Haploidentical Family Donor Transplantation

Haploidentical or half matched donor BMT is the only treatment option available for patients of blood disorders, who have been advised BMT, but do not have a fully HLA matched family donor or a matched unrelated donor. Before starting the success story of Haploidentical Transplantation, we must understand certain basic facts about the following:-

What is Haploidentical Transplantation?

Haploidentical Bone Marrow Transplantation (BMT) is a procedure in which, instead of fully HLA matched family donor, a half HLA matched parent or sibling is the donor for bone marrow or blood stem cells.

What is the scientific basis for Haploidentical Family Donor BMT? Is BMT possible from a half matched unrelated Donor?

The saying that ‘nature is the mother of all inventions’ is not without reason. HLA antigens are inherited as a set from each of the parents. A mother nurtures a baby in her womb for 9 months without rejecting it even though the paternal HLA antigens inherited by the baby should cause a rejection. This is nature’s example of development of tolerance and thus, a child and the mother are natural donors for each other in most cases even though they are only half matched in their HLA antigens.

Based on the pioneering work by doctors from Italy, BMT from a half matched (Haploidentical) donor from the family was developed.

Due to the absence of this ‘natural law of tolerance’, BMT from a half matched unrelated donor is not possible.

What is a ‘Graft’,‘Graft Failure’and ‘Graft Versus Host Disease (GVHD)’?

For doing a successful Transplantation, doctors need the Bone Marrow or Stem Cell enriched blood of a donor, which can be transfused into the patient to replace his diseased Bone Marrow. This marrow or stem cell enriched blood is called the ‘GRAFT’.

GRAFT FAILURE: When the donor blood stem cells do not seed the patient’s bone marrow, either due to

• Inadequate amount of donor stem cells.
• Rejection or destruction by the residual cells in the patient.

GRAFT VERSUS HOST DISEASE (GVHD): When cells of the immune system from the donor’s Graft attacks the body of the patient, recognising it as foreign. This only happens with BMT and not with solid organ transplantation.

GVHD is of Two Types

Acute: This is a sudden onset inflammation of skin, gut and liver, resulting in skin rash, diarrhoea and jaundice respectively.

Chronic: This is more like a slowly developing thickening and tightening of skin, dryness of eyes and mouth and joint pains etc.

What is a GRAFT composed of?

The graft has various cells with a definite role to play and consists of:-

• CD 34 Cells (Stem Cells) which are required for replenishing the patient’s marrow with healthy stem cells.
• T Cells which are further sub classified into TCRαβ and TCRγΔ. T cells are double edged weapons, they protect us from viruses and react against tumour cells. When they are transfused into host (patient) they may react violently, if they do not recognise the host’s tissues/organs and this may lead to Graft Versus Host Disease (GVHD). In the same way residual T cells in the patient can reject the donor GRAFT and cause GRAFT FAILURE.
• B Cells protect us from various infections and assist the T Cell in accelerating the process of Graft Versus Host Disease (GVHD).
• NK Cells are the natural killer cells, They are very unique, because they not only kill the cancer cells, they also protect us from infections. They do not contribute to GVHD.

How is Haploidentical BMT different from other forms of BMT?

BMT from a Haploidentical family donor is associated with a higher risk of both GVHD and Graft Failure. Thus, the success of such BMT depends on the following:

• Selection of the right Haploidentical Donor amongst the family members.
• Deliver the most suitable ‘Conditioning’ therapy to prevent Graft Failure.
• Prevent GVHD by processing the graft or using a combination of immunosuppressive drugs.

What are the indications for a Haploidentical BMT?

The indications for Haploidentical BMT are the same as Matched Family Donor BMT.

Why do we need a centre for Haploidentical BMT?

There are six private and two state-owned BMT centres in Delhi and NCR and one might query intuitively as to ‘why another one?’ To answer this we need to look at the Indian scenario in the field of BMT. It is estimated that over 30,000 patients per year in our country need a BMT to save their lives and the statistics from Indian Stem Cell Transplant Registry reveals that with over 40 centres across the country, only about 1000 transplants are performed annually.

So is our venture just to add a few numbers to the mammoth need of our population? If all the centres performed 4 transplants per month which we are sure they are capable of, the need would be largely met. Then why is that not happening? The answer lies in the fact that BMT is dependent on availability of HLA matched donors from the family. However, this is available to only 20% of the patients by simple law of inheritance. Yet, Europe, USA and Japan meet their needs largely through Volunteer Unrelated Donor Registries which currently boast of 20 million donors. In India, such registries are in their infancy and the chance of finding a match from the foreign registries is less than 10%. More importantly the cost of procuring the blood or marrow products from Europe or USA ranges from 10,000-30,000 USD. Similar transplants can be performed from unrelated cord blood units at a similar cost, but the procedure is more challenging.

Everyone has a donor and we are showing the way!

In a country where alternate donor BMT is rarely available for patients lacking a matched family donor, Haploidentical BMT seems to be a logical option. However, the lack of expertise and infrastructure halted its development. Dharamshila BMT Centre has developed a state-of-the art infrastructure and laboratory facilities to promote the use of Haploidentical Donor BMT in India.

Unique Infrastructure for this life saving procedure “Haploidentical Bone Marrow Transplantation”

The patients undergoing intensive conditioning and T cell depleted stem cells from Haploidentical donors are at the highest risk of infections. Infections mostly come in the form of bacterial infections from the gut or skin of the patient or as resistant bacteria from other infected patients, or as fungal infection through the air. The HVAC system of highest standards has been installed in Dharamshila BMT centre, which is first of its kind in the country. This ensures protection to the patient from all airborne infections, whilst inside the unit.

