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HLA mismatched and NIMA-matched unrelated cord blood transplants

Source agency:

ANZHSN

Date of Submission:

13/04/2010

Date of Printing:

05/02/2012

Disclaimer:

This report is work in progress and should not be used for external distribution without permission from the originating agency. Users should be aware that reports are based on information available at the time of research and often on a limited literature search.

Technology, Company & Licensing

Technology name:

HLA mismatched and NIMA-matched unrelated cord blood transplants

Technology - description:

For many haematological malignancies such as leukaemia, the only available treatment option is allogeneic transplantation of immunologically naive stem cells. Once a patient’s immune system is depleted using chemotherapy and immunosuppressive therapy, donated stem cells are infused back into the patient and the haematopoietic cells repopulate the bone marrow (Wall & Chan 2008). The umbilical cord at delivery is a rich source of haematopoietic stem cells. There can be a greater HLA disparity between donor and recipient when compared to using unrelated (allogeneic) donors of bone marrow (van Rood et al 2009).

When using unrelated donors, HLA matching is considered to be the most important factor for transplantation success.

Studies have demonstrated that some patients who have antibodies against a large number of HLA antigens have not formed antibodies against maternal HLA antigens that the patient did not inherit as part of their genetic make-up, that is the non-inherited maternal antigens (NIMA). Recent research into the use of unrelated cord blood for stem cell transplantation has investigated the role of NIMA. It has been suggested that a reduced level of graft-versus-host disease and hence improved transplantation outcomes, may occur despite HLA mismatches if donors are matched for NIMA (Scaradavou 2010; van Rood et al 2009).

Company or developer:

Not applicable

Reason for database entry:

Innovative treatment with the potential to increase the available donor for patients who require a haematopoietic stem cell transplant to treat haematological malignancies

Technology - stage in early warning process:

Assessment complete

Technology - stage of development:

Experimental - pilot or phase II

Licensing, reimbursement and other approval:

Not applicable

Technology - type(s):

Procedure

Technology - use(s):

Therapeutic

Patient Indication & Setting

Patient indications:

For patients who require a haematopoietic stem cell transplant to treat haematological malignancies.

Disease description and associated mortality and morbidity:

In Australia during 2005, there were 2,591 registered cases of leukaemia, representing 2.6 per cent of all registered cancers. Of these 1,214 were lymphoid leukaemias (C91), 1,310 were myeloid leukaemias (C92-94) and 67 were leukaemias of an unspecified cell type (C95). The age-standardised incidence rate was 12.3 per 100,000 population. During this same period there were 1,417 recorded cases of mortality with leukaemia as the cause of death, with an age standardised mortality rate of 6.6 per 100,000 persons. The majority of these deaths were associated with myeloid leukaemias (866) (AIHW and AACR 2008). For the period 2005-06 there were a total of 51,187 public hospital separations for malignant neoplasms of the lymphoid, haematopoietic and related tissues (ICD-10 code C81-C96). Of these, 9,162 were lymphoid leukaemias (C91), 9,280 were myeloid leukaemias (C92), 204 were monocytic leukaemias (C93), 1,038 and 333 were other leukaemias of a specified and unspecified cell type (C94 and C95), respectively. The separations for these five leukaemias combined represent a total of 104,101 patient days with an average length of stay ranging from 4.0 (C91) to 8.8 (C93) days (AIHW 2010).

In New Zealand during the year 2005, leukaemias represented 3.1 per cent (577 cases) of all cancer registrations and accounted for 3.9 per cent (311 cases) of deaths from all cancers. The age standardised incidence rate per 100,000 population for multiple myeloma and malignant plasma cell neoplasms (C90) and leukaemia (C91–C95) for this period was 4.3 and 10.7, respectively. The age standardised mortality rate per 100,000 population for multiple myeloma and malignant plasma cell neoplasms (C90) and leukaemia (C91–C95) was 2.5 and 5.2, respectively (Ministry of Health 2009).

