B. Bone Marrow and PBSC Transplantation

1. Decision-making in adult thalassemia patients undergoing unrelated bone marrow transplantation: quality of life, communication and ethical issues. Caocci G, Pisu S, Argiolu F, Giardini C, Locatelli F, Vacca A, Orofino MG, Piras E, De Stefano P, Addari MC, Ledda A, La Nasa G. Bone Marrow Transplant. 2006;37:165-9.

In thalassemia major, lifelong need for medical care can have a major impact on physical and physical and psychosocial well-being and quality of life (QoL) of patients and their families. The authors emphasize that patients with thalassemia major are faced with a difficult decision. They can either continue traditional transfusion and chelation therapy, with no chance of complete recovery, or they can accept the high risk of TRM in the hope of obtaining a definitive elimination of the disease with prevention/reversion of its complications.

In this study the authors investigated the communication strategies and the post transplantation QoL in 19 adult thalassemia patients surviving after an unrelated donor BMT. The patients were given two questionnaires: a questionnaire to evaluate pre-transplantation communication factors and the EORTC QLQ-C30 questionnaire to assess global QoL.

All patients were satisfied with the communication modalities employed by the physicians. The global post-transplantation QoL in this cohort was found to be good. The mean global QoL was good (76.4). Twelve of the 19 patients (63%) enjoyed a very good global QoL (81-100), two had a good score (61-80) and four had an intermediate score (41-60). Only one patient had a poor global score. Very good scores were obtained for the physical, emotional, cognitive, role function and social function scales.

In the group of patients who developed chronic GVHD, the global QoL was good (mean score 65.3), whereas in those who did not develop GVHD, the score was very good (mean 81.9). However, the difference in global health status between the two groups was not statistically significant.

Ethical issues: The question that every adult patient must answer after a careful evaluation is whether the 30% mortality following BMT in adult class-3 patients is outweighed by the 70% chance of becoming independent from transfusions and iron-chelation therapy. Any decisions in medicine should be based on respect for patient's autonomy, which must be seen within the larger relational context of the physician-patient relationship. This relationship bears the phenomenological marks of a convenantal exchange rather than a contract: it draws on the physician's virtues and his ability to recognize that the patient he encounters in an obvious position of power maintains the dignity of a person. Although the decision is ultimately the patient's (emphasis added), the physician has the responsibility to assess whether the patient is suitable for BMT.

[Comment: This publication is unusual in stressing the necessity of considering the patient's desires after being informed of the pros and cons of transplantation. This concept is missing from most publications on the subject which omit any such discussion and, by inference, imply that it is solely the physician's role to make the decision.

The mortality rate of 30% stated by Caocci et al for adult patients is much higher than that found when transplanting young transfusion-dependent β-thalassemia patients (generally Lucarelli Class I). Indeed, Dr. Mark Walters reviewed data at the Fourth Annual International Umbilical Cord Blood Transplantation Symposium in May, 2006 indicating that in Lucarelli class 1 and class 2 patients transplanted with marrow from sibling donors, the survival and thalassemia-free survival rates were 87% and 84%, respectively. For class 3 patients <17 years of age who were treated with a conditioning regime providing more intensive chemosuppression, the DFS was 85% and OS was 93%. Unrelated BMT in children with class 1 or 2 thalassemia have an OS of 92% and DFS of 82%, results that are similar to those obtained with sibling BMT. In a multi-center series of patients with hemoglobinopathies treated by HLA-identical sibling umbilical cord blood transplantation (UCBT), 26 of 29 (90%) survive, and 25 (86%) survive disease-free. Overall, the Kaplan-Meier probabilities of survival and event-free survival after sibling UCBT are 89% and 86%, respectively with a median follow-up of 1.3 (range, 0.1 – 7.6) years. Thus, a school of thought suggests that the decision regarding whether or not to transplant should be made at a young age.

