Impact of Total Body Irradiation Technique on Interstitial Pneumonitis and Clinical Outcomes of 623 Patients Undergoing Hematopoietic Cell Transplantation for ALL: 25 Years at the University of Minnesota

Abstract Hematopoietic cell transplantation (HCT) is the only effective long-term treatment for cerebral X-linked adrenoleukodystrophy (X-ALD), a beta-oxidation disorder of very-long-chain fatty acids. The most common cerebral phenotype of X-ALD has a median onset of 7 years and is characterized by adrenal insufficiency, disability, dementia and typically death within months to several years after clinical onset. The international HCT experience from 1982 to 1999 for cerebral X-ALD clearly demonstrated that baseline neurologic and neuropsychological function, degree of disability, and neuroradiologic status predicted outcomes following HCT [Peters C. et al. BLOOD2004;104:881]. The estimated 5-year survival varied with the number of neurologic deficits and the MRI severity score before HCT: 0 or 1 neurologic deficits and MRI severity score less than 9 (n=25), 92% (95% CI, 81%–100%); all other patients (n=37), 45% (95% CI, 23%–67%; P<.01). From 1991 to 2004, 59 consecutive patients with cerebral X-ALD underwent HCT at the University of Minnesota at a median age of 9.1 years (range, 4.0–16.1) from related marrow donors (n=22), unrelated marrow donors (n=23), or unrelated umbilical cord blood donors (n=14). The diagnosis of X-ALD was made on the basis of disease manifestations in 38 boys (64%) rather than family history. The median baseline MRI score was 10 (range, 0.5–19.5). The median follow-up was 3.2 years (range, 0.5–12.3). The two most common conditioning regimens were 1) cyclophosphamide (60 mg/kg/dose IV x 2 days) and total body irradiation (1400 cGy in 7 fractions with complete sparing of the brain) [n=34] and 2) busulfan (1.6 mg/kg/dose every 12 hours IV x 8 doses) and cyclophosphamide (50 mg/kg/day IV x 4 days) [n=18]. Survival was analyzed based upon age at HCT (4–9 years vs. over 9 years, P=NS), donor type (related marrow, unrelated matched marrow, unrelated mismatched marrow and UCB, P=NS), reason for diagnosis (family history vs. disease manifestation, P=.08). Analysis of survival according to the baseline MRI severity score was highly significant (P<.01). Specifically, boys with an MRI severity score <6 [n=12] enjoyed 100% survival at 5 years compared to boys with an MRI severity score greater than or equal to 10 [n=29] whose survival at 5 years was only 35% (95% CI, 9–61%). The leading causes of death in patients with MRI severity score of 6 or greater were X-ALD progression (n=17), GvHD and infection (n=4 each). The University of Minnesota HCT experience for cerebral X-ALD confirms the outstanding results previously reported for patients transplanted at an early stage of disease. It re-emphasizes the importance of serial neuroradiologic monitoring of boys with the biochemical diagnosis of X-ALD and the recommendation that HCT be performed with the earliest evidence of cerebral involvement.

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Salvage Allogeneic Hematopoietic Cell Transplantation with Fludarabine and Total Body Irradiation (3 or 4 Gy) after Failure of First Allografts.

Blood ◽

10.1182/blood.v112.11.3272.3272 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3272-3272

Author(s):

Boglarka Gyurkocza ◽

Thai M. Cao ◽

Rainer F. Storb ◽

Thoralf Lange ◽

Wendy Leisenring ◽

...

Keyword(s):

Cell Transplantation ◽

Umbilical Cord ◽

Total Body Irradiation ◽

Hematopoietic Cell Transplantation ◽

Chronic Gvhd ◽

Hematopoietic Cell ◽

Allogeneic Hematopoietic Cell Transplantation ◽

Unrelated Donor ◽

Idiopathic Myelofibrosis ◽

Total Body

Abstract We analyzed data from 38 patients (median age = 56, range: 8 – 68 years) with acute leukemia (n=15), chronic idiopathic myelofibrosis (n=6), myelodysplastic syndrome with or without myeloproliferative disorder (n=5), chronic myeloid leukemia (n=4), non- Hodgkin lymphoma (n=4), aplastic anemia (n=2), multiple myeloma (n=1) and renal cell carcinoma (n=1), who underwent salvage allogeneic hematopoietic cell transplantation (HCT) for allograft failure. In 14 cases the original donors were used for second HCT, while in 24 cases different donors were identified (Table 1). Conditioning regimens for first HCTs included total body irradiation (TBI; 2 Gy) with or without fludarabine (Flu; n=28), myeloablative regimens (busulfan-cyclophosphamide, n=6; cyclophosphamide-TBI, n=2); and other, cyclophosphamide-anti-thymocyte globulin-based regimens (n=3). Conditioning for salvage HCT consisted of Flu 30 mg/m2/day on days -4 to -2 followed by TBI of 3 (n=24) or 4 (n=14) Gy on day 0. Cyclosporine and mycophenolate mofetil were used for postgrafting immunosuppression. The median time between first and salvage HCTs was 91 (range, 29 to 1004) days. Sustained second grafts were achieved in 34 patients (89%), while grafts failed in 4 patients (11%), all of whom had idiopathic myelofibrosis. With a median follow-up among surviving patients of 2.0 (range, 0.3 to 7.8) years, the 2 and 4 year Kaplan-Meier survival estimates were 49% (95% CI: 31%, 66%) and 42% (95% CI: 23%, 61%), respectively. The 2 year relapse-rate and non-relapse mortality were 36% (95% CI: 20%, 52%) and 25% (95% CI: 11%, 41%), respectively. The cumulative incidences of grades 2–4 acute and moderate-severe chronic graft-versus-host disease (GVHD) at 2 years were 42% and 41%, respectively. Four patients with chronic GVHD discontinued systemic immunosuppressive therapy at a median of 2.5 years. Within the limitations of the small patient numbers studied, TBI dose (3 vs. 4 Gy), same vs. different donors for salvage HCT, donor type (related, unrelated, HLA-haploidentical related vs. double umbilical cord), and HCT comorbidity scores did not appear to affect outcomes. Based on this retrospective multicenter analysis, we conclude that graft failure following allogeneic HCT can be effectively overcome by second transplantation using conditioning with Flu and low dose TBI (3 or 4 Gy), which should be further investigated in a prospective manner. Table 1. Donors in 1st and 2nd HCTs. HLA-MURD: HLA-matched unrelated donor; HLA-MMURD: HLA-mismatched unrelated donor, UCB: umbilical cord blood. 2nd HCT Different Donor 1st HCT Same Donor HLA-MURD HLA-MMURD Double UCB HLA-haploidentical HLA-identical sibling 11 11 - - - - HLA-MURD 17 3 10 4 - - HLA-MMURD 8 - 1 7 - - Double UCB 2 - - - 1 1

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