Dr Lawrence Faulkner

(Medical Director Cure2Children Foundation-Italy and Program Director Sankalp People Tree Centre for Paediatric BMT Bangalore-India.)

May 2017

Contents

• Thalassemia - a disease of the bone marrow
• Regular transfusion, medication and chelation a must
• Bone Marrow Transplantation (BMT) - complete cure from Thalassemia
• Finding donors
• Matched sibling donor (MSD) transplant
• Haploidentical transplant
• Matched Unrelated transplants (MUD)
• HLA typing test
• Getting the reports
• What if my child does not have a match
• Does getting a match mean that my child can be transplanted immediately?
• How much will it cost me?
• Why is BMT cost so variable?
• How do I choose the best centre?
• What factors influence the chance of success?
• Will my child go back to a normal life?
• My child seems to be doing well with supportive care and we are happy with our doctors, should we consider BMT?
• At our thalassemia center we were advised against BMT, how do I know who to believe
• I would like to have more children but am afraid to have another one with thalassemia, how can I avoid it?
• Should I store the placental cord blood if I become pregnant again?
• Donating bone marrow - process and involved risk for the donor.
• What about gene therapy?
• Our Partners

SANKALP PROGRAM FOR THALASSEMIA CURE

• About Us15
• Donors supporting us in our mission15

Thalassemia - a disease of the bone marrow

Thalassemia is a genetic blood disorder in which the bone marrow cannot form healthy red cell. Thalassemia is an inherited blood disorder. "Inherited" means they're passed on from both parents to children through genes. Because of the defect in the bone marrow, the child needs blood transfusions throughout life.

Regular transfusion, medication and chelation a must

The management of thalassemia has improved significantly in the last few years.

If the following aspects are regularly and adequately, practiced, the child can have a near normal life:

• Timely blood transfusions are given (preferably maintaining the hemoglobin > 9 gm/dl).
• Iron chelation therapy is given in adequate dose (maintain serum ferritin below 1000 ng/ml).
• The child regularly undergoes medical tests to prevent any further complications.
• The child receives proper care and treatment.

Some issues, however, may still be unresolved by current best care such as drug or blood transfusion intolerance, infections transmitted with blood,  pain due to bone thinning in older thalassemics and increased cardiovascular risk (pulmonary hypertension). 

Bone Marrow Transplantation (BMT) - complete cure from Thalassemia

BMT is an option for complete cure from thalassemia. BMT is a procedure in which the diseased bone marrow in the child is replaced with bone marrow from a healthy donor.

BMT at a young age, possibly by the age of 15 years, is more successful because the child has fewer complications and the body is healthier. It is necessary for each child with thalassemia to continue to seek proper medical care and management so that whenever in future the option of BMT is available for them, the child is in a reasonably good shape for the procedure.

Finding donors

HLA typing is a test that is used to find whether there is a good donor for the patient or not. The patient can receive the bone marrow from one of the three sources:

• A family member, generally a sibling, who is a complete match.
• As a second choice, partially matched (haploidentical) family members (such as mother, father or sibling), can be used.
• Fully matched unrelated donors can also be used.

Matched sibling donor (MSD) transplant

BMT from siblings is the first choice since it has the highest chances of the patient getting cured. If a patient has a healthy sibling, we may offer free-of-charge HLA typing test.

In general, if the transplant is done by an experienced team there is a 85% chance that the child will be completely cured. There is a 5% chance that the child may die of complications related to the transplant and another 5% chance that the transplant itself may fail. The remaining 5% chance is that your child develops a complication post transplant. Within these 5% serious complications, there is a small possibility that it may need months and sometimes even some years to get completely cured and may increase the risk of death. In-spite of a successful transplant there is a chance that your child may not be able to bear children.

Haploidentical transplant

The mother and father are generally half matches to the child and can be used increasingly successfully. The chance of cure may vary from case to case depending on HLA-typing and other tests which need to be assessed individually. In favourable situations transplantation from partially compatible family donors can be as successful as from fully compatible donors.

