Thalassemia: Management after hematopoietic cell transplantation

INTRODUCTION — Hematopoietic cell transplantation (HCT) is the only widely available curative therapy for thalassemia. A number of potential post-transplant risks and complications must be addressed to ensure the best prognosis.

This topic discusses the care of patients with thalassemia who have undergone HCT, divided into two sections: completion of the transplant (eg, optimizing engraftment and immune status) and subsequent management, including assessment and therapy for excess iron stores; organ damage, which is often related to iron overload; and late complications of transplant such as chronic graft-versus-host disease (GVHD).

A general review of the treatment of thalassemia as well as indications for HCT, pretransplant evaluation, donor selection, stem cell source, conditioning regimen, and immediate post-transplant hematopoietic support are discussed in detail separately. (See "Management of thalassemia" and "Hematopoietic stem cell transplantation for transfusion-dependent thalassemia".)

COMPLETION OF THE TRANSPLANT — Initial post-transplant management focuses on engraftment of the allogeneic hematopoietic cells and restoration of normal immune status. Important aspects of care include assessing and optimizing engraftment, treating infections, managing acute graft-versus-host disease (GVHD), and tapering immunosuppressive therapy.

Engraftment — For transplant to be effective, the donor hematopoietic cells need to engraft sufficiently to support hematopoiesis and non-thalassemic erythropoiesis. Engraftment is typically indicated by return of hematopoiesis in all three cell lines (white blood cells [WBCs], red blood cells [RBCs], and platelets) with decreasing need for transfusional support in the immediate post-transplant period.

The complete blood count (CBC) is monitored daily while the patient is hospitalized and frequently (eg, twice weekly) once the patient has been discharged from the hospital through the second post-transplant month. Once the patient is transfusion-free, hemoglobin analysis and chimerism testing using bone marrow cells are performed to confirm engraftment. Genetic testing can be substituted for hemoglobin analysis but is not routinely performed.

Engraftment status is routinely analyzed in the bone marrow. We perform this assessment at 30 and 60 days post-transplant (days +30 and +60). This includes determination of bone marrow cellularity and the degree of chimerism. If complete chimerism (full engraftment) is established, no further bone marrow examination is scheduled. If the patient is a mixed chimera, additional bone marrow examinations are performed, which we do at days +180, +365, and +730 (ie, at 6, 12, and 24 months). Additional bone marrow examinations are also performed based on clinical indications such as unexplained decreases in hemoglobin levels or decreased proportion of donor hematopoietic cells.

Engraftment is seen in the majority of patients who undergo HCT (eg, in 80 to 90 percent). This rate of engraftment was illustrated in a 2017 series of 176 children and adolescents who underwent allogeneic HCT for transfusion-dependent beta-thalassemia (median age 5.5 years), in which 15 (9 percent) had primary graft rejection and 25 (14 percent) had secondary graft rejection [1]. Most of the secondary graft rejection occurred within the first year (19 of 25 [76 percent]). Of the 17 who had a second transplant due to graft failure, three had graft failure again. Engraftment typically takes two to three weeks, but chimerism can take up to two years to stabilize.

The degree of chimerism (relative contributions of donor and host cells) is routinely assessed as a component of engraftment. Several methods have been used to assess chimerism after HCT. These methods all depend on the ability to detect and quantify a polymorphic marker that differs between donor and recipient. Examples include the following:

●Detection of the Y chromosome (eg, by fluorescence in situ hybridization [FISH]) if the donor and recipient are a different sex

●Molecular typing for polymorphisms in DNA microsatellites (also called short tandem repeats [STRs]) using polymerase chain reaction (PCR) amplification

●Molecular typing for single nucleotide polymorphisms (SNPs) and insertion/deletion polymorphisms using PCR amplification

●Determination of the variable number of tandem repeats (VNTR) by restriction fragment length polymorphism (RFLP) analysis, mostly in nonindustrialized countries

STR analysis remains one of the most commonly used methods, and it can be automated using capillary electrophoresis with fluorescence detection [2]. Standardization of results has been facilitated by an international effort [3].

Possible outcomes range from full donor engraftment, various degrees of mixed chimerism, or graft rejection with thalassemia recurrence or marrow aplasia. It can take up to two years for the source of hematopoiesis to stabilize. Changes have been reported after longer intervals, but this is much less common [4,5].

Full donor engraftment — Full donor engraftment occurs when the donor hematopoietic stem cells (HSCs) are fully responsible for hematopoiesis with no detectable contribution from recipient hematopoietic cells. This is also referred to as "complete chimerism" or "full chimerism." When sustained, it is interpreted as cure of the thalassemia. This is the most common outcome after successful HCT for thalassemia and is seen in 60 to 90 percent of individuals, with higher rates in those with optimal pretransplant and donor characteristics. (See "Hematopoietic stem cell transplantation for transfusion-dependent thalassemia", section on 'Indications and predictors of a good outcome'.)

