Finding time to review my slides and notes has been difficult but I do intend to file these reports as time permits.
We are regularly asked about BMT as a cure for thalassemia and whether it is a course to pursue. This is not an easy question to answer and there are many factors that affect the success rates of BMT. Chief among these factors are the patient's condition and how well they have complied with treatment regimens. Among these factors are chelation, has it been regular or irregular? Is the liver enlarged? And is there the presence of liver fibrosis? Patients who have been consistently regular with chelation and who have low iron loads are the best candidates for BMT. These patients should also have normal size livers without fibrosis. Poorly chelated patients with liver problems are not good candidates for BMT. I will say that this also holds for gene therapy. For the purpose of trials, patients with problems will not even be considered. There are many advancements in treatment coming on a regular basis and that should give a good incentive to patients to comply with today's treatment protocols. Patients are divided into three risk categories. Category 1 is if none of the risk factors are present. This group experiences the highest rate of success in BMT. Category 2 is when one or two of the risk factors are present and in category 3, all three of the risk factors are present. These patients make poor candidates for BMT. Obviously, complying with treatment makes one a much better candidate.
There were two main new developments to report concerning bone marrow transplants to cute thalassemia.
First, one of the great risks with BMT is the drugs used to prepare the patient for the BMT. These are typically chemotherapy drugs and have very harsh side effects. These side effects are complicated by the intended effects of these drugs, which is to kill the patient's bone marrow and to halt the immune system from working so that the immune system does not reject the transplanted bone marrow. One course of research is to find drugs that can do the job without causing so many side effects in the patients. At the symposium, I was able to hear the brilliant Dr Locatelli speak about the latest findings. One key part of the newer approaches is called Reduced Intensity Conditioning (RIC), which some of us are familiar with because of the approach used by Dr Lakshmanan Krishnamurti of Children’s Hospital of Pittsburgh. Sometimes referred to as a kinder gentler form of BMT, great success is being found by using this approach. Dr Locatelli spoke about the findings using the drug treosulfan rather than the traditional bulsulfan conditioning. The use of busulfan, while unable to completely avoid both primary and secondary graft failure, has been associated with relevant complications (such as VOD, TTP) which can significantly contribute to the occurrence of fatalities, especially in adults and patients with classification 3. (VOD, veno-occlusive disease is a condition in which some of the small veins in the liver are blocked. TTP, thrombotic thrombocytopenic purpura, is a clotting problem that occurs in small blood vessels. Both are known complications of BMT). In contrast, findings using treosulfan have shown the following. Treosulfan has been demonstrated to display pronounced killing of both committed and more immature hematopoietic progenitors, as well as immunosuppressive activity against both T-cell and B-cell functions (I can't help but wonder what condition Chuck would be in today if this new protocol was followed). In addition, Treosulfan is easy to administer even in young children, has limited extramedullary toxicity, its pharmacokentics is linear, with reliable exposure and low inter-patient variability (this means the effect is consistent from patient to patient), and very importantly, treosulfan may spare patient fertility.
Second, it has been found that the use of cord blood (CBT) instead of bone marrow or stem cells harvested from the blood, is leading to higher success rates and lower rates of acute graft vs host disease (GVHD). It was found that the rate decreased to about 10% vs 20% with traditional BMT. In additon, mixed chimerism, where both the patient's bone marrow and the transplanted cord blood were both active in the patient was found in significantly higher rates when CBT was done, resulting in much lower rates of acute GVHD, as the two "peacefully co-existed". Mixed chimerism where the donated cells were only 20-25% of the total bone marrow, was sufficient to provide adequate hemoglobin production to remain transfusion free, with Hb levels of 10.5-11. This strongly demonstrates why we will be seeing far more cases like the one in Spain, where an embryo is chosen as an HLA match specifically for the purpose of using the cord blood of the new child to cure the thalassemia or sickle cell of the older sibling. It may sound objectionable to some to produce a child for this purpose, but I want to point out that parents do want another child and picking one specifically as a match to cure another child should not be anything anyone can object to, as the new child will be no less loved.
These are exciting developments in the field of BMT and do make it easier to recommend, as they are implemented. I still have much apprehension about BMT, but when good candidates are used, success rates are quite high. Even though there have been only 16 BMT's for thalassemics since 1996 at Sloan Kettering, they have had a 100% success rate. All patients are alive today and transfusion independent. I have been very wary of BMT after Abdulwahab's experience almost killed him several times, but he is alive and well today, and these new developments in the field have boosted my confidence in BMT when done at one of the top centers that have high success rates. Sorry, but Vellore is not one of these centers, even though I do know a teenage girl from Maldives whose BMT did succeed there. Two other patients from the Maldives died at Vellore during this same period as a result of complications from BMT. Vellore is far less expensive but their success rates are only 65-75%.