Bone marrow transplant

Hello Sir,
I am Shray Mehta from India, a Beta thalassemia patient.  I'd like to have an opinion on my case which I'm describing below.
I received my first blood transfusion at the age of 3 when my parents found about this condition. I was on kelfer for iron chelation therapy and received transfusion for 12 years continously, after every 20 days till the age of 15.
I was then tested for XMN Polymorphism and the results were +/+
The doctor then advised me to start hydroxyurea (500mg) and I responded well to that medicine and for the iron chelation, derijet was started. Me and my parents were overwhelmed with the response hydroxyurea had on me and I maintained hb levels between 9 to 10 grams for six years; i.e. From 15 to 22 no blood transfusions received.
After that since my platelets started to drop, hydroxyurea was discontinued and I was again given blood transfusions.

I recently read about the MUD Bone marrow transplants and was excited to know if I could go for it since I have no siblings. I am really looking forward to your response and want to get rid of this desperately. I need your honest advice about what could be best for me. Your advice will be highly appreciated.

Thank you
Regards
Shray Mehta

HI Shray,

I'm not sure if you would fit the eligibility for a BMT with most BMT centers, as you were transfusion independent for a long time. You may not transfuse often enough to be eligible. How often are you now transfusing? Have you talked to any of the doctors in India doing BMT's about doing one? Dr Ramanan in Pune has done some unrelated BMT's.

I would also like to mention that there is a new drug in trials that increases Hb, and is completely unlike hydroxyurea. The early trials had very good results. The phase 3 trials should start this summer and if all goes well, the drug will make it to market quickly, as it has been fast tracked. The drug is called Luspatercept and one of the doctors involved with this project is Dr Antonio Piga and he will be speaking at the conference in Delhi in September. If you can go, I would advise that you do and hear Dr Piga speak.

I would also like to mention that there is a new drug in trials that increases Hb, and is completely unlike hydroxyurea. The early trials had very good results. The phase 3 trials should start this summer and if all goes well, the drug will make it to market quickly, as it has been fast tracked. The drug is called Luspatercept and one of the doctors involved with this project is Dr Antonio Piga and he will be speaking at the conference in Delhi in September. If you can go, I would advise that you do and hear Dr Piga speak.

Thanks Andy for the coming good news...

Dear Andy,

Is Luspatercept only for MDS Patients?

Lokkhi Maa,

Luspatercept should be helpful to all thal and hopefully sickle cell patients.  If it works as well as the trials indicate it will greatly reduce the burden of the disease.

Hoping for the best and soon!

Sharmin

Hoping for the best and soon!

Hello Sharmin,

Now how is your son..

Thank you Andy for the good news.
Yes I talked to Dr. M.Joseph Jones at Christian Medical hospital at Ludhiana, India.
He did not advise me to go for BMT but he said I could try hydroxyurea again on alternate days.
If it works, then its good or he could try thalidomide on me.
He said dropping of platelets is not a big issue.
And regarding the transfusions, I am going for transfusion in every 20 to 25 days on regular intervals from 8 months now and my ferritin levels have reached 1800.

I also read about Luspatercept in the thalassemia magazine thought doctors here are not really educated about it.
I wish this new drug has to offer something good to us.

Is thalidomide similar to hydrauxia?   How does it help?

I don't know but for my Friends kid, Dr. from Pune started with hydrauxia and later stop hydrauxia and start thalidomide. Its seem to be same family..

It works in a similar way to hydroxyurea, raising HbF and also often can work in synergy with hydroxyurea, improving the performance of the drugs individually.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2809513/

Blood Transfus. 2010 Jan; 8(1): 63–65.
doi:  10.2450/2009.0102-09
PMCID: PMC2809513

