Supportive care with monthly blood transfusions and appropriate medical follow-up will not cure your child, but if followed precisely, may allow your child to live up to 40 or 50 years of age with a good quality of life. The main issue is access to appropriate supportive care and blood transfusions. It is particularly important to assure safe blood, preferably not from family members but from volunteer donors. Pre-transfusion hemoglobin should be kept above 9 g/dL. After the initial 15-20 transfusions, iron from transfused red cells starts to accumulate and may cause harm to your child’s body, especially the heart and liver. This iron build-up is evaluated by measuring ferritin blood levels. When ferritin levels rise above 1,000 ng/mL its time to start iron-removing (chelation) therapy. Your child should be followed by a thalassemia center where the doctors will be able to advise you about supportive care and the different tests needed to assure that he or she will remains as healthy as possible.
Bone Marrow Transplantation(BMT) is the only definitive cure for thalassemia and it consists of replacing your child’s faulty bone marrow stem cells, from which red cells originate, with those obtained from a healthy compatible donor. BMT outcomes have constantly imporved to the point that, in experienced centers, children with a compatible family member can currently expect over 95% cure with normalization of health-related quality of life (see blog article).
HLA-typing is the test required to identify a compatible family donor, generally a brother or sister and more rarely mother or father. HLA-typing can be performed in most countries, costs and reliability however are quite variable. We recommend to do high-resolution sequence-based typing of HLA A, B, C, DRB1, DQB1 and DPB1 (see pubblication). This top-level HLA-typing is offered free-of-cost by Cure2Children thanks to DKMS-Germany (see Free HLA typing project)
The cost of transplant varies and may range from 150,000 USD in western countries. However, Cure2Children has been able to bring down that cost to less than 15,000 USD for matched sibbling BMT and 20.000 USD for haploidentical BMT (including all medical expenses and folow up costs).
BMT as a way of curing children with thalassemia has been successfully performed for almost 40 years in a total of more than 5,000 patients worldwide.
While bone marrow transplantation offers a cure from thalassemia, it cannot be administered without a chances of permanent infertility, on average around 50%. Life long supportive care and blood transfusions, on the other hand, may allow the possibility of having children. This may change with time.
On average a BMT requires a hospital stay of 1.5 to 2 months.
Most children become transfusion-independent within a month of the transplant, this may take a little longer in case of BMT from an AB0.incompatible donor. Late rejections and transplant-related complications, however, may occur and regular check up should be carried out at least for the first years following the BMT, after which the child should resume life as normal without thalassemia.
Bone Marrow Transplantation should be done as soon as possible, while the child is still young. In the best possible situation, however, a transplant can be safely postponed to 6-8 years of age. It should definitely be done before 15 years of age to have a possibility to preserve fertility.
Cure2Children cannot cover the cost of BMT but will offer it in it's partner centers, which are specifically focused on BMT for thalassemia, at a non-profit and all-inclusive rate of 15.000 USD or less for compatible sibling BMT and 20.000 for haploidentical (partially compatible family member) BMT.
Keep in mind that many institutions indicate BMT charges which are limited to the initial hospital period of 45 days and will not cover the whole recovery, generally lasting 1 years. Also, very often complications which may arise during the transplantation are not included in the price quotation. This may also hold true for partial coverage by Central and State governments which is limited to the initial estimated cost of transplantation.
At Cure2Children partner centers BMTs are done at a fixed cost which includes any complications directly associated with the transplantation. The cost of follow-up medication, consultation and labs is also included up-to a year post-BMT.
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In general the iron accumulating from multiple transfusions can be removed from the body quite effectively with chelation therapy, which employs drugs like deferoxamine (Desferal), deferiprone (Ferriprox or Kelfer), or desferasirox (Asunra or Exjade). However, all these drugs may have significant side effects.
Additionally, while the cost of appropriate chelation therapy is variable, it is generally more than $5,000 USD per year. In developing countries the main problem remains access to care and the cost of drugs for chelation, which are well above the average income. Without access to regular chelation therapy and medical follow ups, the majority of children with thalassemia do not reach the age of 10. Some centers may provide subsidized drugs and suppotive care.
Mother, father, and first-degree relatives could be matches, especially if the parents are related. However, while outcomes using a fully compatible mother or sibling are comperable, it is not clear if using a compatible father or non-immediate relative is better than using a partially compatible (haploidentical) mother (see pubblication). In fact, there is initial evidence that a so called haploidentical BMT, that is from a partially compatible family member, might be as good as that from a fully matched sibling. If this observation is confirmed as more experience is accumulated, than other more complex, costly and less safe alternatives like unrelated donors, cord blood banks or seeking further pregnancies to deliver a healthy matched sibling, may loose their value.
Best results and most experience is with standard Bone Marrow Transplantation. For thalassemia there is no strong evidence that cord blood is superior to bone marrow. Thus cord blood collection and storage from a healthy newborn sibling is not recommended. Bone marrow collection can be safely performed on the healthy matched sibling as early as 6 months of life.
