B. Bone Marrow and PBSC Transplantation Page 2

8. Unrelated bone marrow transplantation in high-risk adult thalassaemia patients. La Nasa G, Gacocci G, Argiolu F, et al. Bone Marrow Transplant 2005;35(suppl 2):289 (abstract).

The authors conducted a clinical trial using high-resolution Class I and II HLA typing to select unrelated bone marrow donors for 15 male and 12 female (median age 22 years) high-risk (Class III, Pesaro classification) thalassemia patients. No donor had more than a single allele-level mismatch with the patient.

Conditioning regimens used were busulfan 14 mg/kg, thiotepa 10 mg/kg and cyclophosphamide 120 or 160 mg/kg in 16 cases, and busulfan 14 mg/kg and cyclophosphamide 120 or 160 mg/kg in the remaining 11 cases. GVHD prophylaxis consisted of short-course methotrexate and cyclosporine.

At a median follow-up of 42 months, 20 of 27 (74%) of patients are alive and transfusion independent. Three of 25 (12%) evaluable patients developed grades III-IV GVHD and 8 of 22 (36%) evaluable patients experienced chronic GVHD (2 patients developed extensive chronic GVHD).

The authors indicated that, despite the advances made in the last two decades in transfusion and chelation therapy, complications from iron overload remain a serious problem for thalassemia patients. In addition, continual transfusions and daily chelation therapy are difficult to maintain with advancing age. Therefore, a thalassemia patient without an HLA-identical sibling donor should consider hematopoeitic cell transplantation sooner rather than later, before the patient develops irreversible severe complications of iron overload.

(Comment: The 26% mortality in this series is much higher that would occur were transplants carried out at an early age before complications arise, as recommended by the authors of this report and as practiced by Jaing et al who transplanted young patients without complications of the disease (see ii. Thalassemia C. Umbilical Cord Blood Transplantation, citation #2). In the report of Jaing et al, all 5 patients survived and were cured of thalassemia. However, it should be noted that Dr. Jaing reported at the 3rd Annual International Cord Blood Transplantation Symposium in Los Angeles on June 4, 2005 that he had now performed a total of 9 unrelated cord blood transplants and one patient died (mortality 11%). With modern supportive therapy but without transplantation, 32% of patients can be expected to die by the age of 35, as indicated by Cao et al (seeii. Thalassemia A. Clinical Aspects citation #1) Thus, the recommendation to transplant at a early age before complications arise as suggested by Jaing et al and La Nasa et al appears sound.)

9. Gonadal function of young patients with beta-thalassemia following bone marrow transplantation. Vlachopapadopoulou E, Kitra V, Peristeri J, Goussetis E, Karachaliou F, Petropoulos D, Fotinou A, Michalacos S, Graphakos S. J Pediatr Endocrinol Metab. 2005;18:477-83.

Homozygous β-thalassemia is one of the most common single gene disorders. The traditional therapeutic approach consists of blood transfusions. Patients develop a number of complications including growth failure, hypogonadotropic hypogonadism, diabetes mellitus, cardiac toxicity, liver toxicity and osteoporosis, mainly due to iron toxicity.

Hematopoietic cell transplantation can induce short-and long-term impairment of gonadal function. Patients with β-thalassemia represent a special group, as the pathophysiology of thalassemia and its treatment with blood transfusion can both induce gonadal dysfunction. In this study, the authors report on the gonadal function outcome in 25 patients with β-thalassemia who underwent allogeneic BMT during childhood and adolescence. There were 12 males with a mean age of 13.9 ± 2.8 years, and 13 females with a mean age of 13.4 ± 3.7 years. The conditioning regimen included busulfan and cyclophosphamide and did not include TBI.

The impact of BMT appears to be different in the two sexes. Males seem to be more resistant to gonadal damage. All male patients who were pubertal at the time of transplantation had normal testosterone levels and all but one had normal gonadotropin levels. Only one patient had elevated FSH levels. Furthermore, almost two-thirds of the patients who were prepubertal when they underwent BMT proceeded to normal pubertal development. However, germ cell damage was evident by increased FSH serum levels in 25% of them and small testicular volumes.