Mixed chimerism — Mixed chimerism occurs when both donor and recipient hematopoietic cells are contributing to hematopoiesis at a level that can be detected molecularly. Chimerism is a dynamic condition in which contributions of donor and recipient cells vary greatly as the bone marrow stem cell niche becomes repopulated, which can take up to two years to stabilize (see 'Engraftment' above). Thus, chimerism can be transient (typically defined as during the first two years after transplant) or stable (persisting beyond two years). Some individuals have transient mixed chimerism while others have stable mixed chimerism for years [6-10].

We do not intervene in individuals with mixed chimerism unless they have evidence that the graft is failing (eg, unexplained drop of hemoglobin level or decrease in the ratio of mixed chimerism [eg, from 70 to 50 percent or less]). In these individuals, it is critical to determine whether worsening anemia is in fact due to graft failure (or impending graft failure) as other causes of anemia can arise [11]. Options for individuals with graft failure are discussed below. (See 'Graft failure' below.)

In patients with early mixed chimerism, we monitor the percentage of mixed chimerism regularly. In principle, the degree of chimerism can differ in the bone marrow and peripheral blood or can differ in different cell lines since some progenitor cells may produce more mature progeny than others, although most individuals do not have large variations when chimerism markers are tested in different cell populations.

Dynamic changes in the percentage of donor cells were illustrated in a 1996 study that included 35 individuals who underwent transplant for thalassemia and had persistent mixed chimerism during a one-year period of observation [8]. Of these, 20 gradually converted to full donor hematopoiesis (100 percent donor cells), while the remaining 15 had a functioning graft in coexistence with host cells. It was noted that 20 percent donor engraftment provided a sufficient, stable, and persistent level of hemoglobin production (effective erythropoiesis) to allow transfusion independence and health without signs or symptoms of thalassemia intermedia.

Most individuals with mixed chimerism have sufficient donor hematopoiesis to correct the thalassemic phenotype and avoid transfusions. Some authors have suggested that approximately 3 to 10 percent donor cells is sufficient for functional correction in the hemoglobinopathies based on case reports of stable mixed chimerism with donor hematopoiesis as low as 10 percent [12-14].

Factors that determine the likelihood of mixed chimerism include the following [15,16]:

●Age of the recipient (greater likelihood of mixed chimerism in children than adults).

●Conditioning regimen (greater likelihood of mixed chimerism with lower dose of cyclophosphamide).

●Source of stem cells. It is possible that use of hematopoietic cells from cord blood rather than bone marrow is associated with greater reciprocal tolerance between donor and host hematopoietic cells [17]. In a series that included 27 children with thalassemia who received a cord blood transplant from an HLA identical sibling donor, all showed engraftment with mixed chimerism at the time of hematopoietic engraftment [7]. Approximately one-half converted to full donor chimerism (eight within six months and five within one year), and the remaining 14 showed stable mixed chimerism at a median follow-up of 42 months. By comparison, graft failure occurred in 3 of 42 children (7 percent) in the same series who received bone marrow from a related donor and in 5 of 37 children (14 percent) in the same series who received bone marrow from an unrelated donor.

Mixed chimerism is a risk factor for graft rejection; however, stable mixed chimerism does not adversely affect survival [18]. (See 'Graft failure' below.)

The relationship between mixed chimerism and thalassemia recurrence is illustrated in the following studies:

●A 2008 study involved 97 consecutive patients who underwent HCT for thalassemia and had the percentage of donor and recipient hematopoietic cells assessed using STR markers [19]. Of these 97, 43 (44 percent) had evidence of early mixed chimerism, 50 (52 percent) had full donor engraftment, and four had early graft failure or died in the immediate post-transplant period. Serial analysis of STR markers documented thalassemia recurrence within the first two months in 1 of the 50 with full engraftment and 7 of the 43 with mixed chimerism (2 versus 16 percent). The likelihood of disease recurrence correlated with the percentage of residual host cells.

●A Pesaro series of 295 individuals who underwent HCT for thalassemia and were followed for at least two years found that the proportion of patients with mixed chimerism gradually declined over time following HCT, from 32 percent at two months to 13 percent at one year to 9 percent at two years [6]. Thalassemia recurrence did not occur in any of the 200 individuals with full donor engraftment, whereas 33 of the 95 (35 percent) with mixed chimerism at two months eventually had graft rejection. We also saw a correlation between the percentage of residual host cells and rejection of the graft, with graft rejection in 18 of 19 who had >25 percent host cells versus only 4 of 55 who had <10 percent host cells (95 and 7 percent, respectively).

Other studies have used different cutoffs for the percent of recipient hematopoiesis but have reached similar conclusions regarding a greater likelihood of graft rejection in those with greater percentages of recipient-derived cells [5,20].