Number of Patients:

The Australian Bone Marrow Donor Registry (ABMDR) has the details of 170,000 people who have registered and whose tissue typing details are available for patients needing a transplant. In addition, the ABMDR cord blood network has 20,000 cord blood samples stored with 2,218 donations of umbilical cord blood banked in 2008. In 2008 the ABMDR provided transplants for 337 patients, of whom 182 received a cord blood transplant. Sixty-one patients in Australia received a cord blood transplant while the remaining 121 cord blood transplants from the ABMDR went to patients living in other countries, five of whom lived in New Zealand. Of the 61 patients who received a cord blood transplant in Australia, 37 cord blood units originated in Australia with the remaining 24 originating from overseas. In 2008, 455 new Australian patients requested a search of the register with 270 (60%) of these patients finding a donor. A transplant has already been performed on 134 (30%) of these patients and 136 are still waiting to be transplanted (ABMDR 2009). Similarly, the New Zealand Bone Marrow Donor Registry exists to facilitate stem cell transplants and store cord blood units for patients in New Zealand and as part of the worldwide network of registries, Bone Marrow Donors Worldwide.

Technology - specialities(s):

Paediatrics & neonatology, Oncology & radiotherapy, Immunology & allergy

Technology - setting(s):

Specialist hospital

Setting - further information:

 

Impact

Alternative and/or complementary technology:

Substitution technology

Current Technology:

Conventional stem cell transplantation using either HLA matched or unmatched stem cells sourced from bone marrow, peripheral blood or cord blood is the comparator.

Health Impact:

Using cord blood samples with NIMA mismatches may potentially increase the size of the potential donor pool, increasing the chances of finding a donor.

Diffusion:

In Australia and New Zealand unrelated cord blood stem cell transplantation has been increasingly used over the past decade for patients with haematological malignancies who lack a HLA-matched bone marrow donor. It has been estimated that 20 per cent of all allogeneic transplantations performed in young patients (less than 20 years) use unrelated cord blood as the source of stem cells. Between 1995 and 2005, in Australia and New Zealand, a total of 135 paediatric patients underwent unrelated cord blood transplantation. HLA typing was performed on all cord blood units for HLA-A, HLA-B and HLA-DRB1, however matching for NIMA is not routinely performed. A perfect 6/6 match occurred on 12 per cent of these patients, 46 per cent had a 5/6 match, 41 per cent had a 4/6 match and one per cent had a 3/6 match. Transplant centres in both countries would have the ability and resources to type for NIMA (Petterson et al 2009).

Cost, infrastructure and economic consequences:

Although no cost data was provided for this new technique, it would be envisaged that typing for NIMA would increase the cost of transplantation minimally as HLA typing is already conducted. However, a future cost-effectiveness analysis may identify areas of cost savings if the technique proves to be effective in the reduction of graft-versus- host disease.

Ethical, social, legal, political and cultural impact:

Stem cell transplantation may not be a treatment option for some patients on the grounds of religious beliefs.

Some ethical issues may arise with the increasing use of private cord blood banks as opposed to publicly banked cord samples.

Evidence & Policy

Clinical evidence and safety:

Although several studies were identified which reported on patient outcomes for stem cell transplantation using unrelated cord blood cells (Atsuta et al 2009; Kurtzberg et al 2008; Petterson et al 2009), none of these studies reported on the use of matching for NIMA.

Only one study using matching of NIMA was identified (van Rood et al 2009). This large retrospective case series conducted by the New York Blood Center National Cord Blood Program reported on the outcomes of 1,121 patients transplanted with a single cord blood (CB) unit (level IV intervention evidence). The primary endpoint reported was transplant-related mortality with secondary endpoints including neutrophil and platelet engraftment, acute and chronic graft-versus-host disease, relapse and treatment failure.



Patients did not receive CB with a priori matching of NIMA, however some patients did receive CB with matched NIMA and unmatched HLA serendipitously. The database records of the Cord Blood Program were retrospectively searched to collate information on the NIMA and HLA typing status of patients who received an unrelated cord blood transplant (URCBT).The majority of patients had not received a prior transplantation. At the same HLA mismatch level (1 or 2), patient characteristics did not differ between the matched and unmatched NIMA transplant groups with the exception of a slightly greater proportion of high-risk leukaemias in the 2-HLA mismatch group (41% vs 32%, p=0.038).



Only a total of 62 patients (5.5%) received a matched CB transplant. Of the remaining 1,059 patients, 79 had a mismatched antigen that was identical to a donor NIMA, 25 (2.2%) of whom received CB with one HLA mismatch and 54 (4.8%) had two HLA mismatches. Of the NIMA mismatched patients there were 363 (32.4%) patients with one HLA mismatch and 617 (55.0%) with two HLA mismatches.