Post-menarcheal females seem to be an extremely sensitive group to the deleterious effect of chemotherapy. All post-menarcheal females exhibited amenorrhea and elevated gonadotropin levels. However, the authors have previously reported reversal of ovarian failure in patients treated for Hodgkin's disease up to 9 years post-treatment so that longer follow-up is necessary.

A girl who was transplanted at a younger age (11.1 years) had elevated gonadotropins at the initial post-BMT evaluation, but subsequently she was found with normal gonadotropin levels and she menstruated spontaneously. Other reports have indicated that girls who underwent TBI in preparation for BMT at a younger age have higher possibilities for recovery of ovarian function.

In the group of females who had not entered puberty prior to transplantation due to hyopogonadotropic hypogonadism, it is not easy to assess ovarian toxicity.

10. The cure of thalassemia by bone marrow transplantation. Lucarelli G, Andreani M, Angelucci E. Blood Rev 2002; 16:81-85.

The authors summarized their extensive experience with this report of 886 bone marrow transplants from HLA identical family members in thalassemic patients aged from 1 to 35 years at the time of transplant. Overall thalassemia-free survival was 73%. However, in 124 class 1 patients, thalassemia-free survival was 91% and in 297 class 2 patients it was 84%. For class 3 patients aged less than 17 years, survival was 79% and thalassemia-free survival was 58%. However, preliminary results obtained in 23 class 3 patients younger than 17 years who were transplanted with a new regimen were consistent with >90% thalassemia-free survival.

In a shorter review of the same data, the authors concluded their article by stating that all thalassemic patients, together with their parents and siblings, should be HLA typed and when an HLA-matched donor is available, bone marrow transplantation is mandatory in those thalassemic patients in class 1 and class 2 and in those of class 3 aged less than 17 years. (The cure of thalassemia by bone marrow transplantation. Lucarelli G, Andreani M, Angelucci E. Blood Rev 2002; 16:81-85.

(NOTE: The authors do not comment on the role of cord blood transplants or other sources of matched unrelated donors for those patients who do not have an HLA-matched family member. As with all persons needing a transplant, only a minority will have an HLA-matched family member. The excellent results with HLA-matched family members suggests that attempts should be made to extend this therapy to a wider group of patients in need.)

11. New insights into haematopoietic stem cell transplantation for patients with haemoglobinopathies. Locatelli F, Stefano PD. Br J Haematol. 2004;125:3-11

This is a detailed review by experienced investigators of available information on hematopoietic stem cell transplantation (HSCT) for patients with sickle cell disease and thalassemia with a view to the future management of these disorders. The authors point out that HSCT is the only curative treatment for these patients although it is associated with a risk of complications that can dramatically shorten the life duration of some patients. For this reason HSCT using unrelated donors did not meet consensus until recently. However, recent reports demonstrating that more precise HLA matching using high-resolution molecular typing for both classes I and II loci can reduce transplantation risk have provided the rationale for considering HSCT from unrelated donors. However, it is well known that only 25-30% of patients potentially curable with HSCT have an HLA-compatible family member. The authors indicate that the use of cord blood hematopoietic stem cells can open new scenarios that can make the procedure safer and more readily available. In contrast, they suggest that infusion of a high number of CD34+ cells from an HLA-partially matched relative results in a prolonged state of immune incompetence and causes a remarkable risk of serious, often fatal, infectious complications. They point out that data regarding non-myeloablative strategies indicate that stable donor engraftment is more difficult to achieve in patients with hemoglobinopathies than in adults with malignancy and they do not encourage the use of this approach at present.

12. Bone marrow transplantation for beta-thalassaemia major: the UK experience in two paediatric centres. Lawson SE, Roberts IA, Amrolia P, Dokal I, Szydlo R, Darbyshire PJ. Br J Haematol 2003; 120:289-295.