Graft failure

Overview of graft failure — Failure of the donor hematopoietic cells to engraft can be primary (without any evidence that the donor cells engrafted) or can occur later, following a period of apparent engraftment and hematopoietic recovery [1,21]. The mechanism may be mediated by immunologic rejection of the graft, low stem cell inoculum, or bone marrow insult (eg, from infection or drug toxicity). Graft failure can be associated with recurrence of thalassemia or marrow aplasia, depending on the degree of marrow ablation in the recipient.

●The rate of graft failure in individuals without significant pretransplant iron overload has been estimated to be less than 5 percent [17].

Graft rejection appears to be more of a concern in children than adults. In an old 1997 experience with over 1000 patients, graft rejection at two years affected approximately 7 percent of children, whereas graft rejection was only seen in 4 percent of adults [22].

The limited experience with transplantation in adults does not permit updating of these findings. In modern practice, options for individuals with graft failure include medical therapy or retransplantation from the same or a different donor. If recipient hematopoiesis does not resume (ie, if there is bone marrow aplasia), retransplantation is the only option.

●Medical therapy – Medical therapy with regular transfusions and iron chelation is an option for those with recurrence of thalassemia following HCT. We are most likely to use this approach in individuals who have a complete return of thalassemia due to host hemopoietic reconstitution and do not plan a second transplant in the near future. (See 'Thalassemia recurrence' below.)

Growth factors such as granulocyte-colony stimulating factor (G-CSF) may be used as a temporizing measure in individuals with cytopenias but are not used for severe graft failure with bone marrow aplasia.

●Second transplant – Retransplantation may be an option for individuals who have recurrence of thalassemia. If this approach is pursued, the second transplant can be delayed until the patient recovers from toxicities of the first transplant. Retransplantation is the only option for individuals with marrow aplasia, in which case it is performed urgently. (See 'Thalassemia recurrence' below and 'Marrow aplasia' below.)

The use of donor lymphocyte infusion (DLI) following transplant for thalassemia was illustrated in a series of 19 individuals who were presumed to have impending graft rejection based on an ongoing transfusion requirement, along with a low level of donor hematopoiesis (residual host cells >25 percent) or a decline in donor hematopoiesis in the first two to six months after transplant [23]. Of these individuals, three developed full donor chimerism, nine continued to have mixed chimerism but no longer required transfusions, and seven had graft rejection. DLI therapy was generally well tolerated, with three individuals developing graft-versus-host disease (GVHD). While these results are encouraging, it is not clear what proportion of these individuals had their post-transplant course altered by DLI and what proportion would have had the same outcome without the procedure since many individuals have dynamic changes during the first two years and/or stable mixed chimerism for long periods of time without graft failure. Prudence is required in this situation. (See 'Mixed chimerism' above.)

The mechanism by which DLI can restore donor hematopoiesis is thought to involve an expanded donor immunologic reaction against host hematopoietic cells, similar to the graft-versus-tumor effect seen in hematologic malignancies treated with this approach. (See "Immunotherapy for the prevention and treatment of relapse following allogeneic hematopoietic cell transplantation", section on 'Donor lymphocyte infusion (DLI)'.)

Thalassemia recurrence — The incidence of thalassemia recurrence varies with patient factors and conditioning regimen; the overall rate is approximately 6 to 8 percent of individuals who undergo HCT. It may be more likely in those who receive reduced-intensity conditioning and less likely in adults [24]. (See "Hematopoietic stem cell transplantation for transfusion-dependent thalassemia", section on 'Outcomes: allogeneic transplantation versus medical therapy'.)

Options for the individual with thalassemia recurrence include medical management (resumption of transfusions and chelation therapy) and second transplant, as noted above (see 'Graft failure' above). The optimal approach is unknown; only small series have been published describing management in this setting [21,25].

Thus, the approach is individualized according to the ability of the original donor to provide a second donation, the availability of a different HLA identical donor, and the patient's overall medical condition and ability to tolerate a second transplant. Small series of second transplants suggest that it is best to wait at least a year to allow recovery from the toxic effects of the conditioning regimen, provided that an optimal transfusion and chelation treatment can be offered and accepted. There is no evidence to suggest any benefit from changing to a different donor or a different stem cell source.

Examples of earlier observations include the following:

●A 2008 series reviewed outcomes of a second transplant for recurrence of thalassemia in 16 patients [25]. The median age was nine years and the median interval between transplants was 28 months. Bone marrow was used as a stem cell source in seven and peripheral blood was used in nine. All but two used the same donor as in the first transplant. All received preconditioning with azathioprine, hydroxyurea, and fludarabine and conditioning with busulfan 14 mg/kg, thiotepa 10 mg/kg, and cyclophosphamide 160 mg/kg. The rate of sustained engraftment with the second transplant was 94 percent; the rate of overall survival was 79 percent at a median follow-up of approximately 2.5 years.

