Journal of Hematology - Supplements - Haematologica

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84 Table 2. Neurologic disorders. Table 4. Gastrointestinal disorders. Disease Age/ Disease Conditioning Follow-up Last sex duration regimen 3 mos 6 mos Follow-up/mos (yrs) (yrs) MS 22 M 1 Cy/Ara-C/DXM/ALG PR PR PR/24 MS 46 F 23 FLU/DXM/ALG NR MS 40 M 10 FLU/DXM/ALG PR MYASTHENIA 47 F 28 Cy/ALG PR PR PR/12 CR: complete remission; PR: response >50%; REL: relapse; NR: no response. Disease Age/ Disease Conditioning Follow-up Last sex duration regimen 3 mos 6 mos Follow-up/mos (yrs) (yrs) Auto-Entero. 14 F 13 Cy/ALG PR PR REL/ 12 Crohn’s disease 3 F 2 FLU/ALG PR PR Auto-Entero: Autoimmune enteropathy; CR: complete remission; PR: response >50%; REL: relapse. Table 3. Hematologic disorders. Disease Age/ Disease Conditioning Follow-up Last sex duration regimen 3 mos 6 mos follow-up (yrs) (yrs) (mos) PRCA 44 M 3 Cy/ALG CR CR REL/ 8 PRCA 7 F 2 FLU/ALG NR AITP 4 F 3 FLU/ALG CR CR CR/ 25 CR: complete remission; PR: response >50%; REL: relapse; NR: no response. able to move normally and had a markedly improved electromyogram. She is still in partial remission after 12 months (Table 2). PRCA. Two patients with very severe disease not responsive to steroids, cyclophosphamide, ALG and cyclosporine, requiring blood transfusions every 15-20 days. The first patient became transfusion-free for 6 months with an increased reticulocyte count but relapsed after 6 months. The second patient showed no response to the procedure (see Table 3). AITP. A patient with a life-threatening condition with a fixed platelet level of 100x10 9 /L. Prednisone was gradually tapered down and stopped after 5 months. At the last follow-up, 25 months after HSCT, the patient had a platelet count of 250x10 9 /L having maintained a level above 200x10 9 /L at the times (Table 3). IBD. The patient had been affected by severe Crohn’s disease, involving the entire gastrointestinal tract, since the age of one year. The disease was steroid-dependent and not responsive to azathioprine, cyclosporine, thalidomide, enteral nutrition, or etanercept. The patient had severe side-effects due to long-term steroid treatment. Six months after HSCT the disease was limited to the large bowel and required small doses of steroids (see Table 4). Autoimmune enteropathy. This patient had received total parenteral nutrition since her first years of life. After the procedure her parameters of intestinal absorption improved (ratio mannitol/lactulose, xylose test) without any modification of intestinal biopsy or any clinical advantage. MEAD. After the procedure the patient’s respiratory function improved (increased Sa02 without needing oxygen supplementation). The hemolytic autoimmune anemia disappeared and the patient had a negative Coombs’ test. Cortisone was gradually tapered down with resumption of growth but, after 22 months, it was not possible to interrupt all therapy. No improvement in the IDDM was noted. Discussion The first objective of this study was to assess the feasibility and toxicity of a non-myeloablative conditioning regimen followed by infusion of autologous ex vivo treated hematopoietic stem cells in a cohort of patients, mostly in pediatric age, with severe autoimmune diseases. The procedure was well tolerated; the patients did not suffer any major complications either during the conditioning or after the transplant and spent a short timein hospital. There was no treatmentrelated mortality; this compares with the 8% of TRM of the EBMT/EULAR database and the unacceptable 20% in a subgroup of children affected by juvenile chronic arthritis. 23,24 In terms of effectiveness all but two patients achieved a partial or complete remission but the high rate of early relapse (after a median of 12 months) in the first group treated with low-dose cyclophosphamide led to the cytoxan being replaced by a more immunosuppressive fludarabine-based conditioning regimen. Fludarabine, a nucleotide analog which targets both resting and proliferating lymphocytes, proved to be very effective in the treatment of autoimmune diseases. 25 In the second group of eleven patients 60% are in complete or partial remission after a median followup of 14 months (range 3-25 months). In comparison to other published experiences the number of relapses seems higher but counterbalanced by a lower incidence of undesirable effects. For pediatric patients, who would otherwise suffer persistent handicap by continuous progression of disease, even a short-lived remission can be considered an advantage, especial- haematologica vol. 85(supplement to n. 11):November 2000