The authors indicate that β-thalassaemia major is an important cause of morbidity and premature death in young adults worldwide. There are now more than 800 patients in the UK with β-thalassaemia major or other transfusion-dependent thalassaemias. Although there are reports of improvements in medical management, recent data from the UK Thalassaemia Registry indicate that, despite the availability of good medical treatment, approximately 50% of affected patients in the UK die before the age of 35 years.The authors point out that the only curative treatment available for patients with β-thalassaemia major is BMT, or stem cell transplantation using cord or peripheral blood haemopoietic stem cells. The first successful BMT for thalassaemia major was performed in 1982, and now over 1500 transplants have been performed worldwide. This report describes results of allogeneic BMT in 55 children with β-thalassemia major (median age was 6.4 years) who received a hematopoietic cell transplant from an HLA-matched family member. Although the majority of patients were classified as Pesaro class 2 or 3, transplant-related mortality was low (5.4%). The principal complication was graft rejection accompanied by autologous reconstitution that occurred in 13.2% of transplants. Following modification of the conditioning regimen, the rejection rate fell to 4.6% and remained low. aGVHD of grade II-IV occurred in 31% and cGVHD in 14.5%. They concluded that allogeneic BMT is an important treatment option for children with β-thalassemia major.

13. Outcome of transplantation with unrelated donor bone marrow in children with severe thalassaemia. Hongeng S, Pakakasama S, Chaisiripoomkere W, Chuansumrit A, Sirachainan N, Ungkanont A, Jootar S. Bone Marrow Transplant. 2004;33:377-9.

The authors conducted a study of unrelated donor bone marrow transplantation (BMT) in 11 children with severe thalassaemia. The conditioning regimen consisted of busulphan, cyclophosphamide and antilymphocyte globulin. All received T-cell nondepleted bone marrow. The median marrow-nucleated cell dose was 4.9 x 10(8) /kg (range; 3.5-8.0 x 10(8) /kg). Median time of granulocyte recovery was 16 days (range; 13-21 days), and of platelet recovery was 39 days (range; 14-196). Grade 2-4 acute graft-versus-host disease (GVHD) developed in six patients (54%), and grade 3-4 in one patient (9%). Three (27%) of 11 evaluable patients had chronic GVHD (limited stage). All 11 patients are alive without thalassaemia after a median follow-up time of 397 days (range; 171-814 days). This study lends support to consideration of unrelated donor BMT as an acceptable therapy to cure severe thalassaemia especially in patients who are young and do not yet show irreversible severe complications of iron overload.

14. A new approach for bone marrow transplantation in class 3 thalassemic patients aged less than 17 years. Sodani P, Gaziev D, Polchi P, Erer B, Giardini C, Angelucci E, Baronciani D, Andreani M, Manna M, Nesci S, Lucarelli B, Clift RA, Lucarelli G. Blood 2004;104:1201-3.

When prepared for transplantation with busulfan (BU) 14 mg/kg and cyclophosphamide (CY) 120 - 160 mg/kg, thalassemic patients in risk class 3, aged younger than 17 years, transplanted from HLA identical donors, had a 30% incidence of transplant rejection with recurrence of thalassemia. This, relatively poor, outcome was ascribed to insufficient immune suppression or to inadequate eradication of the thalassemic marrow, or both. In an attempt to enhance both immune suppression and eradication of the thalassemic clones, hydroxyurea, azathioprine and fludarabine were added to the BU and CY. This regimen, called Protocol 26, was applied to 33 consecutive class 3 thalassemic patients aged less than 17 years and was well tolerated with 93% survival. The incidence of recurrent thalassemia after the transplant decreased from 30 to 8 percent. The authors concluded that the protocol presented in this report appears to be a well-tolerated and effective association of drugs for eradication of the hemopoietic system of thalassemic patients.

15. Homozygous alpha-thalassemia treated with intrauterine transfusions and postnatal hematopoietic stem cell transplantation. Thornley I, Lehmann L, Ferguson WS, Davis I, Forman EN, Guinan EC. Bone Marrow Transplant 2003; 32:341-342.

In malaria-endemic Southeast Asia, deletions in the globin gene cluster on chromosome 16 are common, with carrier rates for the most prevalent deletion ranging from 3.5 to 14%. In this report, homozygous thalassemia was confirmed in utero, and the fetus was treated with intra-uterine transfusions. After birth, the patient was supported with RBC transfusions, and at age 23 months was transplanted using bone marrow from his 4-year-old HLA-matched sister. Three years after transplantation, he has attained all appropriate developmental milestones, and is growing with normal velocity. He has no evidence of chronic GVHD. The authors also cite two previous reports of hematopoietic cell transplant for homozygous thalasemia (one of which used cord blood obtained from a sibling mismatched at one MHC locus). Both transplants resulted in a functional hematologic "cure" despite the presence of mixed hematopoietic chimerism in one patient.

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