 |
 |
D. Umbilical Cord Blood Transplantation
- Recent advances in bone marrow transplantation in hemoglobinopathies. Michlitsch JG, Walters MC. Curr Mol Med. 2008;8:675-689.
This is a detailed and authoritative review that discusses the successes, challenges and future direction of HCT for sickle cell disease (SCD) and thalassemia.
Allogeneic hematopoietic cell transplantation (HCT) is currently the only treatment with curative potential for sickle cell disease (SCD) and beta-thalassemia.
Sickle Cell Disease (SCD): More than 250 patients with SCD have been treated by HCT worldwide. The largest reported series have come from the United States, Belgium and France and all have reported similar results after HLA-identical sibling transplantation. In a US/European collaborative study, OS and EFS were 93 and 84%, respectively. In a study from France, OS and EFS were 93% and 86%, and in a study from Belgium, the OS and EFS were 93 and 82%, respectively. Myeloablative conditioning regimens have used a backbone of busulfan (BU) 14-16 mg/kg and cyclophosphamide (CY) 200 mg/kg, with or without ATG or TLI. Post transplant immunosuppression has consisted of cyclosporine (CSP) and methotrexate (MTX). Patients who were considered for HCT had symptoms of SCD, e.g., a history of stroke, recurrent episodes of acute chest syndrome, recurrent painful episodes and/or cerebral vasculopathy.
About 25% of children with SCD developed stable mixed chimerism after HLA-identical sibling HCT. Observations in such patients indicate that stable chimerism, even with a minority of donor cells, can have significant beneficial effect and that full engraftment of donor cells is not a requirement of successful HCT in sickle cell disease.
The cumulative incidence of graft rejection accompanied by autologous recovery is approximately 7 to 10% and appears to be related to the conditioning regimen. In one recent series, the 5-year cumulative incidence of graft rejection was 2.9% in patients who received rabbit ATG as part of their transplant preparation and 22.6% in those who did not.
Pretransplant exposure to blood products may promote an immunological response that interferes with donor engraftment. Thus, targeting younger patients with minimal transfusion exposures may improve outcomes.
Several groups have investigated non-myeloablative conditioning regimens but it has been difficult to identify a regimen that is both sufficiently immunosuppressive to ensure stable engraftment of donor cells and at the same time carry a significantly lower risk of toxicity as compared to conventional myeloablative conditioning regimens. A high percentage of patients experience graft rejection and disease recurrence.
Patients with SCD have an increased risk of adverse neurologic events after HCT. In particular, patients with a history of stoke had an increased risk of intracranial hemorrhage. In one study, after the institution of preventative measures, intracranial hemorrhage did not occur and, although neurologic complications still did occur, these tended to be self-limited events with no long-term sequelae.
Chronic GVHD developed in 19% of 59 patients in the US/European study which was the cause of death in 3 patients. In the French report, the cumulative incidence of cGVHD was 13% with mild forms observed in 11% and extensive forms in 2%.
In general, growth was not impaired after HCT in young children with SCD, but diminished growth was observed when HCT was carried out near or during the adolescent growth spurt. Interestingly, splenic recovery has been observed after successful HCT.
Patients treated by HCT had stabilization of the underlying cerebral vascular disease. In one study, among 29 patients who had a history of stoke before transplantation, 1 patient with graft rejection had a second stroke and 28 survived stroke-free. Sixteen patients had no documented CNS disease before transplantation and all ten studied post transplant had normal MRI appearance and none had a stroke.
Thalassemia: Patients are generally categorized into 3 risk classes on the basis of the number of pre-transplant risk factors, including hepatomegaly, portal fibrosis on liver biopsy and the quality of chelation (adequate if desferoxamine was initiated within 18 months of first transfusion and was administered subcutaneously for 8-10 hours, continuously, 5 or more days per week; inadequate if there was any deviation from that protocol). Class I patients had none of the adverse risk factors, Class II patients had one or two adverse risk factors, and Class III patients had all three.
Recent data from Pesaro now includes 1,003 consecutive patients. 148 Class I patients <17 years of age had an EFS of 87%; 334 Class II patients in the same age group had an EFS of 84%. Recent data regarding Class III patients indicated an EFS of 80% and OS of 94% with a mortality of 7% and a rejection rate of 14%. As with SCD, full engraftment of donor cells does not appear to be a requirement for successful HCT.