BMT from a partially compatible mother (Haploidentical Transplantation) has greatly improved in recent years to the point the preliminary evidence suggests that, in an experienced center, it's as safe and effective as that from a compatible sibling with success rates in the 80% range.
The cost however is superior compared to a matched sibling BMT, in C2C partner centers in India and Pakistan it's around 20.000 USD compared to 15.000 USD for a BMT from a matched sibling.
Transplantation form unrelated donors (bone marrow or cord blood) in Thalassemia generally requires extended compatibility and thus the chances of finding a suitable unrelated donor are not very high especially if the ethnic background is underrepresented in bone marrow donor registries. Unrelated transplant is more risky and much more expensive than either matched-related (from a compatible sibling) or partioally matched-related (haploidentical) donor. C2C does not recommend unrelated BMT for thalassemia.
Generally there is no risk to donor even if he/she is a thalassemia carier. Bone marrow from donor is collected under general anesthesia from upper part of hip bone. The collected bone marrow is replaced very quickly.
In over 400 marrow collection procedures in C2C partner centers we have not had any significant cpmplications.
For related bone marrow donation (generally from a brother or a sister) there is really no age limit, a bone marrow harvest can be safely performed between 6 months (or 8 kg body weight) and 60 years of age if the donor is in good health. It is only for volunteer unrelated donors that the age limit is much narrower, generally between 20 and 40 years of age.
It depends on what is the the pre-BMT condition of your child and on what medical support you can rely on in your area, but it's generally between 4 to 12 months.
in fact, C2C partner institutions will bring to BMT only children without enlarged liver or spleen and with ferritins
Unfortunately many children in poor countries still get Hepatitis C virus (HCV) from multiple transfusions, however, bone marrow transplant outcome is not influenced by this infection. Actually BMT may be even more indicated because HCV worsen liver damage due to iron overload. If Hepatitis C, if still active two years after transplant, it should be treated and followed closely.
Nowadays with affective direct anti-viral therapy with sofosfbuvir and other drugs, thalassemic patients with high HCV RNA copy numbers in blood and increased liver enzymes may be treated before BMT.
Many institutions use expensive drugs, like thiotepa, treosulfan or intravenous busulfan, based on small studies suggesting decreased short-term toxicity in high-risk patients compared to the far less expensive standard oral busulfan which has been used successfully for decades. The use of expensive drugs for high-risk cases is hardly justified when patients can be down-staged into a lower-risk category with aggressive chelation and hydroxyurea therapy. In general, what really makes the difference is how the patient is prepared for BMT rather than the drugs used.
The problem is that too often families are self-referred to transplant centers which do not have the set up for long periods of preparation. This should really be done by thalassemia centers. Moreover, the use of new and more expensive drug combinations like thiotepa and treosulfan, are associated with unknown risks of permanent infertility which may not be the case for the standard combination of oral busulfan with cyclophosphamide.
Many centres do the transplantation for thalassemia within the same setup which has been created keeping in mind the needs of more complicated and higher risk transplantations like those for malignant disorders (cancers). The additional cost of complex air purification systems etc. which are unnecessary for thalassemia transplants get’s added to the transplantation cost inevitably.
Some institutions of course will have substantial overheads and public relations costs which inevitably are borne by patients and their families.
Outcomes can vary widely depending on the experience and dedication of the BMT team involved. The family must take some time to visit different centers, speak with transplant doctors and nurses as well as other families who have undergone BMT in those centers. It is essential and recommended to have transparent and verifiable information on specific thalassemia BMT experience and long-term results.
An important thing to look at, possibly with the help of a third-party medical professionals you know well and trust, is the number and quality of scientific publications from the medical team and professional profiles of the transplant physicains available at Google scholar. Another important question to ask is whether a given transplant center participates in the outcome reporting programs of established international registries like the American CIBMTR or European EBMT. Participation of the transplant service to internationally established quality assurance programs like FACT-JACIE might also be relevant for decision making. How beautiful and flashy the hospital is has little todo with oiutcomes.
The decision whether to undergo BMT might be a difficult one for many families and patients. As a general rule most children born with thalassemia who have regular access to appropriate supportive care may have a long and productive life. However, even if chelation therapy has taken major steps forward and can potentially lead to negative iron balance (that is to remove more iron than that supplied by transfusions), some important complications of thalassemia which are not necessarily related to iron overload, might still be a problem. In a country like India appropriate care may not always be affordable and/or accessible on a long term basis, and most individuals with thalassemia still do not reach adulthood. Lastly, health-related quality of life (HRQoL) is often an issue as well as being able to marry and bear children. Unfortunately, we don’t really know the true frequency of deaths related to thalassemia or the real impact of this disorder on the quality of life of individuals with severe thalassemia living in India. The issue is further compounded by major inequalities in access to health care so that thalassemia has very different severity depending on family socio-economic background or geographical location.