85 ly in terms of steroid-sparing and the opportunity of restarting growth. Moreover this procedure was well tolerated by patients and could be carried out repeatedly in the same subject. Since autologous transplantation cannot modify the genetic status of a patient and T- and B- lymphocytes play a central role in the pathogenesis of autoimmune diseases, the target of the procedure was only lymphoid tissue and both ablative chemotherapy and pharmacologic modulation were aimed at this issue. For this reason the type of blood cell that needed to be infused was the lymphocyte, and the number of CD34 + cells infused was almost irrelevant. The hypothesis that ex vivo treament with vincristine and methylprednisolone induces functional paralysis of lymphocytes followed by an immune tolerance, proven in the recipient of mismatched bone marrow, 27 can only be suggested in the autologous setting. At this point we cannot rule out the possibility that re-infusion of autologous cells could be irrelevant to the outcome and the remission is, in fact, secondary only to intense immunosuppressive treatment. Only randomized trials can confirm the hypothesis that autologous stem cell transplantation offers some advantage over intensive immunoablation without re-infusion of stem cells. Such trials should determine the conditioning regimen with lowest toxicity and identify which subset of patients with autoimmune disease may require an allogeneic graft from a sibling in order to be cured. References 1. Cash JM, Wilder RM. Treatment-resistant rheumatic disease. Rheum Dis Clin N Am 1995; 21:1-270. 2. Markenson JA. World wide trends in the socioeconomic impact and long term prognosis of rheumatoid arthritis. Sem Arthritis Rheu 1991; 21:4-12. 3. Van Bekkum DW, Kinwell-Bohre EPM, Houben PFJ et al. Regression of adjuvant arthritis in rats following bone-marrow transplantation. Proc Soc Natl Sci 1989; 86:1090-4. 4. Knaan-Shanzer S, Houben P, Kinwel-Bohre, et al. Remission induction of adjuvant arthritis in rats by total body irradiation and autologous bone marrow transplantation. Bone Marrow Transplant 1992; 9:31-4. 5. Van Bekkum DW. BMT in experimental autoimmune diseases. Bone Marrow Transplant 1993; 11:183-7. 6. Liu yn JA, Jowitt SN. Resolution of immune mediate diseases following allogeneic bone marrow transplantation for leukemia. Bone Marrow Transplant 1992; 9:31-4. 7. Lowenthal RM, Cohen ML, Atkinson K, Biggs JC. Apparent cure of rheumatoid arthritis by bone marrow transplantation. J Rheumatol 1993; 20:137-40. 8. Marmont A. Immunoablation followed by allogeneic or autologous bone marrow transplantation. A new treatment for severe autoimmune diseases? Stem Cell 1994; 12:125-35. 9. Atkinson K, Dodds A, Miliken S, et al. Autologous blood stem cell transplantation: treatment related mortality of 2%. Aust NZ J Med 1995; 98:589-91. 10. Tyndall A, Gratwohl A, Blood and marrow stem cell transplant in autoimmune disease: a consensus report written on behalf of EULAR and EBMT. Bone Marrow Transplant 1997; 19:643-5. 11. Fassas A, Anagnostopoulos A, Kazis A. Peripheral blood stem cell transplantation in the treatment of progressive multiple sclerosis: first results of a pilot study. Bone Marrow Transplant 1997; 20:631-8. 12. Burt R, Traynor A, Pope R, et al. Treatment of autoimmune disease by intense immunosuppressive conditioning and autologous hematopoietic stem cell transplantation. Blood 1998; 92:3505-514. 13. Martini A, Maccario R, Ravelli A. Marked and sustained improvement after autologous stem cell transplant in a girl with systemic sclerosis. Arthritis Rheum 1999; 42:807-11. 14. Traynor A, Schroeder J, Rosa R, et al. Treatment of severe SLE with high-dose chemotherapy and hematopoietic stem-cell transplantation: a phase I study. Lancet 2000; 356:701-7. 15. Wulfraat N, van Royen A, Bierings M, et al. Autologous hematopoietic stem-cell transplantation in four patients with refractory juvenile chronic arthritis. Lancet 1999; 353:550-3. 16. Jacobsson LT, Knowler WC, Pillemer S, et al. American college of rheumatology 1987 criteria for rheumatoid arthritis. Arthritis Rheum. 1994; 37:1479. 17. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13:227-31. 18. Kurtzke JF. Rating neurological impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983; 33:1444-52. 19. Lanfranchi A, Andolina M, Tettoni K, et al. Functional depletion of T cells by vincristine and methylprednisolone as in vitro model for the prevention of graft versus host disease. Haematologica 1992; 77:11-5. 20. Fragonas A, Perticarari S, Presani G, et al. In vitro Th1/Th2 modulation with vincristine and methylprednisolone: a possibly useful procedure for prevention of graft versus-host disease. Haematologica 2000, in press. 21. Giannini EH, Ruperto N, Ravelli A, et al. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum 1997; 40:1202-9. 22. Felson DT, Anderson JJ, Boers M, et al. American college of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995; 38:727. 23. Tyndall A, Fassas A, Passweg J, et al. Autologous haematopietic stem cell transplant for autoimmune diseases; feasibility and transplant-related mortality. Bone Marrow Transplant 1999; 24:729-34. 24. Vlieger AM; Brinkman D, Quartier P. Infection associated MAS in 3 patients receiving ASCT for juvenile chronic arthritis. Bone Marrow Transplant 2000; 25: S80. 25. Davis J, Fessler B, Tassiulas J, et al. High doses versus Low dose Fludarabine in the treatment of patients with severe refractory rheumatoid arthritis. J Rheumatol 1998; 25: 1694-704. 26. Brodsky RA, Petri M, Smith BD, et al. Immunoablative high doses cyclophosphamide without stem-cell rescue for refractory severe autoimmune diseases. Ann Intern Med 1998; 129:1031-5. 27. De Manzini A, Andolina M, Agosti E, et al. Low incidence of GvHD and rejection after pharmacological ex vivo modulation of bone marrow in 2-3 antigen mismatched BMT. Bone Marrow Transplant 1993; 11:114-7. haematologica vol. 85(supplement to n. 11):November 2000
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