The cumulative incidence of graft rejection among 469 patients less than 17 years of age was 4% in Class I and Class II patients. In most cases, there is autologous recovery if thalassemia major. Patients with graft failure and recovery of host hematopoiesis do not have an urgent need for a second HCT and this consideration should be delayed until toxicity related to the initial conditioning regimen has resolved.
The incidence of grade II-IV aGVHD ranges from 13-31% and cGVHD from 14-27%. The addition of ATG to the conditioning regimen may help to reduce the incidence of GVHD after HCT in thalassemia. In one study, the rates of grade IV aGVHD and cGVHD were 27% and 54% without ATG and were 15% and 17% after a short course of ATG.
Post-transplant phlebotomy is recommended for heavily iron overloaded patients to normalize iron stores safely and effectively.
Sources of donor hematopoietic stem cells other than HLA-matched siblings:
In a cohort of 68 thalassemia patients from 2-37 years of age receiving an unrelated donor allograft after high resolution molecular typing of HLA class I and II loci, the OS and EFS were 96.7% and 80%, respectively, for Class I and Class II patients. For 38 Class III patients OS and EFS were 65% and 54%. The authors comment that these data show that when donor selection is based on stringent HLA compatibility criteria, the results of unrelated donor HCT for thalassemia are comparable to those after HLA-matched sibling HCT.
Umbilical cord blood (UCB) transplants:
There are several reports of successful UCB transplants for thalassemia and SCD. In a report of 44 patients that included 11 with SCD and 33 with thalassemia who received HLA-identical or one antigen mismatched sibling UCB transplantation, the 2-year EFS was 90% and 79% for SCD and thalassemia, respectively. No patient died and, with a median follow-up of 24 months, 36 of the 44 children remained free of disease. In another series of related donor UCB transplantation for hemoglobinopathies, 18 of 22 patients survive event-free. However, only about 14% of SCD patients are predicted to have an HLA-identical sibling donor. In contrast, a search for an unrelated donor UCB involving 40 SCD patients showed that 100% matched at 4 of 6 HLA loci in at least 2 potential UCB units, and 50% matched at 5 of 6 HLA loci in at least a single cord blood unit.
In thalassemia, an argument for early transplantation is supported by the results of transplantation from HLA-identical family members which clearly show that young, good-risk patients have a very high probability of cure with very low rates of early and late TRM. Some advocate that all patients with β-thalassemia major who have an HLA-identical related donor should be referred to HCT. Further, preliminary experience of URD HCT for thalassemia suggests an excellent outcome that mirrors the outcome after HLA-identical sibling HCT. In contrast, for SCD, current indications require patients to have clinical features that portend a poor outcome or significant sickle-related morbidity.
[Comment: Thalassemia and SCD are disorders with high morbidity and early mortality. (See Annotated Bibliography, Category XII, Sickle Cell Disease and Thalassemia) Indeed, a study reported in 2005 indicated that for SCD patients the survival for females was 36.3 years and was 38.7 years for male patients; that is, more than 60% are dead before the age of 40. Further, there is a high frequency and important clinical sequelae of silent and overt strokes. Data indicate that incomplete infarction has far-reaching effects on neurocognitive development and the risk for overt secondary strokes into adulthood. One continues to wonder why there is not more enthusiasm for cure of sickle cell anemia by hematopoietic cell transplantation at a young age before such complications arise and when HCT is most successful even considering the important side effects of that therapy.
As indicated above, some physicians do advocate that all patients with β-thalassemia major who have an HLA-identical related donor should be referred for transplantation. It is also true that when donor selection is based on stringent HLA compatibility criteria, the results of unrelated donor HCT for thalassemia are comparable to those after HLA-matched sibling HCT.
Finally, the point must be emphasized in this Forum that only a small percentage of patients with sickle cell disease can be transplanted using sibling donors or allele matched unrelated adult donors because of the extreme polymorphism of HLA types in this patient population. Umbilical Cord Blood can be the source of hematopoietic stem cells for a far larger percentage of patients because of the less stringent matching requirements. Let us hope that data will become convincing that cord blood transplants are as effective for SCD patients as are matched unrelated donor transplants, as is already becoming evident in transplantation of patients with hematologic malignancies – See Category I. Recent Reviews. ]
- Related umbilical cord blood transplantation in patients with thalassemia and sickle cell disease. Locatelli F, Rocha V, Reed W, Bernaudin F, Ertem M, Grafakos S et al. Blood 2003; 101:2137-2143.