Matched Unrelated transplants (MUD)

These type of transplants are done from matched donors who are unrelated to the patient. For these transplants, the match is found using registries that keep details of the HLA types of voluntary donors. However, these transplants are associated with higher risks of the patient’s death, failure of transplant and post transplant complications. Therefore, we as an organization do not support MUD transplants for thalassemia patients.

HLA typing test

• HLA typing is required to find out if a BMT for your child is possible or not.
• HLA typing is a test that only needs to be done once in a lifetime. So, if you already have got HLA typing done, please bring the report and inform us.
• This test is about Rs 12,000/- in market but is being offered free of cost to the patients by Sankalp India Foundation with support from Cure2Children, Italy and DKMS, Germany. We offer HLA typing to children up-to 18 years.
• We will need to enroll your child on the database and collect some personal information for the sake of unequivocal identification of each family member to be typed. We will also need information that helps us determine the eligibility of the child for free HLA typing. We will provide you a consent form for inclusion in our database. Please read the form and feel free to ask for clarifications from the staff. You must provide your consent for enrolment into our database by signing the form on behalf of your child and your family.

We will need your consent for HLA typing as well. For this you must read, understand and sign a consent form on behalf of yourself, your child and your family.

Getting the reports

It may take anywhere between 90 days to 180 days for us to provide you with the results of HLA typing. The staff will call you once the reports are available. A counseling session will be organised which will help you understand the options you have based upon the results of the HLA typing. In case there is a good donor, you will have the option of seeking Sankalp India Foundation’s assistance for the transplant or you can directly seek help from one of the many BMT centres.

What if my child does not have a good family donor

Rapid progress is being made in the field of haploidentical bone marrow transplantation. We are confident that in near future we will be able to offer transplantations from parents with reasonable chance of success in the great majority of patients. Most children with thalassemia will eventually be cured if they get to transplantation in good conditions so that regular management is extremely important.

Does having a good donor mean that my child can be transplanted immediately?

It is well established that patients with low iron overload and limited organ damage have better transplant 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 some of the 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 other therapies.

Children who are well managed may only need minor course correction and preparation that 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 possible. A child is eventually offered 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.

How much will it cost me?

The cost of bone marrow transplantation ranges from Rs 8.5 lakhs to Rs 20 lakhs in India depending upon which institution is chosen for the transplantation and the preparatory protocols they employ. Transplantations generally are less expensive than the cost of management of thalassemia for several years. Many institutions indicate BMT charges often limited to the initial hospital period of 45 days and may not cover whole recovery, generally lasting 1 to 2 years. Also, most institutions do not cover the complications that may arise during the transplantation.

At Sankalp-Cure2Children centres the transplantations are done at a fixed cost, which includes the cost of managing any complications directly, associated with the transplantation. The cost of follow-up medication, consultation and labs is also included up-to a year. Part of the overall cost is fundraised by Sankalp India Foundation, wherever applicable, part of it can come from the Government. Families cover rest of the cost by either personal contribution or by fundraising.

Why is BMT cost so variable?

Many institutions use expensive drugs, based on some small studies suggesting decreased short-term toxicity in high-risk patients compared to the far less expensive standard drugs which have 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. 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 centres which do not have the set up for long periods of preparation. This should really be done by thalassemia centres. Lastly, the use of new and more expensive drug combinations, are associated with unknown risks of permanent infertility which may not be the case for the standard combinations.

Many centres do the transplantation for thalassemia within the same setup that 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. that 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.

How do I choose the best centre?

Outcomes can vary widely depending on the experience and dedication of the BMT team involved. The family must take some time to visit different centres, speak with transplant doctors and nurses as well as other families who have undergone BMT in those centres. 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 physicians available at Google scholar and other websites. 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.

What factors influence the chance of success?

The chance of success depends primarily on the availability of a suitable donor, generally a matched or favourably mismatched family member (it is important to have accurate and reliable compatibility testing possibly by an internationally accredited laboratory), and on the medical condition of your child. Liver enlargement, spleen enlargement or very high ferritin levels (greater than 5000 ng/mL) might affect outcome. Age is also an important factor, the younger the better. BMT should ideally be performed before age 7 years and probably avoided after 15 years of age.