The major question facing β- thalassemia major patients is whether matched unrelated donors should be used for transplants when a sibling donor is not available. Only a minority of patients in need of transplant (about 30%) are fortunate enough to have sibling donors. At the Symposium, Jaing et al presented data on unrelated cord blood transplantation indicating OS of 87±7% and thalassemia-free survival of 77±9% at experienced centers that did not perform post-thaw wash of the cord blood units.

For a CD with audio and slides used by the lecturers and/or a reprint of the proceedings, send your postal mailing address to symposiumCD@cordbloodforum.org]

2. Outcomes of transplantation with related- and unrelated-donor stem cells in children with severe thalassemia. Hongeng S, Pakakasama S, Chuansumrit A, Sirachainan N, Kitpoka P, Udomsubpayakul U, Ungkanont A, Jootar S. Biol Blood Marrow Transplant. 2006;12:683-7.

In recent years there has been a steady increase in the number of unrelated-donor BMTs in a variety of disorders. There are only 2 case-series reports regarding unrelated BMT in thalassemia and both series have indicated favorable outcomes. (See citation #8 and citation #13) [However, one should also note reports of unrelated umbilical cord blood transplants in thalassemia major - see ii. Thalassemia C. Umbilical Cord Blood Transplantation, citations #2, #3, and #4 ]

The present study investigated outcomes of related and unrelated stem cell transplantations (HSTs) and whether these compare favorably in children with severe thalassemia. Recently published reports indicate that the outcome of unrelated donor transplantations in patients with leukemia is currently comparable to that of transplantation from identical family donors.

The authors reviewed transplantation outcome in 49 consecutive children with severe thalassemia who underwent allogeneic stem cell transplantation with related-donor (n=28) and unrelated-donor (n=21) stem cells between September 1992 and May 2005 in Thailand. Analysis of engraftment, frequency of procedure-related complications, and thalassemia-free survival showed no advantage from use of related-donor stem cells. The 2-year thalassemia-free survival estimate for recipients of related-donor stem cells was 82% compared with 71% in the unrelated-donor stem cell group (P=.42).

The authors concluded that their study provides evidence to support the view that it is quite reasonable to consider unrelated-donor stem cell transplantation an acceptable therapeutic approach in severe thalassemia, at least for patients who are not fully compliant with conventional treatment and do not yet show irreversible severe complications of iron overload.

3. Unrelated bone marrow transplantation for beta-thalassemia patients: The experience of the Italian Bone Marrow Transplant Group. La Nasa G, Argiolu F, Giardini C, Pession A, Fagioli F, Caocci G, Vacca A, De Stefano P, Piras E, Ledda A, Piroddi A, Littera R, Nesci S, Locatelli F. Ann N Y Acad Sci. 2005;1054:186-95.

Bone marrow transplantation (BMT) remains the only potentially curative treatment for patients with thalassemia major. However, most candidates for BMT do not have a suitable family donor. In order to evaluate whether BMT from an HLA-matched unrelated volunteer donor can offer a probability of cure comparable to that obtained when the donor is a compatible sibling, we carried out a study involving 68 thalassemia patients transplanted in six Italian BMT Centers. Thirty-three males and 35 females (age range, 2-37 years; median age, 15) were transplanted from unrelated volunteer donors, all selected using high-resolution molecular typing of both HLA class I and II loci. Fourteen patients were classified in risk class 1; 16 in risk class 2; and 38 in risk class III of the Pesaro classification system. Nine patients (13%) had either primary or secondary graft failure. Fourteen patients (20%) died from transplant-related causes. Grade II-IV acute graft-versus-host disease (GVHD) developed in 24 cases (40%), and chronic GVHD in 10 cases (18%). Overall survival (OS) in the cohort of 68 patients was 79.3% (CI 67-88%), whereas the Kaplan-Meier estimates of disease-free survival (DFS) with transfusion independence was 65.8% (CI 54-77%). In the group of 30 thalassemic patients in risk classes 1 and 2, the probability of OS and DFS were 96.7% (CI 90-100%) and 80.0% (CI 65-94%), respectively, whereas in the 38 patients in class 3 OS was 65.2% (CI 49-80%) and DFS was 54.5% (CI 38-70%). These data show that when donor selection is based on stringent compatibility criteria, the results of unrelated transplantation in thalassemia patients are comparable to those obtained when the donor is a compatible sibling.