●A 1999 series described outcomes of a second transplant in 32 patients, 21 (66 percent) of whom had thalassemia recurrence [21]. The remaining 11 patients had aplastic bone marrow. The median age was 7.7 years and the median interval between transplants was approximately two years. Following the second transplant, one patient died before engraftment could be evaluated, five had transient engraftment followed by autologous reconstitution, and 16 (52 percent) had sustained engraftment. Overall survival was 49 percent at 14 years; survival was worse in the group with thalassemia recurrence (29 percent).

The absence of subsequent reports underlines the unwillingness to carry out a second transplant after recurrence of thalassemia.

Marrow aplasia — Bone marrow aplasia occurs when the donor HSCs fail to engraft and the patient's bone marrow remains ablated. Persistent aplasia is rare. These patients are at risk for life-threatening infections from neutropenia and bleeding from thrombocytopenia, and they require ongoing transfusional support, similar to individuals with very severe aplastic anemia. Urgent retransplantation should be pursued as this is the only available salvage approach.

Infections — Profound immunosuppression from HCT increases the risk of viral, bacterial, and fungal infections. Each center has protocols to minimize the risks of infections, monitor for development of infections, and effectively treat infections when they occur. Expanded discussions are presented in separate topic reviews:

●Prophylactic antibiotics (including pneumocystis prophylaxis) are given to individuals who have received myeloablative conditioning and those with prolonged neutropenia. (See "Prevention of infections in hematopoietic cell transplant recipients".)

●Antivirals are given to individuals who are seropositive for certain viruses such as herpes simplex virus (HSV) and varicella zoster virus (VZV); for other viruses such as cytomegalovirus, options include serial monitoring and/or antiviral prophylaxis, as discussed in detail separately. (See "Prevention of viral infections in hematopoietic cell transplant recipients".)

●Immunizations are given following return of immune competence (table 1); live vaccinations are not used in those with active GVHD or ongoing immunosuppression [26]. (See "Immunizations in hematopoietic cell transplant candidates and recipients".)

Treatment of these infections is presented separately. (See "Overview of infections following hematopoietic cell transplantation".)

Graft-versus-host disease — Graft-versus-host disease (GVHD) is classically defined as acute if it occurs within the first 100 days after HCT and chronic if it begins after 100 days. Clinical features can also be used to distinguish findings more typical of acute rather than chronic GVHD at times beyond the first 100 days.

Weaning immunosuppressive therapy — Immunosuppressive therapy to reduce the risk of GVHD is routinely administered following infusion of the donor hematopoietic cells. (See "Hematopoietic stem cell transplantation for transfusion-dependent thalassemia", section on 'Graft-versus-host disease prophylaxis'.)

Following HCT, the immunosuppressive therapy can be weaned slowly, beginning at 60 days post-transplant (ie, at day +60). The weaning schedule is calculated to have the patient be free of immunosuppression before the one-year post-transplant follow-up evaluation. The taper may be done more slowly than that used for individuals treated with HCT for hematologic malignancies, in which tapering is done more rapidly to allow a graft-versus-tumor effect to emerge earlier in the transplant course.

Immunosuppression may need to be increased or the taper slowed if the individual develops acute GVHD. (See 'Acute GVHD' below.)

Acute GVHD — Typical features of acute GVHD include maculopapular rash, diarrhea, and increasing serum bilirubin concentration. The frequency of organ involvement and other details of presentation and evaluation are discussed separately. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease".)

The incidence of clinically significant acute GVHD in individuals who have undergone HCT for thalassemia has been reported in the range of approximately 25 percent, with higher rates in those who received stem cells from sources other than bone marrow [1].

Good outcomes after acute GVHD depend on rapid recognition and treatment, which is discussed in more detail separately (see "Treatment of acute graft-versus-host disease"). The degree of iron overload before transplant also influences outcome. This was illustrated in a review of patients with acute GVHD that found increasing mortality (but not increased GVHD incidence) with increasing iron overload (27, 48, and 84 percent for low-, intermediate-, and high-risk patients, respectively) [17].

Chronic GVHD — Typical features of chronic GVHD include sclerotic skin changes resembling lichen planus or scleroderma, pulmonary obstructive and/or restrictive changes with bronchiolitis obliterans, and gastrointestinal and liver involvement. (See "Cutaneous manifestations of graft-versus-host disease (GVHD)" and "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes" and "Clinical manifestations and diagnosis of chronic graft-versus-host disease".)

Chronic GVHD is the most serious long-term complication of HCT for thalassemia and a major contributor to post-transplant morbidity and mortality, as illustrated by the following:

●In a 2017 series of 176 individuals with thalassemia who survived at least one year after transplant, only three patients (2 percent) developed chronic GVHD; however, two of the three deaths in the series were due to chronic GVHD complications [1].