Optimal response to thalidomide in a patient with thalassaemia major resistant to conventional therapy
Nicoletta Masera,1 Luisa Tavecchia,2 Marietta Capra,2 Giovanni Cazzaniga,2 Chiara Vimercati,1 Lorena Pozzi,1 Andrea Biondi,1 and Giuseppe Masera1
Author information ► Article notes ► Copyright and License information ►
This article has been corrected. See Blood Transfus. 2010 July; 8(3): 216.
This article has been cited by other articles in PMC.
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Introduction
Beta-thalassaemia major is a hereditary anaemia resulting from defects in β-globin production. The coexistence of hereditary persistence of foetal haemoglobin (HbF) during adult life in patients with β-thalassaemia reduces the severity of the disease; these patients have a mild disorder, sometimes not even requiring chronic transfusions. The clinical benefit of increased HbF, first inferred in 19761, is due to a decrease in the imbalance between β and non-β-chains and the consequent reduction of haemolysis. Many drugs have been studied as inducers of HbF for patients with β-thalassaemia and sickle cell disease. Hydroxyurea is currently used in moderate to severe forms of sickle cell disease2,3 and in some cases of thalassaemia intermedia4,5. Other inducers of HbF synthesis, such as butyrate6, 5-azacytidine7 and, more recently, decitabine, have also been shown to induce HbF in patients with sickle cell disease8. However, these HbF inducers have shown only a modest effect in the majority of β-thalassaemia patients as well as some degree of toxicity. As a result, they have not been used routinely in clinical practice. Thalidomide, a drug known for its immunomodulating and anti-angiogenic properties, has recently been demonstrated to induce γ-globin gene expression and to increase the proliferation of erythroid cells9,10. Only one patient affected by β-thalassaemia major treated successfully with thalidomide has been described so far11.

We report here the case of a young girl with β-thalassaemia (β+/β°) in a very severe clinical condition who could not be given any further transfusions because of the occurrence of severe post-transfusion reactions and who showed an outstanding response to thalidomide.

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Case description
The patient, affected by β-thalassaemia major IVS1-6/cd44-C, was born in Albania and is now 20 years old. From the age of 1 year, she was transfused in Albania every 3–4 months, maintaining very low haemoglobin values (in the range of 5–7 g/dL). Splenectomy was performed when she was 4 years old. She came to Italy at 9 years of age, affected by severe anaemia with a haemolytic component (Hb: 4.5 g/dL, HbF: 38%, very low haptoglobin levels), significant erythroblastosis (320×103/mL), dilated cardiomyopathy, severe bone deformities (particularly of the lower limbs and face) and enormous hepatic enlargement accompanied by significant pain in the region of the liver. Repeated transfusion attempts proved ineffective because of massive post-transfusion acute haemolysis, despite negative compatibility matches. Direct and indirect Coombs’ tests were not conclusive for an antibody-mediated haemolytic process. Treatment with high-dose steroids and cyclophosphamide was started, with no improvement.

At 10 years of age, she was started on 10 mg/kg/die of hydroxyurea, with a partial response in terms of haemoglobin levels (Hb: 6.5–7 g/dL, HbF: 50%) and an improvement of hepatic function, although haemolytic indices remained high. The possibility of a bone marrow transplant from an unrelated donor (both brothers were HLA incompatible) was excluded because of the patient’s very poor general condition. Given the impossibility of ruling out an autoimmune aetiology of the haemolytic component of the anaemia (direct Coombs’ test seldom slightly positive) and based on the severity of her clinical condition, the girl was again treated with immunosuppressive therapy (high-dose steroids and cyclophosphamide) at 12 years of age, without any response. At 15 years old she was treated with three cycles of rituximab, without any relevant response in terms of haemoglobin levels. After an extensive immuno-haematological investigation, a specific Scianna-1 allo-antibody was identified in the serum.

At 16 years old, the girl was transfused with two units of Scianna-negative red blood cells, which were found through the International Blood Bank (American Donor Program), but even these did not produce an increase in haemoglobin levels and induced further haemolysis (Hb pre-transfusion: 5 g/dL, Hb post-transfusion: 3.5 g/dL). At this point, it was agreed that the patient should not be transfused any more.

The girl was treated with diuretics, ACE-inhibitors, digitalis for congestive chronic heart failure, a platelet anti-aggregant drug for thrombocytosis (platelet count: 900 – 1,000 × 109/L), bisphosphonates and calcium for severe osteoporosis and folic acid.

The dose of hydroxyurea was progressively increased to 30–35 mg/kg/die maintaining values of Hb between 5–6 g/dL with HbF 40%.

The clinical picture remained stable (allowing the girl to walk for short distances and to attend school, although not regularly) until March 2008 (age: 20 years), when a progressive decrease in haemoglobin values was detected, reaching a nadir of 3.7 g/dL in May. There were no signs of infection but there was important clinical worsening with severe heart failure and initial lung oedema. The patient was treated with high doses of diuretics, digitalis and ACE-inhibitors. On the basis of a similar case reported12 and considering the lack of therapeutic options available, the girl was started on treatment with thalidomide 75 mg/kg/die. Informed consent was obtained regarding the experimental nature of the treatment and its possible teratogenic effects. The patient was advised of the risks in pregnancy and she accepted this limitation. The dose of hydroxyurea was progressively reduced until the drug was discontinued in December 2008.