Many thalassemis centers have had bad experiences referring patients form BMT and their position may be understandable. As mentioned above (How do I choose the best center?) outcomes can vary widely depending on the experience and dedication of BMT centers.
The short answer is no.
Why than many families with a child with thalassemia collect and store cord blood? Unfortunately, this is a consequence of business-oriented and unscientific practices ignoring evidence-based medical recommendations. We are referring to private banks storing your newborn child cord blood for a fee. You could consider donating cord blood to public cord blood banks which store the cord free of charge as a useful source of transplantable stem cell for unrelated individuals.
There is no clear medical indication to the use of your child’s own cord blood and very few transplants have been done for thalassemia using compatible newborn sibling cord blood because it is generally considered safer to wait until the compatible newborn reaches 8-10 kg at around one year of age, and can donate fresh bone marrow. Cord blood is associated with increased rejection and more infectious risk related to delayed recovery of white blood cells which will also substantially increase costs and hospital stay.
In our view cord blood use for thalassemia transplantation is medically not indicated, largely profit-driven and ethically questionable.
The ideal cure for thalassemia would be to selectively correct the faulty gene in the relevant cell type in a safe, effective and affordable way. However, it is quite difficult to incorporate a new functional gene in any cell type, and adequate hemoglobin production requires a particularly active gene. The advantage of gene therapy (GT) is that the same hematopietic stem cell (HSC) of the patient is used and thus immunosuppression is not required, in fact, the patient’s own bone marrow is collected and incubated with viral vectors capable of “infecting” the stem cell with the missing normal hemoglobin gene. This corrected autologous bone marrow is than infused back into the patient after the administration of drugs capable of reducing the amount of defective thalassemic marrow, so called myeloablative drugs, similarly to what is also used for BMT. In BMT however myeloablative drugs are combined with immunosuppressive drugs while in GT only myeloablative drugs are generally administered. The lack of immunosuppression and of graft versus host reactions are the primary reasons why GT is potentially more tolerable compared to BMT and can be potentially applied to any patient at any age. However, BMT strategies are improving in parallel with GT so that is is increasingly possible to transplant between partially compatible individuals and older thalassemics. Last but not least the issue of cost and accessibility: BMT cost can vary between 8 to 40 lakhs INR depending on available donor type, while at present GT technology and regulatory issues make it quite expensive so that the preparation of gene-corrected marrow is currently costing in the range of 7 crores INR.
It should also be borne in mind that BMT has been done in over 4.000 thalassemic individuals while GT has only been tested in a handful of patients with still little follow up. Many uncertainties remain in terms of long-term safety and efficacy. Also GT seems to still struggle to induce full transfusion-independence in the most common type (β0/β0) of severe thalassemia. Lastly, GT protocols are incorporating increasingly aggressive drugs to get rid of the diseased marrow which may compromise fertility.
At present most young children with a compatible donor are expected to do very well with BMT and waiting for GT might not be justified, while for older patients or those lacking a compatible donor it is more difficult to provide sound recommendations.
In general we discourage families to plan for another kid purely with the intention of finding a donor for the child suffering from thalassemia. Do keep in mind that the chance of a match with a sibling is only 25%.
If you want to have a another child irrespective of whether the next child is a match, you must get screening done in the first 12 weeks of pregnancy. Prenatal diagnosis of thalassemia is relatively straight forward by Chrionic Villus Sampling or CVS.
Biomedical technology also allows to select and implant an embryo which is thalassemia-free and HLA-compatible, and is called as Preimplantation Genetic Diagnosis or PGD.This is not legalized in some countries (e.g. India), is expensive and only partially successful.
It is well established that patients with low iron overload and limited organ damage get better outcomes on being transplanted. Once there is a match, we do a detailed pre-transplantation evaluation to assess both the patient and the donor. Fortunately, today it is possible to control both high iron levels and reverse organ damage using appropriate medication. Based upon your child’s condition the physicians will initiate the process of preparing the child for the transplantation – a process known as down-staging using aggressive iron chelation and hydroxyurea therapy.
Children who are well managed may only need minor course correction and preparation which could happen in a few weeks. For the others, depending upon the extent of existing damage to the body, the child may take anywhere between 3 months to a year to be able to reverse as much damage as is possible. A child is eventually offered the transplantation when the medical team is convinced that enough has been done to prepare the child for superior outcome.
It may be possible that some children do not respond to the down-staging process adequately. For such families, the physicians will reevaluate the risk-benefits of transplantation and share the same with the families, enabling them to make informed decision.
These answers have been prepared by:
- Dr. Lawrence Faulkner, Cure2Children medical team coordinator
- Dr. Sadaf Khalid, Cure2Children Pakistan branch coordinator