Twenty Four Bedded Dharamshila BMT Centre have 4 dedicated rooms for Haploidentical Bone Marrow Transplants. Each Room is equipped with dedicated Air Handling Unit, Anteroom for each BMT Room (for maintaining 12-15 hepafiltered fresh air changes per hour, with positive air pressure) as per class 1000 clean rooms; stainless steel doors, vinyl flooring and wall cladding for maintaining clean surfaces, which will definitely help in improving outcomes in Blood and Marrow stem cell transplantations. Each BMT Room has been furnished like an ICU with double outlets for oxygen, vaccum, six parameter monitors, infusion pumps, syrings pumps and crash cart. Sick patients with zero white blood counts cannot be taken out of the BMT unit, as this will entail risking their life. Therefore, there is a provision for stand by ventilators, Dialysis machine, Ultrasound and X-Ray Machine in the BMT Unit.

Clinimacs using MACS Technology Clinimacs provides the state-of-the-art technology to select and separate individual cell components for Haploidentical BMT.

Total Body Irradiation is an essential part of conditioning for BMT, but often results in serious long term toxicities. With VMAT technology, we can target the entire bone marrow at much higher doses without exposing other organs such as heart, lungs, liver or kidneys to the detrimental effect of radiation. Our Radiation Oncologists have developed this technique to improve the outcome of patients undergoing BMT.

To support the hapaloidentical BMT Programme, Dharamshila BMT Lab provides

• 8-colour Flow-cytometry based diagnostics for Leukemia, Lymphoma and Aplastic Anemia
• Detection of Minimal Residual Disease (MRD)
• Molecular diagnosis for Leukemia
• HLA typing, NK Cell Genotyping and CD34 + Stem Cell Estimation
• Comprehensive donor selection for Haplo-identical BMT based on NK-KIR Profile.
• Magnetic Separation of Cells using MACS Technology.
• Long Term Cryopreservation of Stem Cells at -1960 C liquid nitrogen freezer in vapour phase
• Conventional and Real Time PCR for Viral Pathogens
• Drug Levels for BMT.

Our Team

Dr. Suparno Chakrabarti and Dr. Sarita Jaiswal pioneered the first Haploidentical BMT program in India. Their work and research has been widely presented and published in the last two years. Having performed over 20 such transplants, they wanted to develop this procedure further. Dr. Sarita Jaiswal trained under Prof. Franco Aversa from Italy, who is the pioneer of Haploidentical BMT. Prof Aversa and others have developed a completely new approach to Haploidentical BMT using Clinimacs based depletion of TCRalfabeta and CD19 cells from the stem cell product, which has drastically reduced the rate of complications and mortality experienced earlier. This is a labour intensive technology and carrying out such transplants without the right expertise or infrastructure can be disastrous. The experience at University of Parma under Prof Aversa amazed Dr Sarita as to how well such transplants can be carried out with the right expertise if a supportive infrastructure is provided.

Our Research on Haploidentical BMT

• Jaiswal S et al.Contrasting Patterns of Alloreactivity Amongst Malignant and Nonmalignant Diseases Receiving Haploidentical PBSC GRAFT and Post-Transplant Cyclophosphamide. (Poster no 473). 2013 BMT tandem meeting.
• Jaiswal S et al. Persistently High GAM Levels Are Associated with Nonrelapse Mortality in HCT Recipients Irrespective of Invasive Aspergillosis: A Prospective Cohort Study. (Poster no 305). 2013 BMT tandem meeting.
• Jaiswal S et al. Second Haploidentical PBSC Transplantation From the Same Donor After Early Relapse without Gvhd in Patients with Acute Leukemia. (Poster no 474). 2013 BMT tandem meeting.
• Jaiswal S et al. Is Haploidentical Family Donor Transplantation The Best Form Of Alternative Donor HCT In Developing Countries? BTG 2013, Hongkong.
• Jaiswal S. Is Haploidentical Family Donor Transplantation The Best Form Of Alternative Donor HCT In Developing Countries? (ORAL PRESENTATION) ESH EBMT TRAINING COURSE ON HCT, ITALY, APRIL 2013.
• Jaiswal S. NK Alloreactive Donor Is Associated With Reduced Relapse In Refractory AML But High Nonrelpase Mortality In Patients With Aplastic Anemia Following T-Replete Haploidentical PBSCT With Post Transplant. 18th Congress of EHA, 2013.
• Jaiswal S et al. Comparable Outcome Of Haploidentical And Matched Sibling Donor Peripheral Blood Stem Cell Transplantation For High Risk Aplastic Anemia. 1st International Workup on Haploidentical Transplantation, 2013.
• Jaiswal S et al. Comparable Outcome Of Haploidentical And Matched Sibling Donor Peripheral Blood Stem Cell Transplantation Following Myeloablative Conditioning For Poor Risk Acute Myeloid Leukemia. 1st International Workup on Haploidentical Transplantation, 2013.
• Jaiswal S. Natural Killer Cells: A New Weapon in The Armamentarium. National Cancer Congress, 2014, DNSH (Dharamshila Narayana Superspeciality hospital), Delhi, 2014.
• Jaiswal S et al. Outcome Of Haploidentical PBSC Transplantation For High Risk Aplastic Anemia With Post-Transplant Cyclophosphamide Is Similar To Matched Sibling PBSCT And Depends On Choice Of Donors: Adverse Effect Of Natural Killer Cell Alloreactivity. 40th Annual Meeting of the European Society for Blood and Marrow Transplantation: April 2014 .Milan, Italy.
• Jaiswal S et al. Comparable Outcome Of Haploidentical And Matched Sibling Donor Peripheral Blood Stem Cell Transplantation Following Myeloablative Conditioning For Poor Risk Acute Myeloid Leukemia. 40th Annual Meeting of the European Society for Blood and Marrow Transplantation: April 2014 .Milan, Italy.