Haemoglobin values progressively and rapidly increased (1 month after starting thalidomide treatment Hb: 7.2 g/dL; after 8 months: Hb: 9.0 g/dL, HbF: 73%). The levels of erythroblasts remained high, although showing a slight decrease (53×103/mL). The response to thalidomide is impressive Therapy was well tolerated and no signs of neuropathy appeared. At the time of writing this report (January 2009) the patient’s haematological and clinical conditions are good and even the cardiological therapy has been tapered down.

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Discussion
The mechanisms by which thalidomide increases erythropoiesis and induces γ-globin gene expression and HbF production9,10 as well as its possible synergistic effect with hydroxyurea11, have been described recently, the immunomodulatory action of the drug being well-recognised. A possible role of thalidomide and its derivatives (pomalidomide and lenalidomide) in the treatment of sickle cell disease and other β-haemoglobinopathies has been suggested10,12, but clinical experience is limited to just one young Mexican woman with β-thalassaemia major, who responded brilliantly to thalidomide11.

We believe that thalidomide should be considered in dramatic cases of thalassaemias which cannot be treated with transfusions and do not respond to hydroxyurea. Extensive biological and clinical studies are required to define the potential use of thalidomide in thalassaemia and other haemoglobinopathies, and to evaluate and monitor its possible side effects.

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Figure 1
Figure 1
Haemoglobin (Hb) and foetal haemoglobin (HbF) values with different treatments throughout the years.
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References
1. Wood WG, Weatherall DJ, Clegg JB. Interaction of heterocellular hereditary persistence of foetal haemoglobin with beta thalassaemia and sickle cell anaemia. Nature. 1976;264:247–9. [PubMed]
2. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on frequency of painful crises in sickle cell anaemia. N Engl J Med. 1995;332:1317–22. [PubMed]
3. Platt OS, Orkin SH, Dover G, et al. Hydroxyurea enhances fetal haemoglobin production in sickle cell anemia. J Clin Invest. 1984;74:652–6. [PMC free article] [PubMed]
4. Fucharoen S, Siritanaratkul N, Winichagoon P, et al. Hydroxyurea increases haemoglobin F levels and improves the effectiveness of erythropoiesis in beta thalassemia haemoglobin E disease. Blood. 1996;87:887–92. [PubMed]
5. Hajjar FM, Pearson HA. Pharmacologic treatment of thalassemia intermedia with hydroxyurea. J Pediatr. 1994;125:490. [PubMed]
6. Candido EP, Reeves R, Davie JR. Sodium butyrate inhibits histone deacetylation in cultured cells. Cell. 1978;14:105–13. [PubMed]
7. Ley TG, De Simone J, Anagnou NP, et al. 5-azacytidine selectively increases gamma-globin synthesis in a patient with beta+ thalassemia. N Engl J Med. 1982;307:1469. [PubMed]
8. De Simone J, Koshy M, Dorn L, et al. Maintenance of elevated fetal hemoglobin levels by decitabine during dose interval treatment of sickle cell anemia. Blood. 2002;99:3905–8. [PubMed]
9. Aerbajinai W, Zhu J, Gao Z, et al. Thalidomide induces γ-globin gene expression through increased reactive oxygen species-mediated p38 MAPK signaling and histone H4 acetylation in adult erythropoiesis. Blood. 2007;110:2864–71. [PMC free article] [PubMed]
10. Moutouh-de Parseval LA, Verhelle D, Glezer E, et al. Pomalidomide and lenalidomide regulate erythropoiesis and fetal haemoglobin production in human CD34+ cells. J Clin Invest. 2008;118:248–58. [PMC free article] [PubMed]
11. Aguilar-Lopez LB, Delgado Lamas JL, Rubio-Jurado B, et al. Thalidomide therapy in a patient with thalassemia major. Blood Cells Mol Dis. 2008;41:136–7. [PubMed]
12. Trompeter S, Roberts I. Haemoglobin F modulation in childhood sickle cell disease. Br J Haematol. 2008;144:308–16. [PubMed]

This corrects the article "Optimal response to thalidomide in a patient with thalassaemia major resistant to conventional therapy" in volume 8 on page 63.
In the article “Optimal response to thalidomide in a patient with thalassaemia major resistant to conventional therapy” Blood Transfus 2010; 8:63–5 there is a typing error on page 64: the dose of thalidomide is incorrectly stated to be 75 mg/kg/die. The correct dose is 75 mg/die.

Our apologies for the mistake.