[Comment: The authors suggest that the use of stringent compatibility criteria were the basis for their excellent results. Improved results can be expected in transplantation outcomes when using adult stem cell donors when high resolution HLA typing is used to match donor and recipient. However, this may not be the case in cord blood transplantation. Indeed, Kogler et al have reported that high-resolution typing hardly improves long-term clinical outcome in cord blood transplantation. (See IX. HLA Matching, Citation #5) Thus, cord blood transplants using unrelated donors and a high cell dose (easily obtainable in young patients) even without stringent compatibility criteria may be a feasible option in transplantation of patients with thalassemia.]

4. Allogeneic stem cell transplantation from unrelated donor for class 3 beta-thalassemia major using reduced-intensity conditioning regimen. Zhu KE, Gu J, Zhang T. Bone Marrow Transplant. 2006;37:111-2.

The authors point out that patients classified as class 3 in the Pesaro classification who had evidence of organ damage from iron-overload had poor outcomes after hematopoietic cell transplantation, and were more likely to experience transplant-related mortality or disease recurrence. One approach to reduce transplant-related mortality is to use reduced-intensity stem cell transplantation (RIST). The authors describe successful transplantation from 6/6 matched unrelated donors using reduced-intensity conditioning for two children with class 3 thalassemia major who had evidence of organ damage.

The conditioning regimen was composed of cyclosphosphamide, busulfan, fludarabine and rabbit ATG. As GVHD prophylaxis patients received cyclosporine and methotrexate. Mycophenolate mofetil was administered from day –1 to day +30.

One year after transplant, the first patient had 100% donor cells and had no clinical features of thalassemia, although his cardiac and pulmonary functions were still slightly decreased, and his Karnofsky score was 90. At two years posttransplant, the second patient also had 100% donor cells, had no clinical features of thalassemia, her cardiac and pulmonary functions were normal, and the Karnofsky score was 100.

The authors point out that, owing to its immunosuppressive potency and additional myeloablation, fludarabine has been included into the nonmyeloablative regimen. As far as the authors were aware, there has been no previous experience with reduced-intensity conditioning in children with thalassemia major undergoing unrelated donor transplantation. This regimen appears to be well tolerated, leading to durable engraftment.

5. Complete substitution of cyclophosphamide by fludarabine and ATG in a busulfan-based preparative regimen for children and adolescents with beta-thalassemia. Sauer M, Bettoni C, Lauten M, Ghosh A, Rehe K, Grigull L, Beilken A, Welte K, Sykora KW. Bone Marrow Transplant. 2005;36:383-7.

The authors reiterate the known fact that allogeneic HCT represents the only rational therapeutic modality to cure β-thalassemia. HCT from a genotypically identical family donor has dramatically improved the prognosis of patients with homozygous -thalassemia. Young patients transplanted at an early stage of the disease were reported to have a disease-free survival of 91% and a mortality risk of 8%.

The authors cite evidence that there is a strong correlation between blood levels of various cyclophosphamide metabolites and VOD. They postulated that the formation of these metabolites depletes the liver of glutathione (GSH) resulting in significant toxicity. Fludarabine, however, is not known to deplete the GSH content and this might be of increasing importance in patients entering HCT with pre-existing liver damage. In addition, nucleoside analogs such as fludarabine are reported to exert synergistic effects with alkylating agents such as busulfan. Therefore, the authors replaced cyclophosphamide completely by fludarabine in a busulfan-based conditioning regimen for children and adolescents with thalassemia. The goal of this pilot study was to determine whether a combination of 180 mg/m² fludarabine, ATG, and 14 mg/kg busulfan can provide donor-derived engraftment after allogeneic BMT from matched related family donors without an increased incidence and severity of transplant-related complications.