●In a 2016 series of 1140 patients from the European Society for Blood and Marrow Transplantation (EBMT) Registry who survived at least 100 days after transplant, the two-year risk of developing chronic GVHD was 15 percent for limited disease and 6 percent for extensive disease [22]. The risk of developing chronic GVHD increased with unrelated donors.

Our approach to monitoring, preventing, and treating chronic GVHD is similar to that in other underlying diseases treated with HCT, with the exception that there is no need to maintain a graft-versus-tumor effect. Thus, a slower tapering of prophylactic immunosuppression is scheduled compared with that used in hematologic malignancies. (See 'Weaning immunosuppressive therapy' above and "Treatment of chronic graft-versus-host disease".)

Severe chronic GVHD may interfere with treatment of excess iron stores, as discussed below. (See 'Iron stores' below.)

Other transplant toxicities — Transplant-related mortality from other complications appears to be a greater concern in adults than children. Data from the European Society for Blood and Marrow Transplantation (EBMT) have suggested that the age of 14 years is a threshold above which transplant toxicities increase more significantly [22].

LONG-TERM MANAGEMENT

Iron stores

Estimation of iron stores — Clinically significant thalassemia leads to iron overload from ineffective erythropoiesis that is exacerbated by chronic transfusions. This is mitigated by pretransplantation iron chelation, but excess iron stores are often seen, even among those receiving chelation therapy. This was illustrated in a 2017 series of 176 children and adolescents with beta thalassemia who underwent HCT [1]. Despite pretransplant iron chelation in 87 percent of the patients, the median pretransplant ferritin level was 1638 ng/mL, and the median liver iron content calculated from magnetic resonance imaging (MRI) or liver biopsy was 4.1 mg/g dry weight or 6.5 mg/g dry weight, respectively.

Following successful engraftment, excess iron should be removed to reduce organ damage, which may exacerbate (or be exacerbated by) toxicities of the conditioning regimen, graft-versus-host disease (GVHD), or medications. Phlebotomy is typically used for iron removal as long as erythropoiesis is sufficient to allow it.

We typically wait to address excess iron stores until approximately 12 to 18 months after transplant or after the patient has discontinued the calcineurin inhibitor and other transplant-related medications for approximately six months (which may be longer than 18 months after transplant in some cases). This allows the patient to recover from the procedure, develop adequate immune function, and increase their hemoglobin level as much as possible before starting phlebotomy (calcineurin inhibitors have a mild depressive effect on erythropoiesis). Earlier treatment is not usually necessary since no significant progression of liver disease has been observed when comparing liver biopsies taken at baseline and at 18 months after transplantation [27].

There appears to be a very good correlation between hepatic iron concentration using liver biopsy and total body iron stores, provided the liver biopsy specimen is adequate (≥1 mg dry weight) and cirrhosis is absent. This was illustrated in our series of 25 patients who underwent HCT for thalassemia and subsequently had determination of liver iron by biopsy and total body iron stores by serial phlebotomy, which allows determination of the number of units that can be removed before the iron stores normalize (serum ferritin <100 ng/mL) [28]. This study showed a strong correlation between liver iron and total body iron, as illustrated in the figure (figure 1), and allowed us to calculate that total body iron stores in mg/kg body weight are approximately equal to the hepatic iron concentration multiplied by 10.6. The correlation of liver iron with total body stores was much better than the correlation of serum ferritin with total body iron stores as long as the liver biopsy contained ≥1 mg dry weight.

In modern practice, iron stores can be determined by liver MRI.

Targets for iron removal — The ideal target for iron reduction in patients who are post-HCT for thalassemia is unknown. Ideally, the iron load should be reduced to normal. Our practice largely extrapolates from data in hereditary hemochromatosis, which suggest that the following goals are appropriate:

●Liver iron <1.6 mg/g dry weight

●Serum ferritin <100 ng/mL for patients treated with phlebotomy (<300 ng/mL for those treated with chelation)

●Transferrin saturation (TSAT) in the normal range

Cardiac iron, liver iron, and serum ferritin often correlate. A normal TSAT indicates the absence of iron reactive oxygen species in the circulation [29,30]. In the absence of more specific diagnostic tools, "normal" TSAT is a rational endpoint for the iron removal strategy [29,31].

Comparison of iron removal methods — The two methods of iron removal are phlebotomy and iron chelation. Both methods are effective. Their advantages, disadvantages, differ substantially (table 2), highlighting the need to incorporate patient values and preferences in the choice between them. For most individuals with excess iron stores who have access to phlebotomy and can tolerate the procedure, we suggest phlebotomy based on its low risk of adverse events and low cost; however, some individuals may use chelation if they are not able to tolerate phlebotomy, and others may reasonably choose chelation for other reasons. The cost of oral iron chelators has significantly decreased in modern times, facilitating their use.