Forty-four children with hemoglobinopathies (thalassemia, n = 33; sickle cell disease, n = 11) received cord blood transplants from related donors (most receiving full matched grafts; three were 1-locus mismatched grafts). The median number of nucleated cells infused was 4.0 X 107/kg. Engraftment was obtained in 86.4% of transplants; median time to neutrophil and platelet engraftments were 23 and 39 days, respectively. No patient died, and 36 of 44 children remain free of disease, with a median follow-up of 24 months (range 4-76 months). No grade III-IV acute GVHD occurred; 2 of 36 patients at risk developed limited chronic GVHD. The authors concluded that related cord blood transplantation offers a good probability of success and is associated with a low risk of GVHD.
(NOTE: Laughlin indicates that the low incidence of GVHD in this study compares favorably with the 15-25% incidence of chronic GVHD observed in children receiving HLA-matched sibling allogeneic bone marrow grafts. Thalassemia and sickle cell disease are among the most common genetic disorders, affecting several million children and young adults worldwide. UCB allogeneic transplantation for hemoglobinopathies. Laughlin M. Blood 2003;101: 2077-2078.)
- Transplantation of unrelated placental blood cells in children with high-risk sickle cell disease. Adamkiewicz TV, Mehta PS, Boyer MW, Kedar A, Olson TA, Olson E, Chiang KY, Maurer D, Mogul MJ, Wingard JR, Yeager AM. Bone Marrow Transplant. 2004;34:405-11.
The authors evaluated unrelated placental blood cell transplantation (UPBCT) after a preparative regimen of busulfan, cyclophosphamide and antithymocyte globulin in three children with sickle cell disease (SCD). All three patients (ages 12.5, 6 and 3 years) had apparent ischemic cerebrovascular accidents at ages 5, 5, and 2 years, respectively, and all patients had residual hemipareses with evidence of brain infarction on magnetic resonance imaging and cerebral arterial occlusions on magnetic resonance angiography. All 3 patients had additional complications of SCD such as recurrent pain crises, seizures, recurrent TIAs, and splenic sequestration crisis. The placental blood cell units were matched with the recipients at four of six HLA-A, HLA-B and HLA-DRB1 antigens. The TNC doses were 2.7, 7.1 and 10.3 x 10(7) cells/kg at cryopreservation. Neutrophil engraftment at levels above 0.5 x 10(9)/l occurred at 23, 38 and 42 days after UPBCT, and platelet levels above 50 x 10(9)/l without transfusions occurred at 62, 81 and 121 days after UPBCT. All patients developed acute graft-versus-host disease which resolved after methylprednisolone therapy, and the oldest child developed extensive chronic GVHD of skin and liver which resolved after treatment after approximately 28 months. One patient had graft failure and complete autologous hematopoietic recovery at 4.5 months posttransplant. Two patients have complete donor hematopoietic chimerism without detectable hemoglobin S or symptoms of SCD. All patients are alive and off all immunosuppressive agents at 40, 44 and 61 months, respectively. The two patients who remained 100% donor chimeras have play-performance scores of 100%. The authors suggest that further studies of UPBCT for SCD are needed but should be restricted to pediatric patients with high-risk manifestations of SCD.
(Comment: The authors offer very conservative recommendations regarding transplantation of SCD patients, that is, they limited their study to children with SCD-associated cerebrovascular accidents (CVAs). All patients in this report had residual hemipareses with evidence of brain infarction on magnetic resonance imaging and cerebral arterial occlusions on magnetic resonance angiography. One patient who was cured of his SCD is receiving special education because of his initial cerebral ischemic events.
Is the sickle cell disease community best served by waiting until irreversible complications of SCD occur prior to being considered a candidate for cure by transplantation? Is waiting until brain infarcts develop the optimal approach to transplantation in SCD? For a discussion of this aspect of transplantation in sickle cell disease, go to the Home page, click on Interactive Forums, Medical Professionals, or click here.