A multivariate analysis of the relative risk of all the study endpoints was conducted in patients undergoing transplantation with zero, one or two HLA mismatches, by match for a non-inherited maternal antigen. Despite low patient numbers in each of the sub-analyses groups, there were some significant differences between HLA mismatched patients with NIMA matching compared to those without NIMA matching.



The three-year cumulative probability of transplant-related mortality was 46 per cent and was lower in the NIMA matched patients than in the non-NIMA matched pairs (relative risk 0.7, 95% CI [0.5, 0.97], p=0.034). This effect was strengthened when patients were stratified for age, as there was a significant decrease in transplant-related mortality in patients older than 10 years who had one HLA mismatch (RR 0.6, 95% CI [0.4, 0.99], p= 0.048) or zero or more HLA mismatches (RR 0.6, 95% CI [0.3, 0.9], p=0.012). A similar improvement was reported in patients older than 10 years for overall mortality (RR 0.6 95% CI [0.4, 0.9], p=0.022) and transplant failure (RR 0.6 95% CI [0.4, 0.9], p=0.02)

Economic evaluation:

 

Ongoing research:

 

Ongoing or planned HTA:

This technology appears to be slowly diffusing into Australia and New Zealand. HealthPACT have agreed to disseminate this information to the relevant bodies including the Australian Bone Marrow Donor Registry’s Cord Blood National Management Committee. No further review by HealthPACT is required.

Web link:

http://www.horizonscanning.gov.au/

References and sources:

ABMDR (2009). Annual Report 2008, Australian Bone Marrow Donor Registry, Sydney. Available from: http://www.abmdr.org.au/dwnload/ABMDR_2008%20Annual%20Report_Oct09_LR.pdf

AIHW (2010). AIHW National Hospital Morbidity Database [Internet]. Australian Institute of Health and Welfare. Available from: http://d01.aihw.gov.au/cognos/cgi-bin/ppdscgi.exe?DC=Q&E=/AHS/pdx0708 [Accessed 16th February].

AIHW and AACR (2008). Cancer in Australia: an overview, 2008, Australian Institute of Health and Welfare and Australasian Association of Cancer Registries, Canberra. Available from: http://www.aihw.gov.au/publications/can/ca08/ca08.pdf

Atsuta, Y., Suzuki, R. et al (2009). 'Disease-specific analyses of unrelated cord blood transplantation compared with unrelated bone marrow transplantation in adult patients with acute leukemia', Blood, 113 (8), 1631-1638.

Blacklock, H. A., Teague, L. & Patton, N. (2005). 'Volunteer cord blood banking and transplantation', N Z Med J, 118 (1208), U1255.

Kurtzberg, J., Prasad, V. K. et al (2008). 'Results of the Cord Blood Transplantation Study (COBLT): clinical outcomes of unrelated donor umbilical cord blood transplantation in pediatric patients with hematologic malignancies', Blood, 112 (10), 4318-4327.

Ministry of Health (2009). Cancer: New Registrations and Deaths 2005, New Zealand Ministry of Health, Wellington. Available from: http://www.moh.govt.nz/moh.nsf/pagesmh/8414/$File/cancer-2005-revised-jul09v7.pdf

Petterson, T. E., Gabriel, M. et al (2009). 'Outcome following unrelated cord blood transplant in 136 patients with malignant and non-malignant diseases: a report from the Australian and New Zealand children's haematology and oncology group', Bone Marrow Transplant, 43 (3), 207-215.

Scaradavou, A. (2010). 'Unrelated umbilical cord blood unit selection', Semin Hematol, 47 (1), 13-21.

Sullivan, M., Browett, P. & Patton, N. (2005). 'Private umbilical cord blood banking: a biological insurance of dubious future benefit!', N Z Med J, 118 (1208), U1260.

van Rood, J. J. & Oudshoorn, M. (2009). 'When selecting an HLA mismatched stem cell donor consider donor immune status', Curr Opin Immunol, 21 (5), 538-543.

van Rood, J. J., Stevens, C. E. et al (2009). 'Reexposure of cord blood to noninherited maternal HLA antigens improves transplant outcome in hematological malignancies', Proc Natl Acad Sci U S A, 106 (47), 19952-19957.

Wall, D. A. & Chan, K. W. (2008). 'Selection of cord blood unit(s) for transplantation', Bone Marrow Transplant, 42 (1), 1-7.

Wikipedia (2010). Allogeneic and autologous transplantation [Internet]. Available from: http://en.wikipedia.org/wiki/Main_Page [Accessed 10th February].

Notes:

See summary on web site for full data tables