The following describes experience with phlebotomy and chelation in thalassemia following HCT:

●A 2017 trial randomly assigned 26 children and adolescents who had undergone HCT for thalassemia and had evidence of excess iron stores (serum ferritin >500 ng/mL on two occasions and liver iron >3 mg/g dry weight) to be treated with phlebotomy or the oral iron chelator deferasirox and monitored for one year [32]. Iron stores were greatly reduced in both arms as measured by serum ferritin level or R2 MRI for liver iron concentration. There was a trend towards greater reduction in ferritin with phlebotomy and a trend towards greater reduction in liver iron with chelation. Adverse events were seen in five phlebotomy patients (four with difficult venous access and one with emotional distress) and two chelation patients (one with rash and one with increased liver function tests). Most of the phlebotomy patients' parents expressed a desire to switch to chelation because time off work and time spent in appointments would be reduced. However, this trial was very small. Additional randomized trials have not been performed.

●Experience is greater with phlebotomy than with chelation in the post-HCT setting, with decades of long-term follow-up from observational studies demonstrating safety and efficacy in reducing iron stores [33-36]. Small series have also shown phlebotomy to be associated with improvements in cardiac function and liver function (in combination with antiviral therapies if the patient has hepatitis C virus [HCV] infection) [33,37,38]. There are no data demonstrating an effect of phlebotomy on post-HCT survival.

●Experience with chelation for thalassemia-related iron overload in the pretransplant setting is presented separately; this includes observational studies demonstrating that chelation is effective for iron removal and suggesting that chelation is associated with improved survival compared with no chelation (in individuals treated during the pre-chelation era). (See "Iron chelators: Choice of agent, dosing, and adverse effects", section on 'Iron chelation in transfusion-dependent thalassemia'.)

For individuals with mixed chimerism, we use chelation rather than phlebotomy. Chelation and phlebotomy are not combined unless the individual has very severe iron overload (eg, >15 mg/g dry weight) and requires more intensive therapy.

Iron removal (chelation or phlebotomy) may not be tolerated in individuals with more severe GVHD. However, those with mild GVHD may tolerate either of these methods, and iron removal may improve organ function. Thus, the decision to initiate iron removal in an individual with chronic GVHD as well as the choice between iron removal methods depends on the extent of excess iron deposition and GVHD severity, as well as the sites affected by GVHD.

Patients who can tolerate phlebotomy — Phlebotomy is our preferred method of iron removal for patients with excess iron stores as long as they can tolerate the procedure, as discussed above (see 'Comparison of iron removal methods' above). Typically, we consider the patient able to tolerate phlebotomy as long as the hemoglobin level is ≥10 g/dL.

The general phlebotomy protocol that we use has not changed in decades and consists of the following steps [33]:

●6 mL/kg of blood is withdrawn every 14 days.

●Phlebotomy is delayed if the hemoglobin is <9.5 g/dL or the systolic blood pressure is significantly below the patient's baseline. Patients who are ill or symptomatic are evaluated as appropriate, and phlebotomy is reinstituted once it is clear the individual is recovered and/or feeling well.

●Routine laboratory testing to assess hemoglobin level and iron stores includes a complete blood count (CBC) before each phlebotomy, liver and kidney function testing at baseline and then every three months, and serum ferritin every two months.

This protocol is continued until the serum ferritin concentration is <100 ng/mL (<100 mcg/L) on at least two occasions. Once the ferritin is below 100 ng/mL, no additional testing is required. At this point, patients are free from iron overload and no maintenance therapy is required. The number of phlebotomies required depends on the baseline iron stores and ranges from a few months to several years [33].

In the majority of transplanted thalassemic patients, reduction or normalization of the iron pool results in marked improvement in liver enzymes and liver histology (piecemeal necrosis, intralobular degeneration, and portal inflammation) [33,34]. Patients with early cardiac involvement (subclinical cardiac abnormalities with systolic and/or diastolic dysfunction), as well as overt heart failure, have shown regression of these abnormalities after iron depletion [37,39].

Although well-tolerated in the major of patients, phlebotomy can lead to some adverse effects. In our first series of 41 patients, these included mild and spontaneously reversible thrombocytopenia (five patients), a few episodes of low blood pressure, and a single episode of anemia (hemoglobin 7 g/dL) that quickly reversed after temporary suspension of the program [33].

Patients who require chelation — Some individuals may not be able to tolerate phlebotomy, especially if they have a history of heart failure or difficult venous access. Others may choose chelation rather than phlebotomy for other reasons. In these cases, chelation is an effective method for reducing excess iron stores.

We typically use a goal of serum ferritin <300 ng/mL for individuals treated with chelation following HCT. Deferoxamine has been demonstrated to be effective and safe, and data with deferasirox are accumulating [31,32,40]. Additional considerations in the choice of chelating agent, dosing, monitoring, and management of adverse effects are similar to other nontransplant settings and are discussed in detail separately. One potential issue post-transplant is a concern about drug-induced neutropenia from deferiprone [41]. (See "Iron chelators: Choice of agent, dosing, and adverse effects".)

