) compared to 67% (95% CI 59-75) for alternative donor transplantation, p=0.46. However, survival differed thereafter, with higher survival rates observed after HLA-matched sibling compared to alternative donor transplantation. The 1-year and 5-year probabilities of survival were 65% (95% 53-77) and 62% (95% CI 49 75) after HLA-matched sibling transplants.
The corresponding 1-year and 5-year
probabilities of survival after alternative donor transplants were 50% (95% CI 41-58) and 42% (95% CI 34–51), p=0.04 and p=0.01, respectively. The 10-year probabilities of overall survival after HLA-matched sibling and alternative donor transplantation were 62% (95% CI 49–73) and 39% (95% CI 30–48), respectively p=0.002 (Figure 1). In multivariate analysis, donor type was the only factor associated with mortality; mortality risks were higher after alternative donor compared to HLA-matched sibling donor transplantation (HR 1.65, 95% CI 1.04-2.62, p=0.03). We also explored the effect of age (≤6 versus >6 months) at transplantation and found none (HR 1.05, 95% CI 0.691.58, p=0.83). Among recipients of HLA-matched sibling transplantation, the 5-year probabilities of survival for those transplanted aged less than 6 months versus older than 6 months was 50% (95% CI 31-68) and 71% (95% CI 56-85), p=0.08.
The
8
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corresponding probabilities of survival after alternative donor transplantation were 48% (95% CI 33-63) and 40% (95% CI 29-51), p=0.37. The overall rate of veno-occlusive disease was 19% and interstitial pneumonitis, 21%. Veno-occulsive disease was most frequent after mismatched related donor transplant, occurring in 11 of 25 recipients (44%) compared to 3 of 24 (12.5%) recipients of HLAmatched unrelated donor grafts, 12 of 79 (15%) recipients of HLA-mismatched unrelated donor transplants and 10 of 65 (16%) recipients of HLA-matched sibling donor transplants (p=0.05).
Rates of interstitial pneumonitis was higher after alternative
donor (34 of 128; 27%) compared to HLA-matched sibling donor transplantation (7 of 65; 11%), p=0.01. Neither veno-occlusive disease nor interstitial pneumonitis was associated with transplant period. Among the 94 patients alive at last contact, 77 patients (82%) reported performance scores of 80 (n=16), 90 (n=21) or 100 (n=39). The remaining patients reported scores of 60 or 70 (n=10) or lower (n=5). A performance score was not reported for 2 patients, although 1 is attending school and the other patient was aged 2 years at last contact. Among the 55 patients who are now aged 6 – 17 years, 45 are attending school (mainstream or special education). Three patients are now 18 years or older and all attended school. The reporting forms do not distinguish between school types. For 73 of the 94 (78%) patients who are alive, data on extramedullary hematopoiesis, cranial nerve dysfunction and motor function were available. Complete resolution of hepatosplenomegaly was reported, and serum calcium was within the normal range for these patients within 1-2 years after transplantation. Visual impairment was common
9
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occurring in 51 of 73 patients (70%). Fifteen patients reported normal visual acuity preand post-transplant and in 7 patients, visual acuity improved post-transplantation. For the remaining patients there was persistent visual impairment despite sustained engraftment. In contrast, hearing was reported as normal for most patients (57 of 73; 78%). Hearing was impaired in 16 patients pre-transplant with improvement in only 8 patients post-transplant. Pre- and post-transplant gross motor milestones were in keeping with chronologic age for most patients (48 of 68; 70%).
Gross motor milestones were
delayed in 20 patients pre-transplant but 14 of these patients demonstrated improvement post-transplant. Dentition was reported as normal in 62 patients (85%) pre- and post-transplant. Of the 11 patients with abnormal dentition pre-transplant, there was improvement for 6 patients. Chimerism data were available for 64 of 94 patients. Chimerism testing was more frequent after alternative donor transplant (46 of 53 patients) compared to HLA-matched sibling donor transplant (18 of 41).
Among the 46 recipients of alternative donor
transplant, 29 (63%) were reported to be 96% - 100% donor, 6 (13%) were reported 1090% donor and 11 (24%), 5% or lower donor chimerism.
Among the 18 recipients of
HLA-matched sibling donor transplant, 7 (39%) reported 96% - 100% donor, 7 (39%) were reportedly 10-90% donor and 4 (22%), 5% or lower donor chimerism. All patients with mixed chimerism are alive with sustained hematopoietic recovery; their median follow up was 6 years (range 2 – 12).
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Causes of Death Ninety-nine of 193 patients died (Table 2). Most deaths (86 of 99; 89%) occurred within the first year after transplantation. There were 10 deaths between 1 – 5 years after transplantation and 3 deaths beyond 5 years. In both donor groups, graft failure was the predominant cause of death, accounting for 50% of deaths (12 of 24) after HLA-matched sibling and 43% of deaths (32 of 75) after alternative donor transplants. There were another 12 deaths (infection n=3, interstitial pneumonitis/adult respiratory distress syndrome n=2, veno-occlusive disease n=5, GVHD n=1, not reported n=1) after HLA-matched sibling transplant and 42 deaths in patients transplanted with alternative donor sources (GVHD n=8, interstitial pneumonitis/adult respiratory distress syndrome n=3, infection n=10, veno-occlusive disease n=8 and organ failure n=11). Of the 3 late deaths (beyond 5 years), two had received alternative donor transplants and died from GVHD and organ failure and the remaining patient, who received an HLA-matched sibling transplant, died from GVHD. Hematopoietic recovery Neutrophil recovery was slow after both HLA-matched sibling and alternative donor transplantation but did not differ between donor groups. The median time to neutrophil recovery after HLA-matched sibling and alternative donor transplantation was 20 days. The day-28 probabilities of neutrophil recovery after HLA-matched sibling and alternative donor transplantation were 66% (95% CI 54-76) and 61% (95% CI 53-60), respectively (p=0.49), Figure 2. The corresponding day-60 probabilities of recovery were 83% (95% CI 73-91) and 73% (95% CI 65-80), p=0.10. Similarly, platelet recovery
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was less than optimal. The day-100 probability of platelet recovery was higher after HLA-matched sibling transplant compared to alternative donor transplant; 67% (95% CI 55-78) and 47% (95% CI 38-56), p=0.007, Figure 3. The median time to recovery after HLA-matched sibling transplant was 41 days compared to 50 days after alternative donor transplant. In multivariate analysis, age at transplantation (odds ratio [OR] 0.78, 95% CI 0.43-1.42, p=0.42, donor type (OR 1.18, 95% CI 0.64-2.21, p=0.59) and transplant period (OR 1.26, 95% CI 0.64-2.48, p=0.50) were not associated with neutrophil recovery. Forty-two patients had primary graft failure (defined as an inability to achieve an absolute neutrophil count ≥0.5 x 109/L) and 25 patients, secondary graft failure (defined as sustained loss of absolute neutrophil count