Five patients with β-thalassemia who were Lucarelli class 2 or 3 were transplanted. Three patients received conditioning with fludarabine (30 mg/m²/day x 6), oral busulfan (3.5 mg/kg/day x 4), and ATG rabbit Fresenius (10 mg/kg/day x 4). Two children received intravenous busulfan instead of oral busulfan at a dose of 2 x 1.4 mg/kg/day x 4 days. All children were transplanted with a fresh bone marrow graft from an HLA-identical sibling.

Overall, 5/5 patients achieved donor engraftment and are alive and well. No GVHD exceeding grade I was observed, and 2/5 children maintained donor chimerism at 100%. Three of the 5 children developed mixed hematopoietic chimerism within the first 50 days after transplantation. Therefore, CSA was started to be tapered before day +60 in those children. In all these three children donor-derived hematopoiesis increased from 75, 95, and 62 to 100, 97, and 89%, respectively. Follow-up times of these patients with early development of mixed hematopoietic chimerism are 2, 3, and 20 months. One patient maintains mixed hematopoietic donor chimerism being between 94 and 97% nearly 5 years after transplant.

6. Bone mineral density in children with thalassaemia major: determining factors and effects of bone marrow transplantation. Leung TF, Hung EC, Lam CW, Li CK, Chu Y, Chik KW, Shing MM, Lee V, Yuen PM. Bone Marrow Transplant. 2005;36:331-6.

The authors point out that osteoporosis and osteopenia are major long-term complications of thalassemia major and affect up to half of such patients. They hypothesized that the diminished bone mineral density (BMD) seen in thalassemia major patients may improve when their disease is cured by BMT. They investigated the effects of acquired factors and BMT on BMD in these patients. In all, 53 patients on regular transfusion (BT group) and 33 patients at 5.7±1.9 years post transplant (BMT group) were recruited. BMD was measured by dual energy X-ray absorptiometry.

Severe BMD deficit of the spine and hip were noted in 62% and 35% of BT group, respectively. Severe BMD deficit was less common among BMT than BT patients (6 vs 35%; P=0.036). The authors concluded that BMD deficit is common in Chinese patients with thalassemia major and transplantation may reverse BMD deficit in these patients.

7. Growth and endocrine function following bone marrow transplantation for thalassemia major. Li CK, Chik KW, Wong GW, Cheng PS, Lee V, Shing MM. Pediatr Hematol Oncol. 2004;21:411-9.

Growth failure and endocrine dysfunction are common in thalassemia major (TM) patients when they are treated by conventional treatment. The endocrine dysfunction is usually due to iron overload after repeated blood transfusion. Desferrioxamine is an effective iron-chelating agent but it also causes growth retardation and skeletal abnormalities.

Thirty-two TM patients who had survived more than 2 years after bone marrow transplantation (BMT) were recruited for growth and endocrine study. The patients all received busulfan, cyclophosphamide and ATG in the conditioning regimen. None of the patients received irradiation and none developed chronic GVHD.

Patients were followed up annually for growth, and the height was expressed as height standard deviation score (HtSDS). The HtSDS at baseline was -1.51 and was more reduced in patients older than 7 years (-1.99) as compared with those younger patients (-0.79) (p =.027). The HtSDS gradually improved after BMT and increased by 0.59 (CI 0.16-1.01) at 5 years after BMT. Forty percent of patients were below 2 SD at time of BMT but this decreased to 15% at the latest assessment.

With a median follow-up of 67 months, ovarian failure was universal among the 10 girls evaluable for puberty and all required hormonal replacement for either induction of puberty or secondary ovarian failure. Eight of 10 boys had spontaneous puberty but 3 of them had gonadal impairment. The cause of the gonadal impairment in males was more likely due to iron-induced damage on endocrine organs before BMT. One patient developed diabetes mellitus and one had growth hormone deficiency after BMT.

In conclusion, improvement of growth after BMT in TM was common, probably related to stopping of further administration of desferrioxamine. However, busulfan-induced ovarian failure was universal in girls, and boys were spared from gonadal failure if transplant was performed early.

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