Assessing and treating organ dysfunction — Approximately 10 to 20 percent of individuals with thalassemia have some degree of organ dysfunction prior to transplant, typically due to excess iron deposition. In many cases, this can be partially or fully reversed, and, in others, attention to iron stores is critical for reducing the risk of further injury.

Additional post-transplant complications unrelated to iron overload and guidelines for their screening and evaluation have been published in a 2012 expert review from several international groups [42]. Typical follow-up is listed in the table (table 3); a more in-depth discussion of post-transplant testing is presented separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor".)

Liver disease — Liver disease that precedes HCT may be due to iron overload and/or viral hepatitis, which may have been contracted from transfusions before laboratory testing and deferral of hepatitis C virus (HCV)-positive units [43]. Possible causes of abnormal liver function after transplant include these preexisting conditions as well as infection, hepatic graft-versus-host disease (GVHD), and hepatic veno-occlusive disease.

Hepatic iron overload and HCV infection are independent risk factors for post-transplant progression of liver disease (figure 2), and development of cirrhosis is a risk factor for hepatocellular cancer, although, in our experience, HCV infection does not appear to increase the risk of hepatic veno-occlusive disease or early mortality [17,44].

With modern effective HCV treatment, very few patients approach HCT with an active virus infection (pre-transplant HCV eradication is recommended). However, experience indicates that the combination of toxic factors has a multiplicative effect on liver damage, supporting the need of complete iron removal after transplantation.

There is some evidence that chronic hepatitis and even cirrhosis are reversible if excess iron is removed (picture 1) [34,38,45]. In a series of 50 individuals who were HCV-seropositive before transplant, five (10 percent) became persistently seronegative after transplant [44]. By contrast, patients who do not have iron removed after transplant tend to have progression of their liver disease [27]. These observations support the practice of assessing and treating excess iron stores. (See 'Iron stores' above.)

Once excess iron is removed, follow-up is directed to other causes of liver disease such as viral hepatitis or chronic GVHD. In an individual free of these complications, obtaining liver function tests once per year is more than adequate unless more frequent or extensive testing is required for another indication, such as drug monitoring.

The risks associated with HCV infection and the choice of appropriate therapy are discussed in detail separately; if possible, HCV should be treated before transplant rather than after transplant to avoid potential bone marrow or other toxicity of the virus and/or antiviral therapies in the post-transplant period. However, a 2022 study demonstrated a good safety profile for direct acting antiviral therapy for HCV in transplant recipients [46]. (See "Clinical manifestations and natural history of chronic hepatitis C virus infection" and "Overview of the management of chronic hepatitis C virus infection".)

Heart disease — Impaired cardiac function secondary to iron overload can lead to heart failure after HCT. However, heart failure appears to be a rare cause of mortality (<1 percent) in our experience and in other large series [1]. After iron removal, the risk of heart disease is similar to that in individuals undergoing HCT for indications other than thalassemia.

Cardiac function must be accurately monitored during transplant. Fluid retention must be prevented. Intensive pre- or peri-transplant chelation therapy can be considered in symptomatic patients [47].

Endocrine dysfunction — Individuals with thalassemia may have endocrine dysfunction due to thalassemia-related iron overload that precedes transplant. Hypogonadism is the most common endocrine disorder in medically treated patients with thalassemia major, affecting as many as 50 percent of individuals. Impaired glucose tolerance and diabetes mellitus are also common complications of iron overload. (See "Diagnosis of thalassemia (adults and children)", section on 'Endocrine and metabolic abnormalities'.)

In addition to endocrine dysfunction due to iron overload, these individuals may have endocrine dysfunction related to HCT. For those who do not have pretransplant iron overload and iron toxicity, the risk of endocrine dysfunction related to HCT is similar to other pediatric or adolescent patients. Those with pretransplant endocrinopathies may experience worsening and should have specific attention to these abnormalities during follow-up.

The risk of endocrine dysfunction in individuals with thalassemia was illustrated in a series involving 50 children with thalassemia who underwent HCT before puberty (mean age, 11 years) [48]. Of these, 40 percent entered puberty normally despite the usual presence of clinical and hormonal evidence of hypogonadism. Despite these observations, young children transplanted in the early phase of thalassemia appear to have a good prognosis for growth and fertility. Several reports have described successful pregnancies (not requiring assisted reproductive technologies) following HCT [10,49,50]. In principle, iron-related endocrinopathies may be reversed using iron depletion after HCT, but this remains to be demonstrated. (See "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood".)

Cancer — Limited and conflicting data regarding the risk of cancer after HCT have been reported in the thalassemia population.

Solid tumors have been infrequently reported in individuals who have undergone HCT for thalassemia and do not appear to be substantially increased over the rates seen in individuals with thalassemia who have not undergone HCT, although direct comparisons have not been performed in this population.