Will my child go back to a normal life?

Yes, it is very likely that your child will go back to a normal health-related quality of life after BMT, at least with the standard combination followed by donor bone marrow administration for which there is very long-term follow up data. For newer drug combinations with peripheral blood stem cells this is not established.

My child seems to be doing well with supportive care and we are happy with our doctors, should we consider BMT?

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. A study done on a large group of patients in India showed that 50% of even those patients who have access to good care die by the are of 26 years. In a country like India appropriate care may not always be affordable and/or accessible on a long-term basis, and many 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.

At our thalassemia center we were advised against BMT, how do I know who to believe?

Many thalassemia 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. 

I would like to have more children but am afraid to have another one with thalassemia, how can I avoid it?

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 this is called Preimplantation Genetic Diagnosis or PGD , but is not legalized in India, is quite expensive and only partially successful.

Should I store the placental cord blood if I become pregnant again?

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 that 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.

Donating bone marrow - process and involved risk for the donor.

If your child finds a matched sibling, both of them will be tested thoroughly to check if they are fit for the transplant. Collection of bone marrow is a minor procedure that involves using syringes to extract bone marrow from the hip bone of the donor. The donor child is given anesthesia so that they experience no pain during the process. The donor needs to be admitted in the hospital for about one day. They may experience little pain for a few days after donation but any short- or long-term problems are extremely rare.

Many institutions use peripheral blood stem cell collections (leukapheresis) to take cells from the donor and might provide better short-term engraftment at the cost of substantially increased risk of chronic graft versus host disease (GVHD). This complication has the potential to make quality of life worse than the thalassemia itself.

Please feel free to ask the staff for any clarifications on this topic.

What about gene therapy?

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 haemoglobin production requires a particularly active gene. The advantage of gene therapy (GT) is that the same haematopietic 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 haemoglobin 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 administered. The lack of immunosuppression and of graft versus host reactions are the primary reasons why GT is 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 it's 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 14 crores INR.

It should also be borne in mind that BMT has been done in over 4,000 thalassaemic individuals while GT has only been tested in a much smaller number of patients with relatively short 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 that 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.

Our Partners

Our mission to enable cure for each child suffering from thalassemia has been made possible only with the support and participation of our partner organisations.

Sankalp-Program for Thalassemia Cure

OUR VISION:        Thalassemia free India.

OUR MISSION:     To provide high quality patient focused curative option to children suffering from Thalassemia irrespective of financial background with focus on transparency achieved through technology.

About Us

Sankalp Program for Thalassemia Cure offers Bone Marrow Transplant - the permanent curative option to the children suffering from Thalassemia.

We have forged partnerships that enable reliable BMT on a non-profit basis bringing down the cost of the transplants substantially. The organisation seeks to identify the most suitable candidates and offer them the option of BMT. At the cost equivalent to 4-5 years of thalassemia management, the organisation offers complete cure from the disease.

Our team has vast expertise with BMT for thalassemia. The selection of patients for transplants is being done scientifically and judiciously to ensure that the patients who are most likely to benefit from the transplant are offered the same, keeping aside their financial limitations. We have established a program which will ensure systematic preparation of the chosen kids for transplant and their long-term follow-up – further enhancing the outcome and reducing the cost.

Donors supporting us in our mission

We are able to reach-out to every child who needs cure thanks to the support of all our donors.

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About Dr Lawrence Faulkner, MD

Medical Director Cure2Children Foundation-Italy and Program Director Sankalp People Tree Centre for Paediatric BMT Bangalore-India.

After working for almost 20 years in affluent counties as a pediatrician specialized in blood disorders such as thalassemia and sickle cell disease, Dr. Faulkner decided to dedicate himself, full- time, to international medicine by collaborating with professionals and institutions in developing countries committed to the cure of children with severe hematological diseases. He has enabled the setting up of 7 bone marrow transplantation centers in the developing countries – the centers which went on to achieve world class outcomes. Dr Faulkner is also an inspector for JACIE (Joint Accreditation Committee ISCT-EBMT).

Let’s give life a better chance!