A retrospective nationwide study from France that followed 99 transplant patients for a median of 12 years did not observe cancer development; the median age at the time of transplant was 5.9 years [51].

A large report involving almost 20,000 individuals who underwent HCT for a variety of underlying disorders found an increased risk of solid tumors compared with the general population, but many of these individuals may have had underlying malignancies, may have received total-body irradiation as part of the conditioning regimen (which we do not use in thalassemia), and/or may have been treated with cytotoxic chemotherapy other than that used for HCT. Thus, extrapolation to the thalassemia population may not be appropriate [52].

Quality of life — Quality of life is a major consideration, especially as many HCT recipients will be young children at the time of their transplant. Studies that have evaluated quality of life following HCT for thalassemia have found quality of life to be good, with levels of education, employment, and mental health to be similar to the general population and better than those of individuals with thalassemia who did not undergo HCT [49].

As examples:

●A 2013 study assessed quality of life in a cohort of 109 patients who had undergone HCT for thalassemia at a median follow-up of 23 years (range, 12 to 30) [49]. Results of surveys evaluating general health and sociodemographic variables were mostly similar to peers in the general population and similar to or better than scores in a control group of 124 individuals with thalassemia who had not undergone HCT. Mental health, education level, employment status, marital status, living arrangements, and birth rate were compatible with normal living patterns. The greatest predictor of impaired quality of life was the presence of chronic GVHD.

●A 2008 study assessed quality of life in 24 individuals with thalassemia who underwent HCT compared with 74 individuals with thalassemia who were treated medically [53]. The median follow-up after HCT was 6.5 years (range, 1 to 14). Results of questionnaires about health, use of medical aids, and interpersonal relationships found better ratings for those who underwent HCT, even after adjusting for comorbidities. Quality of life tended to improve with a greater duration of time since HCT. The only area for which the score was lower in the transplant group was related to school; participants noted distress about absence from school caused by the time required for treatments.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sickle cell disease and thalassemias".)

SUMMARY AND RECOMMENDATIONS

●Engraftment – Initial post-transplant management focuses on engraftment of the allogeneic hematopoietic cells and restoration of normal immune status. (See 'Completion of the transplant' above.)

•Engraftment and chimerism are routinely assessed in the bone marrow. The degree of chimerism is determined using markers that differ between donor and recipient (Y chromosome, short tandem repeats). It can take up to two years for the source of hematopoiesis to stabilize. (See 'Engraftment' above.)

•Mixed chimerism is a risk factor for graft rejection; however, some patients have stable mixed chimerism that does not adversely affect survival. (See 'Mixed chimerism' above.)

•Graft failure can be due to rejection of the donor cells with recurrence of thalassemia or to bone marrow aplasia. Therapeutic options include donor lymphocyte infusions (DLI), medical therapy, or retransplantation from the same or a different donor. (See 'Graft failure' above.)

●Immune status – Infection prophylaxis, immunizations (table 1), and prompt treatment of infections is critical during recovery from hematopoietic stem cell transplantation. (See "Prevention of infections in hematopoietic cell transplant recipients" and "Prevention of viral infections in hematopoietic cell transplant recipients" and "Immunizations in hematopoietic cell transplant candidates and recipients" and "Overview of infections following hematopoietic cell transplantation".)

●GVHD prophylaxis – Immunosuppressive therapy to reduce the risk of graft-versus-host disease (GVHD) can be weaned slowly in individuals with thalassemia (typically over the course of one year, which is slower than in individuals with hematologic malignancies) since there is not a need to promote graft-versus-tumor effect. Therapy for GVHD is presented separately. (See "Hematopoietic stem cell transplantation for transfusion-dependent thalassemia", section on 'Graft-versus-host disease prophylaxis' and 'Graft-versus-host disease' above and "Treatment of acute graft-versus-host disease" and "Treatment of chronic graft-versus-host disease".)

●Iron stores – Iron stores must be addressed following engraftment, even if iron chelation was used before transplant. We typically wait to assess and treat excess iron stores until approximately 18 months after transplant or after the patient has discontinued cyclosporin and other transplant-related medications for approximately six months. Phlebotomy and iron chelation therapy are both effective; their advantages and disadvantages differ (table 2); patient values and preferences impact decision-making. For most individuals with excess iron stores who have access to and can tolerate phlebotomy, we suggest phlebotomy rather than chelation (Grade 2C). Some individuals may reasonably choose chelation. (See 'Iron stores' above.)

●Long-term care – Organ dysfunction due to iron overload, transplant toxicity, infection, and/or other causes, is assessed as summarized in the table (table 4). Cancer prevalence and quality of life are similar to individuals with thalassemia treated medically. (See 'Assessing and treating organ dysfunction' above and 'Cancer' above and 'Quality of life' above.)